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Over 20 years of progress in radiation oncology: Seminoma
Over 20 Years of Progress in Radiation Oncology: Seminoma Gillian M. Thomas During the past 20 years, significant changes have occurred in the management of seminoma. Survival has improved by approximately 10%, and now 97% of patients are cured. Reductions in the numbers of patients irradiated, the volumes irradiated, and the doses used should reduce morbidity. The 1973 Patterns of Care Study (PCS) and the planned new study proffer statements of consensus on optimal care and evaluate compliance with guidelines. Specific changes in investigation, including measurement of the serum tumor markers beta human chorionic gonadotropin (~HCG) and alphafetoprotein (AFP) and computed tomography (CT) or magnetic resonance imaging (MRI) evaluation of the retroperitoneum, better evaluate disease extent. For stage I disease, a reduction in the total dose of infradiaphragmatic irradiation to 2,500 cGy is recommended. An option for surveillance reduces unnecessary therapy in 80% and may improve fertility. The
significance of disease bulk in stage II has been recognized, and treatment has been refined. The maximal radiation dose now recommended for stage II disease is 3,500 cGy. CT definition of radiation target volumes minimizes the risk of geographic miss. Prophylactic mediastinal irradiation is no longer recommended. Chemotherapy, usually now bleomycin, etoposide, and cisplatin, produces high cure rates for stage liD, III, and IV disease and has become the standard management. Controversy still surrounds optimal therapy for stage IIC disease. Unresolved questions include cost benefit and quality of life issues surrounding optimal management for stage I disease, inguinal scrotal irradiation in stage I and II disease, and identification of the least toxic but effective chemotherapy for specific subgroups of patients with advanced disease. Copyright 9 1997 by W.B. Saunders Company
oday, more than ever, the delivery of health care is being scrutinized with respect to developing quality assurance measures for the evaluation of patients with disease and the outcomc, s of treatment deliwu'ed. While other areas of oncology have only recently responded to economic and public pressures to develop treatment practice guidelines, ~ the Patterns of Care Study (PCS) dew, loped in the 1970s tbr radiation therapy was prescient of the current process by nearly 20 years. In 1976 gxamcr and Herring ~ published the lh'st report on the PCS, "A Nationwide Evaluation of the Practice of Radiation Therapy in Cancer Management." The PCS was conceived to undertake a "comprehensive nationwide study of patterns of cancer care in radiation therapy," with a basic concept that "all patients suffering ti'om cancer deserve an equally high level of aftercare," irrespective of who delivers that care? Inherent in this concept is the
belief that all patients should have care that is consistent with the best current management. Testiculm" seminoma was one of the specific tumor sites addressed in the PCS, and this article will review both the changes in process and the changes in outcome that have resuhed ti'om the PCS and ti-om other publications in the 20-year period since the study was conceived. Unresolved questions with respect to investigation and management of patients with seminoma requiring future research will be outlined.
T
From the 1)epartment~ r?/ Radiation Oncolog~ and Otz~tetric~ and (;ynecolog~,, University ~!/'Toronto, Toronto-Sunnylmx~k Regional Cancer Center, 7bwnto, Canada. Supported ~_ Grants No. CA(~435 and CA15978 and Contract No. NO I-CM-8727.~om the National Cancerh~ftitute, Bethesda, MD. "lhe opinions and a~sertiomcontainedherein are the private views qf the author and are not to be construed m representingthe ~?[fidalviews ~ffthe National CancerIr~titute. Address reprint requests to GiUian M. Thomas, MD, Department qf Radiation Oncolo~y, University qJ"Toronto, Toronto-Sunnybrook Regional Cancer Center, 2075 Bayview Ave, Toronto, Ontario, M4N 3M5, Canada. Copyright 9 1997by W.B. Saunders Company 1053-4296"/9 7/0 702-0008505.00/ 0
Changes in Process In the 1980 newsletter :~and the 1981 publication t t he results of the PCS process survey were reported. Experts ill the field had developed a consensus nfbest current management, which had been organized into a decision tree (Figure 1)? The process survey was then conducted on patients evaluated and treated in 1973 using questions based on the decision tree. The process survey was conducted in 459 patient records randomly chosen from 163 radiation facilities in the United States. The facilities were chosen because they represented the spectrum of patient volumes, locations, and affiliations with universities that reflected the strata across the United States national practice. For the purposes of study, the staging system used was the modification of the Walter Reed system (Table 1).4 The recommended minimum diagnostic
Seminars in Radiation Oncology, Vol 7, No 2 (April), 1997:pp 135-145
135
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Gillian M. Thomas
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Figure 1. Decision tree for the management of various stages and extents of testicular seminoma. Reprinted by permission of the publisher from "Patterns of Care Outcome Studies: Results of the National Practice in Seminoma of the Testis," Hanks et al, IntJ-Radiat OncolBiolPhys 7:1413-1417. Copyright 1982 by Elsevier Science Inc.4
evaluation then considered necessary for patient evaluation included a medical history and physical examination, chest x-ray, lymphangiogram, and a complete blood cell (CBC) count. The survey showed that only 62% of patients had a lymphangiogram to assess retroperitoneal nodes. More commonly, the intravenous pyelogram (IVP) was used (in 75% of patients), which is insensitive except for excluding large volume retroperitoneal disease that deviates the ureters. At that time, the serum tumor markers that help distinguish seminomatous from nonseminomatous tumors, ie, alphafetoprotein (AFP) and beta human chorionic gonadotropin ([3HCG), were not available, although 41% of those surveyed did obtain urinary gonadotropin levels. Ninety-six percent of patients had a chest x-ray to exclude mediastinal disease. At that time, it was not common practice for the managing oncologist to state the disease stage; in only 33% of patient records was clinical stage stated.
Treatment Process Survey Radiation therapy in the 1960s and 1970s constituted the only definitive curative management for testicular seminoma, as curative chemotherapy had not yet been identified. The exquisite radiation sensitivity of testicular seminoma was well known and formed the basis for the development of the decision tree, which outlined the best current management. The currently accepted underpinnings for delivery of radiation therapy to the appropriate treatment volume include treatment simulation for all patients. However, in the 1973 survey, only 61% of patients had treatment simulation, although 87% did have portal films to aid in specifying the treatment volume. The decision tree (Figure 1) 4 reflected a PCS consensus that patients with stage I disease (ie, with no evidence of retroperitoneal adenopathy by physical examination, lymphangiogram, or IVP) should be
Progress in Seminoma
Table 1. Modification of Walter Reed Staging System Stage I: Cancer confined to the testicle as determined by clinical and radiographic studies and by orchiectomy. Should subsequent retroperitoneal node dissection reveal microscopic loci of cancer in nodes, clinical stage does not change, but subgroups should be formed. Stage IA: Tumor confined to one testi, no clinical or roentgenographic evidence of spread beyond; may include excretory or retrograde urography, lymphangiography, inferior venacavography, and chest roentgenography. Stage IB: Same as stage IA, but found to have histologic evidence of metastases to iliac or paraaortic lymph nodes at time of retroperitoneal lymph node dissection. Stage IC: Tumor limited to the testis, but no lymph node assessment done by IVP, inferior venacavography, lymphangiography, or exploratory laparotomy.* Stage II: Clinical or radiographic evidence of metastases to femoral, paraaortic, iliac, or inguinal nodes; no demonstrable metastases above the diaphragm or to visceral organs. Stage III: Clinical or roentgenographic evidence of metastases above the diaphragm or other distant metastases to body organs. *Modificationof Waher Reed system;added Ibr this analysis. Reprinted by permission of the publisher li'om "Patterns of Care Outcome Studies: Results of the National Practice in Seminomaof the Testis," Hanks et al, IntJ Radiat OncolBiol Phys 7:1413-1417. Copyright 1982by Elsevier ScienceInc.~
treated with external beam irradiation to the paraaortic and ipsilateral ilio-inguinal nodes including the orchiectomy scar. Options at that time were included for prophylactic irradiation of the mediastinum and the supraclavicular areas. The survey of practice showed that 27% of patients with Stage I disease not only received infradiaphragmatic irradiation, but also had prophylactic irradiation of the mediastinum and/or supraclavicular regions. Eighty-live percent of patients receiving infradiaphragmatic irradiation had the recommended paraaortic and ipsilateral iliac irradiation, whereas the remainder either had paraaortic and bilateral iliac irradiation or, rarely, paraaortic irradiation only. No information is available as to how often the orchiectomy scar was encompassed in the radiation volume or whether testicular shielding was used for the remaining testicle. Similarly, while it was a recommendation to include the scrotum and/or contralateral ilio-inguinal nodes in the radiation volume if there had been scrotal interference, no data are available documenting how often the practice was followed. For patients with stage II disease (ie, identified
137
disease in lymph nodes below the diaphragm), the PCS consensus was that prophylactic mediastinal and supraclavicular irradiation should be given with an option to treat the contralateral ilio-inguinal nodes. Bilateral iliac irradiation was performed in 35% of patients with stage II disease. So firmly was the view held that prophylactic mediastinal irradiation was necessary that the PCS publication stated that "an alarming 19% of stage II patients did not receive prophylactic radiation above the diaphragm. ''4 The PCS consensus with respect to optimal radiation dosage was based on numerous publications 512 and recommended that prophylactic treatment of areas without clinical or radiologic evidence of disease did not require doses in excess of 30 Gy. While the evidence was good in support of this recommendation, the survey showed that supporting data published in reputable journals one to two decades prior had not appropriately impacted on radiation oncologists to change their practice. Fifty-three percent of patients with stage I disease surveyed received over 30 Gy in prophylactic treatment of the retroperitoneal lymph nodes, with more than one third of these receiving over 35 Gy. For macroscopic epithelial cancers, standard teaching in radiation oncology suggests that increasing tumor volumes require increasing radiation doses for cure. Without specific knowledge of the shape of the dose-control curve tbr seminoma, it was anticipated that tbr patients with stage II disease, higher doses than those used [br adjuvant therapy would be delivered. In thct, the survey suggested there was very little use of increased doses [br clinical disease. Whereas in patients with stage I disease, 53% of those surveyed had received doses in excess of 30 Gy, only 62% of patients with stage II disease had received doses in excess of 30 Gy. A lack of consistency in choosing doses tbr adjuvant therapy was demonstrated, as 17% and 29% of those receiving prophylactic mediastinal irradiation for stage I and stage II disease, respectively, received doses in excess of 30 Gy.
