Current Management of Anal Canal Cancer

Current Management of Anal Canal Cancer Bernard J. Cummings Combined-modality therapy consisting of radiation therapy and 5-fluorouracil plus mitomycin remains the standard treatment for localized anal canal cancer, permitting preservation of organ function and achieving high response and survival rates. Current trials are evaluating the ability to deliver higher doses of radiation therapy over shorter intervals. Currently, the most common indication for radical surgery is failure of chemoradiation. Metastatic disease is less responsive to chemoradiation treatment. Neoadjuvant and adjuvant strategies are being evaluated, and additional drugs including capecitabine, irinotecan, and oxaliplatin are being assessed in treatment of localized and advanced disease. Semin Oncol 32(suppl 9):S123-S128 © 2005 Elsevier Inc. All rights reserved.

C

ancers of the anal canal are uncommon, with an annual incidence in North America of slightly less than 1 per 100,000 persons, approximately one tenth that of cancer of the rectum.1 These rare cancers have provided a dramatic illustration of the ability of carefully constructed multimodality therapy to preserve organ function while matching or surpassing the survival rates achieved by organ-sacrificing extirpative resection.

Pathology Classification The current World Health Organization classification of anal canal cancers recommends the single term “anal squamous cell carcinoma,” rather than the several subtypes described in previous classifications, such as basaloid (cloacogenic) and large cell keratinizing and nonkeratinizing.2 This change reflects the availability for examination in current practice of only small biopsy samples, the mixed histopathologic features of many tumors, and poor reproducibility of subtype classification among different observers. This change also mirrors, although for different reasons, the common practice in clinical studies of grouping the histologic subtypes as “epidermoid” cancers because of the similarities of their natural history and response to modern treatments. Adenocarcinomas, squamous cell carcinomas with mucous microcysts, and small cell (anaplastic) carcinoma subtypes continue to be

Princess Margaret Hospital/University of Toronto, Toronto, Ontario, Canada. Dr Cummings has no significant financial relationships to disclose. Address reprint requests to Bernard J. Cummings, Department of Radiation Oncology, Princess Margaret Hospital/University of Toronto, 610 University Ave, Toronto, Ontario M5G 2M9, Canada; e-mail: [email protected]

0093-7754/05/$-see front matter © 2005 Elsevier Inc. All rights reserved. doi:10.1053/j.seminoncol.2005.04.019

classified separately2 but are not considered further in this discussion.

Evaluation and Staging The anal region lies at the distal transition between embryologic endoderm and ectoderm. The anal canal is 3 to 4 cm long. It extends from the upper border of the anal sphincter muscles and puborectalis muscles of the anorectal ring to the lowermost edge of the sphincter muscles. Surrounding the anal orifice over a 5-cm radius is the perianal skin. The anatomic extent of the cancer provides the most reproducible prognostic information,3 and forms the basis of current staging systems.4,5 Extrapelvic metastases are associated with the worst prognosis. The size of the primary tumor, in the absence of metastases, is the most useful predictor of survival and of local control and preservation of anorectal function. Spread to regional nodes (the perirectal, internal iliac, and inguinal node groups) is an adverse factor for survival in most series, and in some also for control of the primary tumor. A survey of nearly 50 reports on cytogenetic, flow cytometric, immunohistochemical, and other investigations, such as serum markers, indicated that those studies so far offer insights on pathogenesis but not guidance to prognosis or treatment selection for the individual.6 The size of the primary tumor is generally established by direct clinical measurement. Imaging studies such as computed tomography, magnetic resonance imaging, or transanal ultrasound are more useful for assessing the depth of infiltration through the sphincter muscles and into adjacent organs. In collected historical series, inguinal node metastases were present at diagnosis in approximately 20% (range, 9% to 40%) of patients and based on late relapse rates, subclinS123

