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Malignant melanoma: current state of primary and adjuvant treatment
Critical Reviews in Oncology/Hematology 45 (2003) 245 /264 www.elsevier.com/locate/critrevonc
Malignant melanoma: current state of primary and adjuvant treatment Timothy M. Pawlik, Vernon K. Sondak * Division of Surgical Oncology, University of Michigan Medical School, Ann Arbor, MI 48109-0031, USA Accepted 18 June 2002
Contents 1. Introduction 2. Prevention
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3. Treatment of the primary tumor
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4. Surgical treatment of regional metastatic melanoma
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5. Adjuvant therapy for high-risk melanoma . . . . . . . . 5.1. Overview . . . . . . . . . . . . . . . . . . . . . . . . 5.2. Nonspecific immunostimulants . . . . . . . . . . . 5.3. Cytotoxic chemotherapy . . . . . . . . . . . . . . . 5.4. Interferons . . . . . . . . . . . . . . . . . . . . . . . 5.4.1. High-dose interferon-a . . . . . . . . . . . . . 5.4.2. Low-dose interferon-a . . . . . . . . . . . . . 5.4.3. Intermediate dose interferon-a . . . . . . . . 5.5. Vaccine therapy . . . . . . . . . . . . . . . . . . . . 5.6. Granulocyte/macrophage colony-stimulating factor 5.7. Radiation therapy . . . . . . . . . . . . . . . . . .
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6. Conclusion
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Abstract Metastatic malignant melanoma remains a highly lethal disease with an incidence that continues to rise. Management of melanoma includes definitive local, regional and distant control. There is substantial prospective and retrospective data to base the extent of both primary as well as adjuvant therapy. The results of these trials have on occasion been at odds. A critical assessment of the available information pertaining to the adjuvant treatment of cutaneous melanoma is needed. This review provides a critical assessment of the current data that is available to guide both primary resection as well as adjuvant therapy. To date, current trials have shown little promise with nonspecific immunostimulants and cytotoxic chemotherapy. In contrast, dose interferon-a2b has been shown to improve relapse-free survival and likely improves melanoma-specific survival as well. Based on the available data, interferon-a2b remains the adjuvant therapy of choice for high-risk patients treated outside clinical trials, and the appropriate control arm for clinical trials evaluating new or modified adjuvant regimens. # 2002 Elsevier Science Ireland Ltd. All rights reserved.
* Corresponding author. Present address: 3306 Cancer Center, 1500 East Medical Center Drive, Ann Arbor, MI 48109-0932, USA. Tel.: /1-734936-7938; fax: /1-734-647-9647. E-mail address: [email protected] (V.K. Sondak). 1040-8428/02/$ - see front matter # 2002 Elsevier Science Ireland Ltd. All rights reserved. PII: S 1 0 4 0 - 8 4 2 8 ( 0 2 ) 0 0 0 8 0 - X
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Keywords: Melanoma; Sentinel node biopsy; Adjuvant therapy; Interferon a; Vaccines
1. Introduction Melanoma represents an enormous medical challenge. The incidence of melanoma in the USA is at least 50 000 new cases per year, or about 3% of all newly diagnosed cancers [1]. Approximately 1 in 87 Americans alive today will develop melanoma in their lifetime, and the incidence of melanoma continues to increase faster than any other cancer. The mortality rates for melanoma, however, are not increasing at the same rate. Presumably, this is because patients are presenting at an earlier stage of tumor development. Over the past 30 years there has been a change in the distribution and stage of melanoma found at diagnosis, with an increasing number of thinner lesions (i.e. B/1 mm thick) noted on presentation. Prognosis in malignant melanoma depends upon tumor thickness, ulceration, and nodal status [2 /4]. Patients presenting with thicker lesions or regional nodal metastases have a significantly poorer prognosis. Stage IIB melanoma (T3b/T4a, thickness /4 mm) is associated with a about a 60% 5-year median survival when no ulceration is present, compared to 40% when ulceration is found (Stage IIC) [5]. With Stage III disease, only 49% of all patients with nodal metastases survive 5 years (37% at 10 years), but the range of melanoma-specific survival is large, ranging from 13% at 5 years for patients with the highest combination of risk factors (ulceration of the primary, high regional lymph node burden) to 69% at 5 years for the lowest combination of predictive factors [2]. In the majority of patients, melanoma does not recur locally and it is therefore presumed that micrometastatic disease prior to surgical excision accounts for the high relapse rates in these ‘high-risk’ patients. The very poor prognosis of melanoma once it has metastasized beyond the regional nodes, and its relative resistance to available chemotherapeutic agents, has prompted a search for effective adjuvant therapy using a variety of different approaches. Effective adjuvant therapy for high-risk patients has been a long sought and elusive goal. Over 100 randomized clinical trials involving a host of different agents showed no convincing evidence of a survival advantage for adjuvant therapy [6]. Most of these trials were small studies employing heterogeneous groups of patients with varying risks of recurrence. Often being flawed and underpowered to detect significant results, these adjuvant trials were little more than litanies of presumed ineffective agents. Thus, until recently there was little benefit in identifying which patients were likely to develop recurrent disease because there was no medical treatment available for those deemed at high-risk. All
this changed abruptly with the approval by the United States Food and Drug Administration of interferon-a2b for the post-surgical adjuvant therapy of high-risk melanoma in late 1995. Shortly thereafter, the results of the Eastern Cooperative Oncology Group (ECOG) 1684 trial that prompted this approval were published [7]. Since that time a number of additional clinical trials involving interferon as well as other immunomodulatory therapies such as vaccines have been published. The results of these adjuvant therapy trials have on occasion been at odds. A critical assessment of the available information pertaining to the adjuvant treatment of cutaneous melanoma is needed.
2. Prevention Melanoma incidence is subject to large geographic and ethnic variations. An inverse correlation of melanoma incidence with latitude and with degree of skin pigmentation has been observed [8]. Cutaneous malignant melanoma is predominantly, but by no means exclusively, a disease of fair-skinned people who burn easily and rarely tan. The reasons for the rising incidence of melanoma are not clear but may be related to an increased exposure to ultraviolet radiation from sunlight that reaches the earth’s surface. The most important lifestyle alteration for a patient diagnosed with melanoma is education about sun avoidance and protection. Sunscreens with a sun protection factor (SPF) of 30 or higher are recommended. Sun avoidance should also be stressed.
3. Treatment of the primary tumor Whenever possible, the principal treatment modality for primary cutaneous melanoma is surgery. For melanoma, the tumor thickness (Breslow depth of invasion) is the single variable that most accurately determines therapy and prognosis. Diagnosed early, well over 90% of primary melanomas can be cured with surgical excision alone. Local control of a primary melanoma requires wide excision of the tumor or biopsy site down to the deep fascia with a margin of normalappearing skin. Limited excisions, such as excisional biopsies, are associated with local recurrence rates in the range of 30 /60% [9]. Historically, the optimal extent of wide excision had been somewhat controversial. More recently, a number of randomized clinical trials have clarified this issue.
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The first randomized study involving surgical margins for melanomas less than 2 mm thick was reported by the World Health Organization (WHO) Melanoma Group [10]. Patients with primary melanomas less than 2 mm thick were prospectively randomly assigned to receive excision with margins of either 1 cm (narrow) or 3 cm (wide). A total of 612 patients were entered into the study, 305 having narrow excisions and 307 having wide excisions. There were no local recurrences among patients with melanomas thinner than 1 mm, regardless of the excision margin. In the 100 patients with melanomas 1/2 mm thick, there were four local recurrences. All four patients had received 1 cm margin excisions. Most importantly, however, there was no difference between the two groups in the disease-free and overall survival rates after a median follow-up of 55 months. Recently the WHO Melanoma Program Trial 10 was updated with 15 year follow-up. The outcome of this trial after 15 years again showed no difference in overall survival and disease-free survival for the two study arms. There has been some criticism to this study because the group who underwent narrow excision had a higher local recurrence incidence (8 versus 3), but this difference was not statistically significant [11]. The WHO Melanoma Group trial clearly demonstrated that a narrow excision margin for thin (i.e. B/1 mm) melanomas is safe and provides excellent local control. The optimal width of surgical excision for intermediate thickness melanomas was addressed by three prospective randomized studies. A multi-institutional prospective randomized trial from France compared a 5 cm margin with a 2 cm margin in 319 patients with melanomas 0/2 mm thick. There was no difference in local recurrence rate or survival [11]. The Intergroup Melanoma Committee conducted a randomized prospective study evaluating 2 cm versus 4 cm margins of excision for intermediate thickness melanomas (1 /4 mm) [12]. This study involved 468 patients with localized melanomas who were observed for a median of 6 years after excision. The local recurrence rate was 0.8% for patients who had 2 cm margins and 1.7% for those who had 4 cm margins; the difference was not statistically significant. Of note, there was a statistically significant difference in the need for skin grafts, with 46% of the 4 cm group requiring skin grafts whereas only 11% of the 2 cm group did. More recently, the Intergroup Melanoma Surgical Trial has published their long-term 10-year follow-up results. The 10-year survival rates were not significantly different for patients who had received 2 cm versus 4 cm margins of excision (70% versus 77%) [13]. These data strongly demonstrate that a 2 cm margin for intermediate thickness melanomas (1 /4 mm) is not only safe and sufficient, but also significantly decreases the extra expense and morbidity associated with a skin graft. Finally, the Swedish Melanoma Study Group compared 2 cm versus 5 cm margins of excision
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in 989 patients with melanomas /0.8 mm and 0/2 mm thick. Local recurrences occurred in 1% of patients, equally distributed between the two groups, and there were no differences in recurrence-free or overall survival between the two study arms [14]. For lesions more than 4 mm thick, the empirical data is not as strong. No prospective randomized trials have been performed to date. A retrospective review of 278 patients with thick primary melanomas showed no difference in local recurrence, disease-free survival, or overall survival after a median follow-up of 27 months for excision margins in excess of 2 cm [15]. In summary, there is substantial prospective and retrospective data to base recommendations regarding the extent of surgical excision for primary melanomas. For lesions 0/1.0 mm, the WHO data clearly indicate that margins of 1 cm provide excellent results. For lesions measuring 1 /4 mm, the available data demonstrate that 2 cm margins are not only comparable to wider surgical margins in terms of local recurrence and survival, but also dramatically decrease the need for skin grafting. For thicker melanomas, retrospective data supports the use of 2 cm margins. Regardless of the thickness of the tumor and the margin size chosen, following any wide excision there should be histologic verification of negative margins. The presence of atypical melanocytic hyperplasia at any contiguous margin should lead to a wider excision.
4. Surgical treatment of regional metastatic melanoma Surgical excision of metastases to regional lymph nodes is potentially curative therapy. Only 10% of patients have clinical evidence of nodal metastases upon initial presentation; about 85% have localized disease and the remaining 5% have distant metastases [16]. Historically, there was a substantial amount of controversy over the value of an elective lymph node dissection (ELND) versus the surgical excision of only clinically positive lymph nodes, a so-called ‘therapeutic’ lymph node dissection. The advent of the sentinel lymph node technique has further changed the nature of this debate [3,17,18]. Given that interferon-a2b is now approved for stage III disease, the status of regional lymph nodes has taken on even greater importance. In the past when no adjuvant therapy was available, lymph node status perhaps was not as critical. Now, however, accurate staging will dictate who is offered adjuvant therapy. A review of the data surrounding clinical staging of regional lymph node disease is fundamental to any discussion of adjuvant therapy. Physical examination is the mainstay of clinical staging of the regional nodes. Any palpable nodes that are E/1/1.5 cm in maximum diameter or very hard or fixed to adjacent structures must be considered suspi-
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cious for metastatic involvement. Elective removal of clinically normal regional nodes by lymphadenectomy is more controversial. Advocates of the ELND claim that resection of occult metastases in the regional nodes could prevent disseminated disease and therefore lead to improved disease free survival as well as overall survival. Several retrospective studies and two prospective studies have attempted to address this issue. In 1985, Balch et al. published a retrospective review of 10-year survival statistics for patients with localize melanomas (stage I and II) who underwent wide excision alone, compared with those who underwent wide excision plus ELND [19]. Patients with intermediate thickness melanomas (0.76 /4 mm) who underwent wide excision plus ELND had a significantly higher survival rate than those who had wide excision alone, even after the analysis was stratified for tumor sites. In contrast, there was no survival benefit for ELND in patients with either thin ( 0/0.75 mm) or thick (E/4 mm) lesions. Similarly, a second retrospective review in 1988 again suggested a survival advantage for ELND compared to clinical staging of regional nodes and subsequent therapeutic node dissection only in patients with documented nodal recurrence [20]. However, it has been suggested that a number of unaccounted variables may have played a role in the choice of treatment between ELND and observation, thus calling the conclusions into question [21]. In contrast to the data derived from retrospective reviews, a number of prospective studies addressing ELND have found no survival benefit for patients treated with ELND [13,22,23]. The WHO Melanoma Group randomized patients to receive either wide excision plus ELND (n /267) or wide excision with subsequent therapeutic lymphadenectomy if clinically indicated (n /286) [22]. Analysis of this data revealed no difference in survival between the two treatment groups as a whole or in any subgroups. With follow-up now at greater than 20 years, this trial still shows no statistical improvement in either survival or disease-free interval [11]. At 8 years of follow-up, the WHO Trial 14 which compared excision only to excision plus ELND in patients with melanoma of the trunk showed a borderline difference in survival, benefiting patients undergoing ELND [11]. A small study conducted by the Mayo Clinic found no disease-free or overall survival advantage to ELND [23]. Finally, a recent report on the long-term 10-year follow-up of patients with intermediate thickness (i.e. 1 /4 mm) melanomas in the Intergroup Melanoma Trial showed no significant difference in survival for patients randomly assigned to either observation or elective node dissection after local excision [13]. The sentinel lymph node biopsy procedure is based on the concept that lymphatic fluid from defined anatomic regions of skin drains to a specific initial node or nodes (‘sentinel nodes’) prior to disseminating to other nodes
in the same or nearby basins. Morton et al. first articulated this concept and described a reliable method for operative identification and removal of the sentinel node draining the site of a cutaneous melanoma [24]. More importantly, this same group showed that the pathologic status of the sentinel node accurately determines whether melanoma cells have metastasized to that specific lymph node basin [25]. Other institutions have recapitulated these results, confirming that melanoma patients with pathologically negative sentinel nodes have detectable metastases in non-sentinel nodes less than 5% of the time [26 /29]. An important aspect of sentinel node biopsy is a detailed histologic examination of the sentinel lymph nodes. Identification of micrometastases in sentinel nodes is enhanced by careful sectioning of the node (step-sectioning) as well as the use of immunohistochemical staining with anti-S-100, anti-MART-1 or HMB-45 (anti-gp100) antibodies [30]. Even microscopic foci of melanoma detected only by immunohistochemical staining are clinically significant. In fact, sentinel lymph node status is the most important predictor of survival for patients with melanoma. Gershenwald et al. reported that patients were 6.43 times more likely to survive with a negative rather than a positive sentinel lymph node, making the predictive impact of sentinel node status superior to any other prognostic factor [31]. In this retrospective review of the combined experience of the M.D. Anderson Cancer Center and the H. Lee Moffitt Cancer Center, there was a significant difference in 3-year disease-free survival between sentinel lymph node-positive and sentinel lymph node-negative patients (55.8% versus 88.5%; P B/0.001). A negative sentinel lymph node biopsy was associated with a 58.6% increase in the proportion of patients surviving with recurrence [31]. Similarly, in a separate prospective cohort study of 200 melanoma patients, a statistically significant difference in 3-year overall survival (93% versus 67%) and disease free survival (88% versus 58%) was found between sentinel Table 1 Clinical outcomes of sentinel lymph node biopsy precedure Study/year SLN-positive patients
SLN-negative patients
P value
Morton et al. [25] 3-y OS 74 3-y DFS 50
94 89
Gershenwald et al. [31] 3-y DFS 55.8
88.5
B/0.001
Gershenwald et al. (2000) 3-y OS 64.4 3-y DFS 58
89.8 88
0.006 B/0.001
Jansen et al. [32] 3-y OS 67 3-y DFS 58
93 88
B/0.001 B/0.001
/ /
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lymph node-negative and sentinel lymph node-positive patients [32]. Collectively, these studies provide compelling evidence that sentinel lymph node biopsy is a powerful prognostic tool in the staging of melanoma (Table 1). Given the demonstrated prognostic power of sentinel lymph node biopsy, elucidating the indications for the use of sentinel lymph node biopsy becomes central. Several clinical factors correlate with the likelihood of lymph node involvement and thus influence the decision regarding sentinel lymph node biopsy. Belli et al. reported sentinel lymph node positivity rates of 16% in lesions thicker than 1.0 mm, with 7% positivity for lesions between 1.00 and 1.9 mm, 11% positivity for lesions between 2.0 and 2.9 mm, and 20% positivity for lesions thicker than 3.0 mm [33]. Among the 829 patients in a WHO study, sentinel lymph node positivity rates of 2% ( B/1.0 mm), 7% (1.0 /1.99 mm), 13% (2.0 / 2.99 mm), and 31% (E/3.0 mm) were reported. In addition to Breslow depth, Clark’s level has been reported to be independently important in predicting lymph node involvement for thin melanomas [2]. Although few studies present rates of sentinel lymph node positivity in terms of Clark’s levels, data from the Multicenter Selective Lymphadenectomy Trial showed a 14% sentinel lymph node positivity rate for Clark’s level 3 lesions, rising to 20.6% for Clark’s level 4 and 31.2% for Clark’s level 5 lesions [25]. Finally, ulceration has been shown to be associated with sentinel lymph node positivity. Ulceration is defined by the AJCC as the absence of an intact epidermis overlying a portion of the primary melanoma based on pathologic microscopic observation of the histologic sections [17]. Gershenwald et al. found that 43.5% of the sentinel lymph nodepositive patients had ulcerated primaries, while only 20.2% of the sentinel lymph node-negative patients had tumor ulceration [31]. Based on this data, as well as additional corroborating studies, the sentinel lymph node biopsy procedure should be routinely considered for primary melanomas thicker than 1.0 mm and selectively applied for tumors 1.0 mm or less, when ulceration is present and perhaps if the lesion is classified as Clark level 4 or higher [34,35]. Sentinel lymph node biopsy should also be strongly considered for lesions of uncertain depth (shave biopsies or significant regression). Sentinel lymph node biopsy plays a central role in staging the regional lymph nodes and is the standard of care in many major melanoma centers [33]. The finding of metastatic disease, even microscopic foci detected only by immunohistochemical staining, is sufficient to warrant complete lymph node dissection and consideration of adjuvant therapy. Historically, the distinction between clinical staging and pathologic staging has not been emphasized in many adjuvant therapy clinical trials. The widespread use of sentinel lymph node
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lymphadenectomy has identified a group of stage III patients whose prognosis is superior to patient with clinically defined nodes. This has resulted in a wide range of survival rates among various subgroups of pathologic stage III patients because of ‘upstaging’ based on a direct examination of the sentinel lymph nodes by histopathologic examination [36]. Furthermore, stage II melanoma patients who were clinically staged have significantly inferior survival rates as compared with those whose lymph nodes were determined to be tumor free by pathologic examination of the sentinel lymph node [37]. This heterogeneity in the stage II and III patient populations that has occurred since the introduction of the sentinel lymph node biopsy procedure has not been appreciated in many of the adjuvant therapy trials. Currently, the compelling prognostic value of knowing the nodal status makes sentinel lymph node biopsy indispensable to accurate staging, and thus a key component of future studies examining adjuvant therapy.
