- Email: [email protected]
Long-Term Followup Results of 1 Cycle of Adjuvant Bleomycin, Etoposide and Cisplatin Chemotherapy for High Risk Clinical Stage I Nonseminomatous Germ Cell Tumors of the Testis
Long-Term Followup Results of 1 Cycle of Adjuvant Bleomycin, Etoposide and Cisplatin Chemotherapy for High Risk Clinical Stage I Nonseminomatous Germ Cell Tumors of the Testis Dirk H. Westermann, Hubert Schefer, George N. Thalmann, Evanthia Karamitopoulou-Diamantis, Martin F. Fey and Urs E. Studer* From the Departments of Urology (DHW, GNT, UES), Medical Oncology (HS, MFF) and Pathology (EKD), University of Bern, Bern, Switzerland
Purpose: We evaluated the long-term outcome after 1 cycle of adjuvant modified bleomycin, etoposide and cisplatin chemotherapy in patients who underwent orchiectomy for high risk clinical stage I nonseminomatous germ cell tumor of the testis. Materials and Methods: Between 1995 and 1999 a consecutive series of 44 patients underwent orchiectomy for clinical stage I nonseminomatous germ cell tumor of the testis, followed by a single postoperative cycle of adjuvant modified bleomycin, etoposide and cisplatin for vascular or lymphatic tumor invasion, and/or a predominance (50% or greater) of embryonal carcinoma. Results: Four of the 44 patients were excluded from analysis. Of the patients 35 had no evidence of disease at a median followup of 99 months (range 60 to 134). One patient with progression after 13 months showed complete remission after 3 cycles of salvage bleomycin, etoposide and cisplatin chemotherapy but he died of pneumonia 4 weeks after the third course. Two patients underwent orchiectomy for contralateral testis cancer at 18 and 42 months, respectively, followed by an additional 3 cycles of adjuvant chemotherapy. They remained relapse-free for 4 and 92 months, respectively. The former patient was lost to followup after 4 months. Two other patients were disease-free at 10 and 31 months, respectively, and were lost to followup thereafter. Late side effects were tinnitus in 3 patients and involuntary childlessness in 3, of whom 2 had cryptorchidism of the contralateral testis. Nine patients fathered children. Conclusions: One cycle of bleomycin, etoposide and cisplatin effectively decreases the risk of relapse in patients with high risk stage I nonseminomatous germ cell tumor of the testis. It has minimal side effects and can be a valuable alternative to retroperitoneal lymph node dissection. Key Words: testis; neoplasms, germ cell and embryonal; testicular neoplasms; chemotherapy
In several studies patients considered to be at risk for disseminated disease underwent to 2 cycles of adjuvant combination chemotherapy with excellent long-term results.6 –10 Nevertheless, chemotherapy related toxicity is still a cause for concern and it may adversely affect patient well-being. To further decrease exposure to chemotherapy with its risk of toxicity while maintaining its adjuvant protective effect, we used a single cycle of adjuvant BEP in patients with high risk stage I NSGCT. We report long-term relapse rates, toxicity and fertility.
urrently 3 management modalities are possible in patients who have undergone orchiectomy for clinical stage I NSGCT, including surveillance, RPLND and adjuvant chemotherapy with BEP in those at high risk. Surveillance protocols show relapse rates of about 30% due to undetected micrometastases1,2 and patients must be treated with several cycles of salvage chemotherapy after relapse. Early identification of patients at risk for relapse would be desirable but the inaccuracy of available imaging techniques precludes the definitive exclusion of micrometastases in clinical stage I NSGCT. However, histology of the primary tumor allows risk stratification concerning occult metastases based on high risk factors, such as VI and/or the predominance of EC.3–5 RPLND is the most accurate staging procedure for stage I NSGCT. However, 70% to 80% of such patients undergo unnecessary surgery with lymph nodes negative on histology and relapses outside the RPLND field may still occur.
C
PATIENTS AND METHODS Eligibility Between 1995 and 1999, 44 patients with newly diagnosed clinical stage I NSGCT with histologically confirmed EC predominance (greater than 50%) in the primary tumor and/or VI were enrolled with their informed consent in this prospective, phase II clinical study. All patients had no clinical evidence of metastatic disease on normal chest x-ray or CT, and normal CT of the abdomen and pelvis. Preoperative increased tumor markers (alpha fetoprotein, beta-human chorionic gonadotropin and lactate dehydrogenase) were required to be normal after orchiectomy. For histological ex-
Submitted for publication May 16, 2007. * Correspondence: Department of Urology, University Hospital of Bern, CH-3010 Bern, Switzerland (telephone: ⫹41/31/632 36 41; FAX: ⫹41/31/632 21 80; e-mail: [email protected]).
