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Evolution in management of testicular seminoma: population-based outcomes with selective utilization of active therapies
original article
Annals of Oncology 22: 808–814, 2011 doi:10.1093/annonc/mdq466 Published online 6 October 2010
Evolution in management of testicular seminoma: population-based outcomes with selective utilization of active therapies 1
Division of Medical Oncology, Department of Medicine; 2Division of Radiation Oncology, Department of Surgery, British Columbia Cancer Agency/University of British Columbia, Vancouver Cancer Centre, Vancouver, Canada; 3Earle A Chiles Research Institute, Providence Cancer Center, Portland; 4Institute of Urology, USC/Norris Comprehensive Cancer Center, Los Angeles, USA; 5Department of Urological Sciences, UBC, The Prostate Centre at Vancouver General Hospital, Vancouver, Canada; 6Division of Hematology and Medical Oncology, Department of Medicine, Oregon Health & Science University Knight, Cancer Institute, Portland, USA
Received 30 May 2010; revised 16 July 2010; accepted 22 July 2010
original article
Background: In this article, we report the evolution of treatment with increased use of active surveillance for stage I disease as well as risk-adapted chemotherapy for disseminated disease and associated outcomes of testicular seminoma in a contemporary population-based cohort. Methods: All patients with histologically confirmed seminoma referred from 1999 to 2008 to the British Columbia Cancer Agency or Providence Cancer Center were retrospectively reviewed. Both institutions manage 90% of testicular cancers in their respective area. Results: A total of 649 patients were included. Clinical stage (CS) distribution: CSI/II/III n = 545/87/17. For CSI, there was a progressive and marked decrease in the utilization of prophylactic radiation (RT), and corresponding increase in the use of active surveillance. No deaths related to seminoma were reported in CSI patients. CSII or CSIII patients received RT or International Germ Cell Cancer Collaborative Group (IGCCCG) risk-appropriate chemotherapy with 101 of 104 patients being in long-term remission and 3 patients dying from treatment complications. For the entire seminoma population, <1% of patients died of seminoma or treatment after a median follow-up of 47 months (range 2–130 months). Conclusions: Progressive application of policies of active surveillance and earlier initiation of IGCCCG risk-adapted chemotherapy result in nearly universal control for all patients presenting with seminoma while reducing the burden of treatment. Key words: active surveillance, chemotherapy, radiation, seminoma
introduction Management of testicular germ cell tumors is undergoing a quiet evolution. The older paradigms of adjuvant therapies for patients with local disease, regional management for regional disease and inconsistent application of systemic therapy are being rapidly replaced. Much of this change has been spurred by the increased appreciation of short- and longterm effects of all treatment modalities and increased confidence in the cisplatin-based chemotherapy safety net. As well, ‘personalized’ therapy whereby patients receive defined amounts of treatment of their individual clinical situation has become an appropriate clinical objective. The cornerstones of modern management for testicular cancer are well developed in *Correspondence to: Prof. C. R. Nichols, Earle A Chiles Research Institute, Providence Cancer Center, 4805 NE Glisan St, Ste 2N 35 Portland, OR 97213, USA. Tel: +001-503215-6259; Fax: +001-503-215-6841; E-mail: [email protected]
various guidelines but are just beginning to fully penetrate care pathways in the United States and elsewhere. These cornerstones include a strong move to minimize adjuvant treatments in clinical stage (CS) I disease, minimize regional therapies such as surgery or radiation (RT) therapy as primary management of CSII disease by early utilization of systemic chemotherapy, stringent application of risk-adapted cisplatin, etoposide and bleomycin (BEP) as the systemic therapy and, importantly, centralized coordination of care and specialized technologies sometimes required in patients such as postchemotherapy retroperitoneal lymphadenectomy, radiotherapy or salvage chemotherapy. In testicular nonseminoma, these modern principles have been validated and the algorithm of care generally embraced with excellent outcomes and cure rates in excess of 95% for CSII and 80%–85% for advanced metastatic nonseminoma patients [1–4]. With central coordination of care and
ª The Author 2010. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: [email protected]
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C. Kollmannsberger1, S. Tyldesley2, C. Moore3, K. N. Chi1, N. Murray1, S. Daneshmand4, P. Black5, G. Duncan2, B. Hayes-Lattin6 & C. Nichols3*
original article
Annals of Oncology
materials and methods All patients with histologically confirmed pure seminoma referred from 1999 to 2008 to the British Columbia Cancer Agency (BCCA; British Columbia, Canada) as well as through the Oregon Testis Cancer Program (Portland, Oregon) were retrospectively reviewed. The study was approved by the respective ethics boards of the participating centers. The BCCA with its four cancer centers and 18 to 20 genitourinary medical and RT oncologists is involved in the management of 90% of all testicular cancer cases in British Columbia. Over 80% of Oregon State’s testicular cancer patients are seen and managed by a single provider (Providence Health Care/CRN). Over the past decade, surveillance has been increasingly utilized as the preferred treatment option for all patients with CSI seminoma irrespective of risk status. As well, primary International Germ Cell Cancer Collaborative Group (IGCCCG) classification risk-stratified chemotherapy has been progressively utilized for regional disease and disseminated disease [7]. Initial staging after orchiectomy included computed tomographic (CT) scans of the abdomen, CT scan or X-ray of the chest and tumor markers a-fetoprotein, human chorionic gonadotropin and lactate dehydrogenase. Normal chest and abdominopelvic imaging were required as the criteria of CSI. Metastatic disease was classified according to the IGCCCG as well as the tumor–node–metastasis/International Union Against Cancer classification. Patients with CSI disease were informed about all their treatment options including adjuvant RT, surveillance and, as of 2005, adjuvant carboplatin [8, 9]. Adjuvant chemotherapy consisted of one to two cycles of singleagent carboplatin at a dose of area under the curve 7 [8, 9]. Adjuvant RT consisted of 25 Gy in 15 fractions over 3 weeks with anterior to posterior parallel pair technique using megavoltage photons. Fields were usually restricted to the paraaortic chain (i.e. T10/T11 interspace to the L5/S1
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interspace). Paraaortic and ipsilateral pelvic treatment was used only on rare occasion [1]. Patients with metastatic disease received a treatment recommendation for either RT (stage IIA/B only) or cisplatin-based chemotherapy based on the IGCCCG classification as their primary treatment modality. Good prognosis disease patients received three cycles of BEP or four cycles of etoposide/cisplatin (EP). Patients with intermediate prognosis received primarily four cycles of BEP. CSII seminoma patients who received RT were usually treated with 35 Gy in 20–25 fractions with standard paraaortic and ipsilateral pelvic techniques [4]. Twenty-five gray was delivered to the paraaortic and ipsilateral pelvic lymph nodes in 15–20 fractions over 3–4 weeks with anterior to posterior parallel pair technique using megavoltage photons. Subsequently, a boost of 10 Gy in five fractions was given to the nodal mass with a margin using an anterior to posterior parallel pair technique. Patient data including demographics, pathology, stage, management, response data and follow-up were abstracted from the charts. Follow-up was done according to institutional policy including chest Xrays, CT scans of abdomen/pelvis and tumor markers. Management of CSI seminoma generally included two to six CT scans over the first 3 years for patients receiving carboplatin or surveillance with no or very few CT scans for patients receiving primary RT. Utilization of CT scans and positron emission tomography scans for patients treated definitively with chemotherapy was sparse and primarily reserved for patients with significant residual disease. If patients had been discharged from the center, current status was obtained through contact with the primary care physician or local oncologist. Relapse-free as well as disease-specific survival intervals were measured from the date of orchiectomy to date of relapse and date of death from seminoma or last contact, respectively. Median follow-up was calculated from the date of orchiectomy to date of death or last follow-up. Comparisons between treatment groups were made using chi-square test for categorical variables and Student’s t-test for continuous variables. A P value of £0.05 was considered significant. The relationship between treatment-year and management was assessed by linear regression of treatment-year versus proportion of cases treated with a particular treatment. All statistical analysis was carried out using SPSS Statistical Software. Relapse-free survival and overall survival rates were calculated using the Kaplan–Meier method and compared using log-rank test.