5. Adjuvant therapy for high-risk melanoma 5.1. Overview Most of the adjuvant therapy trials in melanoma reported to date have suffered from one or more methodologic problems that limit the degree of confidence which can be placed in their results. All but a few of the randomized trials had less than 250 patients per arm. To put this in perspective, detection of a clinically meaningful 5% increase in 5-year survival in a two arm trial would require enrollment of over 1250 patients per arm (80% power). Some studies have not used a notreatment control of any kind, relying instead on putatively inactive agents (such as the Vaccinia viral oncolysate trial in which Vaccinia alone was used as the control, or the current John Wayne Cancer Institute allogeneic vaccine trials where BCG is the control). If the study result is negative, the question of unrecognized activity of the control group arises [38,39]. Another problem has been the known or potential imbalance of recognized prognostic factors between the treatment and control arms. This has limited the generalizability of some results. Compounding the problems inherent in trials with small sample sizes and potentially imbalanced risk factors is the inclusion of heterogeneous groups of atrisk patients in many of the adjuvant trials conducted to date. Current thinking, based in part on the TNM system for melanoma employed in 2000, would stratify patients into risk categories as low risk (stage IA: negative lymph nodes with a primary tumor 0/1.0 mm without ulceration; stage IB: negative lymph nodes with primary 0/1.0 mm with ulceration or primary 1.01 /2.0
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Table 2 Staging of primary cutaneous melanoma (A) TNM classification T classification T1 0/1.0 mm T2
1.01 /2.0 mm
T3
2.01 /4.0 mm
T4
/4.0 mm
N classification N1 Metastasis in one lymph node N2
Metastasis in 2 /3 lymph nodes or in-transit metastasis with no nodal involvement
N3
4 or more metastatic lymph nodes or matted lymph nodes or in-transit metastasis with nodal involvement
M classification M1 Distant metastasis
(a) without ulceration, level II or III (b) with ulceration or level IV or V (a) without ulceration (b) with ulceration (a) without ulceration (b) with ulceration (a) without ulceration (b) with ulceration (a) micrometastasis (b) macrometastasis (a) micrometastasis (b) macrometastasis (c) in-transit metastasis with no nodal involvement
(a) skin, subcutaneous, or lymph node metastasis, normal LDH (b) lung metastasis, normal LDH (c) all other visceral or any distant metastasis with elevated LDH
(B) Pathologic stage grouping 0 IA IB IIA IIB IIC IIIA IIIB
IIIC
IV
Tis T1a T1b T2a T2b T3a T3b T4a T4b any T1-4a any T1-4a any T1-4b any T1-4b any T1-4a any T1-4a any T1-4a/b
N0 N0 N0 N0 N0 N0 N0 N0 N0 N1a N2a N1a N2a N1b N2b N2c
M0 M0 M0 M0 M0 M0 M0 M0 M0 M0 M0 M0 M0 M0 M0 M0
any any any any
N1b N2b N3 any N
M0 M0 M0 M1
T1-4b T1-4b T1-4a/b T
mm without ulceration), intermediate risk (stage IIA: negative lymph nodes with primary tumor 1.01 /2.0 mm with ulceration or primary 2.01 /4.0 mm without ulceration), high-risk (stage IIB: negative lymph nodes with primary tumor 2.01 /4.0 mm with ulceration or primary tumor /4.0 mm without ulceration; stage III: any T1-4a primary with regional metastases) or very high-risk (resected stage IV: any T, any N, with distant metastases [17] (Table 2). Patients with non-cutaneous
primaries, multiple (/10) positive nodes or gross extracapsular extension appear to be at higher risk than the average ‘high-risk’ patient, but precisely where they should fit into this classification scheme remains to be defined. On the other hand, arbitrarily excluding some members of a risk group from clinical trials (e.g. those patients with positive nodes from an unknown primary) serves no useful purpose and reduces the available patient population for accrual.
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The methodologic problems enumerated above are present to some extent in virtually every trial conducted to date. They make comparisons of trials difficult, even when the trials are purporting to study similar interventions, and they preclude lending serious weight to the results of subset analyses. In the sections that follow, we provide an overview of the adjuvant melanoma trials reported thus far, focusing primarily on randomized, controlled trials that incorporate a no-treatment arm.
5.2. Nonspecific immunostimulants Morton et al. demonstrated that intralesional injection of viable BCG organisms could lead to the regression of intradermal melanoma metastases [40]. Even more significantly, Morton showed that uninjected lesions occasionally regressed. This graphic documentation of the ability of the human immune system to destroy melanoma stimulated the conduct of a host of clinical trials using BCG in the adjuvant setting. Although several non-randomized trials using historical controls and two small randomized trials of intralesional or intralymphatic BCG showed a statistically significant benefit in favor of BCG [41 /44], multiple other randomized trials failed to substantiate this benefit [45 /53]. The WHO Trial 6 was a multicenter randomized study with four arms: dimethyltriazenoimidazole carboxamide (DTIC), BCG, DTIC combined with BCG, and no adjuvant treatment. Follow-up at 15 years revealed no difference in overall survival between the treatment groups [11,48,54]. In addition, a small randomized trial employing the methanol extraction residue of BCG was performed in ocular melanoma and showed no beneficial effect of treatment [55]. Virtually all of these trials were small and employed heterogeneous populations at intermediate and high-risk of recurrence, making definitive conclusions difficult. Corynebacterium parvum is another microbe which can stimulate the human immune system, but has an advantage over BCG in that viable organisms are not required for efficacy. Adjuvant treatment with C. parvum has been compared to observation in two studies, neither of which demonstrated a significant overall benefit for C. parvum [56,57]. C. parvum was also compared directly to BCG (without an untreated control group) in two adjuvant trials. Lipton et al. found a statistically significant disease-free survival advantage for the subgroup of patients with positive nodes who were treated with C. parvum , but no such advantage for node-negative patients [58]. In contrast, Balch et al. conducted a slightly larger trial and found a nonsignificant increase in median survival in favor of the BCG-treated patients [59]. As a consequence of this conflicting data, C. parvum has never found widespread acceptance as a therapeutic agent in melanoma.
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Levamisole is an anthelminthic drug for which various immunomodulatory properties have been reported [60]. Four randomized, controlled trials of levamisole in melanoma have been conducted. In three of the four, no benefit for levamisole therapy was identified [61 /63]. In one study, a significant increase in 5-year survival was seen in favor of levamisole. The significance of this difference disappeared, however, in multivariate analysis */raising the possibility that the findings resulted from an imbalance of prognostic factors rather than a true treatment effect [46]. Finally, there have been a number of other nonspecific immunostimulants that have been examined without evidence of efficacy. Transfer factor, an extract of disrupted leukocytes purported to transfer delayed-type hypersensitivity and act as a nonspecific immunostimulant [64], was tested in two small randomized, controlled trials and was found not to be efficacious [65,66]. Isoprinosine, a mixture of inosine, adedoben and dimepranol with putative immunostimulatory properties, has been tested in the adjuvant therapy of melanoma in several small randomized trials [67,68]. A suggestion of improved disease-free survival seen in one study was not confirmed in the other. A single small study of the thymic factor thymostimulin suggested a short-term advantage in disease-free and overall survival in favor of the treated group [69], but two other studies did not [69,70]. Thus, there is no compelling evidence for the efficacy of nonspecific immunostimulants in the adjuvant treatment of melanoma. Consequently, their use should occur only in an investigational setting. 5.3. Cytotoxic chemotherapy Adjuvant therapy for melanoma has been attempted with nearly every cytotoxic drug that has become available to clinical investigators throughout the years. Despite this, no studies have demonstrated a confirmed benefit of adjuvant chemotherapy in melanoma patients at high-risk for relapse. Single agents with recognized but minimal activity against advanced disease include dacarbazine (DTIC), the nitrosoureas (lomustine (BCNU), carmustine (CCNU) and semustine (methylCCNU)), the vinca alkaloids (vincristine, vinblastine and vindesine), cisplatin, paclitaxel and bleomycin [71]. Single-agent therapy with dacarbazine results in objective responses in 18/22% of patients with measurable metastatic disease [71]. Numerous studies have been performed looking at DTIC as a postsurgical adjuvant [11,48,63,72], and these trials provided no evidence that DTIC has significant efficacy in that setting. Multiagent cytotoxic therapy has similarly been unfruitful in the adjuvant setting. Karakousis and Emrich found no benefit for the combination of DTIC and estramustine in a small, three-arm study comparing
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multiagent chemotherapy or BCG to a no-treatment control group [50]. Four two-arm, randomized controlled trials of multiagent chemotherapy have been performed. A trial using BCNU, dactinomycin and vincristine [73], and a small trial of DTIC, CCNU and vincristine [74] both suggested a benefit for multiagent chemotherapy, while two other trials did not [75,76]. Several small trials have also explored postoperative adjuvant therapy with DTIC plus BCG, with [63,77] or without a no-treatment arm [52,78/81]. DTIC plus BCG did not appear to have any efficacy in the adjuvant setting; this result was perhaps predictable given the lack of activity of the individual agents in the adjuvant setting and the absence of any suggestion of synergy between them. Until and unless randomized trials in advanced disease confirm efficacy of cytotoxic chemotherapy, adjuvant therapy with cytochemotherapy should be considered only in the context of a clinical trial [82]. 5.4. Interferons Interferons are glycoproteins with a variety of immunomodulatory and anti-tumor effects. Interferon enhances expression of class I and II major histocompatibility complex (MHC) molecules and up regulates expression of critical costimulatory molecules such as B7 [83,84]. Interferons can also enhance antigen presentation by dendritic cells /cells which seem to have a critical role in tumor-specific cytotoxic T cell response [85]. Furthermore, interferons inhibit angiogenesis, which may be a critical step in the development of micrometastatic disease [86]. There is also evidence of a direct antiproliferative effect and unconfirmed evidence that interferons can induce melanoma-specific tumor antigens [85]. Finally, interferons are immunomodulatory and stimulate natural killer cells and LAK cells and have been shown in vivo to lyse tumor cells directly [85]. For all of these reasons, interferons appeared to be an attractive potential adjuvant therapy and have been studied extensively in patients with melanoma. In 1980, Bart et al. reported on the inhibition of B16 melanoma in vitro and in vivo by murine interferon [87]. Subsequent phase I studies using partially purified leukocyte interferon at doses below 10 /106 U/day resulted in few responses [88]. Subsequently, more purified forms of both interferon gamma and alpha have been investigated. The immunologic activities of interferon-g have been extensively characterized, including in melanoma patients [89 /92]. These studies provided a compelling rationale for the use of interferon-g in the adjuvant treatment of melanoma [93]. A randomized trial performed within the Southwest Oncology Group, however, failed to indicate any benefit for adjuvant treatment with an immunologically active dose of
interferon-g in patients at intermediate and high-risk of recurrence [94]. The results of this trial were disclosed early because of a suggestion that the treatment arm actually fared worse than the control arm [95]. This disclosure prompted the National Cancer Institute of Canada to close its adjuvant therapy trial comparing levamisole and interferon-g. A total of 89 patients were entered onto the NCI-Canada study when it was closed; there was no apparent difference in disease-free or overall survival between the two groups [96]. The European Organization for Research and Treatment of Cancer (EORTC) 18 871 trial similarly showed no favorable impact of interferon on relapse-free survival in stage III melanoma patients [97]. Other studies have corroborated the finding that interferon-g is ineffective as adjuvant therapy for intermediate and high-risk melanomas and is similarly inactive in patients with advanced melanoma [11,92]. Unlike interferon-g, interferon-a does possess a reasonable degree of activity against metastatic melanoma [84], in addition to a broad range of immunologic effects [84,99]. There have been multiple randomized trials assessing the use of interferon-a in high-risk melanoma patients. These trials have investigated a variety of interferon-a dose levels and treatment schedules. For review purposes the studies can be divided into those involving high-dose regimens, low-dose regimens, and intermediate-dose regimens. 5.4.1. High-dose interferon-a The North Central Cancer Treatment Group (NCCTG) used high-doses of interferon-a2a (20 MU/ m2 i.m. for 3 days/week for 3 months) in patients with resected stage II or III melanoma and showed no significant benefit in overall survival [100]. Subset analysis showed a significant benefit in relapse-free survival among the 160 patients with node-positive disease. Overall survival was also better in the nodepositive patients who received interferon-a2a (47% versus 39%), but this did not reach statistical significance. The relatively small overall sample size, as well as the small number of node-positive patients (160 out of 262), make any definitive conclusions from this study tenuous at best. In a study by ECOG (E1684) a significant benefit on both disease-free survival and overall survival was found in patients randomized to receive high-dose interferona2b for 1 month (20 MU/m2/day i.v. for 5 days each week) followed by 11 months of intermediate dose therapy (10 MU/m2/day s.c. three times a week) compared to observation alone after surgery [7]. The regimen was deliberately chosen to be at or near the maximally tolerated dose for interferon-a. Both nodepositive and high-risk node negative (T4pN0) patients were included; the majority of patients had relapsed in their regional nodes after prior wide excision. All