0022-5347/08/1791-0163/0 THE JOURNAL OF UROLOGY® Copyright © 2008 by AMERICAN UROLOGICAL ASSOCIATION
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aminations multiple tissue sections were taken less than 1 cm apart, embedded in paraffin and stained with hematoxylin and eosin. Tumors were classified according to the WHO classification. Immunohistochemical staining was used to confirm the presence of VI. A confirmatory review of the slides was done by an experienced uropathologist (EKD). Chemotherapy Chemotherapy was started within 4 weeks after orchiectomy. All patients had creatinine clearance more than 60 ml per minute. All patients received 1 cycle of a modified BEP combination chemotherapy regimen (20 mg/m2 bleomycin, 40 mg/m2 cisplatin and 120 mg/m2 etoposide), which was administered intravenously on days 1 to 3. Bleomycin was given as a continuous intravenous infusion during 72 hours to decrease pulmonary toxicity. Followup Patients were followed at 3-month intervals during years 1 and 2, and at 6-month intervals during years 3 through 5. History, physical examination and serum tumor markers were determined at each visit. Chest x-ray, CT or ultrasound of the abdomen, blood count, creatinine, aspartate aminotransferase and alkaline phosphatase were performed twice yearly until year 5. Thereafter patients were evaluated once per year with physical examination and tumor markers. Examinations such as ultrasound of the remaining testis and retroperitoneum, CT of the abdomen or chest x-ray were only performed upon suspicion of relapse. At last evaluation all patients completed a questionnaire to assess physical and mental well-being, and sexual function/fertility after chemotherapy, as published previously.11 Late adverse events were graded according to National Cancer Institute criteria. Followup time to relapse or death was calculated from the date of orchiectomy. RESULTS Four of the 44 patients were excluded from analysis, including 1 for insisting on 2 courses of BEP and 3 for having less than 50% EC on histopathological reevaluation. The remaining 40 patients with a median age of 32.7 years (range 18.2 to 44.7) had 50% or more EC (median 70%) in the orchiectomy specimen. Nine patients had pure EC (100%), 17 had VI and/or lymphatic invasion, and 14 had VI in combination with EC (table 1).
TABLE 1. Histopathological risk factors in patients undergoing orchiectomy for clinical stage I NSGCT of testis No. pts Median mos followup (range) No. stage: pT1 pT2 pT3 Primary tumor histological components: No. EC No. pure EC No. predominant EC (50 or greater) Median % EC No. VI ⫹/or lymphatic invasion: Present Absent No. VI ⫹ EC
40 96 (10–134) 35 4 1 40 9 39 70 17 23 14
Median followup in the 40 patients meeting high risk criteria was 96 months (range 10 to 134). Of the 40 patients 35 showed no evidence of disease during a median followup of 99 months (range 60 to 134). One of the 40 patients had pulmonary metastases 13 months after orchiectomy. He received 3 BEP cycles and was in complete remission when he died of pneumonia complicated by acute respiratory distress syndrome 4 weeks after course 3. Complete remission was confirmed at autopsy. There were no signs of bone marrow aplasia. Two patients had germ cell tumors of the contralateral testis 18 and 42 months after orchiectomy, respectively. The first patient had clinical stage I predominantly EC with parts of immature teratoma. He was given 3 courses of BEP and showed no signs of disease 4 months after chemotherapy but was then lost to followup. The second patient had EC and mature teratoma. He was placed on surveillance and experienced retroperitoneal relapse after 3 months. He was given 3 cycles of BEP and remained relapse-free at 92 months. Three of the 40 patients, including 1 of the mentioned patients with a contralateral testis tumor, had a short recurrence-free followup of only 10, 22 and 31 months, respectively, and they were lost to followup thereafter. One patient was diagnosed with lymph node negative rectal cancer with VI 5 years after orchiectomy. He underwent surgery plus adjuvant chemotherapy and has remained recurrence-free for 36 months. At last followup all patients stated that they were doing well without mental or physical problems attributable to cytotoxic treatment. No pulmonary adverse effects were observed and most patients were physically active. Serum creatinine, electrolytes, calcium and magnesium were normal. The patient given additional treatment for retroperitoneal recurrence after diagnosis of a contralateral testis tumor was discovered to have grade II peripheral polyneuropathy after 4 cycles of chemotherapy. Three patients complained of intermittent tinnitus after chemotherapy, including 1 with disturbing grade II tinnitus. No patient complained of hearing impairment or other ototoxic side effects and no patient had clinical signs of cardiotoxicity. Of the 40 patients 34 (85%) completed the questionnaire on fertility and sexual function at a median followup of 107 months (range 83 to 142). Before cytotoxic treatment none had erectile dysfunction, decreased libido or ejaculatory disorders. Of the 34 patients 19 (56%) had fathered children and 1 (3%) was involuntarily childless due to oligoasthenoteratozoospermia. The remaining 14 patients were voluntarily childless. After cytotoxic treatment no patient experienced sexual or ejaculatory dysfunction and the 2 who underwent bilateral orchiectomy were on testosterone replacement. Nine patients (26%) fathered children who are well and 3 patients (9%) were involuntarily childless. One of these 3 men is the mentioned patient with preoperative oligoasthenoteratozoospermia and 2 had cryptorchidism of the remaining testicle. The remaining 22 patients did not elect to father children after chemotherapy. One of the 4 excluded patients had clinical stage I seminoma of the contralateral testis 38 months after orchiectomy. He was given radiation therapy and remained relapsefree at 79 months. The other 3 patients remained tumorfree. None of the 4 patients experienced adverse effects except grade I tinnitus in the patient treated with 2 cycles of BEP.