B.J. Cummings

S124 Table 1 Randomized Trials of RT Alone Versus RT, 5-FU, and Mitomycin-C

3-year outcomes (percent) Study

Treatment

UKCCCR11 (n ⴝ 585)

5-FU 1,000 mg/m2/24 hr for 96 hrs or 750 mg/m2/24 hrs for 120 hr, wks 1 and 5 Mitomycin-C 12 mg/m2 d1 of wk 1. RT 45 Gy in 4 or 5 wks Boost RT 15 Gy 6 wks later v RT alone P value 5-FU 750 mg/m2/24 hrs for 120 hrs wks 1 and 5 Mitomycin-C 15 mg/m2 d1 of wk 1 RT 45 Gy in 5 wks Boost RT 15-20 Gy 6 wks later v RT alone P value

EORTC12 (n ⴝ 103)

Local-Regional Control

Cause-Specific Survival

Overall Survival

61

72

65

39 <.0001 65

61 .02 –

58 .25 70

55 .02

– –

65 .17

Abbreviations: RT, radiation therapy; 5-FU, 5-fluorouracil; EORTC, European Organization for Research and Treatment of Cancer; UKCCCR, United Kingdom Coordinating Committee on Cancer Research.

ically in a further 10% to 25%.6 Pelvic and inferior mesenteric metastatic nodes were found in 26% (range, 10% to 40%).7 Only the inguinal and lower perirectal lymph nodes can be assessed by physical examination. Because as many as half the nodes palpated in the inguinal regions are enlarged because of causes other than metastasis, fine needle aspiration biopsy or simple excision of clinically or radiologically suspicious nodes for histologic examination is recommended. About one half of pelvic node metastases are less than 0.5 cm in size8 and thus below the resolution of commonly performed studies such as computed tomography, magnetic resonance imaging, and transanal ultrasound. The roles of positron emission tomography scanning and of sentinel node biopsy are under investigation. Extrapelvic metastases are generally present in no more than approximately 5% of patients at first evaluation, and are most commonly found on imaging the pelvic (external or common iliac) or paraortic nodes, liver, and lungs. In the absence of localizing symptoms, additional studies are usually limited to liver and renal function tests and complete blood count.

Treatment of Localized Cancer Combined-Modality Treatment Following the initial description in 1974 by Nigro et al9 of complete clinical and histopathologic regression of anal squamous cancers in response to a regimen of moderate-dose radiation with concurrent chemotherapy intended as preoperative adjuvant therapy, it was found that the combination used, namely radiation, 5-fluorouracil (5-FU) and mitomycin-C, was also effective as definitive treatment. Radical surgery came to be deferred and reserved for residual cancer. A study of the patients entered in the US National Cancer Data

Base in 1998, at a time when similar numbers of patients were treated by traditional radical surgery or by combined radiation and chemotherapy, showed similar survival rates for the two treatment approaches.10 It is now considered that a randomized trial comparing radical surgery and combined-modality therapy would not be ethical or acceptable to patients, given the requirement for permanent colostomy associated with surgical procedures such as abdominoperineal resection. Three randomized trials have established combined-modality therapy, using radiation, 5-FU, and mitomycin, with salvage surgery where indicated, as the standard treatment of squamous cell cancer of the anal canal.11-13 In the United Kingdom11 and European12 trials, the combination was found to be superior to the same schedule of radiation alone, resulting in significantly better rates of primary tumor control and colostomy-free survival (Table 1). The UK trialists also found better cause-specific survival. The improvement in overall survival rates was not statistically significant in either trial. In both studies, acute morbidity, particularly hematologic, skin, gastrointestinal, and genitourinary morbidity, was increased by combined radiation and chemotherapy, but the risks of late morbidity were comparable. In the UK trial, six deaths (2%) were attributed to combined-modality treatment,11 as was one (2%) in the European Organization for Research and Treatment of Cancer (EORTC) study.12 In the former trial there were two treatment-related deaths (0.7%) among those treated by radiation alone but no deaths from toxicity occurred in the corresponding group in the EORTC trial. In the third trial, conducted in North America by the Radiation Therapy Oncology Group (RTOG) and Eastern Cooperative Oncology Group (ECOG), it was shown that the combination of 5-FU and mitomycin-C with radiation was