results From 1999 to 2008, 649 patients with seminomas were treated at our two institutions. All patients were included in this analysis and represent an unselected population. The vast majority of patients presented with CSI disease [n = 545 (84%)]. Metastatic disease at initial presentation was diagnosed in 104 (16%) patients, with 87 (13%) having CSII and 17 (3%) CSIII disease. Overall survival was excellent. After a median follow-up of 44 months (range 2–130) for all patients, 640 patients (99%) are alive and no patient has died of seminoma.
stage I Three hundred and thirteen patients underwent active surveillance, 159 adjuvant RT and 73 patients adjuvant carboplatin therapy (Table 1). For completeness, Table 1 also shows the distribution of and differences in previously proposed prognostic factors such as tumor size and rete testis
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specialized services, these simplified management algorithms can be applied successfully across large populations and vast geographies. Testicular seminoma is marked by less aggressive biological behavior and outstanding chemotherapy and RT sensitivity. Approximately 85% of testicular seminoma patients present with CSI disease and only 15% of these patients relapse after orchiectomy [5, 6]. Cure rates for seminoma have approached 100% for CSI disease for several decades, exceeded 90% for good-risk regional disease and 75%–80% for those rare patients with disseminated disease [4, 6]. The principles of modern management of seminoma are nearly identical to those of nonseminoma. The majority of CSI patients will not require any therapy after orchiectomy, making any adjuvant treatment a substantially less attractive option. Although regional therapeutic RT is curative for 80%–90% of low and modest volume CSII patients, it is associated with substantial late effects and does not reliably cure all of these patients. However, metastatic disease is exquisitely sensitive to chemotherapy, almost always is of favorable prognosis amenable to three cycles of BEP and almost always chemotherapy prevents a second relapse of the disease and the necessity of additional therapy. In this article, we describe clinical outcomes with progressive incorporation of these cornerstones of management over the last decade in a centrally managed, large population-based experience with testicular seminoma.
original article
Annals of Oncology
Table 1. Characteristics and treatment outcomes of clinical stage I patients N = 545
Active surveillance (n = 313)
Median age Primary tumor Rete invasion Yes No Unknown Tumor size £4 cm >4 cm Unknown LVI Yes No Unknown Relapses
37 [range 18–83]
39 [range 19–76]
36 [range 19–62]
67 (21%) 181 (58%) 65 (21%)
41 (26%) 55 (35%) 63 (39%)
29 (40%) 27 (37%) 17 (23%)
209 (67%) 83 (26%) 21 (7%)
69 (43%) 83 (53%) 7 (4%)
29 (40%) 44 (60%) 0%
Adjuvant carboplatin (n = 73)
P value 0.08 <0.0001
<0.0001
<0.0001 20 230 63 47
(6%) (74%) (20%) (19.3%)
14 months [3–36 range]
15 (10%) 118 (74%) 26 (16%) 4 (2%) (pelvic LN · 2, supracl. LN ·1,unknown · 1) At 9, 14, 15, 25 months
17 54 2 1
(23%) (74%) (3%) (2%)
At 20 months
47 (100%)
4 (100%)
1 (100%)
32 (68%) 15 (32%) 0
3 (75%) 0 1 (25%)
1 (100%) 0 0
24 (51%) 6 (13%) 17 (36%) 0
4 (100%) 0 0 0
0 1 (100%) 0 0
0 2 (1.3%)
0 0
3 (all after RT)b 5 (1.6%)
311 (99%) 0 2 (1%)
158 (99%) 0 1 (1%)
266 (85%) 15 (5%)
0% 159 (100%)
0% 35 (11%) 34 months [range 2–136]
0% 4 (3%) 65 months [range 3–120]
<0.0001
100% 0 0 0% 0% 73 (100%) 1 (1%) 33 months [range 4–106]
a
One patient was diagnosed with good-risk disease but delayed treatment until progression to intermediate-risk disease. There were two additional patients with synchronous bilateral primaries and four patients who were included in the study for a second primary after successful therapy for a previous primary. c (1· supraclavicular lymph node, 1· abdominal relapse but outside of the RT field and 1· location unknown). CT, computed tomography; DOD, dead of disease; LN, lymph nodes; RPLND, retroperitoneal lymph node dissection; RT, radiation; supracl., supraclavicular. b
invasion in the respective management groups, although these factors could not be confirmed in an independent validation analysis and thus should not be used in clinical practice [10, 11]. The use of adjuvant RT has sharply declined over time, while active surveillance has become the preferred treatment
810 | Kollmannsberger et al.
option over the last years (P = 0.00002) (Figure 1). Adjuvant carboplatin has replaced RT as treatment of those few patients deciding on active treatments. The 5-year relapse-free survival rates were 80.7%, 98% and 98% of patients receiving active surveillance, adjuvant RT or
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Median time to relapse Stage at relapse Gooda Relapse treatment Chemotherapy RT CT + RT Response to treatment CR/PR <1 cm PR Unknown Additional treatment (RPLND, RT for residual disease) Second relapse Second primary testicular cancersc Current status Alive without disease DOD Death other cause Total treatment burden No further therapy RT therapy Chemotherapy Carboplatin Cisplatin based Median follow-up
Adjuvant RT (n = 159)
original article
Annals of Oncology
Figure 1. Stage I treatment by 2-year periods (percentage of all patients seen in the 2-year period).
carboplatin patient after 20 months) or good-risk CSIII disease (four adjuvant RT patients at 9, 14, 15 and 25 months). All of these five patients were successfully salvaged (Table 1). Overall, one patient died of a squamous cell carcinoma of the esophagus, which had initially been diagnosed before his seminoma and another patient from a primitive neuroectodermal tumor. One patient committed suicide. Disease-specific survival for all CSI patients is 100%.