CHEMOTHERAPY FOR NONSEMINOMATOUS GERM CELL TUMORS OF TESTIS DISCUSSION For patients with stage I NSGCT who are at high risk for recurrence adjuvant chemotherapy with 2 courses of BEP is the standard treatment option in Europe.12 Reported longterm relapse rates are between 0% and 6.9%.6 –10 This well tolerated treatment spares most patients additional surgery or further chemotherapy and it renders irregular followup because of poor patient compliance of lesser concern. The current results show that a single cycle of modified BEP chemotherapy effectively decreased the relapse rate to 2.7%, a rate similar to that achieved with 2 cycles of standard BEP, while keeping adverse side effects to a minimum at a median followup of 99 months. One other group applied a single course of standard BEP chemotherapy as an alternative to RPLND plus 2 courses of adjuvant chemotherapy in those with retroperitoneal nodal metastases in patients with clinical stage I NSGCT.13 The results showed that adjuvant chemotherapy had a significantly lower recurrence rate than RPLND. However, followup was rather short and high risk factors were not considered. Another trial with only 1 cycle of adjuvant platinum containing chemotherapy (bleomycin and etoposide with cisplatin or carboplatin) recently showed no malignant tumor recurrence but the cohort was smaller (22 patients) and at lower risk for relapse than ours (table 2).14 The percent of EC and presence of VI in the primary tumor are most predictive of pathological stage II disease despite normal staging CT. The probability of occult disease in clinical stage I NSGCT increases from 4% in patients without embryonal components and no VI to as high as 92% in patients with pure EC and VI.2 In our patients the median proportion of EC and VI was 70% and 43%, respectively, which are percents sufficient to fulfill most published high risk criteria. Surveillance protocols have overall relapse rates of 17% to 38% but 46% to 59% of patients at high risk show metastases,1,15 requiring 3 or 4 courses of chemotherapy with the associated toxicity. Furthermore, patient awareness of the 30% risk of relapse may be a psychological strain. Although strict followup is vital in patients on surveillance, compliance is often low and 30% to 80% of noncompliant patients experience relapse with advanced disease.2 RPLND is considered the primary treatment modality by many investigators. It has excellent long-term results and high cure rates16,17 even in case of relapse. Long-term morbidity can be low but only in the hands of the most experienced surgeons. Postoperative complications develop in 10% to 19% of patients. A major disadvantage is that 70% to 75% of all low stage cancers have negative nodes and are overtreated with RPLND. Nonetheless, the relapse rate following RPLND is about 8% to 10%,16 generally outside the field
TABLE 2. Literature on patients treated with 1 adjuvant chemotherapy cycle for clinical stage I NSGCT Albers et al13
Gilbert et al14
No. pts Relapse risk Chemotherapy regimen
178 Not considered BEP
Median followup No. relapse (%)
47 Mos 2 (1)
22 Moderate Cisplatin/carboplatin, etoposide ⫹ bleomycin 10.2 Yrs 0
165
of RPLND. Therefore, despite RPLND these patients require additional treatment5 and must undergo close long-term followup similar to that of surveillance protocols. RPLND is also not curative in many patients who have positive nodes removed. Of patients with pathological stage II A disease 17% to 35% experience relapse if left untreated after RPLND.16 –18 Unquestionably adjuvant chemotherapy also has shortcomings and its efficacy must be weighed against the possible detrimental side effects. Advocates of primary RPLND claim that the long-term toxicity of cisplatin based chemotherapy justifies surgical treatment. Cisplatin based chemotherapy is typically associated with nephrotoxicity, ototoxicity and neurotoxicity. In the current trial we noted no serious medium term nephrotoxic or ototoxic side effects because cumulative doses remained low and our patients were well hydrated during chemotherapy. In patients given more than 400 mg/m2 cisplatin for metastatic disease a 7-fold increase in cardiovascular events was reported. However, this dose is much higher than that used in the current trial and it was also not observed with the administration of 2 to 4 courses of BEP. As for ototoxicity, 9% of our patients (3 of 34) complained of tinnitus. This is far below the published ototoxicity rates of 20% to 40% in trials using higher cisplatin doses. Most studies of 2 BEP cycles for high risk stage I NSGCT show that chemotherapy produces