Current management of anal canal cancer

S125

Table 2 Randomized Trial of RT and 5-FU With or Without Mitomycin-C 4-Year Outcomes (%) Study

Treatment*

RTOG/ECOG13 (n ⴝ 291)

5-FU 1,000 mg/m2/24 hrs for 96 hrs, wks 1 and 5 Mitomycin-C 10 mg/m2 wks 1 and 5 RT 45-50.4 Gy in 5 to 5.5 wk v RT and 5-FU P value

Local-Regional Control

Disease-Free Survival

Overall Survival

84

73

76

66 <.001

51 <.001

67 .31

Abbreviations: RT, radiation therapy; 5-FU, 5-fluorouracil; ECOG, Eastern Cooperative Oncology Group; RTOG, Radiation Therapy Oncology Group. *Some patients in each arm received 9 Gy/1 wk plus 5-FU/cisplatin 6 wks after initial treatment.

more effective than radiation plus only 5-FU, with significant improvements in colostomy-free survival and disease-free survival, although not in overall survival (Table 2).13 In this study, patients underwent biopsy of the primary tumor site 6 weeks after treatment. Biopsies were positive in 14% of those who received 5-FU only and in 8% who received both drugs with radiation (P ⫽ .14). Where preservation of anal function was thought possible in those with positive biopsies in either treatment group, additional radiation with concurrent 5-FU and cisplatin was administered. As anticipated, hematologic toxicity was increased by mitomycin-C, but other side effects, both early and late, were comparable in both treatment groups. Four of 146 patients (2.7%) who received 5-FU and mitomycin-C died of acute toxicity, compared with 1 of 145 (0.7%) treated with radiation and 5-FU alone. Review of the nonrandomized studies indicates that the combination of radiation, 5-FU, and mitomycin-C has resulted in 5-year survival rates of approximately 80% for cancers up to 2 cm in size (T1), 70% for tumors of 2 to 5 cm (T2), 45% to 55% for larger cancers or those invading adjacent organs (T3 or T4), and 65% to 75% overall.14 The local control rates following radiation and chemotherapy, and excluding salvage treatment, were approximately 90% to 100% (T1), 65% to 75% (T2), 40% to 55% (T3 or T4), and 60% overall, respectively.13 Up to 5% of patients in some series lost anorectal function because of treatment-related morbidity. Milder, but symptomatically troublesome, long-term morbidity such as perineal fibrosis, rectal urgency and diarrhea, and dyspareunia were relatively common.15 Metastases to the regional nodes in the inguinal regions and pelvis are controlled by the chemoradiation schedules used for the primary cancer. In most studies, the 5-year survival rates for patients with regional node metastases are up to 20% lower than in node-negative patients. When inguinal nodes are not invading skin or deep structures, the regional control rate after chemoradiation alone or local excision followed by chemoradiation or radiation alone is usually 80% or better.16,17 Formal node dissection is reserved for patients with residual or recurrent metastases after radiation-based treatment. These patients are at increased risk of postoperative healing problems or chronic lymphedema. The failure rate in clinically normal inguinal nodes not treated prophy-