regional or disseminated disease Only 104 (16%) of all seminoma patients presented with metastatic disease, with the majority having CSII and/or good prognosis disease (Table 2). Initial treatment of CSII consisted of combination chemotherapy in 75% of patients, while RT was used in 22%. All patients with CSIII seminoma underwent chemotherapy as initial therapy. The use of primary chemotherapy for CSII seminoma rose steadily over time, while the use of RT continuously decreased over the same time period (Figure 3) (P = 0.043). Response to treatment was excellent and only three patients received additional treatment of their residual lesion (Table 2). The 5-year actuarial relapse-free survival was 94% for all CSII seminomas, 91.7% for those treated with RT and 95.5% for those treated with CT. Overall, five CSII patients recurred after first-line therapy, all within 3 years after first-line therapy. Three of those had previously received primary RT. All but one relapsed patients received salvage chemotherapy and are continuously disease free. After a median follow-up of 46 (range 2–110) months, no patient has died of seminoma. Actuarial 5-year overall survival rate was 90.7% for CT and 92.3% for RT (P = 0.67) (Table 3). Three patients died during chemotherapy. One patient suffered a massive stroke after cycle 2 of BEP, in the presence of a previously undiagnosed patent foramen ovale and absence of any other thrombosis. The second patient died of a hyperosmolar syndrome secondary to previously undiagnosed diabetes after cycle 2 of BEP and the third patient due to renal failure during high-dose chemotherapy. There were no bleomycin-related hospitalizations or deaths. Two patients died of lung cancer, one 5 years after RT for a stage IIB seminoma and the other 2 years after four cycles of EP for stage IIB seminoma. Both patients had been heavy smokers for many years. One patient died disease free from unknown reasons 10 months after completion of chemotherapy.
discussion
Figure 2. Stage 1 relapse-free survival according to management modality: carboplatin (Carbo; n = 73), radiation (RT; n = 159), surveillance (n = 313).
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The comprehensive results of our large modern series of unselected patients with testicular seminoma are noteworthy. Among this population that included over 100 patients presenting with more advanced disease, none of our 649 patients died of progressive seminoma and the overall death rate from disease or treatment was 1%. This represents the largest reported modern experience of global results in testicular seminoma with excellent outcomes. What is most notable, in our view, is that these results were not achieved with breakthrough technologies, particularly clever thinking by the
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adjuvant carboplatin, respectively (see Figure 2). Median time to relapse was 14 (3–36) months. Of the 47 total relapses, eight (15%) of these patients relapsed beyond 2 years but, to date, none beyond 3 years. All patients relapsed with IGCCCG good prognosis disease, but one patient refused treatment until he developed liver metastases and received four cycles of chemotherapy for intermediate-risk disease. The majority (68%) of patients who relapsed on surveillance received chemotherapy, and all were cured. Of the 15 patients treated with radiotherapy at relapse, 3 patients had a second relapse but were successfully salvaged with chemotherapy. The five patients recurring after adjuvant treatment relapsed with either retroperitoneal lymph nodes >5 cm (one
original article
Annals of Oncology
Table 2. Characteristics and treatment outcomes of clinical stage II and III patients Stage II (n = 87)
Stage III (n = 17)
Median age IGCCCG stage Good IIA IIB IIC Not available Intermediate Initial treatment Chemotherapy RT CT + RT CT + surgery Surgery alone Response to treatment CR/PR <1 cm PR Not evaluable Treatment of residual Surgery RT Observation 5-year relapse rate Post-RT
41 [range 19–68]
45 [range 24–70]
87 10 33 34 10 0
(100%) (11%) (38%) (39%) (11%)
14 (82%)
65 19 1 1 1
(75%) (22%) (1%) (1%) (1%)
Postchemotherapy Time to relapse
Relapse treatment Chemotherapy Current status Alive without disease DOD (all treatment related) Death other cause Death unknown Median follow-up
3 (18%) 17 (100%)
Figure 3. Stage II treatment by 2-year periods (percentage of all patients seen in the 2-year period).
38 (44%) 38 (44%) 11 (12%)
1 (6%) 13 (76%) 3 (18%)
1 (1%) 2 (2%) 84 (97%) 5 (6%) 3 (supraclavicular LN · 2, mediastinal · 1) 2 At 2, 8, 10, 21, 30 months after treatment
0 0 17 (100%) 0 0
5 (100%) 81 (94%) 3 (2%) 2 (2%) 1 (2%) 46 months [range 2–110]
0 n/a
n/a 17 (100%) 0 0 0 40 months [range 4–99]
CT, computed tomography; DOD, dead of disease; IGCCCG, International Germ Cell Cancer Collaborative Group; PR, partial response; RT, radiation; n/a, not applicable.
investigators or at a single academic institution with selected patients. These results were achieved with progressive broad application of emerging and simple principles in management of germ cell tumors; progressive system-wide adoption of a standard of active surveillance of all CSI patients, relying on the effectiveness of combination chemotherapy, centralized coordination of care and specialized technologies, elimination of dual therapies and early institution of definitive therapy when required. With a cause-specific survival rate of 100%, the question has become not ‘how can the disease be cured?’ but rather ‘how can
812 | Kollmannsberger et al.
we retain this excellent cure rate at the least risk of short- and long-term consequences?’ Evolution of care to our current algorithm has almost completely eliminated RT largely due to concerns regarding overtreatment and associated long-term side-effects as well as almost all adjuvant chemotherapy, which results in early definitive treatment of only those patients demonstrating they require treatment. Only a very small proportion of patients favored adjuvant treatment. As expected, adjuvant therapy prevented most of the anticipated relapses, but not all. Followup on the small number of carboplatin-treated patients in particular is too short to ascertain effectiveness and long-term side-effects and this study should not be interpreted as attempting to validate any relative benefit of carboplatin compared with RT therapy. The primary issue which remains is that adjuvant therapy does not improve cure rate and, in absence of reliable prognostic markers, subjects 85% of patients with CSI seminoma to unnecessary treatment and toxicity. Risk-adapted approaches are impossible due to the lack of an independently validated prognostic classification [10, 11]. Currently, within our consortium 80% of patients presenting with CSI seminoma receive active surveillance. There was a statistically significant increase in the use of surveillance from a level of 10% in British Columbia in the early 1990s [12]. Of our 313 CSI patients managed with active surveillance, we have seen the expected relapse rate of 15% with no deaths related to treatment or disease. Our modern results of surveillance for CSI patients are consistent with the experience of other series from Europe and Canada [6, 13] and support their recent consensus statements favoring nonrisk-adapted active surveillance for all CSI seminoma [1, 10, 14]. The majority of relapsed CSI patients (75%) were treated with combination chemotherapy even for low-bulk disease. Therapy, if required, was well tolerated and there were no serious complications of treatment. Results were definitive and predictable and no relapsed CSI patient has recurred after IGCCCG guided chemotherapy. Our approach and the European and Canadian consensus guidelines are somewhat in contrast to the patterns of care for such patients in other geographies in the United States. Many
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N = 104
original article
Annals of Oncology
Table 3. Outcome of all patients treated for seminoma from 1999 to 2008 Stage
Number of patients
5-Year relapse rate (%)
Second relapse, n
5-Year diseasespecific survival (%)
5-Year overall survival (%)
Dead of disease/ treatment, n (%)
Death other cause, n (%)
CSI surv CSI RT CSI Carb CSII RT CSII CT CSII other CSIII CT
313 159 73 19 65 3 17
19.3 2 2 8.3 4.5 0 0
3a (1%) 0 0 0 0 0 0
100 100 100 100 100 100 100
99 99.3 100 92.3 90.7 100 100
0 0 0 0 3 (5%) 0 0
2 1 0 1 2 0 0
(1) (1) (3) (3)
After RT for first relapse. Carb, single-agent carboplatin; CT, primary combination chemotherapy; other, other treatment modalities or combination of treatment modalities; RT, radiation; Surv, surveillance.