no significant long-term ototoxicity.6 – 8,10 Another important factor is the occurrence of life threatening cancers secondary to chemotherapy in patients with germ cell cancer. The risk of secondary leukemia, usually manifesting within 2 to 3 years, is 0.5% to 1% after high dose regimens with cumulative etoposide doses of 2 to 5 gm/m2. In our protocol with only 1 course of modified BEP the total etoposide dose was 0.36 gm/m2, far below the threshold of 2 gm/m2. One of our patients showed colorectal cancer 5 years after chemotherapy and he is now disease-free. It remains unclear whether the cancer was due to the BEP regimen. Systemic chemotherapy cannot prevent contralateral testis cancer and patients with NSGCT of the testis are at a 1.5% to 5% risk of relapse. The 2 of 40 patients (5%) who had bilateral testis tumors in our study are within this range. Testicular tumors may also contain chemo-insensitive teratoma components that can spread to the retroperitoneum in 3% of patients with clinical stage I NSGCT.19 Teratoma may grow after chemotherapy but it should not present an immediate threat to the patient since it can be detected during followup. Resection is possible before it compresses neighboring structures and before it undergoes secondary malignant transformation. An often cited argument against adjuvant chemotherapy is the development of particularly aggressive late relapses resistant to salvage chemotherapy. However, such late relapses occur after high dose chemotherapy for bulky metastatic disease. To our knowledge late chemotherapy resistant relapses have not been reported to date in our setting of clinical stage I disease with low dose chemotherapy. Since almost all patients with NSGCT are young at presentation, special attention must be given to fertility after treatment. Only 30% to 55% of patients with stage I NSGCT have a normal pretreatment sperm count,8,11 while 46% on active surveillance father children. The impact of chemotherapy on spermatogenesis is clearly dose dependent but no
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substantial changes in sperm quality are found following 2 cycles of BEP after a recovery time of at least 9 months.6,8,10 CONCLUSIONS One course of modified BEP chemotherapy shows excellent long-term results in patients with clinical stage I NSGCT at high risk for relapse. Our results are consistent with those achieved with current standard treatment options, including 2 courses of standard or modified BEP. Our protocol provides low toxicity and costs, and lessens the chance of overtreatment. Provided that other studies confirm our results, a single cycle of modified BEP chemotherapy could become standard treatment in patients with high risk clinical stage I NSGCT.
8.
9.
10.
11.
Abbreviations and Acronyms BEP CT EC NSGCT
⫽ ⫽ ⫽ ⫽
bleomycin, etoposide and cisplatin computerized tomography embryonal carcinoma nonseminomatous germ cell tumor of testis RPLND ⫽ retroperitoneal lymph node dissection VI ⫽ vascular invasion
12.
13.
REFERENCES 1.
Al-Tourah AJ, Murray N, Coppin C, Kollmannsberger C, Man A and Chi KN: Minimizing treatment without compromising cure with primary surveillance for clinical stage I embryonal predominant nonseminomatous testicular cancer: a population based analysis from British Columbia. J Urol 2005; 174: 2209. 2. Ernst DS, Brasher P, Venner PM, Czaykowski P, Moore MJ and Reyno L: Compliance and outcome of patients with stage 1 non-seminomatous germ cell tumors (NSGCT) managed with surveillance programs in seven Canadian centres. Can J Urol 2005: 12: 2575. 3. Heidenreich A, Sesterhenn IA, Mostofi FK and Moul JW: Prognostic risk factors that identify patients with clinical stage I nonseminomatous germ cell tumors at low risk and high risk for metastasis. Cancer 1998; 83: 1002. 4. Moul JW, McCarthy WF, Fernandez EB and Sesterhenn IA: Percentage of embryonal carcinoma and of vascular invasion predicts pathological stage in clinical stage I nonseminomatous testicular cancer. Cancer Res 1994; 54: 362. 5. Sweeney CJ, Hermans BP, Heilman DK, Foster RS, Donohue JP and Einhorn LH: Results and outcome of retroperitoneal lymph node dissection for clinical stage I embryonal carcinoma—predominant testis cancer. J Clin Oncol 2000; 18: 358. 6. Bohlen D, Borner M, Sonntag RW, Fey MF and Studer UE: Long-term results following adjuvant chemotherapy in patients with clinical stage I testicular nonseminomatous malignant germ cell tumors with high risk factors. J Urol 1999; 161: 1148. 7. Chevreau C, Mazerolles C, Soulie M, Gaspard MH, Mourey L and Bujan L: Long-term efficacy of two cycles of BEP regi-
14.