lactically ranges from approximately 10% to 25%.14 There is considerable debate over the merits of prophylactic treatment compared with treatment deferred to the time of failure. Prophylactic groin dissection is not recommended because of the high risk of morbidity. However, elective radiation is used widely, with concurrent chemotherapy, and reduces the risk of late node failure in the volume irradiated to less than 5% without significant morbidity.14 Pelvic node metastases are usually diagnosed radiologically, and the response to radiation and chemotherapy is also monitored by imaging, although occasional authors have suggested surgery after preoperative combined-modality treatment.18 The relatively high rates of control of pelvic disease described after combined-modality treatment are generally considered indirect evidence of eradication of metastatic pelvic nodes, although more direct methods of monitoring such metastases are needed. A review of failure patterns from the trials described above has spurred efforts to improve results. The UK investigators categorized the sites of failure in patients dying of cancer (that is, after salvage treatment).11 Among the 289 patients treated with combined-modality therapy, 77 succumbed to cancer. Based on the number randomized, there was locoregional failure alone at the time of death in 13% (49% of the deaths from cancer), locoregional plus distant failure in 3%, and distant metastases only in 7%. This and similar analyses of other studies have led to efforts to reduce locoregional failure and to reduce metastases by improving both the radiation and chemotherapy components of combined-modality therapy. Two important variables in radiation treatment are the total dose and the overall duration of the time during which this is administered. In pooled nonrandomized series, radiation doses of approximately 30 Gy in 3 weeks eradicated up to approximately 90% of cancers smaller than 3 cm in size when combined with 5-FU and mitomycin-C.14 Higher doses, from 45 Gy in 5 weeks to 54 Gy in 6 weeks, sometimes supplemented by additional radiation to a total of 60 Gy to 65 Gy over approximately 12 weeks total time, control from 65% to 75% of primary cancers larger than 4 cm.14 Several nonrandomized single-institute studies suggest improved control of larger tumors with higher doses.19 Total doses on

B.J. Cummings

S126 Table 3 Phase II Studies of RT, 5-FU, and Cisplatin Study

Treatment

Gerard et al26 (n ⴝ 94)

5-FU 1,000 mg/m2/24 hrs for 96 hrs Cis 25 mg/m2 daily for 4 d RT 40 Gy/10/d 1 to 17 plus boost RT d 63 to 64 5-FU 250 mg/m2/24 hrs for 5 d/wk for 6 wks Cis 4 mg/m2/24 hrs for 5 d/wk for 6 wks RT 55 Gy/30/d 1 to 42

Hung et al27 (n ⴝ 92)

Primary Tumor Complete Response for 12 Months or More

5-Yr Survival

81%

84% actuarial

82%

91% actuarial

Abbreviations: RT, radiation therapy; 5-FU, 5-fluorouracil; Cis, cisplatin.

the order of 55 Gy to 70 Gy are now being evaluated in randomized trials. The overall duration of radiation may be prolonged by planned or unplanned interruptions. A common reason for such interruptions is the severity of acute anoproctitis and perianal dermatitis. It is usually possible to resume treatment within 1 to 2 weeks in the setting of these complications. These side effects are related in part to the technique of radiation treatment.14 Some authors have recommended more extended planned interruptions of 6 to 8 weeks to allow partial regression of the tumor and the application of boost radiation to the residual tumor only.11,12,18 However, anal cancers may have the potential to repopulate relatively quickly during treatment. The median potential doubling time of 26 anal cancers was approximately 4 days (range, 1 to 30 days),20 similar to that of cervix cancer. The control by radiation of many cancers, including cervix cancer, decreases by prolongation of the overall duration of radiation. When overall treatment time was studied as a variable, improved results were generally found in those patients with the shorter treatment durations. Although escalated radiation doses and shortened overall treatment times may be beyond the tolerance of some patients,21-23 such schedules are being tested in current trials in North America and Europe. Advances in radiation planning and conformal treatment techniques, or the incorporation in treatment protocols of pharmacologic agents such as amifostine that provide partial protection to normal tissues will likely improve patient tolerance of higher radiation doses. Only a limited range of chemotherapeutic agents and drug schedules has been studied, because of the effectiveness of 5-FU and mitomycin-C and the relative infrequency of anal cancers. Nonrandomized studies of bleomycin given concurrently with radiation did not suggest benefit.24 The RTOG/ ECOG trial found that 5-FU alone, given as two 96-hour infusions (1,000 mg/m2/24 hours), was inferior to 5-FU plus mitomycin-C.13 Single-institution, nonrandomized studies suggested merit to long-term continuous infusions (225 mg/ m2/24 hour for 5 weeks) or multiple repeated 5-day infusions (1,000 mg/m2/24 hours) concurrently with radiation,19,25 but these schedules have not yet been evaluated in randomized trials. The drug combination currently of greatest interest as an alternative to 5-FU plus mitomycin-C is 5-FU plus cisplatin. This regimen has produced high response rates in metastatic anal cancer and as a neoadjuvant (induction) treatment before radiation; cisplatin may enhance the effects of radia-