centers still recommend primary prophylactic RT therapy for all CSI patients. The current National Comprehensive Cancer Network guidelines and many USA oncology texts still list RT therapy as a competitive or primary option for such patients without prejudice. Concerns regarding a global surveillance policy for CSI seminoma include the issue of compliance with a demanding follow-up schedule, health effects and cost of frequent CT scans and risk of late relapse at time points beyond a confined observation period (usually beyond 5 years). In many regards, our and other reports address these issues. In this and almost all series of surveillance, cause-specific survival is 100% and patients relapsing at any time point almost always relapse with a favorable pattern of disease amenable to focal RT or cisplatinbased chemotherapy. Thus, compliance and patient education across large and diverse populations appears to be sufficient to preclude frequent presentations with large volume, difficult to cure seminoma. Second, while clearly a potential problem, late recurrence of seminoma is still very rare [13]. When it does occur, patients are very consistently cured, particularly if they are treatment naive. It also should be emphasized that rare late recurrences occur in patients on surveillance as well as those who have received active adjuvant interventions and early treatment does not guarantee that early or late recurrences will not occur or that continued compliance is not important. The issue of cost and potential toxicity of frequent CT scans is real [15]. Current and future investigations have to refine the suggested schedule of follow-up and match the schedule more precisely with the periods of highest risk. Ongoing approaches include reduction in CT schedule, utilizing low-RT CT-scanning techniques and interspersing magnetic resonance imaging or ultrasound with CT in follow-up. In addition, the identification of reliable molecular or genetic prognostic markers may lead to a reduced schedule of observation for very low-risk patients or adjuvant treatments for patients at very high risk of recurrence. Our results also demonstrate that patients with metastatic seminoma are rare, are mostly diagnosed with early metastatic disease and have an excellent outcome with chemotherapy. The relapse rate after primary combination chemotherapy for regional or disseminated seminoma is exceedingly small [2 of 129 (2%) in our series] and very few patients received
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additional RT therapy, surgery or subsequent chemotherapy. Three cycles of BEP have increasingly replaced RT therapy for CSII disease due to concerns regarding long-term complications, in particular secondary malignancies and cardiac complications [16–20]. Of note, two unusual deaths occurred in our patient population, both in patients with significant previously undiagnosed predisposing comorbidities. Long-term complications after cisplatin-based combination are well described in the literature, but most commonly occur with more extensive regimens and those patients who have received dual or repeat therapy [21]. Nearly all patients receiving chemotherapy in our series received either only three courses of BEP or four courses of EP and thus avoiding large cumulative doses of cisplatin, etoposide or bleomycin more frequently associated with long-term complications. Our current treatment algorithm that utilizes surveillance for all CSI patients and chemotherapy only for disseminated disease has almost completely eliminated patients receiving dual therapies. We have irrevocably entered an era of minimizing therapy for testicular seminoma, the most common subtype of testicular cancer. Early-stage patients are reliably cured without adjuvant therapies. Given the low overall risk of relapse with CSI seminoma, the lack of prospectively validated markers to identify a high-risk population [6, 10, 11] and the potential for late toxicity with radiotherapy and carboplatin, active surveillance with treatment at relapse appropriate to the clinical setting is the emerging standard of care for CSI seminoma. With adherence to existing and evolving guidelines and centralized coordination of care, such an approach can be delivered across the spectrum of medical care delivery systems and be carried out reliably at a variety of community settings. IGCCCG stage-adapted BEP chemotherapy is now widely used and largely has replaced RT therapy as the treatment of choice for regional or disseminated seminoma minimizing the number of patients requiring dual therapy.
acknowledgements These data were in part presented at the 2010 ASCO Genitourinary Cancers Symposium, San Francisco, 5–7th March 2010 and the ASCO Annual Meeting, Chicago, 4–8th June 2010.
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a
original article disclosure The authors declare no conflict of interest.
references
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10. Chung P, Mayhew LA, Warde P et al. Management of stage I seminomatous testicular cancer: a systematic review. Clin Oncol (R Coll Radiol) 2010; 22: 6–16. 11. Chung PW, Daugaard G, Tyldesley S et al. Prognostic factors for relapse in stage I seminoma managed with surveillance: a validation study. J Clin Oncol 2010; 28: 15s (Suppl; Abstr 4535). 12. Tyldesley S, Voduc D, McKenzie M et al. Surveillance of stage I testicular seminoma: British Columbia Cancer Agency Experience 1992 to 2002. Urology 2006; 67: 594–598. 13. Cummins S, Yau T, Huddart R et al. Surveillance in stage I seminoma patients: a long-term assessment. Eur Urol 2009 [Epub ahead of print]. 14. Wood L, Kollmannsberger C, Jewett M et al. Canadian consensus guidelines for the management of testicular germ cell cancer. CUAJ 2010; 4: e19–e38. 15. Tarin TV, Sonn G, Shinghal R. Estimating the risk of cancer associated with imaging related radiation during surveillance for stage I testicular cancer using computerized tomography. J Urol 2009; 181: 627–632. 16. Travis LB, Curtis RE, Storm H et al. Risk of second malignant neoplasms among long-term survivors of testicular cancer. J Natl Cancer Inst 1997; 89: 1429–1439. 17. Meinardi MT, Gietema JA, van der Graaf WT et al. Cardiovascular morbidity in long-term survivors of metastatic testicular cancer. J Clin Oncol 2000; 18: 1725–1732. 18. van den Belt-Dusebout AW, Nuver J, de Wit R et al. Long-term risk of cardiovascular disease in 5-year survivors of testicular cancer. J Clin Oncol 2006; 24: 467–475. 19. Warde P, Gospodarowicz M, Panzarella T et al. Management of stage II seminoma. J Clin Oncol 1998; 16: 290–294. 20. Garcia-del-Muro X, Maroto P, Guma J et al. Chemotherapy as an alternative to radiotherapy in the treatment of stage IIA and IIB testicular seminoma: a Spanish Germ Cell Cancer Group Study. J Clin Oncol 2008; 26: 5416–5421. 21. Fossa SD, Oldenburg J, Dahl AA. Short- and long-term morbidity after treatment for testicular cancer. BJU Int 2009; 104: 1418–1422.