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patients underwent either elective or therapeutic lymph node dissections. Of the 287 patients enrolled in the trial, 89% were node-positive. Interferon improved overall survival improved from 2.8 to 3.8 years and 5-year relapse-free survival improved from 26 to 37% at a median follow-up of 7 years. Similar to the NCCTG trial, the beneficial effect of interferon-a was most pronounced in the node-positive patients. A recent updated analysis of E1684, with 12.6 years of median follow-up, showed a persistent gain in median survival of 13.8 months (45.8 months for the interferon arm versus 32 months for observation) [101]. However, this survival difference was no longer statistically significant, possibly because of deaths from intercurrent illness on both arms overshadowing melanoma-specific mortality with the passage of time. The updated results continue to show a highly significant improvement in relapse-free survival. No benefit was observed in patients with thick primary melanomas (/4 mm) and pathologically negative nodes. Indeed, in the small subset of nodenegative patients, the group randomized to receive interferon-a2b actually fared worse. The results of this subset analysis are, however, virtually impossible to interpret because of the small size of the subset (only 31 evaluable patients) and the presence of a significant imbalance between the treatment and control arms in the percentage of node-negative patients with ulcerated primary tumors. Patients receiving high-dose interferon experienced significant toxicity. Grade 3 toxicity occurred in 67% of patients, 9% of the patients had life-threatening toxicity and 2 patients died from hepatic toxicity. Treatment had to be reduced or discontinued in over half the patients. Although this toxicity was significant, treatment was tolerated by most patients after appropriate dose reductions, and both economic and quality of life analyses revealed results comparable to those for accepted adjuvant therapies in other malignancies [102,103]. As a result of this trial, the FDA approved interferon-a for the adjuvant treatment of high-risk melanoma, specifically including both thick node-negative and node-positive patients. Although the results of the E1684 trial are encouraging, there are a number of problems with the trial which warrant mention. The trial included only 34 patients in whom nodal disease had been established by ELND (as opposed to therapeutic lymph node dissection). This number is too small to answer the crucial question as to whether interferon-a benefits patients with early micrometastatic disease. This is a question that has taken on increasing importance given the advent of sentinel lymph node biopsy. Furthermore patients were not stratified according to the number of positive lymph nodes. Finally, the treatment itself was fairly toxic, resulting in two deaths and requiring dose
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reductions in over half of the patients. Even though quality of life-adjusted survival analysis seemed to justify such toxic therapy, many physicians and patients were reluctant to accept high-dose interferon without further evidence. The Intergroup E1690 study was initiated before a significant impact on survival had been noted in E1684. The study was designed as a confirmation and extension of E1684, and involved 642 patients randomized in a three-arm study to receive the high-dose regimen detailed in E1684, low-dose interferon-a2b (3 MU three times a week for 2 years) or observation only. The results of E1690 confirmed the improvement in relapsefree survival with the high-dose interferon regimen seen in E1684. Similar improvement was not seen when the low-dose regimen was compared to observation. Furthermore, there was no significant improvement in overall survival for either the low or the high-dose interferon groups. These findings were clearly at odds with the findings of E1684 which showed a clear statistical improvement in overall survival in the highdose interferon treated cohort. Perhaps the most surprising finding was that the overall survival in all treatment arms was superior to comparable groups in E1684. There was a striking difference in overall survival between the observation arms of E1684 and E1690, with observation patients faring much better in terms of relapse-free survival and overall survival in E1690 versus E1684. Some of this discrepancy may be attributable to a different demographic profile between the two studies. E1690 included a more favorable population of melanoma patients in that only 75% of accrued patients were node-positive, of whom 51% entered with nodal recurrence. In E1690 25% of patients enrolled were ‘clinical’ stage II, while 11% in E1684 were pathologic stage II. Presumably some of the clinical stage II patients in E1690 would have been pathologic stage III had lymphadenectomies been required in the E1690 trial. The disproportionate incremental improvement in disease-free and overall survival for the observation patients in E1690 relative to those on E1684 also may have been related to the availability of post-relapse interferon, which became available in 1995. A retrospective analysis of E1690 revealed a disproportionate use of interferon-a salvage therapy, particularly in patients who had nodal relapse from stratum I (i.e. T4cN0). This may have influenced the overall survival of the observation arm compared with the high-dose interferon-a arm. Another discrepancy between E1684 and E1690 was the efficacy of interferon-a in relation to lymph node status. In E1690, the improvement in relapse-free survival with the high-dose regime was equivalent for those patients with or without lymph node disease [104]. The discrepancies between these two similar trials served to increase the confusion and
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uncertainty around the use of interferon-a2b in the adjuvant setting. The final high-dose interferon study (E1694) was recently published. This study was initiated to evaluate the efficacy and safety of a ganglioside vaccine in comparison with high-dose interferon-a2b (by now, the FDA-approved standard of care) as adjuvant therapy in high-risk melanoma patients. The ganglioside GM2 is a serologically well-defined melanoma antigen and the most immunogenic ganglioside expressed on melanoma cells [105,106]. Preliminary studies conducted at Memorial Sloan-Kettering Cancer Center demonstrated that administration of GM2 in combination with BCG induced IgM anti-GM2 antibodies, and that this antibody response was correlated with relapse-free and overall survival in AJCC stage III melanoma patients [107,108]. Given the toxicities associated with high-dose interferon, it was felt to be reasonable to evaluate less toxic alternatives such as vaccines using GMK. In E1694, 774 eligible high-risk melanoma patients (deep primary lesions /4.00 mm or regional lymph node metastases) were randomized to receive high-dose interferon-a2b versus GMK, a vaccine composed of GM2 ganglioside conjugated to keyhole limpet hemocyanin, co-administered with the immunologic adjuvant QS-21. The study was closed early by the ECOG Data Safety Monitoring Committee because of the clear superiority of interferon-a2b therapy in terms of both disease-free survival (hazard ratio, 1.47; P /0.003) and overall survival (hazard ratio, 1.52, P /0.018) compared with the vaccine arm. This corresponds to a nearly 50% increase in the risk of relapse and death for patients receiving GMK compared to those treated with interferon-a2b. The estimated 2-year relapse-free survival rate for eligible cases was 62% in the interferon-a2b arm versus 49% in the GMK arm [109]. Furthermore, analysis of the hazard of relapse and death in each stratification group by the number of lymph nodes demonstrated the superiority of interferon-a2b over GMK in all nodal subsets. E1694 also showed a statistically significant benefit in the node-negative
subset of patients. In addition, E1694 further demonstrated that interferon-a2b can be used safely. Among patients in the interferon-a2b arm, only 45 (10%) of 440 patients had to discontinue treatment entirely because of adverse events, and there were no treatment-related deaths. A recent abstract reported updated relapse-free and overall survival data for this trial, and continued to show significant improvement for the interferon arm in both endpoints [110]. Taken together, the ECOG/Intergroup studies have established the relapse-free survival and overall survival benefit of high-dose interferon-a2b. The relapse-free survival benefit of high-dose interferon-a2b has been reported in three adjuvant trials (E1684, E1690 and E1694). The relapse-free survival benefit of high-dose interferon-a2b was consistent and highly significant. The overall survival benefit of interferon-a2b has been demonstrated in two trials: E1684 and E1694, the latter being the largest adjuvant trial for resected high-risk melanoma yet reported. The E1690 trial failed to demonstrate an overall survival benefit of interferona2b, but this may have been secondary to a large number of patients originally assigned to observation crossing over to receive interferon-a2b salvage therapy when they experienced treatment failure in regional nodes. One area that stills needs to be resolved with regards to high-dose interferon is the role of the IV induction phase. This is currently being investigated in the E1967, the Sunbelt melanoma trial, and by groups in Europe. In total, the results of the ECOG trials validate the continued use and benefit of high-dose interferon for the adjuvant therapy of patients with high-risk, resected melanoma (Table 3).
5.4.2. Low-dose interferon-a Low-dose interferon therapy has also been investigated. The WHO 16 trial included 444 node-positive patients randomized to receive a low-dose interferona2a regimen consisting of 3 MU three times a week for 3 years. Initial assessment of the data at 3.3 years revealed a significant relapse-free survival benefit for low-dose
Table 3 Summary of high-dose interferon studies in stage II/III disease Cooperative group
Staging
Total patients
NCCTG 83705 ECOG 1684
T3-4/N/ T4/N/
262 287
ECOG 1690
T4/N/
642
ECOG 1694
T4/N/
880
a
Significant for node positive patients.
Treatment regimen
IFN-a2a (20 MU/m2 IM 3 d/wk for 12 weeks) IFN-a2b (20 MU/m2 IV 5x/wk for 1 mon and then 10 MU/m2 SC 3x/wk for 11 mon) IFN-a2b (20 MU/m2 IV 5x/wk for 1 mon and then 10 MU/m2 SC 3x/wk for 11 mon) IFN-a2b (20 MU/m2 IV 5x/wk for 1 mon and then 10 MU/m2 3x/wk for 11 mon vs GMK/QS-21 for 2 years)
Results
Median follow-up
DFS
OS
/a /
/ /
7 years 7 years
/
/
5 years
/
/
2/1 years
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interferon, but no overall survival advantage [98]. The relapse-free survival was not, however, maintained with further follow-up [11]. Indeed, updated follow-up at 8 years did not show any benefit with regards to diseasefree or overall survival for low-dose interferon-a [11]. E1690 was a three-arm United States Intergroup trial that compared high-dose and low-dose interferon-a2b to observation after surgery (but not directly to one another). This trial demonstrated a non-significant improvement in relapse-free survival for 2 years of low-dose interferon treatment in patients with highrisk stage II and III melanoma. This effect seemed to disappear within 2 years of stopping therapy, whereas patients on the high-dose arm of the same trial had a sustained benefit in relapse-free survival [104]. In 989, the Scottish melanoma group initiated a randomized trial, comparing observation alone with 6 months therapy with low-dose interferon (3 MU subcutaneously twice a week), for patients with primary melanomas of a least 3 mm Breslow thickness or with evidence of regional lymph node involvement. The trial was closed in 1993 with only 95 eligible patients randomized and the 6 year follow-up has recently been reported [111]. In this study, although there was an apparent improvement in disease-free survival (from 9 to 22 months), and overall survival (from 27 to 39 months) with interferon, these differences were not statistically significant [111]. The EORTC 18871 trial also demonstrated that a regimen of very low-dose interferon (1 MU) subcutaneously on alternate days for 1 year did not effect overall survival for patients with high-risk melanoma [97,112]. These results seem to indicate that low-dose interferon is not better than observation alone in highrisk patients. Low-dose interferon-a2 has also been evaluated in intermediate risk patients. Two studies using low-dose regimens in patients with node-negative melanomas showed a beneficial effect on disease-free survival [113,114]. A study by Pehamberger et al. involving 311 patients with Stage II disease given low-dose interferona2a for 1 year showed a significant benefit on diseasefree survival, but not on overall survival when analyzed at 41 months. Similar results were obtained in a study by Grob et al. of 489 patients with Stage II melanoma randomly assigned to receive either 18 months with lowdose interferon-a2a (3 MU subcutaneously three times a week) or observation. Recently another randomized multicenter trial investigating the use of interferon-a as adjuvant therapy for patients with Stage I and II melanoma has come out of Italy [115]. In this study, there was a statistically significant reduction in the incidence of metastasis from 63% in controls to 25% in the treatment arm (3 MU intramuscularly three times a week for 3 years) for Stage II melanoma patients [115]. The overall impression from these studies is that lowdose interferon-a, given as 3 MU for 1 /3 years, may
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serve to delay disease progression, but only during the time of administration. Overall mortality appears to be unaffected in virtually all trials reported to date. Because of the lack of demonstrated durable benefit for low-dose interferon-a, it has not been accepted as adjuvant therapy in the USA, although in the UK interferon-a2a is licensed as adjuvant therapy in patients with Stage II malignant melanoma.
5.4.3. Intermediate dose interferon-a The lack of a survival benefit for low-dose regimens tested to date, coupled with the toxicity of the high-dose regimen, has prompted investigations of regimens containing intermediate doses of interferon. The underlying issue in most of these trials is whether the peak dose or the total dose delivered is most directly correlated with durable antitumor effects and survival prolongation. The EORTC has enrolled more than 1400 node-positive patients onto a three-arm study using an intermediate dosing strategy for interferon-a2b in the adjuvant therapy of melanoma (EORTC 18952). The EORTC 18952 study investigates the efficacy of two intermediate dose regimens of interferon-a2b (10 MU SC daily 5 days per week for 4 weeks, followed by either 10 MU SC three times each week for 1 year (arm A) or 5 MU SC three times each week for 2 years (arm B)) versus observation. With a median follow-up of 1.6 years, the first analysis of EORTC demonstrated a difference among the three treatment arms. The 2-year interferon arm (arm B) exhibited a longer distant metastasis-free interval than the control arm (P /0.026), while the 1year interferon arm demonstrated a trend for improved outcome but as yet no significant impact [112]. Whether any of these effects will translate into a durable impact on overall survival remains to be determined. However, the strong correlation between distant disease-free survival and overall survival for patients with nodepositive melanoma suggests that such a survival impact is likely to emerge. As expected, toxicity has proven to be substantially less with both intermediate-dose regimens than with high-dose interferon-a2b. The Scandinavian Melanoma Cooperative Group is also conducting a three-arm trial investigating similar intermediate dose regimens. Two treatment arms, incorporating the modified induction regimen of the EORTC (10 MU of interferon-a2b 5 days per week for 1 month) followed by a maintenance dose of 10 MU TIW for 12 or 24 months, will be compared with observation. Overall, the role of intermediate-dose interferon therapy in the adjuvant treatment of melanoma remains to be established. As the two noted trials mature any potential role for low-dose interferon may be clarified.