tion whereas mitomycin-C, as used clinically, does not, and the different toxicity profile of cisplatin may be less potentially harmful than that of mitomycin. The results of two studies, one using short-course infusional 5-FU and bolus cisplatin 100 mg/m2 and the other prolonged continuous infusions of 5-FU and cisplatin 4 mg/m2/24 hours for 6 weeks are shown in Table 3.26,27 Randomized trials in progress address the value of combining 5-FU and cisplatin with radiation therapy rather than 5-FU and mitomycin-C (UK, US), and short versus prolonged infusions of 5-FU (France). Surgery Although local excision can be effective treatment for superficial well-differentiated or moderately differentiated squamous cell cancers up to approximately 2 cm in size that have not invaded the sphincter muscles, characteristics associated with a risk of node metastases less than 5%,28,29 many centers now manage even small anal cancers by combined-modality treatment. Others have achieved excellent results in smaller tumors with radiation alone and continue to reserve combined chemoradiation for larger cancers.18,30,31 Currently, the most common indication for radical surgery is failure of chemoradiation. Other occasional indications include inability to tolerate radiation or chemoradiation, or incontinence caused by irreversible sphincter damage or a vaginal fistula. A few patients require surgery for complications of chemoradiation or radiation treatment. Early random biopsies from the site of the primary cancer are not helpful and do not appear to improve the effectiveness of salvage surgery. False-negative biopsies are common,32 and premature biopsy of a slowly regressing tumor mass may lead to unnecessary sacrifice of anorectal function because residual masses after chemoradiation may take several months to regress fully.17 However, the development of a hard-edged ulcer after previous healing, an enlarging mass, or increasing pain at the site of the primary tumor site are suggestive of recurrence that should be confirmed by biopsy. The results of salvage abdominoperineal resection or composite resection of the distal bowel and adjacent structures vary considerably. Five-year survival rates range from as low as 0% to better than 50%.7,33-35 Local recurrence rates approach 50% even among patients with apparently complete resections.7,33-35 The surgery is complex, frequently entailing reconstructive surgery in tissues damaged by prior radiation and chemotherapy, and morbidity rates are high. Similarly