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1. Krege S, Beyer J, Souchon R et al. European consensus conference on diagnosis and treatment of germ cell cancer: a report of the second meeting of the European Germ Cell Cancer Consensus group (EGCCCG): part I. Eur Urol 2008; 53: 478–496. 2. Duran I, Sturgeon JF, Jewett MA et al. Initial versus recent outcomes with a nonrisk adapted surveillance policy in stage I non-seminomatous germ cell tumors (NSGCT). J Clin Oncol 2007; 25(18S) (Abstr 5021). 3. Kollmannsberger C, Moore C, Chi KN et al. Non-risk-adapted surveillance for patients with stage I nonseminomatous testicular germ-cell tumors: diminishing treatment-related morbidity while maintaining efficacy. Ann Oncol 2009; 21: 1296–1301. 4. Krege S, Beyer J, Souchon R et al. European consensus conference on diagnosis and treatment of germ cell cancer: a report of the second meeting of the European Germ Cell Cancer Consensus Group (EGCCCG): part II. Eur Urol 2008; 53: 497–513. 5. Powles TB, Bhardwa J, Shamash J et al. The changing presentation of germ cell tumours of the testis between 1983 and 2002. BJU Int 2005; 95: 1197–1200. 6. Warde P, Gospodarowicz M. Evolving concepts in stage I seminoma. BJU Int 2009; 104: 1357–1361. 7. Mead G. International Germ Cell Consensus Classification: a prognostic factorbased staging system for metastatic germ cell cancers. International Germ Cell Cancer Collaborative Group. J Clin Oncol 1997; 15: 594–603. 8. Oliver RT, Mason MD, Mead GM et al. Radiotherapy versus single-dose carboplatin in adjuvant treatment of stage I seminoma: a randomised trial. Lancet 2005; 366: 293–300. 9. Aparicio J, Germa JR, Garcia del Muro X et al. Risk-adapted management for patients with clinical stage I seminoma: the Second Spanish Germ Cell Cancer Cooperative Group study. J Clin Oncol 2005; 23: 8717–8723.
Annals of Oncology
Annals of Oncology 22: 808–814, 2011 doi:10.1093/annonc/mdq466 Published online 6 October 2010
Evolution in management of testicular seminoma: population-based outcomes with selective utilization of active therapies 1
Division of Medical Oncology, Department of Medicine; 2Division of Radiation Oncology, Department of Surgery, British Columbia Cancer Agency/University of British Columbia, Vancouver Cancer Centre, Vancouver, Canada; 3Earle A Chiles Research Institute, Providence Cancer Center, Portland; 4Institute of Urology, USC/Norris Comprehensive Cancer Center, Los Angeles, USA; 5Department of Urological Sciences, UBC, The Prostate Centre at Vancouver General Hospital, Vancouver, Canada; 6Division of Hematology and Medical Oncology, Department of Medicine, Oregon Health & Science University Knight, Cancer Institute, Portland, USA
Received 30 May 2010; revised 16 July 2010; accepted 22 July 2010
original article
Background: In this article, we report the evolution of treatment with increased use of active surveillance for stage I disease as well as risk-adapted chemotherapy for disseminated disease and associated outcomes of testicular seminoma in a contemporary population-based cohort. Methods: All patients with histologically confirmed seminoma referred from 1999 to 2008 to the British Columbia Cancer Agency or Providence Cancer Center were retrospectively reviewed. Both institutions manage 90% of testicular cancers in their respective area. Results: A total of 649 patients were included. Clinical stage (CS) distribution: CSI/II/III n = 545/87/17. For CSI, there was a progressive and marked decrease in the utilization of prophylactic radiation (RT), and corresponding increase in the use of active surveillance. No deaths related to seminoma were reported in CSI patients. CSII or CSIII patients received RT or International Germ Cell Cancer Collaborative Group (IGCCCG) risk-appropriate chemotherapy with 101 of 104 patients being in long-term remission and 3 patients dying from treatment complications. For the entire seminoma population, <1% of patients died of seminoma or treatment after a median follow-up of 47 months (range 2–130 months). Conclusions: Progressive application of policies of active surveillance and earlier initiation of IGCCCG risk-adapted chemotherapy result in nearly universal control for all patients presenting with seminoma while reducing the burden of treatment. Key words: active surveillance, chemotherapy, radiation, seminoma
introduction Management of testicular germ cell tumors is undergoing a quiet evolution. The older paradigms of adjuvant therapies for patients with local disease, regional management for regional disease and inconsistent application of systemic therapy are being rapidly replaced. Much of this change has been spurred by the increased appreciation of short- and longterm effects of all treatment modalities and increased confidence in the cisplatin-based chemotherapy safety net. As well, ‘personalized’ therapy whereby patients receive defined amounts of treatment of their individual clinical situation has become an appropriate clinical objective. The cornerstones of modern management for testicular cancer are well developed in *Correspondence to: Prof. C. R. Nichols, Earle A Chiles Research Institute, Providence Cancer Center, 4805 NE Glisan St, Ste 2N 35 Portland, OR 97213, USA. Tel: +001-503215-6259; Fax: +001-503-215-6841; E-mail: [email protected]
various guidelines but are just beginning to fully penetrate care pathways in the United States and elsewhere. These cornerstones include a strong move to minimize adjuvant treatments in clinical stage (CS) I disease, minimize regional therapies such as surgery or radiation (RT) therapy as primary management of CSII disease by early utilization of systemic chemotherapy, stringent application of risk-adapted cisplatin, etoposide and bleomycin (BEP) as the systemic therapy and, importantly, centralized coordination of care and specialized technologies sometimes required in patients such as postchemotherapy retroperitoneal lymphadenectomy, radiotherapy or salvage chemotherapy. In testicular nonseminoma, these modern principles have been validated and the algorithm of care generally embraced with excellent outcomes and cure rates in excess of 95% for CSII and 80%–85% for advanced metastatic nonseminoma patients [1–4]. With central coordination of care and
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C. Kollmannsberger1, S. Tyldesley2, C. Moore3, K. N. Chi1, N. Murray1, S. Daneshmand4, P. Black5, G. Duncan2, B. Hayes-Lattin6 & C. Nichols3*
original article
Annals of Oncology
materials and methods All patients with histologically confirmed pure seminoma referred from 1999 to 2008 to the British Columbia Cancer Agency (BCCA; British Columbia, Canada) as well as through the Oregon Testis Cancer Program (Portland, Oregon) were retrospectively reviewed. The study was approved by the respective ethics boards of the participating centers. The BCCA with its four cancer centers and 18 to 20 genitourinary medical and RT oncologists is involved in the management of 90% of all testicular cancer cases in British Columbia. Over 80% of Oregon State’s testicular cancer patients are seen and managed by a single provider (Providence Health Care/CRN). Over the past decade, surveillance has been increasingly utilized as the preferred treatment option for all patients with CSI seminoma irrespective of risk status. As well, primary International Germ Cell Cancer Collaborative Group (IGCCCG) classification risk-stratified chemotherapy has been progressively utilized for regional disease and disseminated disease [7]. Initial staging after orchiectomy included computed tomographic (CT) scans of the abdomen, CT scan or X-ray of the chest and tumor markers a-fetoprotein, human chorionic gonadotropin and lactate dehydrogenase. Normal chest and abdominopelvic imaging were required as the criteria of CSI. Metastatic disease was classified according to the IGCCCG as well as the tumor–node–metastasis/International Union Against Cancer classification. Patients with CSI disease were informed about all their treatment options including adjuvant RT, surveillance and, as of 2005, adjuvant carboplatin [8, 9]. Adjuvant chemotherapy consisted of one to two cycles of singleagent carboplatin at a dose of area under the curve 7 [8, 9]. Adjuvant RT consisted of 25 Gy in 15 fractions over 3 weeks with anterior to posterior parallel pair technique using megavoltage photons. Fields were usually restricted to the paraaortic chain (i.e. T10/T11 interspace to the L5/S1