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5.5. Vaccine therapy Vaccine therapy is designed to elicit a host immune response to known or unknown tumor-associated antigens. To date, only a limited number of melanomaassociated antigens have been defined, and vaccines have been developed for only a few of these. Thus, few trials haven been conducted which include as part of the study appropriate monitoring to verify that the desired immunologic endpoint has been achieved. The lack of a no-treatment control arm has also complicated the interpretation of many of these studies. Since only a few melanoma-associated antigens have been defined, and since those few that are known may not be present or may not be sufficiently immunogenic in a given individual to mediate tumor regression, a number of investigators have worked with autologous tumor vaccines. This approach is limited to individuals with sufficient accessible tumor to prepare a vaccine. Such patients generally have a poor overall prognosis and are likely to have significant residual tumor burden, making them less-than-ideal candidates for any immunotherapeutic approach. Even in those cases, only enough tumor is usually obtained to provide for a limited number of vaccinations. Furthermore, the technical complexities inherent in procuring tumor and preparing a vaccine have, to date, hampered attempts to perform multi-institutional trials to formally test the efficacy of autologous tumor vaccines. Two small randomized trials (15 and 31 patients, respectively) comparing irradiated or neuraminidase-treated autologous tumor cells plus BCG to a control group found that the treatment group appeared to fare no better or perhaps even worse than the control [116 /118]. In addition, a somewhat larger randomized, controlled trial of adjuvant therapy with autologous tumor cells plus BCG in renal cell carcinoma failed to show any evidence of benefit for vaccine treatment [119]. Nonetheless, single-institution studies incorporating historical controls [120 /122], as well as the potential to genetically modify tumor cells to be more immunogenic [123,124], continue to stimulate interest in this approach. Since patients with resected nodal and distant metastases */ the population most amenable to autologous vaccine approaches */are now considered candidates for adjuvant therapy with high-dose interferon, it is likely that future trials of this approach will be conducted in conjunction with this therapy. Allogeneic tumor cell vaccines, generally prepared from cultured cell lines or lysates thereof, offer several important advantages over autologous tumor cell vaccines: they are readily available and can be standardized, preserved and distributed in a manner akin to any other therapeutic agent. These properties allow for the use of multiple vaccinations over months or years and enable the performance of large-scale, multi-institutional clin-
ical trials. The majority of trials that have been completed to date, however, were small, single institution studies. None of these trials demonstrated an unequivocal benefit for immunotherapy with allogeneic tumor cells administered in conjunction with BCG when compared to an untreated [49,125] or a BCG-treated control group [126]. Considerable uncertainty remains as to the optimal immunologic adjuvant to use in conjunction with an allogeneic tumor cell vaccine, but there is certainly reason to suspect that BCG may not be ideal [127,128]. Also controversial is the role of immunomodulators given concomitantly with vaccination, such as low-dose cyclophosphamide. Two randomized studies have been conducted in which allogeneic melanoma vaccines were administered without or with cyclophosphamide given for 3 days prior to vaccination. The results of these studies have been conflicting, with one suggesting no detectable difference [129] and one suggesting a decrease in suppressor cell activity and augmented antibody response [130]. The Southwest Oncology Group has recently completed a large (/600 patients), randomized trial comparing an allogeneic melanoma cell lysate (Melacine† ) co-administered with detoxified endotoxin/mycobacterial cell wall skeleton (DETOX), given without cyclophosphamide, to an untreated control group in patients with intermediate thickness, node-negative melanoma (S9035). The primary aim of this trial was to determine the effect of the vaccine on relapse-free survival; effects on survival will be evaluated in a future analysis [131]. A major secondary aim of the trial was to determine if the effectiveness of the vaccine varied based on patients’ HLA Class I allele expression [132]. HLA Class I alleles differentially present protein antigens as peptides to CD8/ T cells. Patients expressing various Class I types may therefore differ in their response to cell lysate-based cancer vaccines. Previously, Mitchell et al. reported a strong association between patient HLA phenotype and evidence of clinical benefit from Melacine, with a significantly greater proportion of stage IV melanoma patients who expressed at least two of the following five alleles: HLA-A2, A28, B44, B45 and C3 (referred to collectively as M5) showing clinical benefit than those patients expressing only zero or one of these alleles. In total, 689 patients were randomized to S9035; 89 (13%) were deemed ineligible, mainly because the tumor was too thin (42 patients) or too thick (23 patients) on central pathology review. Thirteen eligible patients refused assigned treatment: seven on the observation arm (four received vaccines off-protocol) and six on the vaccine arm. Most toxicity was local */granulomas or sterile abscesses*/and there was no autoimmune toxicity. After a median follow-up of 4.1 years, 95 events (recurrences or deaths) occurred among 300 eligible patients randomized to vaccine versus 106 events among 300 eligible patients randomized to observation (P /
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0.30). In total, 553 of 689 patients enrolled were HLA typed (80% of the total, 294 vaccine and 259 observation arm patients). There was no single HLA Class I allele that independently conveyed a significant impact on outcome, either for the vaccine or the control arms. In contrast, however, the 81 patients in the vaccine arm expressing E/2 of M5 alleles had a superior disease-free survival than the corresponding 70 patients with 0/2 M5 matches in the observation arm (4-year disease-free survival 87% versus 64%, P /0.0001). Vaccine arm patients expressing E/2 of M5 alleles also had superior disease-free survival than those in the vaccine arm with 0 /1 HLA matches (4-year disease-free survival 87% versus 64%, P /0.004). The specific alleles contributing the major component of this effect were HLA-A2 and C3, suggesting that melanoma tumor antigens presented by HLA-A2 and C3 may be critical in protecting vaccinated patients from disease relapse. Further investigation of adjuvant vaccine approaches for intermediate-thickness, node-negative melanoma is clearly warranted and analysis of HLA Class I expression should be a routine part of future vaccine trials. An alternative approach to allogeneic vaccination involves the use of viruses to lyse the tumor cells prior to inoculation. In theory, the admixture of viral and tumor proteins would provoke an intense immune response that would lead to recognition and rejection of tumor cells by the host. A pilot study of melanoma patients treated with Newcastle disease virus lysates of either autologous or allogeneic tumor cells for 5 years suggested an improved survival compared to historical controls [133]. This observation prompted two larger randomized trials using Vaccinia viral lysates of allogeneic tumor. One trial incorporated a control arm in which patients were treated with Vaccinia virus alone, without tumor cells [38]. The other trial used a notreatment control arm [134]. Both studies demonstrated no evidence of benefit for the Vaccinia oncolysate treatment. Although it is possible that a small immunomodulatory effect of Vaccinia virus by itself could have obscured the beneficial effect of the viral oncolysate in one trial [39], the negative results of the other trial suggest that this is not the case. The results of these two randomized trials, in such marked contrast to the beneficial effect seemingly found in a non-randomized trial [133], emphasizes yet again the perils of relying on historical controls in evaluating melanoma therapy [135]. Vaccination with autologous or allogeneic tumor represents an attempt to convey antitumor immunity by exposing the patient to a variety of tumor-associated antigens. Decades of research have identified and defined a number of antigens present on melanoma cells that could potentially serve as targets for the human immune response. Gangliosides are a group of related glycolipids present on melanoma cells and some
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non-neoplastic cells (particularly neural tissues). Ganglioside GD3 is distributed widely on melanocytes, nevi and practically all melanomas, as well as some normal tissues, and naturally occurring anti-GD3 antibodies are rare. Administration of a monoclonal antibody to GD3 (in conjunction with macrophage-colony stimulating factor) resulted in objective regression of melanoma metastases in the rare patient [136]. As mentioned previously, ganglioside GM2 is expressed on a large percentage of melanoma specimens but is rarely detected on normal tissues, and about 5% of melanoma patients have naturally-occurring anti-GM2 antibodies. Patients with anti-ganglioside antibodies appear to have a better prognosis than those without antibodies [107,137]. Livingston et al. conducted a randomized trial comparing adjuvant therapy of node-positive melanoma with BCG to treatment with BCG plus purified GM2 ganglioside. The overall analysis revealed no significant difference between the two treatment arms [108]. Interpretation was hampered by the small size of the trial and the fact that there was an imbalance between the two arms with respect to the number of patients with preexisting anti-GM2 antibodies. Since the completion of that study, the investigators have focused on ways to increase the humoral response to GM2 vaccination. By conjugating the GM2 to the xenogeneic protein keyhole limpet hemocyanin and replacing the BCG with the saponin-derived adjuvant QS-21, they were able to achieve high levels of IgG and IgM anti-GM2 antibodies in a very high percentage of patients. As mentioned previously, in E1694 adjuvant therapy with GM2-KLH/QS-21 was shown to be inferior to interferon. GM2-KLH/QS-21 is currently being evaluated in comparison to observation alone in a large EORTC study in stage II melanoma patients. Another technique for stimulating an immune response to non-protein antigens such as gangliosides is by administration of anti-idiotype antibodies. These ‘antiantibodies’ are antibodies raised against anti-ganglioside antibodies so that the variable region of the antibody is essentially a mirror-image of the ganglioside itself, only composed of protein [138]. When an immune response occurs to this mirror-image protein, it is also crossreactive against the original antigen [139]. To date, antiidiotype antibodies have been produced against GD2 and GD3; these antibodies are just beginning to undergo phase I and II testing and have not yet been evaluated in randomized trials [140,141]. A different vaccination approach has focused on the use of peptide antigens. Eukaryotic cells express thousands of proteins which are presented on the surface of antigen-presenting cells and other cells as antigens for recognition by T cells complexed with Class I and II MHC molecules [142]. The generation and detection of tumor antigen-specific immune responses can theoretically lead to the eradication of tumor cells. Human
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melanoma cells express antigens recognized by cytotoxic lymphocytes. These antigens include antigens created by unique, random mutations and those that are commonly expressed on melanomas from many different patients [143]. The most widely shared melanoma antigens recognized by cytotoxic lymphocytes are derived from melanocyte differentiation proteins including gp100, tyrosinase, MART-1/Melan-A and gp75. A number of prospective studies have investigated the use of melanoma peptide antigen vaccines, often using synthetic peptides modified in anchor residues to result in greater affinity for the relevant MHC molecule. Lee et al. reported on 48 patients with high-risk resected stage III or IV melanoma who were immunized with two tumor antigen epitope peptides derived from gp100209 217 (amino acid sequence IMDQQVPSFV) and tyrosinase368 376 (YMDGTMSQV) emulsified with incomplete Freund’s adjuvant (IFA) [144]. Patients received peptides/IFA with or without interleukin-12, 30 ng/kg, to evaluate the toxicities and immune responses in either arm with time to relapse and survival as secondary end points. Thirty-three of 38 patients demonstrated an immune response by ELISA after vaccination, as did 37 of 42 patients by tetramer assay. Twenty-four of 48 patients relapsed with a median follow-up of 20 months, and 10 patients had died by this time. The authors concluded that a significant proportion of patients with resected melanoma can mount an antigen-specific immune response against the gp100 and tyrosinase peptide vaccines and that IL12 may increase this immune response. The results of a separate phase I trial of a different gp100 peptide vaccine were reported by Slingluff et al. [145]. In this trial, a melanoma vaccine composed of HLA-A2restricted peptide YLEPGPVTA (gp100280 288) with or without a modified T-helper epitope from tetanus toxoid was evaluated to assess safety and immunological response. The vaccines were administered to 22 highrisk patients (stage IIB /IV). Cytotoxic lymphocyte responses to the gp100280 288 peptide were detected in the peripheral blood in 14% of patients. Helper T-cell responses to the tetanus helper peptide were detected in 79% of patients. The overall survival of patients at 4.7 years follow-up was 75%. Four of 14 patients who completed at least six vaccines subsequently developed metastases, all of which were solitary and surgically resectable. Although the results of these studies demonstrate the immunogenicity of peptide antigens and the possible cytotoxic immune responses, they also clearly show how difficult it can be to ascertain whether any immune response is protective against tumor recurrence. Prospective studies with peptide antigen vaccines will be needed to define their role in the adjuvant therapy of melanoma patients.
5.6. Granulocyte/macrophage colony-stimulating factor Granulocyte/macrophage colony-stimulating factor (GM-CSF), a cytokine with a role in the growth and maturation of hematopoietic and dendritic cells, has been incompletely studied in the adjuvant setting. No prospective, randomized, multicenter trials have yet been completed with this agent to support its use in the adjuvant therapy of high-risk melanoma outside clinical investigations. In one phase II trial investigating GM-CSF as surgical adjuvant therapy in patients with stage III or IV melanoma, Spitler et al. showed that GM-CSF prolonged overall and disease-free survival as compared to matched historical controls [146]. This has prompted a number of prospective intergroup trials which are currently investigating the potential function of GM-CSF. One such trial is the ECOG trial E4697 which is evaluating GM-CSF (alone or administered with an HLA-A2 restricted multi-epitopic peptide vaccine) in patients following resection of distant metastases or local or regional nodal disease after adjuvant interferon therapy [147]. Definitive recommendations regarding the use of GM-CSF in the adjuvant setting for melanoma must await the results of these trials. 5.7. Radiation therapy The role of adjuvant radiation therapy in the management of melanoma remains unclear. It should rarely be employed for definitive treatment of a primary melanoma site. The main role of adjuvant radiation is the treatment of the nodal basin after resection of regionally advanced melanoma. Only one small randomized trial of adjuvant radiotherapy has been completed in cutaneous melanoma, and this produced no benefit [148]. This study utilized conventional radiation fractions and a treatment break, both currently felt to be suboptimal for melanoma. Several non-randomized studies have suggested that postoperative radiation to the neck or axilla after radical lymph node dissection decreases regional recurrence rates in node-positive patients [31,34,149]. However, a case-review study by Shen et al. looking at adjuvant radiotherapy after positive lymph node dissections in the head and neck showed that the low incidence of cervical recurrence after regional lymph node dissection did not justify the routine use of postoperative radiation [150]. The Radiation Therapy Oncology Group initiated a randomized trial of postoperative radiation using larger treatment fractions in patients undergoing neck dissections for melanoma. Accrual to this trial was slow, however, and the trial ultimately closed due to a failure to meet its accrual goal [151]. Until larger randomized trials are conducted, it is reasonable to consider postoperative radiation therapy in patients with gross extracapsular
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extension [29] or multiple (10 or more) involved lymph nodes. From several reports, the most effective radiation schedules involve large doses per fraction. For nodal irradiation, a common regimen is 3500 cGy in 10 days, delivered at 350 cGy per day 5 days per week. Since patients who are candidates for radiation therapy are also candidates for adjuvant interferon-a2b therapy, the optimal timing for integrating radiation with interferon will need to be determined. In the absence of definitive data, we defer the start of radiation until after the completion of the initial month of intravenous interferon and administer it during the subcutaneous phase of treatment. Interferon may act as a radiosensitizer; some patients appear to have more acute toxicity when give radiation and interferon than when given the same dose of radiation alone.
6. Conclusion Metastatic malignant melanoma remains a highly lethal disease; hence, the prevention of its development is a clinical priority. Prevention should include sunscreens with a SPF of 30 or higher, as well as protective clothing and sun avoidance. Despite attempts at prevention, the incidence of melanoma in the USA continues to climb with at least 50 000 new cases per year. Management of melanoma must include definitive local, regional and distant control. There is substantial prospective and retrospective data to base the extent of surgical excision for primary melanoma. For lesions B/ 1.0 mm, margins of 1 cm provide excellent control. For lesions measuring 1 /4 mm, 2 cm margins produce excellent local control, while dramatically reducing the need for skin grafting. For thicker melanomas, retrospective data supports the use of 2 cm margins. Regarding diagnosis and control of regional disease, the advent of the sentinel lymph node biopsy technique has revolutionized the surgical approach. Elective node dissection has not been shown to provide therapeutic benefit and should be abandoned. Rather sentinel lymph node biopsy should play a central role in staging the regional lymph nodes and is the standard of care in many, if not all, major melanoma centers. The finding of metastatic disease, even microscopic foci detected only by immunohistochemical staining, is sufficient to warrant completion lymph node dissection and consideration of adjuvant therapy. Improvements in our understanding of the prognosis and staging of melanoma have allowed us to better categorize patients based on their risk of developing metastatic disease, permitting the development of logical strategies using adjuvant therapies with toxicity profiles that are appropriate based on the level of risk for recurrence. Adjuvant therapies with nonspecific immunostimulants and cytotoxic chemotherapy have shown little promise. In
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contrast, high-dose interferon-a2b improves relapsefree survival and likely improves melanoma-specific survival as well. Interferon-a2b is the adjuvant therapy of choice for high-risk patients treated outside clinical trials, and the appropriate control arm for clinical trials evaluating new or modified adjuvant regimens. The toxicity of high-dose interferon, however, is substantial and limits both patient and physician acceptance. Alternate interferon dosing schedules (intermediate or low-doses) may have potential merit, but as of yet have not been shown to improve survival. New approaches with vaccines and biochemotherapy (combinations of immunomodulatory cytokines and cytotoxic chemotherapy) hold promise, but should still be confined to carefully designed and conducted clinical trials in order to best determine what advantages, if any, they provide over current therapy. The ongoing importance of clinical trials in the adjuvant therapy of melanoma can hardly be overstated. Evaluating the benefits of future therapies will require larger clinical trials than have yet been conducted, because small differences in outcome may prove to be important. Increasing the success of adjuvant therapy for melanoma will require an ongoing commitment to conduct scientifically and statistically sound randomized clinical trials. To this end, patients with stage II and III disease should be encouraged to participate in welldesigned trials assessing a variety of adjuvant therapies.
Reviewers Danielle Lienard , CHUV (Centre Hospitalier Universitaire Vaudois), Centre Pluridisciplinaire d’Oncologie Niveau 06, rue du Bugon 46, CH-1011 Lausanne, Switzerland. Sanjiv S. Agarwala , Associate Director, Melanoma Center, University of Pittsburgh Cancer Institute, Montefiore Hospital, 200 Lothrop Street 7 Main N, Pittsburgh, PA 15213-2582, USA. Michael B Atkins , Beth Israel Deaconess Medical Center, Kirsten Brookline Ave, Boston, MA 022155400, USA.
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T.M. Pawlik, V.K. Sondak / Critical Reviews in Oncology/Hematology 45 (2003) 245 /264 [115] Rusciani L, Petraglia S, Alotto M, et al. Postsurgical adjuvant therapy for melanoma. Cancer 1997;79:2354 /60. [116] McIllmurray MB, Embleton MJ, Reeves WG, et al. Controlled trial of active immunotherapy in management of stage IIB malignant melanoma. Br Med J 1977;1(6060):540 /2. [117] McIllmurray MB, Reeves WG, Langman MJS, et al. Active immunotherapy in melanoma. Br Med J 1978;1(6112):579. [118] Aranha GV, McKhann CF, Grage TB, et al. Adjuvant immunotherapy of malignant melanoma. Cancer 1979;43:1297 /303. [119] Galligioni E, Quaia M, Merlo A, et al. Adjuvant immunotherapy treatment of renal carcinoma patients with autologous tumor cells and Bacillus Calmette-Guerin. Five-year results of a prospective randomized study. Cancer 1996;77:2560 /6. [120] McCulloch PB, Dent PB, Blajchman M, et al. Recurrent malignant melanoma: effect of adjuvant immunotherapy on survival. Cancer Med Assoc 1977;117:33 /6. [121] Berd D, Maguire HC, Mastrangelo MJ. Treatment of human melanoma with a hapten-modified autologous vaccine. Ann NY Acad Sci 1993;690:147 /52. [122] Berd D, Maguire HC, Nathan FN, et al. Autologous, DNPmodified vaccine as post-surgical adjuvant treatment of stages III and IV melanoma. Proc Am Soc Clin Oncol 1996;15:554. [123] Dranoff G, Jaffee E, Lazenby A, et al. Vaccination with irradiated tumor cells engineered to secrete murine granulocyte-macrophage colony stimulating factor stimulates potent, specific, and long-lasting anti-tumor immunity. Proc Natl Acad Sci USA 1993;90:3539 /43. [124] Arca MJ, Krauss JC, Strome SE, et al. Diverse manifestations of tumorigenicity and immunogenicity displayed by the poorly immunogenic B16-BL6 melanoma transduced with cytokine genes. Cancer Immunol Immunother 1996;42:237 /45. [125] Morton DL. Ajuvant immunotherapy of malignant melanoma: status of clinical trials at UCLA. Int J Immunother 1986;2:31 /6. [126] Hedley DW, McElwain TJ, Currie GA. Specific active immunotherapy does not prolong survival in surgically treated patients with stage IIB melanoma and may promote early recurrence. Br J Cancer 1978;37:491 /6. [127] Schultz N, Oratz R, Chen D, et al. Effect of DETOX as an adjuvant for melanoma vaccine. Vaccine 1995;13:503 /8. [128] Helling F, Zhang A, Shang A, et al. GM2-KLH conjugate vaccine: increase immunogenicity in melanoma patients after administration with immunological adjuvant QS-21. Cancer Res 1995;55:2783 /8. [129] Oratz R, Dugan M, Roses DF, et al. Lack of effect of cyclophosphamide on the immunogenicity of a melanoma antigen vaccine. Cancer Res 1991;51:3643 /7. [130] Hoon DSB, Foshag LJ, Nizze AS, et al. Suppressor cell activity in a randomized trial of patients receiving active specific immunotherapy with melanoma cell vaccine and low dosages of cyclophosphamide. Cancer Res 1990;50:5358 /64. [131] Sondak VK, Liu P-Y, Tuthill RJ, et al. Adjuvant immunotherapy of resected, intermediate-thickness node-negative melanoma with an allogeneic tumor vaccine. Overall results of a randomized trial of the Southwest Oncology Group. JCO 2002;20:2058 /66. [132] Sosman JA, UngerJM, Liu P-Y, Flaherty LE, Park MS, Kempf RA, Thompson JA, Terasaki PI, Sondak VK: Adjuvant immunotherapy of resected, intermediate-thickness node-negative melanoma with an allogenic tumor vaccine. Impact of HLA Class I antigen expression on outcome. JCO 2002;20:2067 /75. [133] Cassel WA, Murray DR, Phillips HS. A phase II study on the postsurgical management of stage II malignant melanoma with a Newcastle disease virus oncolysate. Cancer 1983;52:856 /60. [134] Hersey P, Coates P, McCarthy WH. Active immunotherapy following surgical removal of high risk melanoma: present status and future prospects. SBT93: Society for Biological Therapy,
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Biographies Timothy M. Pawlik, M.D., M.P.H. recieved his undergraduate degree from Georgetown University and his M.D., M.P.H. degrees from Tufts University
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School of Medicine. Recently having finished his surgical residency at the University of Michigan in Ann Arbor, Michigan he is now beginning a Surgical Oncology Fellowship at MD Andeson, Houston, Texas. Vernon K. Sondak , M.D. received his undergraduate and M.D. degrees from Boston University, prior to residency training at the University of California, Los
Angeles. In 1987, he joined the faculty at the University of Michigan Medical Center, Ann Arbor, MI, USA. He is currently Professor of Surgery in the Division of Surgical Oncology. Dr Sondak specializes in the treatment of soft tissue tumors, including melanomas and sarcomas, and is the Chair of the Melanoma and Surgery Committees of the Southwest Oncology Group.