Current Practice In the intervening years between those first reports of investigating and managing testicular seminoma, numerous developments have occurred that have significantly facilitated progress in the investigation and management of patients with testicular seminoma. These developments include simpler and more universally available radiologic tests to assess the retroperitoneum; particularly, computed tomogra-
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GiUian M. Thomas
phy (CT) scanning. The development of immunoassays for AFP and [3HCG is of significant help in eliminating the possibility of the presence of occult nonseminomatous tumor elements and in deciding appropriate treatment. Additionally, specific information has been gathered on the patterns of disease dissemination and patterns of failure after standard therapy used in the 1960s and 1970s. How these developments have influenced the process of the investigation and management of patients with seminoma will be reviewed, and the magnitude of the impact on outcomes of therapy will be presented. Lymphangiography, while still considered the most sensitive method of evaluating the retroperitoneal nodes, is a time-consuming, invasive radiologic test. By 1982 recommendations for its use had largely been supplanted by the use of the abdominopelvic CT scan. The scan has the advantage of being noninvasive, widely accessible in North America, and more precise in delineating the size and location of enlarged nodes. It allows more accurate planning of radiation fields and should minimize geographic miss. In only one circumstance is the lymphangiogram, with its increased sensitivity for small volume disease, deemed more useful; that is, for patients considered for surveillance. This will be discussed subsequently. It is now accepted that AFP elevations in histologically pure seminoma signify the presence of occult nonseminomatous tumor elements. This has resulted in changes in therapy and improved outcome, as such patients are now usually treated as for appropriatestage nonseminomas, with curative chemotherapy rather than radiation. Before the availability of AFP and [3HCG, approximately 40% of those treated for pure seminoma but sustaining recurrences or death from disease actually had nonseminomatous tumor elements present. Since recurrence and death from pure seminoma are much more uncommon than for nonseminomatous tumors, the tumor migration out of the seminoma category to nonseminoma caused by this diagnostic test probably inflates slightly the overall sulvival reported now for pure seminoma. In the 1973 survey treatment simulation was only performed in 61% of patients. The planned new survey will assess whether this has improved in the last two decades.
Changes in Outcome A review of outcome data and, specifically, the patterns of failure after use of the previously recommended radiation treatment fields has led to recom-
mendations for significant changes in radiation practice, including a reduction in the volume irradiated and modifications in the doses used for occult and overt disease. Hanks et al 4 reported in the PCS report that after standard infradiaphragmatic irradiation and prophylactic mediastinal irradiation (PMI) in 27% of patients, the relapse rate for patients with stage I disease was 4% (11 of 262 patients). While this good outcome was attributed to the efficacy of the radiation used in eradicating microscopic disease, it was impossible to analyze the appropriateness of the radiation doses used (53% of patients received in excess of 30 Gy) or the contribution of PMI to the outcome. Mediastinal relapse had occurred in 4 of 11 relapsing patients, but three of these occurred in unstaged patients. Subsequent to the PCS report, a large single institution series documented excellent outcomes for patients with stage I disease treated more conservatively with elective irradiation of the subdiaphragmatic nodes only and with the dose limited to only 2,500 cGy in 3 weeks. 7 The 3-year disease-free (NED) rate associated with this modestdose infradiaphragmatic irradiation was 95% (56 of 59 patients), and, within the statistical limits of such comparisons, appeared "equal to that achieved with PMI" at 90% (18 of 20 patients). O f importance in this retrospective review was the observation that there were no disease recurrences within the treatment field. Multiple reviews in the 20-year interval since have confirmed that infield relapse does not occur even with doses as low as 25 Gy and that the omission of mediastinal irradiation in patients staged with modern techniques results in extremely rare mediastinal relapse, which, when it occurs, is salvageable with further therapy (Table 2). 2~ Thus, in 20 years, the management of stage I seminoma with radiation has been refined to reduce the elective radiation dose used and to abandon the use of mediastinal irradiation. Reported NED rates and cause-specific smadvals in stage I seminoma are now 97% and 99%, respectively. Even in the 1950s, when some patients had occult nonseminomas and some had undetected macroscopic disease, the incidences of tumor relapse and death from seminoma were 4.5% (108 of 2,376 patients) and 2.3% (54 of 2,376 patients), respectively. 21 Many of the patients reported were treated in the era when effective salvage therapy with platinum-based chemotherapy had not been identified. Given these excellent results, there has been reluctance to modify the now-standard, modest-dose, adju-
139
Progressin Seminoma
Table 2. Patterns of Relapse After Adjuvant Radiotherapy for Stage I Seminoma
Study
Fossa et a114 Hamilton et a115 Lester et al I~s Thomas 17 Schultz et al TM Lai et a119 Zagars and Babaian 2~ Total
No. of Patients
249 99 232 33 150 424 95 162 1,444
Radiation Dose (Gy)
No. of No. of Patients Abdominal Relapsing Relapses
40 (10-50) 36 30 25 25 33-35 24-30 25 25
13 5 4 2 8 2 6 40 (3%)
1 0 0 1 (15 Gy) 0 1 0 1 (No RT)
Media~tinal and S/C On~
Other
7
6
3
2
1
2
0 3
2 4
1
1
3
2
Cause-Specific Survival(%)
99 100 93 99 99 100 97 99
Abbreviations: S/C, supraclavicular;RT, radiotherapy. Reprinted with permission.13 vant postorchidectomy infradiaphragmatic irradiation.
ReducingToxicity It was, however, recognized that treatment was accompanied with some late morbidity, including dose-related gastrointestinal morbidity, impaired fertility, and possible induction of late malignancies. 14,15,22One impetus to reduce the radiation dose used tbr treatment of stage I seminoma was the thct that doses of 35 to 40 Gy in 2-Gy fractions produced signilicant dyspepsia in 6% and fi'ank peptic ulceration in 3% of patients. H The PCS data showed a bowel complication rate tbr the doses then used tbr all stages of disease of 2.4%, 4 and similar data from the Royal Marsden Hospital (Sutton, UK) 15 conlirmed a 6% incidcnce of peptic ulceration in those irradiated. However, PCS data indicated that intestinal obstruction and ulceration decreased to 2% with doses between 25 and 35 Gy. These control and complication data support an improvement in therapeutic ratio achieved by reduction of radiation dose tot subclinical disease to 25 Gy. While patients with testicular tumors have impaired spermatogenesisf ~2~' dose-related additional impairment occurs after radiation, although the magnitude is difficult to assess. With adequate shielding, the dose to the remaining testicle can be reduced to 1% of the prescribed mid-plane radiation dose, 2ti but it is clear that the proximity of the testes to the edge of the radiation field, ie, the placement of the interior border of the volume, affects the dose received by the testicle. The consensus in the original PCS report suggested that elective irradiation in stage I seminoma should include the inguinal scar. It is not known whether radiation oncologists are still
routinely irradiating the inguinal region, and it is methodologically impossible to determine whether this inferior extension of the field with the increased scattered dose to the remaining testicle positively affects relapse-free survival. The third significant morbidity of radiation for testicular seminoma is a small but significant increased risk of induction of second solid tumors and leukemia. 14,27-30 With a vicw to further reducing morbidity in seminoma and minimizing unncccssary treatment, several alternative therapeutic options haw~ been explored. Clinical trials r surveillance of patients with well-staged stage I seminoma have been conducted. The initiation of these trials resulted from a better knowledge r the natural history and routes r dissemination of seminoma, better radiologic tests to assess disease cxtcnt, and the ability to predict probable rates and sites of relapse if treatment were withheld. The slow, orderly progression of seminoma metastasizing ti-om the primary and sequentially spreading through the retroperitoneal and then the mediastinal and supraclavicular nodes was recognized. Hematogenous spread from pure seminoma is extremely rare, with only 3% of patients with supradiaphragmatic or hematogenous diseasc. Effective salvage cisplatin-based chemotherapy had also been identified. 31 Surgical staging series had reported that the incidence r undetected retroperitoneal disease in those without obvious palpable abdominal disease was less than 20%Y Results of surveillance studies are shown in Table 3Y ~ The risk of relapse after surveillance is 15% to 18%. Ninety-six percent of relapses occur in the retroperitoneum or inguinal regions; and while the majority of relapses occur in the first 2 years after orchiectomy, intervals may be prolonged, ranging from 2 months to 7 years postorchidec-
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GiUian M. Thomas
Table 3. Results of Surveillance Studies in Seminoma No. of patients Median months of follow up Percent (no.) of relapses Median months to relapse Retroperitoneal or inguinal relapses only/total Second relapse/total Percent (no.) having chemotherapy Percent survival
RMI-F 9
D A T E C A 33
Toronto j3
Total
113 37 15 (13) 15 12/13 5/13 6 (6) 100
261 30 18.8 (49) 13.5 48/49 4/49 6 (16) 99.6
209 48 13 (28) 12 26/28 3/28 3 (8) 99.5
583 15.4 (90) -86/90 (95.6%) 12/90 5 (30) 99.7
Abbreviations:RMH,RoyalMarsdenHospital;DATECA,DanishTesticularCarcinomaStudyGroup. Reprinted with permission.13 tomy.32 Salvage rates with appropriately directed radiation to the retroperitoneum or chemotherapy for those with supradiaphragmatic or hematogenous dissemination result in overall survivals close to 100%. Factors predicting for relapse on surveillance have been investigated. On multivariate analysis, the only factor of independent significance was the size of the primary tumor, with relapse rates of 36% when tumors were greater than 6 cm in size.33 For tumors less than 3 em in size, relapse occurred in only 6%. Surveillance, when practiced carefully with scanning of the retroperitoneum every 4 to 6 months, has been demonstrated to be a safe and effective alternative management to standard postoperative infradiaphragmatic irradiation for stage I seminoma. It avoids treatment for the majority of patients but increases costs associated with repeated CT scanning. The choice of its use as an alternative to irradiation remains a matter of the physician's philosophy, the patient's wishes, the patient's projected compliance with surveillance, and the relative costs of the two approaches. The prevalence of its use will be assessed in the new PCS survey. To avoid the relatively high comparative relapse rates on surveillance and still decrease radiation morbidity, reduced radiation volumes have been investigated as another alternative for stage I disease. This choice, to exclude the pelvic field and treat the paraaortic nodes only, was based on the rationale that fewer than 5% of patients were expected to have involved pelvic lymph nodes in well-staged disease. A randomized trial in 478 patients with stage I disease and no prior inguinal surgery was conducted comparing standard irradiation with an inferior border at the mid-obdurators to paraaortic irradiation only from T 11 to L5. 34As expected, the 2-year relapse-free survival rates were not significantly different at 96% and 97%, respectively. Myelotoxicity and azoospermia were significantly reduced in the group treated
with paraaortic irradiation alone, although, as expected with identical upper abdominal irradiation, peptic ulceration rates of 8% did not differ between the two groups. While the investigators concluded that paraaortic irradiation alone may be standard treatment, they have observed with only 2 years of follow up a 2% pelvic failure rate. If paraaortic irradiation becomes an accepted standard management, surveillance of the pelvis will be required. 34 Finally, 20 years after the PCS studies and multiple other publications have shown the excellent therapeutic ratio associated with modest-dose infradiaphragmatic irradiation, some investigators are treating stage I disease with short courses of chemotherapy, usually one or two injections of platinum agents. 35 The relative benefits of this management will be assessed in a Medical Research Council of the United Kingdom study comparing short courses of platinum-containing chemotherapy with radiotherapy.