15.
16.
17.
18.
19.
men in high-risk stage I nonseminomatous testicular germ cell tumors with embryonal carcinoma and/or vascular invasion. Eur Urol 2004; 46: 209. Cullen MH, Stenning SP, Parkinson MC, Fossa SD, Kaye SB and Horwich AH: Short-course adjuvant chemotherapy in high-risk stage I nonseminomatous germ cell tumors of the testis: a Medical Research Council report. J Clin Oncol 1996; 14: 1106. Oliver RT, Ong J, Shamash J, Ravi R, Nagund V and Harper P: Long-term follow-up of Anglian Germ Cell Cancer Group surveillance versus patients with stage 1 nonseminoma treated with adjuvant chemotherapy. Urology 2004; 63: 556. Pont J, Albrecht W, Postner G, Sellner F, Angel K and Holtl W: Adjuvant chemotherapy for high-risk clinical stage I nonseminomatous testicular germ cell cancer: long-term results of a prospective trial. J Clin Oncol 1996; 14: 441. Bohlen D, Burkhard FC, Mills R, Sonntag RW and Studer UE: Fertility and sexual function following orchiectomy and 2 cycles of chemotherapy for stage I high risk nonseminomatous germ cell cancer. J Urol 2001; 165: 441. Schmoll HJ, Souchon R, Krege S, Albers P, Beyer J and Kollmannsberger C: European consensus on diagnosis and treatment of germ cell cancer: a report of the European Germ Cell Cancer Consensus Group (EGCCCG). Ann Oncol 2004; 15: 1377. Albers P, Siener R, Krege S, Schmelz K, Dieckmann KP and Heidenreich A: One course of adjuvant PEB chemotherapy versus retroperitoneal lymph node dissection in patients with stage I non-seminomatous germ-cell tumors (NSGCT): results of the German Prospective Multicenter Trial (Association of Urological Oncology [AUO]/German Testicular Cancer Study Group Trial 011-94). J Clin Oncol, suppl., 2006; 24: 4512. Gilbert DC, Norman AR, Nicholl J, Dearnaley DP, Horwich A and Huddart RA: Treating stage I nonseminomatous germ cell tumours with a single cycle of chemotherapy. BJU Int 2006; 98: 67. Roeleveld TA, Horenblas S, Meinhardt W, van de Vijver M, Kooi M and ten Bokkel Huinink WW: Surveillance can be the standard of care for stage I nonseminomatous testicular tumors and even high risk patients. J Urol 2001; 166: 2166. Hermans BP, Sweeney CJ, Foster RS, Einhorn LE and Donohue JP: Risk of systemic metastases in clinical stage I nonseminoma germ cell testis tumor managed by retroperitoneal lymph node dissection. J Urol 2000; 163: 1721. Stephenson AJ, Bosl GJ, Motzer RJ, Kattan MW, Stasi J and Bajorin DF: Retroperitoneal lymph node dissection for nonseminomatous germ cell testicular cancer: impact of patient selection factors on outcome. J Clin Oncol 2005; 23: 2781. Donohue JP, Thornhill JA, Foster RS, Rowland RG and Bihrle R: Clinical stage B non-seminomatous germ cell testis cancer: the Indiana University experience (1965–1989) using routine primary retroperitoneal lymph node dissection. Eur J Cancer 1995; 31A: 1599. Sheinfeld J, Motzer RJ, Rabbani F, McKiernan J, Bajorin D and Bosl GJ: Incidence and clinical outcome of patients with teratoma in the retroperitoneum following primary retroperitoneal lymph node dissection for clinical stages I and IIA nonseminomatous germ cell tumors. J Urol 2003; 170: 1159.