Malignant melanoma: current state of primary and adjuvant treatment Timothy M. Pawlik, Vernon K. Sondak * Division of Surgical Oncology, University of Michigan Medical School, Ann Arbor, MI 48109-0031, USA Accepted 18 June 2002
Contents 1. Introduction 2. Prevention
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5. Adjuvant therapy for high-risk melanoma . . . . . . . . 5.1. Overview . . . . . . . . . . . . . . . . . . . . . . . . 5.2. Nonspecific immunostimulants . . . . . . . . . . . 5.3. Cytotoxic chemotherapy . . . . . . . . . . . . . . . 5.4. Interferons . . . . . . . . . . . . . . . . . . . . . . . 5.4.1. High-dose interferon-a . . . . . . . . . . . . . 5.4.2. Low-dose interferon-a . . . . . . . . . . . . . 5.4.3. Intermediate dose interferon-a . . . . . . . . 5.5. Vaccine therapy . . . . . . . . . . . . . . . . . . . . 5.6. Granulocyte/macrophage colony-stimulating factor 5.7. Radiation therapy . . . . . . . . . . . . . . . . . .
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Abstract Metastatic malignant melanoma remains a highly lethal disease with an incidence that continues to rise. Management of melanoma includes definitive local, regional and distant control. There is substantial prospective and retrospective data to base the extent of both primary as well as adjuvant therapy. The results of these trials have on occasion been at odds. A critical assessment of the available information pertaining to the adjuvant treatment of cutaneous melanoma is needed. This review provides a critical assessment of the current data that is available to guide both primary resection as well as adjuvant therapy. To date, current trials have shown little promise with nonspecific immunostimulants and cytotoxic chemotherapy. In contrast, dose interferon-a2b has been shown to improve relapse-free survival and likely improves melanoma-specific survival as well. Based on the available data, interferon-a2b remains the adjuvant therapy of choice for high-risk patients treated outside clinical trials, and the appropriate control arm for clinical trials evaluating new or modified adjuvant regimens. # 2002 Elsevier Science Ireland Ltd. All rights reserved.
* Corresponding author. Present address: 3306 Cancer Center, 1500 East Medical Center Drive, Ann Arbor, MI 48109-0932, USA. Tel.: /1-734936-7938; fax: /1-734-647-9647. E-mail address: [email protected] (V.K. Sondak). 1040-8428/02/$ - see front matter # 2002 Elsevier Science Ireland Ltd. All rights reserved. PII: S 1 0 4 0 - 8 4 2 8 ( 0 2 ) 0 0 0 8 0 - X
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Keywords: Melanoma; Sentinel node biopsy; Adjuvant therapy; Interferon a; Vaccines
1. Introduction Melanoma represents an enormous medical challenge. The incidence of melanoma in the USA is at least 50 000 new cases per year, or about 3% of all newly diagnosed cancers [1]. Approximately 1 in 87 Americans alive today will develop melanoma in their lifetime, and the incidence of melanoma continues to increase faster than any other cancer. The mortality rates for melanoma, however, are not increasing at the same rate. Presumably, this is because patients are presenting at an earlier stage of tumor development. Over the past 30 years there has been a change in the distribution and stage of melanoma found at diagnosis, with an increasing number of thinner lesions (i.e. B/1 mm thick) noted on presentation. Prognosis in malignant melanoma depends upon tumor thickness, ulceration, and nodal status [2 /4]. Patients presenting with thicker lesions or regional nodal metastases have a significantly poorer prognosis. Stage IIB melanoma (T3b/T4a, thickness /4 mm) is associated with a about a 60% 5-year median survival when no ulceration is present, compared to 40% when ulceration is found (Stage IIC) [5]. With Stage III disease, only 49% of all patients with nodal metastases survive 5 years (37% at 10 years), but the range of melanoma-specific survival is large, ranging from 13% at 5 years for patients with the highest combination of risk factors (ulceration of the primary, high regional lymph node burden) to 69% at 5 years for the lowest combination of predictive factors [2]. In the majority of patients, melanoma does not recur locally and it is therefore presumed that micrometastatic disease prior to surgical excision accounts for the high relapse rates in these ‘high-risk’ patients. The very poor prognosis of melanoma once it has metastasized beyond the regional nodes, and its relative resistance to available chemotherapeutic agents, has prompted a search for effective adjuvant therapy using a variety of different approaches. Effective adjuvant therapy for high-risk patients has been a long sought and elusive goal. Over 100 randomized clinical trials involving a host of different agents showed no convincing evidence of a survival advantage for adjuvant therapy [6]. Most of these trials were small studies employing heterogeneous groups of patients with varying risks of recurrence. Often being flawed and underpowered to detect significant results, these adjuvant trials were little more than litanies of presumed ineffective agents. Thus, until recently there was little benefit in identifying which patients were likely to develop recurrent disease because there was no medical treatment available for those deemed at high-risk. All
this changed abruptly with the approval by the United States Food and Drug Administration of interferon-a2b for the post-surgical adjuvant therapy of high-risk melanoma in late 1995. Shortly thereafter, the results of the Eastern Cooperative Oncology Group (ECOG) 1684 trial that prompted this approval were published [7]. Since that time a number of additional clinical trials involving interferon as well as other immunomodulatory therapies such as vaccines have been published. The results of these adjuvant therapy trials have on occasion been at odds. A critical assessment of the available information pertaining to the adjuvant treatment of cutaneous melanoma is needed.
2. Prevention Melanoma incidence is subject to large geographic and ethnic variations. An inverse correlation of melanoma incidence with latitude and with degree of skin pigmentation has been observed [8]. Cutaneous malignant melanoma is predominantly, but by no means exclusively, a disease of fair-skinned people who burn easily and rarely tan. The reasons for the rising incidence of melanoma are not clear but may be related to an increased exposure to ultraviolet radiation from sunlight that reaches the earth’s surface. The most important lifestyle alteration for a patient diagnosed with melanoma is education about sun avoidance and protection. Sunscreens with a sun protection factor (SPF) of 30 or higher are recommended. Sun avoidance should also be stressed.
3. Treatment of the primary tumor Whenever possible, the principal treatment modality for primary cutaneous melanoma is surgery. For melanoma, the tumor thickness (Breslow depth of invasion) is the single variable that most accurately determines therapy and prognosis. Diagnosed early, well over 90% of primary melanomas can be cured with surgical excision alone. Local control of a primary melanoma requires wide excision of the tumor or biopsy site down to the deep fascia with a margin of normalappearing skin. Limited excisions, such as excisional biopsies, are associated with local recurrence rates in the range of 30 /60% [9]. Historically, the optimal extent of wide excision had been somewhat controversial. More recently, a number of randomized clinical trials have clarified this issue.
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The first randomized study involving surgical margins for melanomas less than 2 mm thick was reported by the World Health Organization (WHO) Melanoma Group [10]. Patients with primary melanomas less than 2 mm thick were prospectively randomly assigned to receive excision with margins of either 1 cm (narrow) or 3 cm (wide). A total of 612 patients were entered into the study, 305 having narrow excisions and 307 having wide excisions. There were no local recurrences among patients with melanomas thinner than 1 mm, regardless of the excision margin. In the 100 patients with melanomas 1/2 mm thick, there were four local recurrences. All four patients had received 1 cm margin excisions. Most importantly, however, there was no difference between the two groups in the disease-free and overall survival rates after a median follow-up of 55 months. Recently the WHO Melanoma Program Trial 10 was updated with 15 year follow-up. The outcome of this trial after 15 years again showed no difference in overall survival and disease-free survival for the two study arms. There has been some criticism to this study because the group who underwent narrow excision had a higher local recurrence incidence (8 versus 3), but this difference was not statistically significant [11]. The WHO Melanoma Group trial clearly demonstrated that a narrow excision margin for thin (i.e. B/1 mm) melanomas is safe and provides excellent local control. The optimal width of surgical excision for intermediate thickness melanomas was addressed by three prospective randomized studies. A multi-institutional prospective randomized trial from France compared a 5 cm margin with a 2 cm margin in 319 patients with melanomas 0/2 mm thick. There was no difference in local recurrence rate or survival [11]. The Intergroup Melanoma Committee conducted a randomized prospective study evaluating 2 cm versus 4 cm margins of excision for intermediate thickness melanomas (1 /4 mm) [12]. This study involved 468 patients with localized melanomas who were observed for a median of 6 years after excision. The local recurrence rate was 0.8% for patients who had 2 cm margins and 1.7% for those who had 4 cm margins; the difference was not statistically significant. Of note, there was a statistically significant difference in the need for skin grafts, with 46% of the 4 cm group requiring skin grafts whereas only 11% of the 2 cm group did. More recently, the Intergroup Melanoma Surgical Trial has published their long-term 10-year follow-up results. The 10-year survival rates were not significantly different for patients who had received 2 cm versus 4 cm margins of excision (70% versus 77%) [13]. These data strongly demonstrate that a 2 cm margin for intermediate thickness melanomas (1 /4 mm) is not only safe and sufficient, but also significantly decreases the extra expense and morbidity associated with a skin graft. Finally, the Swedish Melanoma Study Group compared 2 cm versus 5 cm margins of excision
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in 989 patients with melanomas /0.8 mm and 0/2 mm thick. Local recurrences occurred in 1% of patients, equally distributed between the two groups, and there were no differences in recurrence-free or overall survival between the two study arms [14]. For lesions more than 4 mm thick, the empirical data is not as strong. No prospective randomized trials have been performed to date. A retrospective review of 278 patients with thick primary melanomas showed no difference in local recurrence, disease-free survival, or overall survival after a median follow-up of 27 months for excision margins in excess of 2 cm [15]. In summary, there is substantial prospective and retrospective data to base recommendations regarding the extent of surgical excision for primary melanomas. For lesions 0/1.0 mm, the WHO data clearly indicate that margins of 1 cm provide excellent results. For lesions measuring 1 /4 mm, the available data demonstrate that 2 cm margins are not only comparable to wider surgical margins in terms of local recurrence and survival, but also dramatically decrease the need for skin grafting. For thicker melanomas, retrospective data supports the use of 2 cm margins. Regardless of the thickness of the tumor and the margin size chosen, following any wide excision there should be histologic verification of negative margins. The presence of atypical melanocytic hyperplasia at any contiguous margin should lead to a wider excision.