Stage II In the PCS, 28% of patients (107 of 379) were considered to have stage II disease, although 10% did not have the retroperitoneum evaluated. Bulk of retroperitoneal involvement was not evaluated. The expert opinion captured in the decision tree (Figure 1) 4 recommended prophylactic mediastinal irradiation with an additional option to treat the contralateral pelvic nodes. With the treatment delivered, the relapse rate was only 5%. The observed mediastinal failure rate in those without retroperitoneal evaluation was attributed to the lack of use of the recommended prophylactic mediastinal irradiation in those with probable retroperitoneal disease. The excellent outcome for the remainder was attributed to the use of infradiaphragmatic irradiation and PMI. Recommendations for PMI had been extrapolated from
Progress in Seminoma
141
Table 4. Radiotherapy Results in Nonbulky Stage II Seminomas
Study Bayens et al s7 Lindeman and Tiver 3~ Thomas et aP 9 Mason and Kearsleya~ Mason and Kearsley4~ Hunter and Peschel al Evensen et a142 Sagerman et al as Ball et a144 Ellerbroek et al as Jackson et a146 Lai et al n9 Tombolini et al a7 Lederman et al 4~ Andrews et al as Total
Size Criterion (cm)
Disease-Free Survival (%)
<5 <5 Nonpalpable <5 5-10 <5 <5 <5 <5 <5 Nonpalpable <5 <5 <5 <5
22/29 (76) 8/9 (89) 37/40 (93) 24/25 (96) 10/12 (87) 15/15 (100) 23/24 (96) 19/21 (90) 28/33 (85) 7/8 (88) 26/29 (90) 31/33 (94) 20/20 (100) 24/25 (95) 16/17 (94) 310/340 (91)
Salvage (%) 4/7 1/1 0/3 0/1 0/2
(57)* (100) (0)* (0)* (0)* -1/1 (100) 2/2 (100)* 2/5 (40) 0/1 (0) 0/3 (0) 1/2 (50) -0/1 (0)* 1/1 (100)* 12/30 (40)
Overall Survival (%)
Median Follow Up, Years (range)
26/29 (90) 9/9 (100) 37/40 (93) 24/25 (96) 10/12 (87) 15/15 (100) 24/24 (100) 21/21 (100) 30/33 (91) 7/8 (88) 26/29 (90) 32/33 (97) 20/20 (100) 24/25 (96) 17/17 (100) 322/340 (95)
7.5 (0.8-13) 4.2 (1.2-9) NS 6.2 (3-19.6) 6.2 (3-19.6) 9 (1-24) 6.2 (2-13) 8.5 (0.5-20) 7.5 (3-17) Minimum 2 NS 6.7 (1-24) 3.5 (2-11.6) 6 (1-17) 8.6 (0.5-21)
Abbreviation: NS, not stated. *Treated with cisplatin-based salvage chemotherapy. Reprinted with permission. 3ti l y m p h o m a t o u s t u m o r s where prophylactic irradiation of the next echelon of uninvolved nodes was r e c o m m e n d e d , but no detailed analysis e x a m i n e d the additional benefits provided by such t h e r a p y in seminoma. It was, however, recognized that the
overall risk of relapse after s t a n d a r d infradiaphragmatic and s u p r a d i a p h r a g m a t i c irradiation increased with increasing bulk of i n f r a d i a p h r a g m a t i c disease (Tables 4 and 5). 7,n:~,36"~6Initial r a d i o t h e r a p y cures ->90% of non-bulky stage II disease, and salvage with
Table 5. Radiotherapy Results in Bulky Stage II Seminomas
Study Jackson et al ~i Doornbos et al 7 Laukkanen et al s() Ellerbroek et aP s Thomas et al s' Read et al sl Herman et aP 2 Zagars and Babaian s:~ Andrews et al 4~ Ball et aP a Hunter and Peschel al Martinelli sa Sagerman et al a:~ Mason and Kearsleya~' Green et al ss Evensen et ala2 Smalley et al s~ Bayens et aP 7 Lindeman and Tiver sa Total
Yea~ of Study
Size Criterion(cm)
Disease-flee Survival (%)
Salvage (%)
Overall Survival (%)
Median FoUow Up, Yea~ (range)
1942-1978 1944-1971 1948-1983 1956-1983 1958-1976 1960-1978 1960-1981 1960-1982 1962-1984 1963-1979 1964-1984 1965-1985 1966-1985 1968-1985 1969-1980 1971-1981 1971-1982 1975-1985 1980-1987
Palpable > 10 Palpable >5 Palpable Palpable Palpable Palpable >5 >5 >5 Palpable >5 >10 >6 >5 >5 >5 >5
13/16 (83) 11/22 (5(I) 17/23 (74) 8/15 (53) 22/46 (48) 30/67 (45) -7/10 (70)ll 3/4 (75) 14/23 (61) 3/3 (100) 4/4 (100) 10/11 (91) 8/12 (67) 17/18 (94) 38/48 (79) 16/20 (80) 7/9 (78) 4/5 (80) 232/356 (65)
(I/3 (0) 3/11 (27) 3/6 (50) 1/7 (14) 7/24 (29) 8/37 (22) -0/3 (0) 1/1 (100)w 3/9 (33) --1/1 (100) 1/4 (25)w 0/1 (0) 5/10 (50) 4/4 (100)w 1/2 (50) 1/1 (100) 39/124 (31)
13/16 (83) 14/22 (61) 21/23 (91)* 9/15 (60) 29/46 (63) (63)]" 100/109 (92)~ 7/10 (70)11 4/4 (100) 17/23 (74) 3/3 (100) 4/4 (100) 11/11 (100) 9/12 (75) 17/18 (94) 42/48 (88) 20/20 (100) 8/9 (89) 5/5 (100) 375/465 (81)
NS NS 7.6 (2-26) Minimum 2 NS Minimum 4
*Disease-specific survival. tEstimated from actuarial survival curves. ~Cause-specific survival. w or carboplatin used in salvage therapy. [lOne patient relapsing with 13HCGelevation excluded. Reprinted with permission)ci
Median 6.6 8.6 (0.5-21) 7.5 (3-17) 9 (1-24) 3.5 (15) 8.5 (0.5-20) 6.2 (3-19.6) 4 (1-11) 6.2 (2-13) 4.6 (24) 7.5 (.8-13) 4.2 (1.2-9)
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Gillian M. Thomas
appropriate radiation or chemotherapy results in overall cures of 95%. Subsequent to the PCS, analyses of patterns of failure in patients with stage II disease treated without PMI clarified that mediastinal relapse with non-bulky stage II disease was extremely rare and that the additional survival benefit attributable to PMI was only 0.4%.39,57 Subsequently, longterm follow-up data from the PCS indicate that mediastinal irradiation is associated with significant increased risk of death from intercurrent disease and cardiopulm0nary cause, thus supporting the contention that PMI is no longer indicated for patients with infradiaphragmatic nodal disease less than 5 cm in transverse diameter (stage IIA/B). The abandonment of PMI in small volume stage II disease has not compromised survival and has reduced unnecessary treatment and morbidity. A survey of 600 radiation oncologists conducted in the United States in 1987 indicated that 62% of physicians no longer use PMI. The next planned PCS survey in seminoma will determine whether further reductions in the use of PMI in stage II non-bulky disease have occurred.