Purpose: We evaluated the long-term outcome after 1 cycle of adjuvant modified bleomycin, etoposide and cisplatin chemotherapy in patients who underwent orchiectomy for high risk clinical stage I nonseminomatous germ cell tumor of the testis. Materials and Methods: Between 1995 and 1999 a consecutive series of 44 patients underwent orchiectomy for clinical stage I nonseminomatous germ cell tumor of the testis, followed by a single postoperative cycle of adjuvant modified bleomycin, etoposide and cisplatin for vascular or lymphatic tumor invasion, and/or a predominance (50% or greater) of embryonal carcinoma. Results: Four of the 44 patients were excluded from analysis. Of the patients 35 had no evidence of disease at a median followup of 99 months (range 60 to 134). One patient with progression after 13 months showed complete remission after 3 cycles of salvage bleomycin, etoposide and cisplatin chemotherapy but he died of pneumonia 4 weeks after the third course. Two patients underwent orchiectomy for contralateral testis cancer at 18 and 42 months, respectively, followed by an additional 3 cycles of adjuvant chemotherapy. They remained relapse-free for 4 and 92 months, respectively. The former patient was lost to followup after 4 months. Two other patients were disease-free at 10 and 31 months, respectively, and were lost to followup thereafter. Late side effects were tinnitus in 3 patients and involuntary childlessness in 3, of whom 2 had cryptorchidism of the contralateral testis. Nine patients fathered children. Conclusions: One cycle of bleomycin, etoposide and cisplatin effectively decreases the risk of relapse in patients with high risk stage I nonseminomatous germ cell tumor of the testis. It has minimal side effects and can be a valuable alternative to retroperitoneal lymph node dissection. Key Words: testis; neoplasms, germ cell and embryonal; testicular neoplasms; chemotherapy
In several studies patients considered to be at risk for disseminated disease underwent to 2 cycles of adjuvant combination chemotherapy with excellent long-term results.6 –10 Nevertheless, chemotherapy related toxicity is still a cause for concern and it may adversely affect patient well-being. To further decrease exposure to chemotherapy with its risk of toxicity while maintaining its adjuvant protective effect, we used a single cycle of adjuvant BEP in patients with high risk stage I NSGCT. We report long-term relapse rates, toxicity and fertility.
urrently 3 management modalities are possible in patients who have undergone orchiectomy for clinical stage I NSGCT, including surveillance, RPLND and adjuvant chemotherapy with BEP in those at high risk. Surveillance protocols show relapse rates of about 30% due to undetected micrometastases1,2 and patients must be treated with several cycles of salvage chemotherapy after relapse. Early identification of patients at risk for relapse would be desirable but the inaccuracy of available imaging techniques precludes the definitive exclusion of micrometastases in clinical stage I NSGCT. However, histology of the primary tumor allows risk stratification concerning occult metastases based on high risk factors, such as VI and/or the predominance of EC.3–5 RPLND is the most accurate staging procedure for stage I NSGCT. However, 70% to 80% of such patients undergo unnecessary surgery with lymph nodes negative on histology and relapses outside the RPLND field may still occur.
C
PATIENTS AND METHODS Eligibility Between 1995 and 1999, 44 patients with newly diagnosed clinical stage I NSGCT with histologically confirmed EC predominance (greater than 50%) in the primary tumor and/or VI were enrolled with their informed consent in this prospective, phase II clinical study. All patients had no clinical evidence of metastatic disease on normal chest x-ray or CT, and normal CT of the abdomen and pelvis. Preoperative increased tumor markers (alpha fetoprotein, beta-human chorionic gonadotropin and lactate dehydrogenase) were required to be normal after orchiectomy. For histological ex-
Submitted for publication May 16, 2007. * Correspondence: Department of Urology, University Hospital of Bern, CH-3010 Bern, Switzerland (telephone: ⫹41/31/632 36 41; FAX: ⫹41/31/632 21 80; e-mail: [email protected]).
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Vol. 179, 163-166, January 2008 Printed in U.S.A. DOI:10.1016/j.juro.2007.08.172
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aminations multiple tissue sections were taken less than 1 cm apart, embedded in paraffin and stained with hematoxylin and eosin. Tumors were classified according to the WHO classification. Immunohistochemical staining was used to confirm the presence of VI. A confirmatory review of the slides was done by an experienced uropathologist (EKD). Chemotherapy Chemotherapy was started within 4 weeks after orchiectomy. All patients had creatinine clearance more than 60 ml per minute. All patients received 1 cycle of a modified BEP combination chemotherapy regimen (20 mg/m2 bleomycin, 40 mg/m2 cisplatin and 120 mg/m2 etoposide), which was administered intravenously on days 1 to 3. Bleomycin was given as a continuous intravenous infusion during 72 hours to decrease pulmonary toxicity. Followup Patients were followed at 3-month intervals during years 1 and 2, and at 6-month intervals during years 3 through 5. History, physical examination and serum tumor markers were determined at each visit. Chest x-ray, CT or ultrasound of the abdomen, blood count, creatinine, aspartate aminotransferase and alkaline phosphatase were performed twice yearly until year 5. Thereafter patients were evaluated once per year with physical examination and tumor markers. Examinations such as ultrasound of the remaining testis and retroperitoneum, CT of the abdomen or chest x-ray were only performed upon suspicion of relapse. At last evaluation all patients completed a questionnaire to assess physical and mental well-being, and sexual function/fertility after chemotherapy, as published previously.11 Late adverse events were graded according to National Cancer Institute criteria. Followup time to relapse or death was calculated from the date of orchiectomy. RESULTS Four of the 44 patients were excluded from analysis, including 1 for insisting on 2 courses of BEP and 3 for having less than 50% EC on histopathological reevaluation. The remaining 40 patients with a median age of 32.7 years (range 18.2 to 44.7) had 50% or more EC (median 70%) in the orchiectomy specimen. Nine patients had pure EC (100%), 17 had VI and/or lymphatic invasion, and 14 had VI in combination with EC (table 1).