4. Surgical treatment of regional metastatic melanoma Surgical excision of metastases to regional lymph nodes is potentially curative therapy. Only 10% of patients have clinical evidence of nodal metastases upon initial presentation; about 85% have localized disease and the remaining 5% have distant metastases [16]. Historically, there was a substantial amount of controversy over the value of an elective lymph node dissection (ELND) versus the surgical excision of only clinically positive lymph nodes, a so-called ‘therapeutic’ lymph node dissection. The advent of the sentinel lymph node technique has further changed the nature of this debate [3,17,18]. Given that interferon-a2b is now approved for stage III disease, the status of regional lymph nodes has taken on even greater importance. In the past when no adjuvant therapy was available, lymph node status perhaps was not as critical. Now, however, accurate staging will dictate who is offered adjuvant therapy. A review of the data surrounding clinical staging of regional lymph node disease is fundamental to any discussion of adjuvant therapy. Physical examination is the mainstay of clinical staging of the regional nodes. Any palpable nodes that are E/1/1.5 cm in maximum diameter or very hard or fixed to adjacent structures must be considered suspi-
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cious for metastatic involvement. Elective removal of clinically normal regional nodes by lymphadenectomy is more controversial. Advocates of the ELND claim that resection of occult metastases in the regional nodes could prevent disseminated disease and therefore lead to improved disease free survival as well as overall survival. Several retrospective studies and two prospective studies have attempted to address this issue. In 1985, Balch et al. published a retrospective review of 10-year survival statistics for patients with localize melanomas (stage I and II) who underwent wide excision alone, compared with those who underwent wide excision plus ELND [19]. Patients with intermediate thickness melanomas (0.76 /4 mm) who underwent wide excision plus ELND had a significantly higher survival rate than those who had wide excision alone, even after the analysis was stratified for tumor sites. In contrast, there was no survival benefit for ELND in patients with either thin ( 0/0.75 mm) or thick (E/4 mm) lesions. Similarly, a second retrospective review in 1988 again suggested a survival advantage for ELND compared to clinical staging of regional nodes and subsequent therapeutic node dissection only in patients with documented nodal recurrence [20]. However, it has been suggested that a number of unaccounted variables may have played a role in the choice of treatment between ELND and observation, thus calling the conclusions into question [21]. In contrast to the data derived from retrospective reviews, a number of prospective studies addressing ELND have found no survival benefit for patients treated with ELND [13,22,23]. The WHO Melanoma Group randomized patients to receive either wide excision plus ELND (n /267) or wide excision with subsequent therapeutic lymphadenectomy if clinically indicated (n /286) [22]. Analysis of this data revealed no difference in survival between the two treatment groups as a whole or in any subgroups. With follow-up now at greater than 20 years, this trial still shows no statistical improvement in either survival or disease-free interval [11]. At 8 years of follow-up, the WHO Trial 14 which compared excision only to excision plus ELND in patients with melanoma of the trunk showed a borderline difference in survival, benefiting patients undergoing ELND [11]. A small study conducted by the Mayo Clinic found no disease-free or overall survival advantage to ELND [23]. Finally, a recent report on the long-term 10-year follow-up of patients with intermediate thickness (i.e. 1 /4 mm) melanomas in the Intergroup Melanoma Trial showed no significant difference in survival for patients randomly assigned to either observation or elective node dissection after local excision [13]. The sentinel lymph node biopsy procedure is based on the concept that lymphatic fluid from defined anatomic regions of skin drains to a specific initial node or nodes (‘sentinel nodes’) prior to disseminating to other nodes
in the same or nearby basins. Morton et al. first articulated this concept and described a reliable method for operative identification and removal of the sentinel node draining the site of a cutaneous melanoma [24]. More importantly, this same group showed that the pathologic status of the sentinel node accurately determines whether melanoma cells have metastasized to that specific lymph node basin [25]. Other institutions have recapitulated these results, confirming that melanoma patients with pathologically negative sentinel nodes have detectable metastases in non-sentinel nodes less than 5% of the time [26 /29]. An important aspect of sentinel node biopsy is a detailed histologic examination of the sentinel lymph nodes. Identification of micrometastases in sentinel nodes is enhanced by careful sectioning of the node (step-sectioning) as well as the use of immunohistochemical staining with anti-S-100, anti-MART-1 or HMB-45 (anti-gp100) antibodies [30]. Even microscopic foci of melanoma detected only by immunohistochemical staining are clinically significant. In fact, sentinel lymph node status is the most important predictor of survival for patients with melanoma. Gershenwald et al. reported that patients were 6.43 times more likely to survive with a negative rather than a positive sentinel lymph node, making the predictive impact of sentinel node status superior to any other prognostic factor [31]. In this retrospective review of the combined experience of the M.D. Anderson Cancer Center and the H. Lee Moffitt Cancer Center, there was a significant difference in 3-year disease-free survival between sentinel lymph node-positive and sentinel lymph node-negative patients (55.8% versus 88.5%; P B/0.001). A negative sentinel lymph node biopsy was associated with a 58.6% increase in the proportion of patients surviving with recurrence [31]. Similarly, in a separate prospective cohort study of 200 melanoma patients, a statistically significant difference in 3-year overall survival (93% versus 67%) and disease free survival (88% versus 58%) was found between sentinel Table 1 Clinical outcomes of sentinel lymph node biopsy precedure Study/year SLN-positive patients
SLN-negative patients
P value
Morton et al. [25] 3-y OS 74 3-y DFS 50
94 89
Gershenwald et al. [31] 3-y DFS 55.8
88.5
B/0.001
Gershenwald et al. (2000) 3-y OS 64.4 3-y DFS 58
89.8 88
0.006 B/0.001
Jansen et al. [32] 3-y OS 67 3-y DFS 58
93 88
B/0.001 B/0.001
/ /
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lymph node-negative and sentinel lymph node-positive patients [32]. Collectively, these studies provide compelling evidence that sentinel lymph node biopsy is a powerful prognostic tool in the staging of melanoma (Table 1). Given the demonstrated prognostic power of sentinel lymph node biopsy, elucidating the indications for the use of sentinel lymph node biopsy becomes central. Several clinical factors correlate with the likelihood of lymph node involvement and thus influence the decision regarding sentinel lymph node biopsy. Belli et al. reported sentinel lymph node positivity rates of 16% in lesions thicker than 1.0 mm, with 7% positivity for lesions between 1.00 and 1.9 mm, 11% positivity for lesions between 2.0 and 2.9 mm, and 20% positivity for lesions thicker than 3.0 mm [33]. Among the 829 patients in a WHO study, sentinel lymph node positivity rates of 2% ( B/1.0 mm), 7% (1.0 /1.99 mm), 13% (2.0 / 2.99 mm), and 31% (E/3.0 mm) were reported. In addition to Breslow depth, Clark’s level has been reported to be independently important in predicting lymph node involvement for thin melanomas [2]. Although few studies present rates of sentinel lymph node positivity in terms of Clark’s levels, data from the Multicenter Selective Lymphadenectomy Trial showed a 14% sentinel lymph node positivity rate for Clark’s level 3 lesions, rising to 20.6% for Clark’s level 4 and 31.2% for Clark’s level 5 lesions [25]. Finally, ulceration has been shown to be associated with sentinel lymph node positivity. Ulceration is defined by the AJCC as the absence of an intact epidermis overlying a portion of the primary melanoma based on pathologic microscopic observation of the histologic sections [17]. Gershenwald et al. found that 43.5% of the sentinel lymph nodepositive patients had ulcerated primaries, while only 20.2% of the sentinel lymph node-negative patients had tumor ulceration [31]. Based on this data, as well as additional corroborating studies, the sentinel lymph node biopsy procedure should be routinely considered for primary melanomas thicker than 1.0 mm and selectively applied for tumors 1.0 mm or less, when ulceration is present and perhaps if the lesion is classified as Clark level 4 or higher [34,35]. Sentinel lymph node biopsy should also be strongly considered for lesions of uncertain depth (shave biopsies or significant regression). Sentinel lymph node biopsy plays a central role in staging the regional lymph nodes and is the standard of care in many major melanoma centers [33]. The finding of metastatic disease, even microscopic foci detected only by immunohistochemical staining, is sufficient to warrant complete lymph node dissection and consideration of adjuvant therapy. Historically, the distinction between clinical staging and pathologic staging has not been emphasized in many adjuvant therapy clinical trials. The widespread use of sentinel lymph node
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lymphadenectomy has identified a group of stage III patients whose prognosis is superior to patient with clinically defined nodes. This has resulted in a wide range of survival rates among various subgroups of pathologic stage III patients because of ‘upstaging’ based on a direct examination of the sentinel lymph nodes by histopathologic examination [36]. Furthermore, stage II melanoma patients who were clinically staged have significantly inferior survival rates as compared with those whose lymph nodes were determined to be tumor free by pathologic examination of the sentinel lymph node [37]. This heterogeneity in the stage II and III patient populations that has occurred since the introduction of the sentinel lymph node biopsy procedure has not been appreciated in many of the adjuvant therapy trials. Currently, the compelling prognostic value of knowing the nodal status makes sentinel lymph node biopsy indispensable to accurate staging, and thus a key component of future studies examining adjuvant therapy.
5. Adjuvant therapy for high-risk melanoma 5.1. Overview Most of the adjuvant therapy trials in melanoma reported to date have suffered from one or more methodologic problems that limit the degree of confidence which can be placed in their results. All but a few of the randomized trials had less than 250 patients per arm. To put this in perspective, detection of a clinically meaningful 5% increase in 5-year survival in a two arm trial would require enrollment of over 1250 patients per arm (80% power). Some studies have not used a notreatment control of any kind, relying instead on putatively inactive agents (such as the Vaccinia viral oncolysate trial in which Vaccinia alone was used as the control, or the current John Wayne Cancer Institute allogeneic vaccine trials where BCG is the control). If the study result is negative, the question of unrecognized activity of the control group arises [38,39]. Another problem has been the known or potential imbalance of recognized prognostic factors between the treatment and control arms. This has limited the generalizability of some results. Compounding the problems inherent in trials with small sample sizes and potentially imbalanced risk factors is the inclusion of heterogeneous groups of atrisk patients in many of the adjuvant trials conducted to date. Current thinking, based in part on the TNM system for melanoma employed in 2000, would stratify patients into risk categories as low risk (stage IA: negative lymph nodes with a primary tumor 0/1.0 mm without ulceration; stage IB: negative lymph nodes with primary 0/1.0 mm with ulceration or primary 1.01 /2.0
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Table 2 Staging of primary cutaneous melanoma (A) TNM classification T classification T1 0/1.0 mm T2
1.01 /2.0 mm
T3
2.01 /4.0 mm
T4
/4.0 mm
N classification N1 Metastasis in one lymph node N2
Metastasis in 2 /3 lymph nodes or in-transit metastasis with no nodal involvement
N3
4 or more metastatic lymph nodes or matted lymph nodes or in-transit metastasis with nodal involvement
M classification M1 Distant metastasis
(a) without ulceration, level II or III (b) with ulceration or level IV or V (a) without ulceration (b) with ulceration (a) without ulceration (b) with ulceration (a) without ulceration (b) with ulceration (a) micrometastasis (b) macrometastasis (a) micrometastasis (b) macrometastasis (c) in-transit metastasis with no nodal involvement
(a) skin, subcutaneous, or lymph node metastasis, normal LDH (b) lung metastasis, normal LDH (c) all other visceral or any distant metastasis with elevated LDH
(B) Pathologic stage grouping 0 IA IB IIA IIB IIC IIIA IIIB
IIIC
IV
Tis T1a T1b T2a T2b T3a T3b T4a T4b any T1-4a any T1-4a any T1-4b any T1-4b any T1-4a any T1-4a any T1-4a/b
N0 N0 N0 N0 N0 N0 N0 N0 N0 N1a N2a N1a N2a N1b N2b N2c
M0 M0 M0 M0 M0 M0 M0 M0 M0 M0 M0 M0 M0 M0 M0 M0
any any any any
N1b N2b N3 any N
M0 M0 M0 M1
T1-4b T1-4b T1-4a/b T
mm without ulceration), intermediate risk (stage IIA: negative lymph nodes with primary tumor 1.01 /2.0 mm with ulceration or primary 2.01 /4.0 mm without ulceration), high-risk (stage IIB: negative lymph nodes with primary tumor 2.01 /4.0 mm with ulceration or primary tumor /4.0 mm without ulceration; stage III: any T1-4a primary with regional metastases) or very high-risk (resected stage IV: any T, any N, with distant metastases [17] (Table 2). Patients with non-cutaneous
primaries, multiple (/10) positive nodes or gross extracapsular extension appear to be at higher risk than the average ‘high-risk’ patient, but precisely where they should fit into this classification scheme remains to be defined. On the other hand, arbitrarily excluding some members of a risk group from clinical trials (e.g. those patients with positive nodes from an unknown primary) serves no useful purpose and reduces the available patient population for accrual.
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The methodologic problems enumerated above are present to some extent in virtually every trial conducted to date. They make comparisons of trials difficult, even when the trials are purporting to study similar interventions, and they preclude lending serious weight to the results of subset analyses. In the sections that follow, we provide an overview of the adjuvant melanoma trials reported thus far, focusing primarily on randomized, controlled trials that incorporate a no-treatment arm.
5.2. Nonspecific immunostimulants Morton et al. demonstrated that intralesional injection of viable BCG organisms could lead to the regression of intradermal melanoma metastases [40]. Even more significantly, Morton showed that uninjected lesions occasionally regressed. This graphic documentation of the ability of the human immune system to destroy melanoma stimulated the conduct of a host of clinical trials using BCG in the adjuvant setting. Although several non-randomized trials using historical controls and two small randomized trials of intralesional or intralymphatic BCG showed a statistically significant benefit in favor of BCG [41 /44], multiple other randomized trials failed to substantiate this benefit [45 /53]. The WHO Trial 6 was a multicenter randomized study with four arms: dimethyltriazenoimidazole carboxamide (DTIC), BCG, DTIC combined with BCG, and no adjuvant treatment. Follow-up at 15 years revealed no difference in overall survival between the treatment groups [11,48,54]. In addition, a small randomized trial employing the methanol extraction residue of BCG was performed in ocular melanoma and showed no beneficial effect of treatment [55]. Virtually all of these trials were small and employed heterogeneous populations at intermediate and high-risk of recurrence, making definitive conclusions difficult. Corynebacterium parvum is another microbe which can stimulate the human immune system, but has an advantage over BCG in that viable organisms are not required for efficacy. Adjuvant treatment with C. parvum has been compared to observation in two studies, neither of which demonstrated a significant overall benefit for C. parvum [56,57]. C. parvum was also compared directly to BCG (without an untreated control group) in two adjuvant trials. Lipton et al. found a statistically significant disease-free survival advantage for the subgroup of patients with positive nodes who were treated with C. parvum , but no such advantage for node-negative patients [58]. In contrast, Balch et al. conducted a slightly larger trial and found a nonsignificant increase in median survival in favor of the BCG-treated patients [59]. As a consequence of this conflicting data, C. parvum has never found widespread acceptance as a therapeutic agent in melanoma.
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Levamisole is an anthelminthic drug for which various immunomodulatory properties have been reported [60]. Four randomized, controlled trials of levamisole in melanoma have been conducted. In three of the four, no benefit for levamisole therapy was identified [61 /63]. In one study, a significant increase in 5-year survival was seen in favor of levamisole. The significance of this difference disappeared, however, in multivariate analysis */raising the possibility that the findings resulted from an imbalance of prognostic factors rather than a true treatment effect [46]. Finally, there have been a number of other nonspecific immunostimulants that have been examined without evidence of efficacy. Transfer factor, an extract of disrupted leukocytes purported to transfer delayed-type hypersensitivity and act as a nonspecific immunostimulant [64], was tested in two small randomized, controlled trials and was found not to be efficacious [65,66]. Isoprinosine, a mixture of inosine, adedoben and dimepranol with putative immunostimulatory properties, has been tested in the adjuvant therapy of melanoma in several small randomized trials [67,68]. A suggestion of improved disease-free survival seen in one study was not confirmed in the other. A single small study of the thymic factor thymostimulin suggested a short-term advantage in disease-free and overall survival in favor of the treated group [69], but two other studies did not [69,70]. Thus, there is no compelling evidence for the efficacy of nonspecific immunostimulants in the adjuvant treatment of melanoma. Consequently, their use should occur only in an investigational setting. 5.3. Cytotoxic chemotherapy Adjuvant therapy for melanoma has been attempted with nearly every cytotoxic drug that has become available to clinical investigators throughout the years. Despite this, no studies have demonstrated a confirmed benefit of adjuvant chemotherapy in melanoma patients at high-risk for relapse. Single agents with recognized but minimal activity against advanced disease include dacarbazine (DTIC), the nitrosoureas (lomustine (BCNU), carmustine (CCNU) and semustine (methylCCNU)), the vinca alkaloids (vincristine, vinblastine and vindesine), cisplatin, paclitaxel and bleomycin [71]. Single-agent therapy with dacarbazine results in objective responses in 18/22% of patients with measurable metastatic disease [71]. Numerous studies have been performed looking at DTIC as a postsurgical adjuvant [11,48,63,72], and these trials provided no evidence that DTIC has significant efficacy in that setting. Multiagent cytotoxic therapy has similarly been unfruitful in the adjuvant setting. Karakousis and Emrich found no benefit for the combination of DTIC and estramustine in a small, three-arm study comparing