Bulky Stage II In contrast with the excellent results for the treatment of non-bulky stage II disease with primary radiation therapy, results for bulky disease, defined by whether the maximum transverse size of a mass on CT scan is greater than 5 cm or 10 cm or simply by the presence of a palpable mass, are distinctly worse (Table 4).36 There is both a significant risk for overall relapse when infradiaphragmatic irradiation and PMI are used and a further increased risk for mediastinal relapse when PMI was omitted. 53 The exclusion of AFP-positive patients (ie, nonseminomatous) does not significantly diminish these risks. In the past two decades, it has been established that pure seminoma is also exquisitely sensitive to platinum-based chemotherapy) 1Chemotherapy was successful in salvaging the majority of patients who had relapsed after radiation and additionally provides cures in those with extensive disease not previously cured with radiation alone. Optimal therapy for patients with bulky stage II seminoma (>5 cm in diameter) is one of the most controversial areas remaining in the management of testicular seminoma. While previously all patients had been treated with radiation alone, knowledge of the efficacy of chemotherapy has resulted in significant changes in practice. The Commission on Cancer of the American College of Surgeons (ACOS) conducted two surveys of patients
with seminoma treated between 1970 and 1975 and in 1983. For patients with clinical stage II disease, the use of surgery and radiation alone decreased from 93.3% to 78.6%, with a concomitant increase in the use of chemotherapy. Further studies have delineated one obvious group of patients with extremely bulky disease (stage IID disease, >10 cm in transverse diameter) where there is general agreement that initial chemotherapy is preferred because of the unsatisfactory results with primary radiation. Relapse rates are approximately 40% even when PMI is given (Table 6). 40.42,58-62 Salvage chemotherapy is potentially hazardous after PMI and infradiaphragmatic irradiation, so primary cisplatin-containing combination chemotherapy is preferred. Similar considerations exist for rare patients with stage III and IV disease (supradiaphragmatic nodal disease or parenchymal involvement). While results in the original PCS survey showed a relapse rate of at least 30% after radiation alone, other series suggested cure in only 35% of patients and usually in those with nodal rather than parenchymal disease and without bulky abdominal disease. The necessity for salvage chemotherapy in the majority of patients treated with multiple radiation volumes is a relative contraindication to the use of initial radiation therapy, and this has led to a change in practice documented in the 1987 survey of ACOS. For stage III disease, the use of surgery and radiation was reduced from 62.2% to 15.8%, with a concomitant increase in the use of chemotherapy (less than 15% of patients received no chemotherapy). Optimal management of patients with stage IIC disease (5 to 10 cm in transverse diameter) remains unresolved. Twenty years ago PMI was considered the norm, but even with its use, disease-free and overall survival rates with primary irradiation are
Table 6. Outcome After Radiation Therapy for Patients With Stage IIA/B Disease (<5 cm in diameter) Study
Mason and Kearsley4~ Evensen et a142 Zagars59 Gregory and Peckham6~ Kellokumper-Lehtinen and Halme 61 Epstein et a169 Hunter and Pesche141 Total *Exactnumber unknown. Reprinted with permission.58
Xo. q Patients
25 24 18 39 66 16 15 203
No. Relapsing
1 1 1 5 10 0 0 18 (9%)
De~d of Disease
0 0 1* 2 2 0 0 5 (2%)
Progressin Seminoma
only 65% and 80%, respectively (Table 5).:~iWhile it is unclear that exactly comparable patient groups are being reported, and while many patients are given additional radiation, chemotherapy trials in advanced disease using either platinum, velban, bleomycin (PVB) or platinum-containing chemotherapy of bleomycin, etoposide, platinum (BEP) given tbr three or four cycles report disease-free survivals of 92%. Toxicity is lowest with three cycles ofBEP/:~ Two decades later, there appears to be no uniform agreement about optimal therapy for patients with stage II disease. Management options include (1) initial treatment with infradiaphragmatic irradiation and treatment of relapse at any site with cisplatincontaining combination chemotherapy; (2) initial treatment with chemotherapy tbllowed by either observation of residual masses or consolidation radiation therapy; or (3) inii'adiaphragmatic and supradiaphragrnatic irradiation with chemotherapy for subsequent relapses. Data can be generated in support of any of these approaches, but the third is deemed to be the least satisfactory as 10% to 20% of patients failing infradiaphragmatic and supradiaphragmatic irradiation will require salvage chemotherapy. Survival rates are similar regardless of the initial approach used, but the toxicity profiles for each approach vary, as does the frequency of salwtge therapy required in each. Aecumulated results of fiw: series of patients with stage IIC disease record a relapse rate after irradiation, usually including PMI, ot"4% (4 of48 t)atients). H,~z:':u;"-I;:~The overall su,'viwtl is 90%. If infradiaphragmatie irradiation only is used for stage IIC diseasc, the probability of relapse in the mediastinum or at distant sites increases to approximately 20%. Chemotherapy will salvage approximately 80% of relapsing patients, producing cure rates probably comparable to those achieved with initial infradiaphragmatic irradiation with PMI. In an attempt to rigorously compare initial chemotherapy with initial in&adiaphragmatie irradiation, the Radiation Therapy Oncolog'y Group of the United States started a phase III study, but the study was closed for lack of patient accrual. Results from the planned PCS survey of seminoma will be awaited with interest to determine the most common practice in the management of patients with stage IIC disease. When initial chemotherapy is used for the management of patients with stage IIC, liD, III, and IV disease, residual masses may exist in as many as 75% of patients. ~i4Controversy surrounds the use of consolidation radiation therapy to sites of initial bulky
143
disease or for residual masses and the use of surgical excision. Surgical series have shown that only 10% to 12% of residual masses have viable seminoma cells; most have fibrosis only. Routine irradiation of residual masses implies the overtreatment of 85% to 90% of patients and does not appear indicated. Only the series from Memorial Sloan-Kettering Hospital (New York, NY) has documented an unusually high incidence of residual disease at surgery/~ In that series, 5 of 14 patients (36%) had apparently viable tumor present immediately after chemotherapy if the residual mass was in excess of 3 crn in diameter. While the risk of viable residual disease is probably slightly higher for larger rather than smaller masses, 65 the 12% overall average risk of residual microscopic disease in the surgical series appears to be more in keeping with the reported relapse rates in the Royal Marsden Hospital report of 11%/6,67 A policy of observation of residual masses after chemotherapy would spare the majority of patients unnecessalT treatment but would imply that repeated CT assessment is necessary to ensure that masses are not progressing. The use of consolidation radiation therapy after chemotherapy will be evaluated in the planned PCS survey.
Summary Ill the past two decades, the investigation and management of patients with testicular seminoma has changed substantially. Overall surviwds have imlmwed by approximately 10%, and radiation toxicity has been decreased by reductions in the fi'equency of use and in the doses and w)lumes used. Improvements in survival and reduction in morbidity may be attributed to improvements in radiologic tests that more accurately assess disease extent and to intbrmatiun delineating rates and t)atterns of failure after various treatments. The integration of platinumcontaining chcmotherapy into the managemcnt of patients with more advanced disease has led to improved survivals for the rare patients with stage IID, III, and IV disease. Given the excellent therapeutic ratio associated with current therapeutic approaches and the refinements of the use of radiation and chemotherapy, it is doubtful that there is room tbr substantial gains over the next two decades. Carethl measures of quality of life after various treatment options may resolve optimal definitions of therapy in controversial areas such as the use of inguinal scrotal irradiation, management of stage I and stage IIC disease, the use of
144
Gillian M. Thomas
consolidation radiation therapy after chemotherapy, and the tailoring of chemotherapy to reduce morbidity and maximize cure rates for different risk groups.
Acknowledgment I thank radiation oncologists, physicists, and staff throughout the United States whose support is essential to the PCS.
References 1. Browman GP, Levine MN, Mohide EA, et al: The Practice Guidelines Development Cycle: A conceptual tool for practice guidelines development and implementation. J Clin Oncol 13:502-512, 1995 2. Kramer S, Herring D: The Patterns of Care Study: A nationwide evaluation of the practice of radiation therapy in cancer management. Int J Radiat Oncol Biol Phys 1:1231-1236, 1976 3. Maier JG: Seminoma of the testis. Patterns of Care Study Newsletter (August), Philadelphia, PA, American College of Radiology, 1980 4. Hanks GE, Herring DF, Kramer S: Patterns of Care Outcome Studies: Results of the national practice in seminoma of the testis. Int J Radiat Oncol Biol Phys 7:1413-1417, 1982 5. Castro JR, Gonzalez M: Results in treatment of pure seminoma of the testis. A m J Roentgenol 111:355-359, 197 t 6. Dixon FJ, Moore RA: Tumors of the male sex organs, in: Atlas of Tumor Pathology (Vol Sec VIII, Fasc 31 b and 32). Washington, DC, Armed Forces Institute of Pathology, 1951 7. DoornbosJF, Hussey DH,Johnson DE: Radiotherapy for pure seminoma of the testis. Thera Radiol 116:401-404, 1975 8. Kurohara S, George FW, Dykhuisen RF, et al: Testicular tumors. Cancer 20:1089-1098, 1967 9. Maier JG, Mittenmeyer BT, Sulak MH: Treatment and prognosis in seminoma of the testis.J Uro199:72-78, 1968 10. Patton JE, Mallis N: Tumors of the testis. J Urol 81:457-461, 1959 11. Smithers D, Wallace ENK, Wallace DM: Radiotherapy for patients with tumors of the testicle. BrJ Uro143:83-92, 1971 12. Ytedral DO, BradfieldJS: Seminoma of the testicle: Prophylactic mediastinal irradiation versus peraortic and pelvic irradiation alone. Cancer 30:628-633, 1972 13. Thomas GM: The treatment of patients with stage I seminoma of the testis, in Vogelzang NJ, Scardino PT, Shipley WS, et al (eds): Comprehensive Textbook of Genitourinary Oncology. Baltimore, MD, Williams & Wilkins, 1995, pp 1028-1038 14. Fossa SD, Aass N, Kaalhus O: Radiotherapy for testicular seminoma stage I: Treatment results and long-term postirradiation morbidity in 365 patients. IntJ Radiat Oncol Biol Phys 16:383-388, 1989 15. Hamilton C, Horwich A, Easton D, e t a | : Radiotherapy for stage I seminoma testis: Results of treatment and complications. Radiother Oncol 6:115-120, 1986 16. Lester SG, MorphisJG, Hornback NB: Testicular seminoma: Analysis of treatment results and failures. IntJ Radiat Oncol Biol Phys 12:353-358, 1986 17. Thomas GM: Controversies in the management of testicular seminoma. Cancer 55:2296-2302, 1985 18. Schultz HP, ArendsJ, Barlebo H, et al: Testicular carcinoma