TABLE 1. Histopathological risk factors in patients undergoing orchiectomy for clinical stage I NSGCT of testis No. pts Median mos followup (range) No. stage: pT1 pT2 pT3 Primary tumor histological components: No. EC No. pure EC No. predominant EC (50 or greater) Median % EC No. VI ⫹/or lymphatic invasion: Present Absent No. VI ⫹ EC
40 96 (10–134) 35 4 1 40 9 39 70 17 23 14
Median followup in the 40 patients meeting high risk criteria was 96 months (range 10 to 134). Of the 40 patients 35 showed no evidence of disease during a median followup of 99 months (range 60 to 134). One of the 40 patients had pulmonary metastases 13 months after orchiectomy. He received 3 BEP cycles and was in complete remission when he died of pneumonia complicated by acute respiratory distress syndrome 4 weeks after course 3. Complete remission was confirmed at autopsy. There were no signs of bone marrow aplasia. Two patients had germ cell tumors of the contralateral testis 18 and 42 months after orchiectomy, respectively. The first patient had clinical stage I predominantly EC with parts of immature teratoma. He was given 3 courses of BEP and showed no signs of disease 4 months after chemotherapy but was then lost to followup. The second patient had EC and mature teratoma. He was placed on surveillance and experienced retroperitoneal relapse after 3 months. He was given 3 cycles of BEP and remained relapse-free at 92 months. Three of the 40 patients, including 1 of the mentioned patients with a contralateral testis tumor, had a short recurrence-free followup of only 10, 22 and 31 months, respectively, and they were lost to followup thereafter. One patient was diagnosed with lymph node negative rectal cancer with VI 5 years after orchiectomy. He underwent surgery plus adjuvant chemotherapy and has remained recurrence-free for 36 months. At last followup all patients stated that they were doing well without mental or physical problems attributable to cytotoxic treatment. No pulmonary adverse effects were observed and most patients were physically active. Serum creatinine, electrolytes, calcium and magnesium were normal. The patient given additional treatment for retroperitoneal recurrence after diagnosis of a contralateral testis tumor was discovered to have grade II peripheral polyneuropathy after 4 cycles of chemotherapy. Three patients complained of intermittent tinnitus after chemotherapy, including 1 with disturbing grade II tinnitus. No patient complained of hearing impairment or other ototoxic side effects and no patient had clinical signs of cardiotoxicity. Of the 40 patients 34 (85%) completed the questionnaire on fertility and sexual function at a median followup of 107 months (range 83 to 142). Before cytotoxic treatment none had erectile dysfunction, decreased libido or ejaculatory disorders. Of the 34 patients 19 (56%) had fathered children and 1 (3%) was involuntarily childless due to oligoasthenoteratozoospermia. The remaining 14 patients were voluntarily childless. After cytotoxic treatment no patient experienced sexual or ejaculatory dysfunction and the 2 who underwent bilateral orchiectomy were on testosterone replacement. Nine patients (26%) fathered children who are well and 3 patients (9%) were involuntarily childless. One of these 3 men is the mentioned patient with preoperative oligoasthenoteratozoospermia and 2 had cryptorchidism of the remaining testicle. The remaining 22 patients did not elect to father children after chemotherapy. One of the 4 excluded patients had clinical stage I seminoma of the contralateral testis 38 months after orchiectomy. He was given radiation therapy and remained relapsefree at 79 months. The other 3 patients remained tumorfree. None of the 4 patients experienced adverse effects except grade I tinnitus in the patient treated with 2 cycles of BEP.