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multiagent chemotherapy or BCG to a no-treatment control group [50]. Four two-arm, randomized controlled trials of multiagent chemotherapy have been performed. A trial using BCNU, dactinomycin and vincristine [73], and a small trial of DTIC, CCNU and vincristine [74] both suggested a benefit for multiagent chemotherapy, while two other trials did not [75,76]. Several small trials have also explored postoperative adjuvant therapy with DTIC plus BCG, with [63,77] or without a no-treatment arm [52,78/81]. DTIC plus BCG did not appear to have any efficacy in the adjuvant setting; this result was perhaps predictable given the lack of activity of the individual agents in the adjuvant setting and the absence of any suggestion of synergy between them. Until and unless randomized trials in advanced disease confirm efficacy of cytotoxic chemotherapy, adjuvant therapy with cytochemotherapy should be considered only in the context of a clinical trial [82]. 5.4. Interferons Interferons are glycoproteins with a variety of immunomodulatory and anti-tumor effects. Interferon enhances expression of class I and II major histocompatibility complex (MHC) molecules and up regulates expression of critical costimulatory molecules such as B7 [83,84]. Interferons can also enhance antigen presentation by dendritic cells /cells which seem to have a critical role in tumor-specific cytotoxic T cell response [85]. Furthermore, interferons inhibit angiogenesis, which may be a critical step in the development of micrometastatic disease [86]. There is also evidence of a direct antiproliferative effect and unconfirmed evidence that interferons can induce melanoma-specific tumor antigens [85]. Finally, interferons are immunomodulatory and stimulate natural killer cells and LAK cells and have been shown in vivo to lyse tumor cells directly [85]. For all of these reasons, interferons appeared to be an attractive potential adjuvant therapy and have been studied extensively in patients with melanoma. In 1980, Bart et al. reported on the inhibition of B16 melanoma in vitro and in vivo by murine interferon [87]. Subsequent phase I studies using partially purified leukocyte interferon at doses below 10 /106 U/day resulted in few responses [88]. Subsequently, more purified forms of both interferon gamma and alpha have been investigated. The immunologic activities of interferon-g have been extensively characterized, including in melanoma patients [89 /92]. These studies provided a compelling rationale for the use of interferon-g in the adjuvant treatment of melanoma [93]. A randomized trial performed within the Southwest Oncology Group, however, failed to indicate any benefit for adjuvant treatment with an immunologically active dose of
interferon-g in patients at intermediate and high-risk of recurrence [94]. The results of this trial were disclosed early because of a suggestion that the treatment arm actually fared worse than the control arm [95]. This disclosure prompted the National Cancer Institute of Canada to close its adjuvant therapy trial comparing levamisole and interferon-g. A total of 89 patients were entered onto the NCI-Canada study when it was closed; there was no apparent difference in disease-free or overall survival between the two groups [96]. The European Organization for Research and Treatment of Cancer (EORTC) 18 871 trial similarly showed no favorable impact of interferon on relapse-free survival in stage III melanoma patients [97]. Other studies have corroborated the finding that interferon-g is ineffective as adjuvant therapy for intermediate and high-risk melanomas and is similarly inactive in patients with advanced melanoma [11,92]. Unlike interferon-g, interferon-a does possess a reasonable degree of activity against metastatic melanoma [84], in addition to a broad range of immunologic effects [84,99]. There have been multiple randomized trials assessing the use of interferon-a in high-risk melanoma patients. These trials have investigated a variety of interferon-a dose levels and treatment schedules. For review purposes the studies can be divided into those involving high-dose regimens, low-dose regimens, and intermediate-dose regimens. 5.4.1. High-dose interferon-a The North Central Cancer Treatment Group (NCCTG) used high-doses of interferon-a2a (20 MU/ m2 i.m. for 3 days/week for 3 months) in patients with resected stage II or III melanoma and showed no significant benefit in overall survival [100]. Subset analysis showed a significant benefit in relapse-free survival among the 160 patients with node-positive disease. Overall survival was also better in the nodepositive patients who received interferon-a2a (47% versus 39%), but this did not reach statistical significance. The relatively small overall sample size, as well as the small number of node-positive patients (160 out of 262), make any definitive conclusions from this study tenuous at best. In a study by ECOG (E1684) a significant benefit on both disease-free survival and overall survival was found in patients randomized to receive high-dose interferona2b for 1 month (20 MU/m2/day i.v. for 5 days each week) followed by 11 months of intermediate dose therapy (10 MU/m2/day s.c. three times a week) compared to observation alone after surgery [7]. The regimen was deliberately chosen to be at or near the maximally tolerated dose for interferon-a. Both nodepositive and high-risk node negative (T4pN0) patients were included; the majority of patients had relapsed in their regional nodes after prior wide excision. All
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patients underwent either elective or therapeutic lymph node dissections. Of the 287 patients enrolled in the trial, 89% were node-positive. Interferon improved overall survival improved from 2.8 to 3.8 years and 5-year relapse-free survival improved from 26 to 37% at a median follow-up of 7 years. Similar to the NCCTG trial, the beneficial effect of interferon-a was most pronounced in the node-positive patients. A recent updated analysis of E1684, with 12.6 years of median follow-up, showed a persistent gain in median survival of 13.8 months (45.8 months for the interferon arm versus 32 months for observation) [101]. However, this survival difference was no longer statistically significant, possibly because of deaths from intercurrent illness on both arms overshadowing melanoma-specific mortality with the passage of time. The updated results continue to show a highly significant improvement in relapse-free survival. No benefit was observed in patients with thick primary melanomas (/4 mm) and pathologically negative nodes. Indeed, in the small subset of nodenegative patients, the group randomized to receive interferon-a2b actually fared worse. The results of this subset analysis are, however, virtually impossible to interpret because of the small size of the subset (only 31 evaluable patients) and the presence of a significant imbalance between the treatment and control arms in the percentage of node-negative patients with ulcerated primary tumors. Patients receiving high-dose interferon experienced significant toxicity. Grade 3 toxicity occurred in 67% of patients, 9% of the patients had life-threatening toxicity and 2 patients died from hepatic toxicity. Treatment had to be reduced or discontinued in over half the patients. Although this toxicity was significant, treatment was tolerated by most patients after appropriate dose reductions, and both economic and quality of life analyses revealed results comparable to those for accepted adjuvant therapies in other malignancies [102,103]. As a result of this trial, the FDA approved interferon-a for the adjuvant treatment of high-risk melanoma, specifically including both thick node-negative and node-positive patients. Although the results of the E1684 trial are encouraging, there are a number of problems with the trial which warrant mention. The trial included only 34 patients in whom nodal disease had been established by ELND (as opposed to therapeutic lymph node dissection). This number is too small to answer the crucial question as to whether interferon-a benefits patients with early micrometastatic disease. This is a question that has taken on increasing importance given the advent of sentinel lymph node biopsy. Furthermore patients were not stratified according to the number of positive lymph nodes. Finally, the treatment itself was fairly toxic, resulting in two deaths and requiring dose
253
reductions in over half of the patients. Even though quality of life-adjusted survival analysis seemed to justify such toxic therapy, many physicians and patients were reluctant to accept high-dose interferon without further evidence. The Intergroup E1690 study was initiated before a significant impact on survival had been noted in E1684. The study was designed as a confirmation and extension of E1684, and involved 642 patients randomized in a three-arm study to receive the high-dose regimen detailed in E1684, low-dose interferon-a2b (3 MU three times a week for 2 years) or observation only. The results of E1690 confirmed the improvement in relapsefree survival with the high-dose interferon regimen seen in E1684. Similar improvement was not seen when the low-dose regimen was compared to observation. Furthermore, there was no significant improvement in overall survival for either the low or the high-dose interferon groups. These findings were clearly at odds with the findings of E1684 which showed a clear statistical improvement in overall survival in the highdose interferon treated cohort. Perhaps the most surprising finding was that the overall survival in all treatment arms was superior to comparable groups in E1684. There was a striking difference in overall survival between the observation arms of E1684 and E1690, with observation patients faring much better in terms of relapse-free survival and overall survival in E1690 versus E1684. Some of this discrepancy may be attributable to a different demographic profile between the two studies. E1690 included a more favorable population of melanoma patients in that only 75% of accrued patients were node-positive, of whom 51% entered with nodal recurrence. In E1690 25% of patients enrolled were ‘clinical’ stage II, while 11% in E1684 were pathologic stage II. Presumably some of the clinical stage II patients in E1690 would have been pathologic stage III had lymphadenectomies been required in the E1690 trial. The disproportionate incremental improvement in disease-free and overall survival for the observation patients in E1690 relative to those on E1684 also may have been related to the availability of post-relapse interferon, which became available in 1995. A retrospective analysis of E1690 revealed a disproportionate use of interferon-a salvage therapy, particularly in patients who had nodal relapse from stratum I (i.e. T4cN0). This may have influenced the overall survival of the observation arm compared with the high-dose interferon-a arm. Another discrepancy between E1684 and E1690 was the efficacy of interferon-a in relation to lymph node status. In E1690, the improvement in relapse-free survival with the high-dose regime was equivalent for those patients with or without lymph node disease [104]. The discrepancies between these two similar trials served to increase the confusion and
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uncertainty around the use of interferon-a2b in the adjuvant setting. The final high-dose interferon study (E1694) was recently published. This study was initiated to evaluate the efficacy and safety of a ganglioside vaccine in comparison with high-dose interferon-a2b (by now, the FDA-approved standard of care) as adjuvant therapy in high-risk melanoma patients. The ganglioside GM2 is a serologically well-defined melanoma antigen and the most immunogenic ganglioside expressed on melanoma cells [105,106]. Preliminary studies conducted at Memorial Sloan-Kettering Cancer Center demonstrated that administration of GM2 in combination with BCG induced IgM anti-GM2 antibodies, and that this antibody response was correlated with relapse-free and overall survival in AJCC stage III melanoma patients [107,108]. Given the toxicities associated with high-dose interferon, it was felt to be reasonable to evaluate less toxic alternatives such as vaccines using GMK. In E1694, 774 eligible high-risk melanoma patients (deep primary lesions /4.00 mm or regional lymph node metastases) were randomized to receive high-dose interferon-a2b versus GMK, a vaccine composed of GM2 ganglioside conjugated to keyhole limpet hemocyanin, co-administered with the immunologic adjuvant QS-21. The study was closed early by the ECOG Data Safety Monitoring Committee because of the clear superiority of interferon-a2b therapy in terms of both disease-free survival (hazard ratio, 1.47; P /0.003) and overall survival (hazard ratio, 1.52, P /0.018) compared with the vaccine arm. This corresponds to a nearly 50% increase in the risk of relapse and death for patients receiving GMK compared to those treated with interferon-a2b. The estimated 2-year relapse-free survival rate for eligible cases was 62% in the interferon-a2b arm versus 49% in the GMK arm [109]. Furthermore, analysis of the hazard of relapse and death in each stratification group by the number of lymph nodes demonstrated the superiority of interferon-a2b over GMK in all nodal subsets. E1694 also showed a statistically significant benefit in the node-negative
subset of patients. In addition, E1694 further demonstrated that interferon-a2b can be used safely. Among patients in the interferon-a2b arm, only 45 (10%) of 440 patients had to discontinue treatment entirely because of adverse events, and there were no treatment-related deaths. A recent abstract reported updated relapse-free and overall survival data for this trial, and continued to show significant improvement for the interferon arm in both endpoints [110]. Taken together, the ECOG/Intergroup studies have established the relapse-free survival and overall survival benefit of high-dose interferon-a2b. The relapse-free survival benefit of high-dose interferon-a2b has been reported in three adjuvant trials (E1684, E1690 and E1694). The relapse-free survival benefit of high-dose interferon-a2b was consistent and highly significant. The overall survival benefit of interferon-a2b has been demonstrated in two trials: E1684 and E1694, the latter being the largest adjuvant trial for resected high-risk melanoma yet reported. The E1690 trial failed to demonstrate an overall survival benefit of interferona2b, but this may have been secondary to a large number of patients originally assigned to observation crossing over to receive interferon-a2b salvage therapy when they experienced treatment failure in regional nodes. One area that stills needs to be resolved with regards to high-dose interferon is the role of the IV induction phase. This is currently being investigated in the E1967, the Sunbelt melanoma trial, and by groups in Europe. In total, the results of the ECOG trials validate the continued use and benefit of high-dose interferon for the adjuvant therapy of patients with high-risk, resected melanoma (Table 3).
5.4.2. Low-dose interferon-a Low-dose interferon therapy has also been investigated. The WHO 16 trial included 444 node-positive patients randomized to receive a low-dose interferona2a regimen consisting of 3 MU three times a week for 3 years. Initial assessment of the data at 3.3 years revealed a significant relapse-free survival benefit for low-dose
Table 3 Summary of high-dose interferon studies in stage II/III disease Cooperative group
Staging
Total patients
NCCTG 83705 ECOG 1684
T3-4/N/ T4/N/
262 287
ECOG 1690
T4/N/
642
ECOG 1694
T4/N/
880
a
Significant for node positive patients.
Treatment regimen
IFN-a2a (20 MU/m2 IM 3 d/wk for 12 weeks) IFN-a2b (20 MU/m2 IV 5x/wk for 1 mon and then 10 MU/m2 SC 3x/wk for 11 mon) IFN-a2b (20 MU/m2 IV 5x/wk for 1 mon and then 10 MU/m2 SC 3x/wk for 11 mon) IFN-a2b (20 MU/m2 IV 5x/wk for 1 mon and then 10 MU/m2 3x/wk for 11 mon vs GMK/QS-21 for 2 years)
Results
Median follow-up
DFS
OS
/a /
/ /
7 years 7 years
/
/
5 years
/
/
2/1 years
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interferon, but no overall survival advantage [98]. The relapse-free survival was not, however, maintained with further follow-up [11]. Indeed, updated follow-up at 8 years did not show any benefit with regards to diseasefree or overall survival for low-dose interferon-a [11]. E1690 was a three-arm United States Intergroup trial that compared high-dose and low-dose interferon-a2b to observation after surgery (but not directly to one another). This trial demonstrated a non-significant improvement in relapse-free survival for 2 years of low-dose interferon treatment in patients with highrisk stage II and III melanoma. This effect seemed to disappear within 2 years of stopping therapy, whereas patients on the high-dose arm of the same trial had a sustained benefit in relapse-free survival [104]. In 989, the Scottish melanoma group initiated a randomized trial, comparing observation alone with 6 months therapy with low-dose interferon (3 MU subcutaneously twice a week), for patients with primary melanomas of a least 3 mm Breslow thickness or with evidence of regional lymph node involvement. The trial was closed in 1993 with only 95 eligible patients randomized and the 6 year follow-up has recently been reported [111]. In this study, although there was an apparent improvement in disease-free survival (from 9 to 22 months), and overall survival (from 27 to 39 months) with interferon, these differences were not statistically significant [111]. The EORTC 18871 trial also demonstrated that a regimen of very low-dose interferon (1 MU) subcutaneously on alternate days for 1 year did not effect overall survival for patients with high-risk melanoma [97,112]. These results seem to indicate that low-dose interferon is not better than observation alone in highrisk patients. Low-dose interferon-a2 has also been evaluated in intermediate risk patients. Two studies using low-dose regimens in patients with node-negative melanomas showed a beneficial effect on disease-free survival [113,114]. A study by Pehamberger et al. involving 311 patients with Stage II disease given low-dose interferona2a for 1 year showed a significant benefit on diseasefree survival, but not on overall survival when analyzed at 41 months. Similar results were obtained in a study by Grob et al. of 489 patients with Stage II melanoma randomly assigned to receive either 18 months with lowdose interferon-a2a (3 MU subcutaneously three times a week) or observation. Recently another randomized multicenter trial investigating the use of interferon-a as adjuvant therapy for patients with Stage I and II melanoma has come out of Italy [115]. In this study, there was a statistically significant reduction in the incidence of metastasis from 63% in controls to 25% in the treatment arm (3 MU intramuscularly three times a week for 3 years) for Stage II melanoma patients [115]. The overall impression from these studies is that lowdose interferon-a, given as 3 MU for 1 /3 years, may
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serve to delay disease progression, but only during the time of administration. Overall mortality appears to be unaffected in virtually all trials reported to date. Because of the lack of demonstrated durable benefit for low-dose interferon-a, it has not been accepted as adjuvant therapy in the USA, although in the UK interferon-a2a is licensed as adjuvant therapy in patients with Stage II malignant melanoma.
5.4.3. Intermediate dose interferon-a The lack of a survival benefit for low-dose regimens tested to date, coupled with the toxicity of the high-dose regimen, has prompted investigations of regimens containing intermediate doses of interferon. The underlying issue in most of these trials is whether the peak dose or the total dose delivered is most directly correlated with durable antitumor effects and survival prolongation. The EORTC has enrolled more than 1400 node-positive patients onto a three-arm study using an intermediate dosing strategy for interferon-a2b in the adjuvant therapy of melanoma (EORTC 18952). The EORTC 18952 study investigates the efficacy of two intermediate dose regimens of interferon-a2b (10 MU SC daily 5 days per week for 4 weeks, followed by either 10 MU SC three times each week for 1 year (arm A) or 5 MU SC three times each week for 2 years (arm B)) versus observation. With a median follow-up of 1.6 years, the first analysis of EORTC demonstrated a difference among the three treatment arms. The 2-year interferon arm (arm B) exhibited a longer distant metastasis-free interval than the control arm (P /0.026), while the 1year interferon arm demonstrated a trend for improved outcome but as yet no significant impact [112]. Whether any of these effects will translate into a durable impact on overall survival remains to be determined. However, the strong correlation between distant disease-free survival and overall survival for patients with nodepositive melanoma suggests that such a survival impact is likely to emerge. As expected, toxicity has proven to be substantially less with both intermediate-dose regimens than with high-dose interferon-a2b. The Scandinavian Melanoma Cooperative Group is also conducting a three-arm trial investigating similar intermediate dose regimens. Two treatment arms, incorporating the modified induction regimen of the EORTC (10 MU of interferon-a2b 5 days per week for 1 month) followed by a maintenance dose of 10 MU TIW for 12 or 24 months, will be compared with observation. Overall, the role of intermediate-dose interferon therapy in the adjuvant treatment of melanoma remains to be established. As the two noted trials mature any potential role for low-dose interferon may be clarified.