in Denmark, 1976-1980: Stage and selected clinical parameters at presentation. Acta Radiol Onco123:249-253, 1984 19. Lai PP, Bernstein MJ, Ydm H, et al: Radiation therapy for stage I and IIA testicular seminoma. IntJ Radiat Oncol Biol Phys 28:373-379, 1994 20. Zagars GK, Babaian RJ: Stage I testicular seminoma: Rationale for postorchiectomy radiation therapy. IntJ Radiat Oncol Biol Phys 13:155-162, 1987 21. Zagars GK: Management of stage I seminoma: Radiotherapy, in Horwich A (ed): Testicular Cancer Investigation and Management, London, UK, Chapman & Hall, 1991, pp 83-107 22. Coia LR, Hanks GE: Complications from large field intermediate dose infradiaphragmatic radiation: An analysis of the Patterns of Care outcome studies for Hodgkin's disease and seminoma. IntJ Radiat Oncol Biol Phys 15:29-35, 1988 23. Hendry WF, StedronskaJ, Jones CR, et al: Semen analysis in testicular cancer and Hodgkin's disease: Pre- and posttreatment findings and implications for cryopreservation. BrJ Uro155:769-773, 1983 24. BerthelsonJG, Skakkebaek NE: Gonadal function in men with testis cancer. Fertil Steri139:68-75, 1983 25. Fossa SD, Abyholm T, Aakvaag A: Spermatogenesis and hormonal status after orchidectomy for cancer and before supplementary treatment. Eur Urol 10:173-177, 1984 26. Kubo HD, Shipley WU: Reduction of the scatter dose to the testicle outside the radiation treatment fields. Int J Radiat Oncol Biol Phys 8:1741-1745, 1982 27. Kleinerman RA, LiebermannJV, Li FP: Second cancer following cancer of the male genital system in Connecticut, 19351982. NCI Monogr 68:139-147, 1985 28. Osterland A, Rorth M, Prener A. Second cancer following cancer of the male genital system in Denmark, 1943-1980. NCI Monogr 68:341-347, 1985 29. Peckham MJ, Hamilton CR, Horwich A, et al: Surveillance after orchiectomy for stage I seminoma of the testis. BrJ Urol 59:343-347, 1987 30. HayJH, Duncan W, Kerr GR: Subsequent malignancies in patients irradiated in testicular tumours. BrJ Radiol 57:597602, 1984 31. Loehrer PJ, Birch R, Williams S, et al: Cisplatin combination chemotherapy in metastatic seminoma: The Southeastern Cancer Study Group (seg) experience. J Clin Oncol 5:12121220, 1986 32. Warde P, Gospodarowicz MK, Godman PJ, et ah Results of a policy of surveillance in stage I testicular seminoma. Int J Radiat Oncol Biol Phys 27:11-16, 1993 33. yon der Maase H, Specht L, Jacobsen GK, et al: Surveillance following orchiectomy for stage I seminoma of the testis. Euro J Cancer 29A: 1931-1934, 1993 34. Fossa SD, Horwich A, RussellJM, et al: Optimal field size in adjuvant radiotherapy (XRT) of stage I seminoma--a randomised trial. Proc Am Soc Clin Oncol 15:239, 1996 (abstr 595) 35. Oliver RTD, OngJ: Seventeen years experiences of phase I/II studies of single agent platinum compounds as alternatives to radiation for metastatic and stage I seminoma. Proc Am Soc Clin Oncol 15:244, 1996 (abstr 613) 36. Smalley SR, Evans RG: Seminoma: Management of stage lI disease, posttherapy residual masses, and other special considerations, in Vogelzang NJ, Scardino PT, Shipley WS, et al (eds): Comprehensive Textbook of Genitourinary Oncology. Baltimore, MD: Williams & Wilkins, 1995, pp 1038-1049
Progressin Seminoma
37. Bayens YC, Helle PA, Van Putten WL, et al: Orchidectomy followed by radiotherapy in 176 stage I and II testicular seminoma patients: Benefits of a 10-year follow-up study. Radiother Onco125:97-102, 1992 38. Lindeman GJ, Tiver KW: Management of testicular seminoma at Westmead Hospital from 1980 to 1987. Aust N Z J Surg 61:211-216, 1991 39. Thomas GM, Rider WD, Dembo AJ, et al: Seminoma of the testis: Results of treatment and patterns of failure after radiation therapy. Int J Radiat Oncol Biol Phys 8:165-174, 1982 40. Mason BR, KearsleyJH: Radiotherapy tor stage II testicular seminoma: The prognostic influence of tumor bulk. J Clin Oncol 6:1856-1862, 1988 41. Hunter M, Peschel RE: Testicular seminoma: Results of the Yale University experience, 1964-1984. Cancer 64:1608, 1989 42. Evensen JF, Fossa SD, Kjellevold K, et al: Testicular seminoma: Analysis of treatment and failure for stage II disease. Radiother Oncol 4:55-61, 1985 43. Sagerman RH, Kotlove DJ, Regine W, et al: Stage II seminoma: Results of postorchiectomy irradiation. Radiol 172:565568, 1989 44. Ball D, Barrett A, Peckham MJ: The management of metastatic seminoma testis. Cancer 50:2289-2294, 1982 45. Ellerbroek NA, Tran LM, Selch M, et al: Testicular seminoma: A study of 103 cases treated at UCLA. Am J Clin Oncol 11:93-99, 1988 46. Jackson SM, Olivotto I, McLoughlin MG, et al: Radiation therapy tbr seminoma ot" the testis: Results in British Columbia. Can Med AssocJ 123:507-512, 1980 47. Tombolini V, Grapulin L, Maurizi Enrici R, et al: Ruolo della radioteraplia nel trattamento del seminoma del testicolo. Radinl Med 82:334-338, 1991 48. Lederman GS, Herman TS, Jnchelson M, et al: Radiation therapy of seminoma: 17-year experience at the joint center tbr radiation therapy. Radiother Oncol 14:2113-21)8, 1989 49. Andrews CF, Micaily B, Brady LW: Testicular seminoma: Results of a program of megavohage irradiation. Am J Clin Oncol 10:491-495, 1987 50. Laukkanen E, Oliw)tto I, Jackson S: Management of seminoma with bulky abdominal disease. IntJ Radiat Oncol Biol Phys 14:227-233, 1988 5 I. Read G, Robertson AG, Blair V: Radiotherapy in seminoma of the testis. Clin Radio134:469-473, 1983 52. Herman J, Sturgeon J, Thomas GM: Mediastinal prophylactic irradiation in seminoma. Proc Am Suc Clin Oncol 2:133, 1983 (abstr)
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53. Zagars GK, Babaian RJ: The role of radiation in stage II testicular seminoma. IntJ Radiat Oncol Biol Phys 13:163-170, 1987 54. Martinelli DR: La radioterapia dei seminomi in secondo stadio. Acta Biomed 60:279-282, 1989 55. Green N, Broth E, George FW, et al: Radiation therapy in bulky seminoma.J Urol 5:467-469, 1983 56. Smalley SR, EarleJD, Evans RG, et al: Modern radiotherapy results with bulky stages II and III seminoma.J Urol 144:685689, 1990 57. Thomas GM, Gospodarowicz M, Hawkins HVB, et al: Adjuvant mediastinal irradiation for stage II seminoma, in: Adjuvant Therapy in Cancer III. New York, NY, Grune & Stratton, 1981, pp 123-130 58. Thomas GM: Current controversies in the management of testicular seminoma, in MoulJW (ed): Problems in Urology. Philadelphia, PA, Lippincott, 1994 59. Zagars GK: The role of radiotherapy in advanced abdominal metastases from testicular seminoma, inJohnson DE, l-~gothetis CJ, yon Eschenbach AC (ed): Systemic Therapy lor Genitourinary Cancers. Chicago, IL, Year Book Medical Publishers, 1989, pp 292-297 60. Gregory C, Peckham MJ: Results of radiotherapy for stage II testicular seminoma. Radiother Oncol 6:285-292, 1986 61. Kellokumper-Lehtinen P, Halme A: Results of treatment in irradiated testicular seminoma patients. Radiother Onco[ 18:1-8, 1990 62. Epstein BE, Order SE, Zinreich ES: Stage, treatment and results in testicular seminoma. A 12-year rel~rt. Cancer 65:405-41 I, 19911 63. Einhorn LH, Williams SD, Loehrer PJ, et al: Evaluation of optimal duration of chemotherapy in favorable-prognosis disseminatecl germ cell tumors: A Southeastern Cancer Study Group prnt~K:nI.JClin Oncol 7:387-391, 1989 64. Peckham MJ, Horwich A, Hendry WF: Advanced seminoma: Treatment with cis-platinum-based combination chemotherapy or carboplatin (.[MS). Br.J Cancer 52:7-13, 1985 65. Peckham MJ, Husband JE, Barrett A, et al: Orchidectomy alone in testicular stage I non-seminomatous germ cell tumours. Lancet 2:678-680, 1982 66. Stomper PC,Joehelson MS, Friedman E, et al: CT evahmtion of advanced seminoma treated with chemotherapy. Am J Radiat 146:745-748, 1986 67. Thomas GM: Management of metastatic seminoma: Role of radiotherapy, in Horwich A (ed): Testicular Cancer. I~mdon, UK, Chapman and Hall, 1991 pp 117-128
significance of disease bulk in stage II has been recognized, and treatment has been refined. The maximal radiation dose now recommended for stage II disease is 3,500 cGy. CT definition of radiation target volumes minimizes the risk of geographic miss. Prophylactic mediastinal irradiation is no longer recommended. Chemotherapy, usually now bleomycin, etoposide, and cisplatin, produces high cure rates for stage liD, III, and IV disease and has become the standard management. Controversy still surrounds optimal therapy for stage IIC disease. Unresolved questions include cost benefit and quality of life issues surrounding optimal management for stage I disease, inguinal scrotal irradiation in stage I and II disease, and identification of the least toxic but effective chemotherapy for specific subgroups of patients with advanced disease. Copyright 9 1997 by W.B. Saunders Company
oday, more than ever, the delivery of health care is being scrutinized with respect to developing quality assurance measures for the evaluation of patients with disease and the outcomc, s of treatment deliwu'ed. While other areas of oncology have only recently responded to economic and public pressures to develop treatment practice guidelines, ~ the Patterns of Care Study (PCS) dew, loped in the 1970s tbr radiation therapy was prescient of the current process by nearly 20 years. In 1976 gxamcr and Herring ~ published the lh'st report on the PCS, "A Nationwide Evaluation of the Practice of Radiation Therapy in Cancer Management." The PCS was conceived to undertake a "comprehensive nationwide study of patterns of cancer care in radiation therapy," with a basic concept that "all patients suffering ti'om cancer deserve an equally high level of aftercare," irrespective of who delivers that care? Inherent in this concept is the
belief that all patients should have care that is consistent with the best current management. Testiculm" seminoma was one of the specific tumor sites addressed in the PCS, and this article will review both the changes in process and the changes in outcome that have resuhed ti'om the PCS and ti-om other publications in the 20-year period since the study was conceived. Unresolved questions with respect to investigation and management of patients with seminoma requiring future research will be outlined.
T
From the 1)epartment~ r?/ Radiation Oncolog~ and Otz~tetric~ and (;ynecolog~,, University ~!/'Toronto, Toronto-Sunnylmx~k Regional Cancer Center, 7bwnto, Canada. Supported ~_ Grants No. CA(~435 and CA15978 and Contract No. NO I-CM-8727.~om the National Cancerh~ftitute, Bethesda, MD. "lhe opinions and a~sertiomcontainedherein are the private views qf the author and are not to be construed m representingthe ~?[fidalviews ~ffthe National CancerIr~titute. Address reprint requests to GiUian M. Thomas, MD, Department qf Radiation Oncolo~y, University qJ"Toronto, Toronto-Sunnybrook Regional Cancer Center, 2075 Bayview Ave, Toronto, Ontario, M4N 3M5, Canada. Copyright 9 1997by W.B. Saunders Company 1053-4296"/9 7/0 702-0008505.00/ 0
Changes in Process In the 1980 newsletter :~and the 1981 publication t t he results of the PCS process survey were reported. Experts ill the field had developed a consensus nfbest current management, which had been organized into a decision tree (Figure 1)? The process survey was then conducted on patients evaluated and treated in 1973 using questions based on the decision tree. The process survey was conducted in 459 patient records randomly chosen from 163 radiation facilities in the United States. The facilities were chosen because they represented the spectrum of patient volumes, locations, and affiliations with universities that reflected the strata across the United States national practice. For the purposes of study, the staging system used was the modification of the Walter Reed system (Table 1).4 The recommended minimum diagnostic
Seminars in Radiation Oncology, Vol 7, No 2 (April), 1997:pp 135-145
135
136
Gillian M. Thomas
TESTIS (SEMINOMA)
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tad k~ 2-3 we~cs Io'3S00 tad kl $ ~ - 5 weeks to cfir;cJl~ ~ nodes; 3(~) tad In 3-4 v,,g(~s to 4 ~ 0 tad kl 4 . 5 ~ we4Ks to cIk~r ~ nodes v ~ s.~ o(~k=nal t x x ~ ~ ' ~ u ~ a rec~,Jcedr ~ d lot reskX.d _.~.~_ _ _ ~ to I r n s ~ n . m c~ose o~ .~X~Ored In 5-6 wee~)
Figure 1. Decision tree for the management of various stages and extents of testicular seminoma. Reprinted by permission of the publisher from "Patterns of Care Outcome Studies: Results of the National Practice in Seminoma of the Testis," Hanks et al, IntJ-Radiat OncolBiolPhys 7:1413-1417. Copyright 1982 by Elsevier Science Inc.4
evaluation then considered necessary for patient evaluation included a medical history and physical examination, chest x-ray, lymphangiogram, and a complete blood cell (CBC) count. The survey showed that only 62% of patients had a lymphangiogram to assess retroperitoneal nodes. More commonly, the intravenous pyelogram (IVP) was used (in 75% of patients), which is insensitive except for excluding large volume retroperitoneal disease that deviates the ureters. At that time, the serum tumor markers that help distinguish seminomatous from nonseminomatous tumors, ie, alphafetoprotein (AFP) and beta human chorionic gonadotropin ([3HCG), were not available, although 41% of those surveyed did obtain urinary gonadotropin levels. Ninety-six percent of patients had a chest x-ray to exclude mediastinal disease. At that time, it was not common practice for the managing oncologist to state the disease stage; in only 33% of patient records was clinical stage stated.