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interspace). Paraaortic and ipsilateral pelvic treatment was used only on rare occasion [1]. Patients with metastatic disease received a treatment recommendation for either RT (stage IIA/B only) or cisplatin-based chemotherapy based on the IGCCCG classification as their primary treatment modality. Good prognosis disease patients received three cycles of BEP or four cycles of etoposide/cisplatin (EP). Patients with intermediate prognosis received primarily four cycles of BEP. CSII seminoma patients who received RT were usually treated with 35 Gy in 20–25 fractions with standard paraaortic and ipsilateral pelvic techniques [4]. Twenty-five gray was delivered to the paraaortic and ipsilateral pelvic lymph nodes in 15–20 fractions over 3–4 weeks with anterior to posterior parallel pair technique using megavoltage photons. Subsequently, a boost of 10 Gy in five fractions was given to the nodal mass with a margin using an anterior to posterior parallel pair technique. Patient data including demographics, pathology, stage, management, response data and follow-up were abstracted from the charts. Follow-up was done according to institutional policy including chest Xrays, CT scans of abdomen/pelvis and tumor markers. Management of CSI seminoma generally included two to six CT scans over the first 3 years for patients receiving carboplatin or surveillance with no or very few CT scans for patients receiving primary RT. Utilization of CT scans and positron emission tomography scans for patients treated definitively with chemotherapy was sparse and primarily reserved for patients with significant residual disease. If patients had been discharged from the center, current status was obtained through contact with the primary care physician or local oncologist. Relapse-free as well as disease-specific survival intervals were measured from the date of orchiectomy to date of relapse and date of death from seminoma or last contact, respectively. Median follow-up was calculated from the date of orchiectomy to date of death or last follow-up. Comparisons between treatment groups were made using chi-square test for categorical variables and Student’s t-test for continuous variables. A P value of £0.05 was considered significant. The relationship between treatment-year and management was assessed by linear regression of treatment-year versus proportion of cases treated with a particular treatment. All statistical analysis was carried out using SPSS Statistical Software. Relapse-free survival and overall survival rates were calculated using the Kaplan–Meier method and compared using log-rank test.
results From 1999 to 2008, 649 patients with seminomas were treated at our two institutions. All patients were included in this analysis and represent an unselected population. The vast majority of patients presented with CSI disease [n = 545 (84%)]. Metastatic disease at initial presentation was diagnosed in 104 (16%) patients, with 87 (13%) having CSII and 17 (3%) CSIII disease. Overall survival was excellent. After a median follow-up of 44 months (range 2–130) for all patients, 640 patients (99%) are alive and no patient has died of seminoma.
stage I Three hundred and thirteen patients underwent active surveillance, 159 adjuvant RT and 73 patients adjuvant carboplatin therapy (Table 1). For completeness, Table 1 also shows the distribution of and differences in previously proposed prognostic factors such as tumor size and rete testis
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specialized services, these simplified management algorithms can be applied successfully across large populations and vast geographies. Testicular seminoma is marked by less aggressive biological behavior and outstanding chemotherapy and RT sensitivity. Approximately 85% of testicular seminoma patients present with CSI disease and only 15% of these patients relapse after orchiectomy [5, 6]. Cure rates for seminoma have approached 100% for CSI disease for several decades, exceeded 90% for good-risk regional disease and 75%–80% for those rare patients with disseminated disease [4, 6]. The principles of modern management of seminoma are nearly identical to those of nonseminoma. The majority of CSI patients will not require any therapy after orchiectomy, making any adjuvant treatment a substantially less attractive option. Although regional therapeutic RT is curative for 80%–90% of low and modest volume CSII patients, it is associated with substantial late effects and does not reliably cure all of these patients. However, metastatic disease is exquisitely sensitive to chemotherapy, almost always is of favorable prognosis amenable to three cycles of BEP and almost always chemotherapy prevents a second relapse of the disease and the necessity of additional therapy. In this article, we describe clinical outcomes with progressive incorporation of these cornerstones of management over the last decade in a centrally managed, large population-based experience with testicular seminoma.
original article
Annals of Oncology
Table 1. Characteristics and treatment outcomes of clinical stage I patients N = 545
Active surveillance (n = 313)
Median age Primary tumor Rete invasion Yes No Unknown Tumor size £4 cm >4 cm Unknown LVI Yes No Unknown Relapses
37 [range 18–83]
39 [range 19–76]
36 [range 19–62]
67 (21%) 181 (58%) 65 (21%)
41 (26%) 55 (35%) 63 (39%)
29 (40%) 27 (37%) 17 (23%)
209 (67%) 83 (26%) 21 (7%)
69 (43%) 83 (53%) 7 (4%)
29 (40%) 44 (60%) 0%
Adjuvant carboplatin (n = 73)
P value 0.08 <0.0001
<0.0001
<0.0001 20 230 63 47
(6%) (74%) (20%) (19.3%)
14 months [3–36 range]
15 (10%) 118 (74%) 26 (16%) 4 (2%) (pelvic LN · 2, supracl. LN ·1,unknown · 1) At 9, 14, 15, 25 months
17 54 2 1
(23%) (74%) (3%) (2%)
At 20 months
47 (100%)
4 (100%)
1 (100%)
32 (68%) 15 (32%) 0
3 (75%) 0 1 (25%)
1 (100%) 0 0
24 (51%) 6 (13%) 17 (36%) 0
4 (100%) 0 0 0
0 1 (100%) 0 0
0 2 (1.3%)
0 0
3 (all after RT)b 5 (1.6%)
311 (99%) 0 2 (1%)
158 (99%) 0 1 (1%)
266 (85%) 15 (5%)
0% 159 (100%)
0% 35 (11%) 34 months [range 2–136]
0% 4 (3%) 65 months [range 3–120]
<0.0001
100% 0 0 0% 0% 73 (100%) 1 (1%) 33 months [range 4–106]
a
One patient was diagnosed with good-risk disease but delayed treatment until progression to intermediate-risk disease. There were two additional patients with synchronous bilateral primaries and four patients who were included in the study for a second primary after successful therapy for a previous primary. c (1· supraclavicular lymph node, 1· abdominal relapse but outside of the RT field and 1· location unknown). CT, computed tomography; DOD, dead of disease; LN, lymph nodes; RPLND, retroperitoneal lymph node dissection; RT, radiation; supracl., supraclavicular. b
invasion in the respective management groups, although these factors could not be confirmed in an independent validation analysis and thus should not be used in clinical practice [10, 11]. The use of adjuvant RT has sharply declined over time, while active surveillance has become the preferred treatment
810 | Kollmannsberger et al.