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5.5. Vaccine therapy Vaccine therapy is designed to elicit a host immune response to known or unknown tumor-associated antigens. To date, only a limited number of melanomaassociated antigens have been defined, and vaccines have been developed for only a few of these. Thus, few trials haven been conducted which include as part of the study appropriate monitoring to verify that the desired immunologic endpoint has been achieved. The lack of a no-treatment control arm has also complicated the interpretation of many of these studies. Since only a few melanoma-associated antigens have been defined, and since those few that are known may not be present or may not be sufficiently immunogenic in a given individual to mediate tumor regression, a number of investigators have worked with autologous tumor vaccines. This approach is limited to individuals with sufficient accessible tumor to prepare a vaccine. Such patients generally have a poor overall prognosis and are likely to have significant residual tumor burden, making them less-than-ideal candidates for any immunotherapeutic approach. Even in those cases, only enough tumor is usually obtained to provide for a limited number of vaccinations. Furthermore, the technical complexities inherent in procuring tumor and preparing a vaccine have, to date, hampered attempts to perform multi-institutional trials to formally test the efficacy of autologous tumor vaccines. Two small randomized trials (15 and 31 patients, respectively) comparing irradiated or neuraminidase-treated autologous tumor cells plus BCG to a control group found that the treatment group appeared to fare no better or perhaps even worse than the control [116 /118]. In addition, a somewhat larger randomized, controlled trial of adjuvant therapy with autologous tumor cells plus BCG in renal cell carcinoma failed to show any evidence of benefit for vaccine treatment [119]. Nonetheless, single-institution studies incorporating historical controls [120 /122], as well as the potential to genetically modify tumor cells to be more immunogenic [123,124], continue to stimulate interest in this approach. Since patients with resected nodal and distant metastases */ the population most amenable to autologous vaccine approaches */are now considered candidates for adjuvant therapy with high-dose interferon, it is likely that future trials of this approach will be conducted in conjunction with this therapy. Allogeneic tumor cell vaccines, generally prepared from cultured cell lines or lysates thereof, offer several important advantages over autologous tumor cell vaccines: they are readily available and can be standardized, preserved and distributed in a manner akin to any other therapeutic agent. These properties allow for the use of multiple vaccinations over months or years and enable the performance of large-scale, multi-institutional clin-
ical trials. The majority of trials that have been completed to date, however, were small, single institution studies. None of these trials demonstrated an unequivocal benefit for immunotherapy with allogeneic tumor cells administered in conjunction with BCG when compared to an untreated [49,125] or a BCG-treated control group [126]. Considerable uncertainty remains as to the optimal immunologic adjuvant to use in conjunction with an allogeneic tumor cell vaccine, but there is certainly reason to suspect that BCG may not be ideal [127,128]. Also controversial is the role of immunomodulators given concomitantly with vaccination, such as low-dose cyclophosphamide. Two randomized studies have been conducted in which allogeneic melanoma vaccines were administered without or with cyclophosphamide given for 3 days prior to vaccination. The results of these studies have been conflicting, with one suggesting no detectable difference [129] and one suggesting a decrease in suppressor cell activity and augmented antibody response [130]. The Southwest Oncology Group has recently completed a large (/600 patients), randomized trial comparing an allogeneic melanoma cell lysate (Melacine† ) co-administered with detoxified endotoxin/mycobacterial cell wall skeleton (DETOX), given without cyclophosphamide, to an untreated control group in patients with intermediate thickness, node-negative melanoma (S9035). The primary aim of this trial was to determine the effect of the vaccine on relapse-free survival; effects on survival will be evaluated in a future analysis [131]. A major secondary aim of the trial was to determine if the effectiveness of the vaccine varied based on patients’ HLA Class I allele expression [132]. HLA Class I alleles differentially present protein antigens as peptides to CD8/ T cells. Patients expressing various Class I types may therefore differ in their response to cell lysate-based cancer vaccines. Previously, Mitchell et al. reported a strong association between patient HLA phenotype and evidence of clinical benefit from Melacine, with a significantly greater proportion of stage IV melanoma patients who expressed at least two of the following five alleles: HLA-A2, A28, B44, B45 and C3 (referred to collectively as M5) showing clinical benefit than those patients expressing only zero or one of these alleles. In total, 689 patients were randomized to S9035; 89 (13%) were deemed ineligible, mainly because the tumor was too thin (42 patients) or too thick (23 patients) on central pathology review. Thirteen eligible patients refused assigned treatment: seven on the observation arm (four received vaccines off-protocol) and six on the vaccine arm. Most toxicity was local */granulomas or sterile abscesses*/and there was no autoimmune toxicity. After a median follow-up of 4.1 years, 95 events (recurrences or deaths) occurred among 300 eligible patients randomized to vaccine versus 106 events among 300 eligible patients randomized to observation (P /
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0.30). In total, 553 of 689 patients enrolled were HLA typed (80% of the total, 294 vaccine and 259 observation arm patients). There was no single HLA Class I allele that independently conveyed a significant impact on outcome, either for the vaccine or the control arms. In contrast, however, the 81 patients in the vaccine arm expressing E/2 of M5 alleles had a superior disease-free survival than the corresponding 70 patients with 0/2 M5 matches in the observation arm (4-year disease-free survival 87% versus 64%, P /0.0001). Vaccine arm patients expressing E/2 of M5 alleles also had superior disease-free survival than those in the vaccine arm with 0 /1 HLA matches (4-year disease-free survival 87% versus 64%, P /0.004). The specific alleles contributing the major component of this effect were HLA-A2 and C3, suggesting that melanoma tumor antigens presented by HLA-A2 and C3 may be critical in protecting vaccinated patients from disease relapse. Further investigation of adjuvant vaccine approaches for intermediate-thickness, node-negative melanoma is clearly warranted and analysis of HLA Class I expression should be a routine part of future vaccine trials. An alternative approach to allogeneic vaccination involves the use of viruses to lyse the tumor cells prior to inoculation. In theory, the admixture of viral and tumor proteins would provoke an intense immune response that would lead to recognition and rejection of tumor cells by the host. A pilot study of melanoma patients treated with Newcastle disease virus lysates of either autologous or allogeneic tumor cells for 5 years suggested an improved survival compared to historical controls [133]. This observation prompted two larger randomized trials using Vaccinia viral lysates of allogeneic tumor. One trial incorporated a control arm in which patients were treated with Vaccinia virus alone, without tumor cells [38]. The other trial used a notreatment control arm [134]. Both studies demonstrated no evidence of benefit for the Vaccinia oncolysate treatment. Although it is possible that a small immunomodulatory effect of Vaccinia virus by itself could have obscured the beneficial effect of the viral oncolysate in one trial [39], the negative results of the other trial suggest that this is not the case. The results of these two randomized trials, in such marked contrast to the beneficial effect seemingly found in a non-randomized trial [133], emphasizes yet again the perils of relying on historical controls in evaluating melanoma therapy [135]. Vaccination with autologous or allogeneic tumor represents an attempt to convey antitumor immunity by exposing the patient to a variety of tumor-associated antigens. Decades of research have identified and defined a number of antigens present on melanoma cells that could potentially serve as targets for the human immune response. Gangliosides are a group of related glycolipids present on melanoma cells and some
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non-neoplastic cells (particularly neural tissues). Ganglioside GD3 is distributed widely on melanocytes, nevi and practically all melanomas, as well as some normal tissues, and naturally occurring anti-GD3 antibodies are rare. Administration of a monoclonal antibody to GD3 (in conjunction with macrophage-colony stimulating factor) resulted in objective regression of melanoma metastases in the rare patient [136]. As mentioned previously, ganglioside GM2 is expressed on a large percentage of melanoma specimens but is rarely detected on normal tissues, and about 5% of melanoma patients have naturally-occurring anti-GM2 antibodies. Patients with anti-ganglioside antibodies appear to have a better prognosis than those without antibodies [107,137]. Livingston et al. conducted a randomized trial comparing adjuvant therapy of node-positive melanoma with BCG to treatment with BCG plus purified GM2 ganglioside. The overall analysis revealed no significant difference between the two treatment arms [108]. Interpretation was hampered by the small size of the trial and the fact that there was an imbalance between the two arms with respect to the number of patients with preexisting anti-GM2 antibodies. Since the completion of that study, the investigators have focused on ways to increase the humoral response to GM2 vaccination. By conjugating the GM2 to the xenogeneic protein keyhole limpet hemocyanin and replacing the BCG with the saponin-derived adjuvant QS-21, they were able to achieve high levels of IgG and IgM anti-GM2 antibodies in a very high percentage of patients. As mentioned previously, in E1694 adjuvant therapy with GM2-KLH/QS-21 was shown to be inferior to interferon. GM2-KLH/QS-21 is currently being evaluated in comparison to observation alone in a large EORTC study in stage II melanoma patients. Another technique for stimulating an immune response to non-protein antigens such as gangliosides is by administration of anti-idiotype antibodies. These ‘antiantibodies’ are antibodies raised against anti-ganglioside antibodies so that the variable region of the antibody is essentially a mirror-image of the ganglioside itself, only composed of protein [138]. When an immune response occurs to this mirror-image protein, it is also crossreactive against the original antigen [139]. To date, antiidiotype antibodies have been produced against GD2 and GD3; these antibodies are just beginning to undergo phase I and II testing and have not yet been evaluated in randomized trials [140,141]. A different vaccination approach has focused on the use of peptide antigens. Eukaryotic cells express thousands of proteins which are presented on the surface of antigen-presenting cells and other cells as antigens for recognition by T cells complexed with Class I and II MHC molecules [142]. The generation and detection of tumor antigen-specific immune responses can theoretically lead to the eradication of tumor cells. Human
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melanoma cells express antigens recognized by cytotoxic lymphocytes. These antigens include antigens created by unique, random mutations and those that are commonly expressed on melanomas from many different patients [143]. The most widely shared melanoma antigens recognized by cytotoxic lymphocytes are derived from melanocyte differentiation proteins including gp100, tyrosinase, MART-1/Melan-A and gp75. A number of prospective studies have investigated the use of melanoma peptide antigen vaccines, often using synthetic peptides modified in anchor residues to result in greater affinity for the relevant MHC molecule. Lee et al. reported on 48 patients with high-risk resected stage III or IV melanoma who were immunized with two tumor antigen epitope peptides derived from gp100209 217 (amino acid sequence IMDQQVPSFV) and tyrosinase368 376 (YMDGTMSQV) emulsified with incomplete Freund’s adjuvant (IFA) [144]. Patients received peptides/IFA with or without interleukin-12, 30 ng/kg, to evaluate the toxicities and immune responses in either arm with time to relapse and survival as secondary end points. Thirty-three of 38 patients demonstrated an immune response by ELISA after vaccination, as did 37 of 42 patients by tetramer assay. Twenty-four of 48 patients relapsed with a median follow-up of 20 months, and 10 patients had died by this time. The authors concluded that a significant proportion of patients with resected melanoma can mount an antigen-specific immune response against the gp100 and tyrosinase peptide vaccines and that IL12 may increase this immune response. The results of a separate phase I trial of a different gp100 peptide vaccine were reported by Slingluff et al. [145]. In this trial, a melanoma vaccine composed of HLA-A2restricted peptide YLEPGPVTA (gp100280 288) with or without a modified T-helper epitope from tetanus toxoid was evaluated to assess safety and immunological response. The vaccines were administered to 22 highrisk patients (stage IIB /IV). Cytotoxic lymphocyte responses to the gp100280 288 peptide were detected in the peripheral blood in 14% of patients. Helper T-cell responses to the tetanus helper peptide were detected in 79% of patients. The overall survival of patients at 4.7 years follow-up was 75%. Four of 14 patients who completed at least six vaccines subsequently developed metastases, all of which were solitary and surgically resectable. Although the results of these studies demonstrate the immunogenicity of peptide antigens and the possible cytotoxic immune responses, they also clearly show how difficult it can be to ascertain whether any immune response is protective against tumor recurrence. Prospective studies with peptide antigen vaccines will be needed to define their role in the adjuvant therapy of melanoma patients.
5.6. Granulocyte/macrophage colony-stimulating factor Granulocyte/macrophage colony-stimulating factor (GM-CSF), a cytokine with a role in the growth and maturation of hematopoietic and dendritic cells, has been incompletely studied in the adjuvant setting. No prospective, randomized, multicenter trials have yet been completed with this agent to support its use in the adjuvant therapy of high-risk melanoma outside clinical investigations. In one phase II trial investigating GM-CSF as surgical adjuvant therapy in patients with stage III or IV melanoma, Spitler et al. showed that GM-CSF prolonged overall and disease-free survival as compared to matched historical controls [146]. This has prompted a number of prospective intergroup trials which are currently investigating the potential function of GM-CSF. One such trial is the ECOG trial E4697 which is evaluating GM-CSF (alone or administered with an HLA-A2 restricted multi-epitopic peptide vaccine) in patients following resection of distant metastases or local or regional nodal disease after adjuvant interferon therapy [147]. Definitive recommendations regarding the use of GM-CSF in the adjuvant setting for melanoma must await the results of these trials. 5.7. Radiation therapy The role of adjuvant radiation therapy in the management of melanoma remains unclear. It should rarely be employed for definitive treatment of a primary melanoma site. The main role of adjuvant radiation is the treatment of the nodal basin after resection of regionally advanced melanoma. Only one small randomized trial of adjuvant radiotherapy has been completed in cutaneous melanoma, and this produced no benefit [148]. This study utilized conventional radiation fractions and a treatment break, both currently felt to be suboptimal for melanoma. Several non-randomized studies have suggested that postoperative radiation to the neck or axilla after radical lymph node dissection decreases regional recurrence rates in node-positive patients [31,34,149]. However, a case-review study by Shen et al. looking at adjuvant radiotherapy after positive lymph node dissections in the head and neck showed that the low incidence of cervical recurrence after regional lymph node dissection did not justify the routine use of postoperative radiation [150]. The Radiation Therapy Oncology Group initiated a randomized trial of postoperative radiation using larger treatment fractions in patients undergoing neck dissections for melanoma. Accrual to this trial was slow, however, and the trial ultimately closed due to a failure to meet its accrual goal [151]. Until larger randomized trials are conducted, it is reasonable to consider postoperative radiation therapy in patients with gross extracapsular
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extension [29] or multiple (10 or more) involved lymph nodes. From several reports, the most effective radiation schedules involve large doses per fraction. For nodal irradiation, a common regimen is 3500 cGy in 10 days, delivered at 350 cGy per day 5 days per week. Since patients who are candidates for radiation therapy are also candidates for adjuvant interferon-a2b therapy, the optimal timing for integrating radiation with interferon will need to be determined. In the absence of definitive data, we defer the start of radiation until after the completion of the initial month of intravenous interferon and administer it during the subcutaneous phase of treatment. Interferon may act as a radiosensitizer; some patients appear to have more acute toxicity when give radiation and interferon than when given the same dose of radiation alone.
6. Conclusion Metastatic malignant melanoma remains a highly lethal disease; hence, the prevention of its development is a clinical priority. Prevention should include sunscreens with a SPF of 30 or higher, as well as protective clothing and sun avoidance. Despite attempts at prevention, the incidence of melanoma in the USA continues to climb with at least 50 000 new cases per year. Management of melanoma must include definitive local, regional and distant control. There is substantial prospective and retrospective data to base the extent of surgical excision for primary melanoma. For lesions B/ 1.0 mm, margins of 1 cm provide excellent control. For lesions measuring 1 /4 mm, 2 cm margins produce excellent local control, while dramatically reducing the need for skin grafting. For thicker melanomas, retrospective data supports the use of 2 cm margins. Regarding diagnosis and control of regional disease, the advent of the sentinel lymph node biopsy technique has revolutionized the surgical approach. Elective node dissection has not been shown to provide therapeutic benefit and should be abandoned. Rather sentinel lymph node biopsy should play a central role in staging the regional lymph nodes and is the standard of care in many, if not all, major melanoma centers. The finding of metastatic disease, even microscopic foci detected only by immunohistochemical staining, is sufficient to warrant completion lymph node dissection and consideration of adjuvant therapy. Improvements in our understanding of the prognosis and staging of melanoma have allowed us to better categorize patients based on their risk of developing metastatic disease, permitting the development of logical strategies using adjuvant therapies with toxicity profiles that are appropriate based on the level of risk for recurrence. Adjuvant therapies with nonspecific immunostimulants and cytotoxic chemotherapy have shown little promise. In
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contrast, high-dose interferon-a2b improves relapsefree survival and likely improves melanoma-specific survival as well. Interferon-a2b is the adjuvant therapy of choice for high-risk patients treated outside clinical trials, and the appropriate control arm for clinical trials evaluating new or modified adjuvant regimens. The toxicity of high-dose interferon, however, is substantial and limits both patient and physician acceptance. Alternate interferon dosing schedules (intermediate or low-doses) may have potential merit, but as of yet have not been shown to improve survival. New approaches with vaccines and biochemotherapy (combinations of immunomodulatory cytokines and cytotoxic chemotherapy) hold promise, but should still be confined to carefully designed and conducted clinical trials in order to best determine what advantages, if any, they provide over current therapy. The ongoing importance of clinical trials in the adjuvant therapy of melanoma can hardly be overstated. Evaluating the benefits of future therapies will require larger clinical trials than have yet been conducted, because small differences in outcome may prove to be important. Increasing the success of adjuvant therapy for melanoma will require an ongoing commitment to conduct scientifically and statistically sound randomized clinical trials. To this end, patients with stage II and III disease should be encouraged to participate in welldesigned trials assessing a variety of adjuvant therapies.
Reviewers Danielle Lienard , CHUV (Centre Hospitalier Universitaire Vaudois), Centre Pluridisciplinaire d’Oncologie Niveau 06, rue du Bugon 46, CH-1011 Lausanne, Switzerland. Sanjiv S. Agarwala , Associate Director, Melanoma Center, University of Pittsburgh Cancer Institute, Montefiore Hospital, 200 Lothrop Street 7 Main N, Pittsburgh, PA 15213-2582, USA. Michael B Atkins , Beth Israel Deaconess Medical Center, Kirsten Brookline Ave, Boston, MA 022155400, USA.
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Biographies Timothy M. Pawlik, M.D., M.P.H. recieved his undergraduate degree from Georgetown University and his M.D., M.P.H. degrees from Tufts University
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School of Medicine. Recently having finished his surgical residency at the University of Michigan in Ann Arbor, Michigan he is now beginning a Surgical Oncology Fellowship at MD Andeson, Houston, Texas. Vernon K. Sondak , M.D. received his undergraduate and M.D. degrees from Boston University, prior to residency training at the University of California, Los
Angeles. In 1987, he joined the faculty at the University of Michigan Medical Center, Ann Arbor, MI, USA. He is currently Professor of Surgery in the Division of Surgical Oncology. Dr Sondak specializes in the treatment of soft tissue tumors, including melanomas and sarcomas, and is the Chair of the Melanoma and Surgery Committees of the Southwest Oncology Group.