Treatment Process Survey Radiation therapy in the 1960s and 1970s constituted the only definitive curative management for testicular seminoma, as curative chemotherapy had not yet been identified. The exquisite radiation sensitivity of testicular seminoma was well known and formed the basis for the development of the decision tree, which outlined the best current management. The currently accepted underpinnings for delivery of radiation therapy to the appropriate treatment volume include treatment simulation for all patients. However, in the 1973 survey, only 61% of patients had treatment simulation, although 87% did have portal films to aid in specifying the treatment volume. The decision tree (Figure 1) 4 reflected a PCS consensus that patients with stage I disease (ie, with no evidence of retroperitoneal adenopathy by physical examination, lymphangiogram, or IVP) should be
Progress in Seminoma
Table 1. Modification of Walter Reed Staging System Stage I: Cancer confined to the testicle as determined by clinical and radiographic studies and by orchiectomy. Should subsequent retroperitoneal node dissection reveal microscopic loci of cancer in nodes, clinical stage does not change, but subgroups should be formed. Stage IA: Tumor confined to one testi, no clinical or roentgenographic evidence of spread beyond; may include excretory or retrograde urography, lymphangiography, inferior venacavography, and chest roentgenography. Stage IB: Same as stage IA, but found to have histologic evidence of metastases to iliac or paraaortic lymph nodes at time of retroperitoneal lymph node dissection. Stage IC: Tumor limited to the testis, but no lymph node assessment done by IVP, inferior venacavography, lymphangiography, or exploratory laparotomy.* Stage II: Clinical or radiographic evidence of metastases to femoral, paraaortic, iliac, or inguinal nodes; no demonstrable metastases above the diaphragm or to visceral organs. Stage III: Clinical or roentgenographic evidence of metastases above the diaphragm or other distant metastases to body organs. *Modificationof Waher Reed system;added Ibr this analysis. Reprinted by permission of the publisher li'om "Patterns of Care Outcome Studies: Results of the National Practice in Seminomaof the Testis," Hanks et al, IntJ Radiat OncolBiol Phys 7:1413-1417. Copyright 1982by Elsevier ScienceInc.~
treated with external beam irradiation to the paraaortic and ipsilateral ilio-inguinal nodes including the orchiectomy scar. Options at that time were included for prophylactic irradiation of the mediastinum and the supraclavicular areas. The survey of practice showed that 27% of patients with Stage I disease not only received infradiaphragmatic irradiation, but also had prophylactic irradiation of the mediastinum and/or supraclavicular regions. Eighty-live percent of patients receiving infradiaphragmatic irradiation had the recommended paraaortic and ipsilateral iliac irradiation, whereas the remainder either had paraaortic and bilateral iliac irradiation or, rarely, paraaortic irradiation only. No information is available as to how often the orchiectomy scar was encompassed in the radiation volume or whether testicular shielding was used for the remaining testicle. Similarly, while it was a recommendation to include the scrotum and/or contralateral ilio-inguinal nodes in the radiation volume if there had been scrotal interference, no data are available documenting how often the practice was followed. For patients with stage II disease (ie, identified
137
disease in lymph nodes below the diaphragm), the PCS consensus was that prophylactic mediastinal and supraclavicular irradiation should be given with an option to treat the contralateral ilio-inguinal nodes. Bilateral iliac irradiation was performed in 35% of patients with stage II disease. So firmly was the view held that prophylactic mediastinal irradiation was necessary that the PCS publication stated that "an alarming 19% of stage II patients did not receive prophylactic radiation above the diaphragm. ''4 The PCS consensus with respect to optimal radiation dosage was based on numerous publications 512 and recommended that prophylactic treatment of areas without clinical or radiologic evidence of disease did not require doses in excess of 30 Gy. While the evidence was good in support of this recommendation, the survey showed that supporting data published in reputable journals one to two decades prior had not appropriately impacted on radiation oncologists to change their practice. Fifty-three percent of patients with stage I disease surveyed received over 30 Gy in prophylactic treatment of the retroperitoneal lymph nodes, with more than one third of these receiving over 35 Gy. For macroscopic epithelial cancers, standard teaching in radiation oncology suggests that increasing tumor volumes require increasing radiation doses for cure. Without specific knowledge of the shape of the dose-control curve tbr seminoma, it was anticipated that tbr patients with stage II disease, higher doses than those used [br adjuvant therapy would be delivered. In thct, the survey suggested there was very little use of increased doses [br clinical disease. Whereas in patients with stage I disease, 53% of those surveyed had received doses in excess of 30 Gy, only 62% of patients with stage II disease had received doses in excess of 30 Gy. A lack of consistency in choosing doses tbr adjuvant therapy was demonstrated, as 17% and 29% of those receiving prophylactic mediastinal irradiation for stage I and stage II disease, respectively, received doses in excess of 30 Gy.
Current Practice In the intervening years between those first reports of investigating and managing testicular seminoma, numerous developments have occurred that have significantly facilitated progress in the investigation and management of patients with testicular seminoma. These developments include simpler and more universally available radiologic tests to assess the retroperitoneum; particularly, computed tomogra-
138
GiUian M. Thomas
phy (CT) scanning. The development of immunoassays for AFP and [3HCG is of significant help in eliminating the possibility of the presence of occult nonseminomatous tumor elements and in deciding appropriate treatment. Additionally, specific information has been gathered on the patterns of disease dissemination and patterns of failure after standard therapy used in the 1960s and 1970s. How these developments have influenced the process of the investigation and management of patients with seminoma will be reviewed, and the magnitude of the impact on outcomes of therapy will be presented. Lymphangiography, while still considered the most sensitive method of evaluating the retroperitoneal nodes, is a time-consuming, invasive radiologic test. By 1982 recommendations for its use had largely been supplanted by the use of the abdominopelvic CT scan. The scan has the advantage of being noninvasive, widely accessible in North America, and more precise in delineating the size and location of enlarged nodes. It allows more accurate planning of radiation fields and should minimize geographic miss. In only one circumstance is the lymphangiogram, with its increased sensitivity for small volume disease, deemed more useful; that is, for patients considered for surveillance. This will be discussed subsequently. It is now accepted that AFP elevations in histologically pure seminoma signify the presence of occult nonseminomatous tumor elements. This has resulted in changes in therapy and improved outcome, as such patients are now usually treated as for appropriatestage nonseminomas, with curative chemotherapy rather than radiation. Before the availability of AFP and [3HCG, approximately 40% of those treated for pure seminoma but sustaining recurrences or death from disease actually had nonseminomatous tumor elements present. Since recurrence and death from pure seminoma are much more uncommon than for nonseminomatous tumors, the tumor migration out of the seminoma category to nonseminoma caused by this diagnostic test probably inflates slightly the overall sulvival reported now for pure seminoma. In the 1973 survey treatment simulation was only performed in 61% of patients. The planned new survey will assess whether this has improved in the last two decades.
Changes in Outcome A review of outcome data and, specifically, the patterns of failure after use of the previously recommended radiation treatment fields has led to recom-
mendations for significant changes in radiation practice, including a reduction in the volume irradiated and modifications in the doses used for occult and overt disease. Hanks et al 4 reported in the PCS report that after standard infradiaphragmatic irradiation and prophylactic mediastinal irradiation (PMI) in 27% of patients, the relapse rate for patients with stage I disease was 4% (11 of 262 patients). While this good outcome was attributed to the efficacy of the radiation used in eradicating microscopic disease, it was impossible to analyze the appropriateness of the radiation doses used (53% of patients received in excess of 30 Gy) or the contribution of PMI to the outcome. Mediastinal relapse had occurred in 4 of 11 relapsing patients, but three of these occurred in unstaged patients. Subsequent to the PCS report, a large single institution series documented excellent outcomes for patients with stage I disease treated more conservatively with elective irradiation of the subdiaphragmatic nodes only and with the dose limited to only 2,500 cGy in 3 weeks. 7 The 3-year disease-free (NED) rate associated with this modestdose infradiaphragmatic irradiation was 95% (56 of 59 patients), and, within the statistical limits of such comparisons, appeared "equal to that achieved with PMI" at 90% (18 of 20 patients). O f importance in this retrospective review was the observation that there were no disease recurrences within the treatment field. Multiple reviews in the 20-year interval since have confirmed that infield relapse does not occur even with doses as low as 25 Gy and that the omission of mediastinal irradiation in patients staged with modern techniques results in extremely rare mediastinal relapse, which, when it occurs, is salvageable with further therapy (Table 2). 2~ Thus, in 20 years, the management of stage I seminoma with radiation has been refined to reduce the elective radiation dose used and to abandon the use of mediastinal irradiation. Reported NED rates and cause-specific smadvals in stage I seminoma are now 97% and 99%, respectively. Even in the 1950s, when some patients had occult nonseminomas and some had undetected macroscopic disease, the incidences of tumor relapse and death from seminoma were 4.5% (108 of 2,376 patients) and 2.3% (54 of 2,376 patients), respectively. 21 Many of the patients reported were treated in the era when effective salvage therapy with platinum-based chemotherapy had not been identified. Given these excellent results, there has been reluctance to modify the now-standard, modest-dose, adju-
139
Progressin Seminoma
Table 2. Patterns of Relapse After Adjuvant Radiotherapy for Stage I Seminoma
Study
Fossa et a114 Hamilton et a115 Lester et al I~s Thomas 17 Schultz et al TM Lai et a119 Zagars and Babaian 2~ Total
No. of Patients
249 99 232 33 150 424 95 162 1,444
Radiation Dose (Gy)
No. of No. of Patients Abdominal Relapsing Relapses
40 (10-50) 36 30 25 25 33-35 24-30 25 25
13 5 4 2 8 2 6 40 (3%)
1 0 0 1 (15 Gy) 0 1 0 1 (No RT)
Media~tinal and S/C On~
Other
7
6
3
2
1
2
0 3
2 4
1
1
3
2
Cause-Specific Survival(%)
99 100 93 99 99 100 97 99
Abbreviations: S/C, supraclavicular;RT, radiotherapy. Reprinted with permission.13 vant postorchidectomy infradiaphragmatic irradiation.