option over the last years (P = 0.00002) (Figure 1). Adjuvant carboplatin has replaced RT as treatment of those few patients deciding on active treatments. The 5-year relapse-free survival rates were 80.7%, 98% and 98% of patients receiving active surveillance, adjuvant RT or
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Median time to relapse Stage at relapse Gooda Relapse treatment Chemotherapy RT CT + RT Response to treatment CR/PR <1 cm PR Unknown Additional treatment (RPLND, RT for residual disease) Second relapse Second primary testicular cancersc Current status Alive without disease DOD Death other cause Total treatment burden No further therapy RT therapy Chemotherapy Carboplatin Cisplatin based Median follow-up
Adjuvant RT (n = 159)
original article
Annals of Oncology
Figure 1. Stage I treatment by 2-year periods (percentage of all patients seen in the 2-year period).
carboplatin patient after 20 months) or good-risk CSIII disease (four adjuvant RT patients at 9, 14, 15 and 25 months). All of these five patients were successfully salvaged (Table 1). Overall, one patient died of a squamous cell carcinoma of the esophagus, which had initially been diagnosed before his seminoma and another patient from a primitive neuroectodermal tumor. One patient committed suicide. Disease-specific survival for all CSI patients is 100%.
regional or disseminated disease Only 104 (16%) of all seminoma patients presented with metastatic disease, with the majority having CSII and/or good prognosis disease (Table 2). Initial treatment of CSII consisted of combination chemotherapy in 75% of patients, while RT was used in 22%. All patients with CSIII seminoma underwent chemotherapy as initial therapy. The use of primary chemotherapy for CSII seminoma rose steadily over time, while the use of RT continuously decreased over the same time period (Figure 3) (P = 0.043). Response to treatment was excellent and only three patients received additional treatment of their residual lesion (Table 2). The 5-year actuarial relapse-free survival was 94% for all CSII seminomas, 91.7% for those treated with RT and 95.5% for those treated with CT. Overall, five CSII patients recurred after first-line therapy, all within 3 years after first-line therapy. Three of those had previously received primary RT. All but one relapsed patients received salvage chemotherapy and are continuously disease free. After a median follow-up of 46 (range 2–110) months, no patient has died of seminoma. Actuarial 5-year overall survival rate was 90.7% for CT and 92.3% for RT (P = 0.67) (Table 3). Three patients died during chemotherapy. One patient suffered a massive stroke after cycle 2 of BEP, in the presence of a previously undiagnosed patent foramen ovale and absence of any other thrombosis. The second patient died of a hyperosmolar syndrome secondary to previously undiagnosed diabetes after cycle 2 of BEP and the third patient due to renal failure during high-dose chemotherapy. There were no bleomycin-related hospitalizations or deaths. Two patients died of lung cancer, one 5 years after RT for a stage IIB seminoma and the other 2 years after four cycles of EP for stage IIB seminoma. Both patients had been heavy smokers for many years. One patient died disease free from unknown reasons 10 months after completion of chemotherapy.
discussion
Figure 2. Stage 1 relapse-free survival according to management modality: carboplatin (Carbo; n = 73), radiation (RT; n = 159), surveillance (n = 313).
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The comprehensive results of our large modern series of unselected patients with testicular seminoma are noteworthy. Among this population that included over 100 patients presenting with more advanced disease, none of our 649 patients died of progressive seminoma and the overall death rate from disease or treatment was 1%. This represents the largest reported modern experience of global results in testicular seminoma with excellent outcomes. What is most notable, in our view, is that these results were not achieved with breakthrough technologies, particularly clever thinking by the
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adjuvant carboplatin, respectively (see Figure 2). Median time to relapse was 14 (3–36) months. Of the 47 total relapses, eight (15%) of these patients relapsed beyond 2 years but, to date, none beyond 3 years. All patients relapsed with IGCCCG good prognosis disease, but one patient refused treatment until he developed liver metastases and received four cycles of chemotherapy for intermediate-risk disease. The majority (68%) of patients who relapsed on surveillance received chemotherapy, and all were cured. Of the 15 patients treated with radiotherapy at relapse, 3 patients had a second relapse but were successfully salvaged with chemotherapy. The five patients recurring after adjuvant treatment relapsed with either retroperitoneal lymph nodes >5 cm (one
original article
Annals of Oncology
Table 2. Characteristics and treatment outcomes of clinical stage II and III patients Stage II (n = 87)
Stage III (n = 17)
Median age IGCCCG stage Good IIA IIB IIC Not available Intermediate Initial treatment Chemotherapy RT CT + RT CT + surgery Surgery alone Response to treatment CR/PR <1 cm PR Not evaluable Treatment of residual Surgery RT Observation 5-year relapse rate Post-RT
41 [range 19–68]
45 [range 24–70]
87 10 33 34 10 0
(100%) (11%) (38%) (39%) (11%)
14 (82%)
65 19 1 1 1
(75%) (22%) (1%) (1%) (1%)
Postchemotherapy Time to relapse
Relapse treatment Chemotherapy Current status Alive without disease DOD (all treatment related) Death other cause Death unknown Median follow-up
3 (18%) 17 (100%)
Figure 3. Stage II treatment by 2-year periods (percentage of all patients seen in the 2-year period).