Current management of anal canal cancer high morbidity rates are seen in patients who require surgery because of the complications of radiation and chemotherapy. Treatment of Metastatic Cancer Metastatic squamous cell cancer presents a puzzle–metastases smaller than many primary tumors readily controlled by moderate doses of radiation and chemotherapy are rarely eradicated by similar treatment. Presumably, this resistance is related to currently unrecognized molecular changes in metastatic anal cancer. Responses have been reported to many single or combination cytotoxic drug treatments or to combinations of drugs and moderate-dose radiation, but the responses are rarely complete and their duration is usually no more than a few months. The drugs studied, although generally in only small numbers of patients, include 5-FU, cisplatin, carboplatin, mitomycin-C, porfiromycin, bleomycin, vincristine, vinblastine, doxorubicin, and methotrexate.7 Recently introduced drugs such as the oral fluoropyrimidines, irinotecan, and oxaliplatin are now under evaluation. The most effective current combination is 5-FU and cisplatin. The usual schedule is a 96-hour or 120-hour continuous infusion of 5-FU 750 to 1,000 mg/m2/24 hours plus a bolus infusion of cisplatin 100 mg/m2 on day 1 or 2, repeated at 4 weekly intervals while tumor response and toxicity permit. In one series of 17 patients with recurrent or metastatic cancer, there were two complete and nine partial responses.36 The combinations of cisplatin/vinblastine/bleomycin and cisplatin/vinblastine/doxorubicin/methotrexate produced a partial response in five of 17 and two of seven patients, respectively.37 Median survival of patients after the diagnosis of metastases remains approximately 9 to 12 months.36-38 Neoadjuvant and Adjuvant Therapy Neoadjuvant or induction chemotherapy is being investigated in randomized trials following the observation of high response rates obtained in pilot studies. As usual, the premise is that drug access is better in unirradiated tumors, and neoadjuvant treatment will lead to improved locoregional control and possibly also to fewer extrapelvic failures. In three pilot studies in which 146 patients received, most commonly, two or three courses of neoadjuvant 5-FU and cisplatin, the cumulative complete response rate was 15%, and the partial response rate was 50%.39-41 Measurable progression was observed in only two patients (1.5%), and there was one death from toxicity. In another study, carboplatin and 5-FU produced one complete response and 13 partial responses (42%) in 31 patients.42 Neoadjuvant chemotherapy with 5-FU and cisplatin is incorporated in current trials in the United States and France. Adjuvant chemotherapy with 5-FU and cisplatin is under evaluation in the United Kingdom, also on the hypothesis that such treatment can improve both locoregional and extrapelvic control rates. Current Trials and New Research Directions At least four large multicenter randomized controlled trials in anal canal cancer are currently in progress. The United Kingdom Coordinating Committee on Cancer Research, Anal Cancer Trial II incorporates a double random-

S127 ization: the first compares 5-FU plus mitomycin-C with 5-FU plus cisplatin concurrently with radiation; the second compares two courses of adjuvant 5-FU plus cisplatin with no adjuvant therapy. The radiation dose is 50.4 Gy in 1.8 Gy fractions over 5.5 weeks without interruption. The North American RTOG 9811 trial randomizes patients to either radiation with concurrent 5-FU/mitomycin-C or initial induction with two courses of 5-FU/cisplatin followed by radiation with concurrent 5-FU/cisplatin. The radiation dose is 59 Gy in total administered as 45 Gy in 1.8 Gy fractions over 5 weeks, followed without interruption by 14 Gy in 2 Gy fractions over 1.5 weeks. The EORTC 22011 trial compares single-dose mitomycin-C and weekly cisplatin given concurrently with radiation to mitomycin-C and prolonged continuous infusion 5-FU concurrently with radiation. The total radiation dose is 59.4 Gy consisting of an initial 36 Gy in 20 fractions of 1.8 Gy over 4 weeks, followed 2 weeks later by 23.4 Gy in 2.5 weeks. Chemotherapy is given during both phases of radiation. The French Federation Francaise de Cancerologie Digestive (FFCD) 9804 trial also includes a double randomization; the first to two courses of neoadjuvant 5-FU/cisplatin, and the second to different doses of boost radiation. In both arms, the base radiation dose is 45 Gy in 25 fractions of 1.8 Gy over 5 weeks with two courses of concurrent 5-FU/cisplatin in the first and last weeks. Two weeks later, the patients receive either 15 Gy or 20 to 25 Gy, according to randomization and tumor response. Chemotherapy is not given concurrently with the boost radiation. Many recently developed drugs such as the fluoropyrimidine capecitabine, oxaliplatin, and irinotecan are being evaluated in pilot studies. The observation of strong epithelial growth factor receptor expression in all 21 archived anal tumor specimens43 has led to proposals to study inhibition of the receptor pathways in anal cancer. Ongoing molecular studies will likely lead to further proposals for trials of targeted therapy.

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