ReducingToxicity It was, however, recognized that treatment was accompanied with some late morbidity, including dose-related gastrointestinal morbidity, impaired fertility, and possible induction of late malignancies. 14,15,22One impetus to reduce the radiation dose used tbr treatment of stage I seminoma was the thct that doses of 35 to 40 Gy in 2-Gy fractions produced signilicant dyspepsia in 6% and fi'ank peptic ulceration in 3% of patients. H The PCS data showed a bowel complication rate tbr the doses then used tbr all stages of disease of 2.4%, 4 and similar data from the Royal Marsden Hospital (Sutton, UK) 15 conlirmed a 6% incidcnce of peptic ulceration in those irradiated. However, PCS data indicated that intestinal obstruction and ulceration decreased to 2% with doses between 25 and 35 Gy. These control and complication data support an improvement in therapeutic ratio achieved by reduction of radiation dose tot subclinical disease to 25 Gy. While patients with testicular tumors have impaired spermatogenesisf ~2~' dose-related additional impairment occurs after radiation, although the magnitude is difficult to assess. With adequate shielding, the dose to the remaining testicle can be reduced to 1% of the prescribed mid-plane radiation dose, 2ti but it is clear that the proximity of the testes to the edge of the radiation field, ie, the placement of the interior border of the volume, affects the dose received by the testicle. The consensus in the original PCS report suggested that elective irradiation in stage I seminoma should include the inguinal scar. It is not known whether radiation oncologists are still
routinely irradiating the inguinal region, and it is methodologically impossible to determine whether this inferior extension of the field with the increased scattered dose to the remaining testicle positively affects relapse-free survival. The third significant morbidity of radiation for testicular seminoma is a small but significant increased risk of induction of second solid tumors and leukemia. 14,27-30 With a vicw to further reducing morbidity in seminoma and minimizing unncccssary treatment, several alternative therapeutic options haw~ been explored. Clinical trials r surveillance of patients with well-staged stage I seminoma have been conducted. The initiation of these trials resulted from a better knowledge r the natural history and routes r dissemination of seminoma, better radiologic tests to assess disease cxtcnt, and the ability to predict probable rates and sites of relapse if treatment were withheld. The slow, orderly progression of seminoma metastasizing ti-om the primary and sequentially spreading through the retroperitoneal and then the mediastinal and supraclavicular nodes was recognized. Hematogenous spread from pure seminoma is extremely rare, with only 3% of patients with supradiaphragmatic or hematogenous diseasc. Effective salvage cisplatin-based chemotherapy had also been identified. 31 Surgical staging series had reported that the incidence r undetected retroperitoneal disease in those without obvious palpable abdominal disease was less than 20%Y Results of surveillance studies are shown in Table 3Y ~ The risk of relapse after surveillance is 15% to 18%. Ninety-six percent of relapses occur in the retroperitoneum or inguinal regions; and while the majority of relapses occur in the first 2 years after orchiectomy, intervals may be prolonged, ranging from 2 months to 7 years postorchidec-
140
GiUian M. Thomas
Table 3. Results of Surveillance Studies in Seminoma No. of patients Median months of follow up Percent (no.) of relapses Median months to relapse Retroperitoneal or inguinal relapses only/total Second relapse/total Percent (no.) having chemotherapy Percent survival
RMI-F 9
D A T E C A 33
Toronto j3
Total
113 37 15 (13) 15 12/13 5/13 6 (6) 100
261 30 18.8 (49) 13.5 48/49 4/49 6 (16) 99.6
209 48 13 (28) 12 26/28 3/28 3 (8) 99.5
583 15.4 (90) -86/90 (95.6%) 12/90 5 (30) 99.7
Abbreviations:RMH,RoyalMarsdenHospital;DATECA,DanishTesticularCarcinomaStudyGroup. Reprinted with permission.13 tomy.32 Salvage rates with appropriately directed radiation to the retroperitoneum or chemotherapy for those with supradiaphragmatic or hematogenous dissemination result in overall survivals close to 100%. Factors predicting for relapse on surveillance have been investigated. On multivariate analysis, the only factor of independent significance was the size of the primary tumor, with relapse rates of 36% when tumors were greater than 6 cm in size.33 For tumors less than 3 em in size, relapse occurred in only 6%. Surveillance, when practiced carefully with scanning of the retroperitoneum every 4 to 6 months, has been demonstrated to be a safe and effective alternative management to standard postoperative infradiaphragmatic irradiation for stage I seminoma. It avoids treatment for the majority of patients but increases costs associated with repeated CT scanning. The choice of its use as an alternative to irradiation remains a matter of the physician's philosophy, the patient's wishes, the patient's projected compliance with surveillance, and the relative costs of the two approaches. The prevalence of its use will be assessed in the new PCS survey. To avoid the relatively high comparative relapse rates on surveillance and still decrease radiation morbidity, reduced radiation volumes have been investigated as another alternative for stage I disease. This choice, to exclude the pelvic field and treat the paraaortic nodes only, was based on the rationale that fewer than 5% of patients were expected to have involved pelvic lymph nodes in well-staged disease. A randomized trial in 478 patients with stage I disease and no prior inguinal surgery was conducted comparing standard irradiation with an inferior border at the mid-obdurators to paraaortic irradiation only from T 11 to L5. 34As expected, the 2-year relapse-free survival rates were not significantly different at 96% and 97%, respectively. Myelotoxicity and azoospermia were significantly reduced in the group treated
with paraaortic irradiation alone, although, as expected with identical upper abdominal irradiation, peptic ulceration rates of 8% did not differ between the two groups. While the investigators concluded that paraaortic irradiation alone may be standard treatment, they have observed with only 2 years of follow up a 2% pelvic failure rate. If paraaortic irradiation becomes an accepted standard management, surveillance of the pelvis will be required. 34 Finally, 20 years after the PCS studies and multiple other publications have shown the excellent therapeutic ratio associated with modest-dose infradiaphragmatic irradiation, some investigators are treating stage I disease with short courses of chemotherapy, usually one or two injections of platinum agents. 35 The relative benefits of this management will be assessed in a Medical Research Council of the United Kingdom study comparing short courses of platinum-containing chemotherapy with radiotherapy.
Stage II In the PCS, 28% of patients (107 of 379) were considered to have stage II disease, although 10% did not have the retroperitoneum evaluated. Bulk of retroperitoneal involvement was not evaluated. The expert opinion captured in the decision tree (Figure 1) 4 recommended prophylactic mediastinal irradiation with an additional option to treat the contralateral pelvic nodes. With the treatment delivered, the relapse rate was only 5%. The observed mediastinal failure rate in those without retroperitoneal evaluation was attributed to the lack of use of the recommended prophylactic mediastinal irradiation in those with probable retroperitoneal disease. The excellent outcome for the remainder was attributed to the use of infradiaphragmatic irradiation and PMI. Recommendations for PMI had been extrapolated from
Progress in Seminoma
141
Table 4. Radiotherapy Results in Nonbulky Stage II Seminomas
Study Bayens et al s7 Lindeman and Tiver 3~ Thomas et aP 9 Mason and Kearsleya~ Mason and Kearsley4~ Hunter and Peschel al Evensen et a142 Sagerman et al as Ball et a144 Ellerbroek et al as Jackson et a146 Lai et al n9 Tombolini et al a7 Lederman et al 4~ Andrews et al as Total
Size Criterion (cm)
Disease-Free Survival (%)
<5 <5 Nonpalpable <5 5-10 <5 <5 <5 <5 <5 Nonpalpable <5 <5 <5 <5
22/29 (76) 8/9 (89) 37/40 (93) 24/25 (96) 10/12 (87) 15/15 (100) 23/24 (96) 19/21 (90) 28/33 (85) 7/8 (88) 26/29 (90) 31/33 (94) 20/20 (100) 24/25 (95) 16/17 (94) 310/340 (91)
Salvage (%) 4/7 1/1 0/3 0/1 0/2
(57)* (100) (0)* (0)* (0)* -1/1 (100) 2/2 (100)* 2/5 (40) 0/1 (0) 0/3 (0) 1/2 (50) -0/1 (0)* 1/1 (100)* 12/30 (40)
Overall Survival (%)
Median Follow Up, Years (range)
26/29 (90) 9/9 (100) 37/40 (93) 24/25 (96) 10/12 (87) 15/15 (100) 24/24 (100) 21/21 (100) 30/33 (91) 7/8 (88) 26/29 (90) 32/33 (97) 20/20 (100) 24/25 (96) 17/17 (100) 322/340 (95)
7.5 (0.8-13) 4.2 (1.2-9) NS 6.2 (3-19.6) 6.2 (3-19.6) 9 (1-24) 6.2 (2-13) 8.5 (0.5-20) 7.5 (3-17) Minimum 2 NS 6.7 (1-24) 3.5 (2-11.6) 6 (1-17) 8.6 (0.5-21)
Abbreviation: NS, not stated. *Treated with cisplatin-based salvage chemotherapy. Reprinted with permission. 3ti l y m p h o m a t o u s t u m o r s where prophylactic irradiation of the next echelon of uninvolved nodes was r e c o m m e n d e d , but no detailed analysis e x a m i n e d the additional benefits provided by such t h e r a p y in seminoma. It was, however, recognized that the
overall risk of relapse after s t a n d a r d infradiaphragmatic and s u p r a d i a p h r a g m a t i c irradiation increased with increasing bulk of i n f r a d i a p h r a g m a t i c disease (Tables 4 and 5). 7,n:~,36"~6Initial r a d i o t h e r a p y cures ->90% of non-bulky stage II disease, and salvage with
Table 5. Radiotherapy Results in Bulky Stage II Seminomas
Study Jackson et al ~i Doornbos et al 7 Laukkanen et al s() Ellerbroek et aP s Thomas et al s' Read et al sl Herman et aP 2 Zagars and Babaian s:~ Andrews et al 4~ Ball et aP a Hunter and Peschel al Martinelli sa Sagerman et al a:~ Mason and Kearsleya~' Green et al ss Evensen et ala2 Smalley et al s~ Bayens et aP 7 Lindeman and Tiver sa Total
Yea~ of Study
Size Criterion(cm)
Disease-flee Survival (%)
Salvage (%)
Overall Survival (%)
Median FoUow Up, Yea~ (range)
1942-1978 1944-1971 1948-1983 1956-1983 1958-1976 1960-1978 1960-1981 1960-1982 1962-1984 1963-1979 1964-1984 1965-1985 1966-1985 1968-1985 1969-1980 1971-1981 1971-1982 1975-1985 1980-1987
Palpable > 10 Palpable >5 Palpable Palpable Palpable Palpable >5 >5 >5 Palpable >5 >10 >6 >5 >5 >5 >5
13/16 (83) 11/22 (5(I) 17/23 (74) 8/15 (53) 22/46 (48) 30/67 (45) -7/10 (70)ll 3/4 (75) 14/23 (61) 3/3 (100) 4/4 (100) 10/11 (91) 8/12 (67) 17/18 (94) 38/48 (79) 16/20 (80) 7/9 (78) 4/5 (80) 232/356 (65)
(I/3 (0) 3/11 (27) 3/6 (50) 1/7 (14) 7/24 (29) 8/37 (22) -0/3 (0) 1/1 (100)w 3/9 (33) --1/1 (100) 1/4 (25)w 0/1 (0) 5/10 (50) 4/4 (100)w 1/2 (50) 1/1 (100) 39/124 (31)
13/16 (83) 14/22 (61) 21/23 (91)* 9/15 (60) 29/46 (63) (63)]" 100/109 (92)~ 7/10 (70)11 4/4 (100) 17/23 (74) 3/3 (100) 4/4 (100) 11/11 (100) 9/12 (75) 17/18 (94) 42/48 (88) 20/20 (100) 8/9 (89) 5/5 (100) 375/465 (81)
NS NS 7.6 (2-26) Minimum 2 NS Minimum 4
*Disease-specific survival. tEstimated from actuarial survival curves. ~Cause-specific survival. w or carboplatin used in salvage therapy. [lOne patient relapsing with 13HCGelevation excluded. Reprinted with permission)ci
Median 6.6 8.6 (0.5-21) 7.5 (3-17) 9 (1-24) 3.5 (15) 8.5 (0.5-20) 6.2 (3-19.6) 4 (1-11) 6.2 (2-13) 4.6 (24) 7.5 (.8-13) 4.2 (1.2-9)
142
Gillian M. Thomas
appropriate radiation or chemotherapy results in overall cures of 95%. Subsequent to the PCS, analyses of patterns of failure in patients with stage II disease treated without PMI clarified that mediastinal relapse with non-bulky stage II disease was extremely rare and that the additional survival benefit attributable to PMI was only 0.4%.39,57 Subsequently, longterm follow-up data from the PCS indicate that mediastinal irradiation is associated with significant increased risk of death from intercurrent disease and cardiopulm0nary cause, thus supporting the contention that PMI is no longer indicated for patients with infradiaphragmatic nodal disease less than 5 cm in transverse diameter (stage IIA/B). The abandonment of PMI in small volume stage II disease has not compromised survival and has reduced unnecessary treatment and morbidity. A survey of 600 radiation oncologists conducted in the United States in 1987 indicated that 62% of physicians no longer use PMI. The next planned PCS survey in seminoma will determine whether further reductions in the use of PMI in stage II non-bulky disease have occurred.