38 (44%) 38 (44%) 11 (12%)
1 (6%) 13 (76%) 3 (18%)
1 (1%) 2 (2%) 84 (97%) 5 (6%) 3 (supraclavicular LN · 2, mediastinal · 1) 2 At 2, 8, 10, 21, 30 months after treatment
0 0 17 (100%) 0 0
5 (100%) 81 (94%) 3 (2%) 2 (2%) 1 (2%) 46 months [range 2–110]
0 n/a
n/a 17 (100%) 0 0 0 40 months [range 4–99]
CT, computed tomography; DOD, dead of disease; IGCCCG, International Germ Cell Cancer Collaborative Group; PR, partial response; RT, radiation; n/a, not applicable.
investigators or at a single academic institution with selected patients. These results were achieved with progressive broad application of emerging and simple principles in management of germ cell tumors; progressive system-wide adoption of a standard of active surveillance of all CSI patients, relying on the effectiveness of combination chemotherapy, centralized coordination of care and specialized technologies, elimination of dual therapies and early institution of definitive therapy when required. With a cause-specific survival rate of 100%, the question has become not ‘how can the disease be cured?’ but rather ‘how can
812 | Kollmannsberger et al.
we retain this excellent cure rate at the least risk of short- and long-term consequences?’ Evolution of care to our current algorithm has almost completely eliminated RT largely due to concerns regarding overtreatment and associated long-term side-effects as well as almost all adjuvant chemotherapy, which results in early definitive treatment of only those patients demonstrating they require treatment. Only a very small proportion of patients favored adjuvant treatment. As expected, adjuvant therapy prevented most of the anticipated relapses, but not all. Followup on the small number of carboplatin-treated patients in particular is too short to ascertain effectiveness and long-term side-effects and this study should not be interpreted as attempting to validate any relative benefit of carboplatin compared with RT therapy. The primary issue which remains is that adjuvant therapy does not improve cure rate and, in absence of reliable prognostic markers, subjects 85% of patients with CSI seminoma to unnecessary treatment and toxicity. Risk-adapted approaches are impossible due to the lack of an independently validated prognostic classification [10, 11]. Currently, within our consortium 80% of patients presenting with CSI seminoma receive active surveillance. There was a statistically significant increase in the use of surveillance from a level of 10% in British Columbia in the early 1990s [12]. Of our 313 CSI patients managed with active surveillance, we have seen the expected relapse rate of 15% with no deaths related to treatment or disease. Our modern results of surveillance for CSI patients are consistent with the experience of other series from Europe and Canada [6, 13] and support their recent consensus statements favoring nonrisk-adapted active surveillance for all CSI seminoma [1, 10, 14]. The majority of relapsed CSI patients (75%) were treated with combination chemotherapy even for low-bulk disease. Therapy, if required, was well tolerated and there were no serious complications of treatment. Results were definitive and predictable and no relapsed CSI patient has recurred after IGCCCG guided chemotherapy. Our approach and the European and Canadian consensus guidelines are somewhat in contrast to the patterns of care for such patients in other geographies in the United States. Many
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N = 104
original article
Annals of Oncology
Table 3. Outcome of all patients treated for seminoma from 1999 to 2008 Stage
Number of patients
5-Year relapse rate (%)
Second relapse, n
5-Year diseasespecific survival (%)
5-Year overall survival (%)
Dead of disease/ treatment, n (%)
Death other cause, n (%)
CSI surv CSI RT CSI Carb CSII RT CSII CT CSII other CSIII CT
313 159 73 19 65 3 17
19.3 2 2 8.3 4.5 0 0
3a (1%) 0 0 0 0 0 0
100 100 100 100 100 100 100
99 99.3 100 92.3 90.7 100 100
0 0 0 0 3 (5%) 0 0
2 1 0 1 2 0 0
(1) (1) (3) (3)
After RT for first relapse. Carb, single-agent carboplatin; CT, primary combination chemotherapy; other, other treatment modalities or combination of treatment modalities; RT, radiation; Surv, surveillance.
centers still recommend primary prophylactic RT therapy for all CSI patients. The current National Comprehensive Cancer Network guidelines and many USA oncology texts still list RT therapy as a competitive or primary option for such patients without prejudice. Concerns regarding a global surveillance policy for CSI seminoma include the issue of compliance with a demanding follow-up schedule, health effects and cost of frequent CT scans and risk of late relapse at time points beyond a confined observation period (usually beyond 5 years). In many regards, our and other reports address these issues. In this and almost all series of surveillance, cause-specific survival is 100% and patients relapsing at any time point almost always relapse with a favorable pattern of disease amenable to focal RT or cisplatinbased chemotherapy. Thus, compliance and patient education across large and diverse populations appears to be sufficient to preclude frequent presentations with large volume, difficult to cure seminoma. Second, while clearly a potential problem, late recurrence of seminoma is still very rare [13]. When it does occur, patients are very consistently cured, particularly if they are treatment naive. It also should be emphasized that rare late recurrences occur in patients on surveillance as well as those who have received active adjuvant interventions and early treatment does not guarantee that early or late recurrences will not occur or that continued compliance is not important. The issue of cost and potential toxicity of frequent CT scans is real [15]. Current and future investigations have to refine the suggested schedule of follow-up and match the schedule more precisely with the periods of highest risk. Ongoing approaches include reduction in CT schedule, utilizing low-RT CT-scanning techniques and interspersing magnetic resonance imaging or ultrasound with CT in follow-up. In addition, the identification of reliable molecular or genetic prognostic markers may lead to a reduced schedule of observation for very low-risk patients or adjuvant treatments for patients at very high risk of recurrence. Our results also demonstrate that patients with metastatic seminoma are rare, are mostly diagnosed with early metastatic disease and have an excellent outcome with chemotherapy. The relapse rate after primary combination chemotherapy for regional or disseminated seminoma is exceedingly small [2 of 129 (2%) in our series] and very few patients received
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additional RT therapy, surgery or subsequent chemotherapy. Three cycles of BEP have increasingly replaced RT therapy for CSII disease due to concerns regarding long-term complications, in particular secondary malignancies and cardiac complications [16–20]. Of note, two unusual deaths occurred in our patient population, both in patients with significant previously undiagnosed predisposing comorbidities. Long-term complications after cisplatin-based combination are well described in the literature, but most commonly occur with more extensive regimens and those patients who have received dual or repeat therapy [21]. Nearly all patients receiving chemotherapy in our series received either only three courses of BEP or four courses of EP and thus avoiding large cumulative doses of cisplatin, etoposide or bleomycin more frequently associated with long-term complications. Our current treatment algorithm that utilizes surveillance for all CSI patients and chemotherapy only for disseminated disease has almost completely eliminated patients receiving dual therapies. We have irrevocably entered an era of minimizing therapy for testicular seminoma, the most common subtype of testicular cancer. Early-stage patients are reliably cured without adjuvant therapies. Given the low overall risk of relapse with CSI seminoma, the lack of prospectively validated markers to identify a high-risk population [6, 10, 11] and the potential for late toxicity with radiotherapy and carboplatin, active surveillance with treatment at relapse appropriate to the clinical setting is the emerging standard of care for CSI seminoma. With adherence to existing and evolving guidelines and centralized coordination of care, such an approach can be delivered across the spectrum of medical care delivery systems and be carried out reliably at a variety of community settings. IGCCCG stage-adapted BEP chemotherapy is now widely used and largely has replaced RT therapy as the treatment of choice for regional or disseminated seminoma minimizing the number of patients requiring dual therapy.
acknowledgements These data were in part presented at the 2010 ASCO Genitourinary Cancers Symposium, San Francisco, 5–7th March 2010 and the ASCO Annual Meeting, Chicago, 4–8th June 2010.
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a
original article disclosure The authors declare no conflict of interest.
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Annals of Oncology