Bulky Stage II In contrast with the excellent results for the treatment of non-bulky stage II disease with primary radiation therapy, results for bulky disease, defined by whether the maximum transverse size of a mass on CT scan is greater than 5 cm or 10 cm or simply by the presence of a palpable mass, are distinctly worse (Table 4).36 There is both a significant risk for overall relapse when infradiaphragmatic irradiation and PMI are used and a further increased risk for mediastinal relapse when PMI was omitted. 53 The exclusion of AFP-positive patients (ie, nonseminomatous) does not significantly diminish these risks. In the past two decades, it has been established that pure seminoma is also exquisitely sensitive to platinum-based chemotherapy) 1Chemotherapy was successful in salvaging the majority of patients who had relapsed after radiation and additionally provides cures in those with extensive disease not previously cured with radiation alone. Optimal therapy for patients with bulky stage II seminoma (>5 cm in diameter) is one of the most controversial areas remaining in the management of testicular seminoma. While previously all patients had been treated with radiation alone, knowledge of the efficacy of chemotherapy has resulted in significant changes in practice. The Commission on Cancer of the American College of Surgeons (ACOS) conducted two surveys of patients
with seminoma treated between 1970 and 1975 and in 1983. For patients with clinical stage II disease, the use of surgery and radiation alone decreased from 93.3% to 78.6%, with a concomitant increase in the use of chemotherapy. Further studies have delineated one obvious group of patients with extremely bulky disease (stage IID disease, >10 cm in transverse diameter) where there is general agreement that initial chemotherapy is preferred because of the unsatisfactory results with primary radiation. Relapse rates are approximately 40% even when PMI is given (Table 6). 40.42,58-62 Salvage chemotherapy is potentially hazardous after PMI and infradiaphragmatic irradiation, so primary cisplatin-containing combination chemotherapy is preferred. Similar considerations exist for rare patients with stage III and IV disease (supradiaphragmatic nodal disease or parenchymal involvement). While results in the original PCS survey showed a relapse rate of at least 30% after radiation alone, other series suggested cure in only 35% of patients and usually in those with nodal rather than parenchymal disease and without bulky abdominal disease. The necessity for salvage chemotherapy in the majority of patients treated with multiple radiation volumes is a relative contraindication to the use of initial radiation therapy, and this has led to a change in practice documented in the 1987 survey of ACOS. For stage III disease, the use of surgery and radiation was reduced from 62.2% to 15.8%, with a concomitant increase in the use of chemotherapy (less than 15% of patients received no chemotherapy). Optimal management of patients with stage IIC disease (5 to 10 cm in transverse diameter) remains unresolved. Twenty years ago PMI was considered the norm, but even with its use, disease-free and overall survival rates with primary irradiation are
Table 6. Outcome After Radiation Therapy for Patients With Stage IIA/B Disease (<5 cm in diameter) Study
Mason and Kearsley4~ Evensen et a142 Zagars59 Gregory and Peckham6~ Kellokumper-Lehtinen and Halme 61 Epstein et a169 Hunter and Pesche141 Total *Exactnumber unknown. Reprinted with permission.58
Xo. q Patients
25 24 18 39 66 16 15 203
No. Relapsing
1 1 1 5 10 0 0 18 (9%)
De~d of Disease
0 0 1* 2 2 0 0 5 (2%)
Progressin Seminoma
only 65% and 80%, respectively (Table 5).:~iWhile it is unclear that exactly comparable patient groups are being reported, and while many patients are given additional radiation, chemotherapy trials in advanced disease using either platinum, velban, bleomycin (PVB) or platinum-containing chemotherapy of bleomycin, etoposide, platinum (BEP) given tbr three or four cycles report disease-free survivals of 92%. Toxicity is lowest with three cycles ofBEP/:~ Two decades later, there appears to be no uniform agreement about optimal therapy for patients with stage II disease. Management options include (1) initial treatment with infradiaphragmatic irradiation and treatment of relapse at any site with cisplatincontaining combination chemotherapy; (2) initial treatment with chemotherapy tbllowed by either observation of residual masses or consolidation radiation therapy; or (3) inii'adiaphragmatic and supradiaphragrnatic irradiation with chemotherapy for subsequent relapses. Data can be generated in support of any of these approaches, but the third is deemed to be the least satisfactory as 10% to 20% of patients failing infradiaphragmatic and supradiaphragmatic irradiation will require salvage chemotherapy. Survival rates are similar regardless of the initial approach used, but the toxicity profiles for each approach vary, as does the frequency of salwtge therapy required in each. Aecumulated results of fiw: series of patients with stage IIC disease record a relapse rate after irradiation, usually including PMI, ot"4% (4 of48 t)atients). H,~z:':u;"-I;:~The overall su,'viwtl is 90%. If infradiaphragmatie irradiation only is used for stage IIC diseasc, the probability of relapse in the mediastinum or at distant sites increases to approximately 20%. Chemotherapy will salvage approximately 80% of relapsing patients, producing cure rates probably comparable to those achieved with initial infradiaphragmatic irradiation with PMI. In an attempt to rigorously compare initial chemotherapy with initial in&adiaphragmatie irradiation, the Radiation Therapy Oncolog'y Group of the United States started a phase III study, but the study was closed for lack of patient accrual. Results from the planned PCS survey of seminoma will be awaited with interest to determine the most common practice in the management of patients with stage IIC disease. When initial chemotherapy is used for the management of patients with stage IIC, liD, III, and IV disease, residual masses may exist in as many as 75% of patients. ~i4Controversy surrounds the use of consolidation radiation therapy to sites of initial bulky
143
disease or for residual masses and the use of surgical excision. Surgical series have shown that only 10% to 12% of residual masses have viable seminoma cells; most have fibrosis only. Routine irradiation of residual masses implies the overtreatment of 85% to 90% of patients and does not appear indicated. Only the series from Memorial Sloan-Kettering Hospital (New York, NY) has documented an unusually high incidence of residual disease at surgery/~ In that series, 5 of 14 patients (36%) had apparently viable tumor present immediately after chemotherapy if the residual mass was in excess of 3 crn in diameter. While the risk of viable residual disease is probably slightly higher for larger rather than smaller masses, 65 the 12% overall average risk of residual microscopic disease in the surgical series appears to be more in keeping with the reported relapse rates in the Royal Marsden Hospital report of 11%/6,67 A policy of observation of residual masses after chemotherapy would spare the majority of patients unnecessalT treatment but would imply that repeated CT assessment is necessary to ensure that masses are not progressing. The use of consolidation radiation therapy after chemotherapy will be evaluated in the planned PCS survey.
Summary Ill the past two decades, the investigation and management of patients with testicular seminoma has changed substantially. Overall surviwds have imlmwed by approximately 10%, and radiation toxicity has been decreased by reductions in the fi'equency of use and in the doses and w)lumes used. Improvements in survival and reduction in morbidity may be attributed to improvements in radiologic tests that more accurately assess disease extent and to intbrmatiun delineating rates and t)atterns of failure after various treatments. The integration of platinumcontaining chcmotherapy into the managemcnt of patients with more advanced disease has led to improved survivals for the rare patients with stage IID, III, and IV disease. Given the excellent therapeutic ratio associated with current therapeutic approaches and the refinements of the use of radiation and chemotherapy, it is doubtful that there is room tbr substantial gains over the next two decades. Carethl measures of quality of life after various treatment options may resolve optimal definitions of therapy in controversial areas such as the use of inguinal scrotal irradiation, management of stage I and stage IIC disease, the use of
144
Gillian M. Thomas
consolidation radiation therapy after chemotherapy, and the tailoring of chemotherapy to reduce morbidity and maximize cure rates for different risk groups.
Acknowledgment I thank radiation oncologists, physicists, and staff throughout the United States whose support is essential to the PCS.
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