CHEMOTHERAPY FOR NONSEMINOMATOUS GERM CELL TUMORS OF TESTIS DISCUSSION For patients with stage I NSGCT who are at high risk for recurrence adjuvant chemotherapy with 2 courses of BEP is the standard treatment option in Europe.12 Reported longterm relapse rates are between 0% and 6.9%.6 –10 This well tolerated treatment spares most patients additional surgery or further chemotherapy and it renders irregular followup because of poor patient compliance of lesser concern. The current results show that a single cycle of modified BEP chemotherapy effectively decreased the relapse rate to 2.7%, a rate similar to that achieved with 2 cycles of standard BEP, while keeping adverse side effects to a minimum at a median followup of 99 months. One other group applied a single course of standard BEP chemotherapy as an alternative to RPLND plus 2 courses of adjuvant chemotherapy in those with retroperitoneal nodal metastases in patients with clinical stage I NSGCT.13 The results showed that adjuvant chemotherapy had a significantly lower recurrence rate than RPLND. However, followup was rather short and high risk factors were not considered. Another trial with only 1 cycle of adjuvant platinum containing chemotherapy (bleomycin and etoposide with cisplatin or carboplatin) recently showed no malignant tumor recurrence but the cohort was smaller (22 patients) and at lower risk for relapse than ours (table 2).14 The percent of EC and presence of VI in the primary tumor are most predictive of pathological stage II disease despite normal staging CT. The probability of occult disease in clinical stage I NSGCT increases from 4% in patients without embryonal components and no VI to as high as 92% in patients with pure EC and VI.2 In our patients the median proportion of EC and VI was 70% and 43%, respectively, which are percents sufficient to fulfill most published high risk criteria. Surveillance protocols have overall relapse rates of 17% to 38% but 46% to 59% of patients at high risk show metastases,1,15 requiring 3 or 4 courses of chemotherapy with the associated toxicity. Furthermore, patient awareness of the 30% risk of relapse may be a psychological strain. Although strict followup is vital in patients on surveillance, compliance is often low and 30% to 80% of noncompliant patients experience relapse with advanced disease.2 RPLND is considered the primary treatment modality by many investigators. It has excellent long-term results and high cure rates16,17 even in case of relapse. Long-term morbidity can be low but only in the hands of the most experienced surgeons. Postoperative complications develop in 10% to 19% of patients. A major disadvantage is that 70% to 75% of all low stage cancers have negative nodes and are overtreated with RPLND. Nonetheless, the relapse rate following RPLND is about 8% to 10%,16 generally outside the field
TABLE 2. Literature on patients treated with 1 adjuvant chemotherapy cycle for clinical stage I NSGCT Albers et al13
Gilbert et al14
No. pts Relapse risk Chemotherapy regimen
178 Not considered BEP
Median followup No. relapse (%)
47 Mos 2 (1)
22 Moderate Cisplatin/carboplatin, etoposide ⫹ bleomycin 10.2 Yrs 0
165
of RPLND. Therefore, despite RPLND these patients require additional treatment5 and must undergo close long-term followup similar to that of surveillance protocols. RPLND is also not curative in many patients who have positive nodes removed. Of patients with pathological stage II A disease 17% to 35% experience relapse if left untreated after RPLND.16 –18 Unquestionably adjuvant chemotherapy also has shortcomings and its efficacy must be weighed against the possible detrimental side effects. Advocates of primary RPLND claim that the long-term toxicity of cisplatin based chemotherapy justifies surgical treatment. Cisplatin based chemotherapy is typically associated with nephrotoxicity, ototoxicity and neurotoxicity. In the current trial we noted no serious medium term nephrotoxic or ototoxic side effects because cumulative doses remained low and our patients were well hydrated during chemotherapy. In patients given more than 400 mg/m2 cisplatin for metastatic disease a 7-fold increase in cardiovascular events was reported. However, this dose is much higher than that used in the current trial and it was also not observed with the administration of 2 to 4 courses of BEP. As for ototoxicity, 9% of our patients (3 of 34) complained of tinnitus. This is far below the published ototoxicity rates of 20% to 40% in trials using higher cisplatin doses. Most studies of 2 BEP cycles for high risk stage I NSGCT show that chemotherapy produces no significant long-term ototoxicity.6 – 8,10 Another important factor is the occurrence of life threatening cancers secondary to chemotherapy in patients with germ cell cancer. The risk of secondary leukemia, usually manifesting within 2 to 3 years, is 0.5% to 1% after high dose regimens with cumulative etoposide doses of 2 to 5 gm/m2. In our protocol with only 1 course of modified BEP the total etoposide dose was 0.36 gm/m2, far below the threshold of 2 gm/m2. One of our patients showed colorectal cancer 5 years after chemotherapy and he is now disease-free. It remains unclear whether the cancer was due to the BEP regimen. Systemic chemotherapy cannot prevent contralateral testis cancer and patients with NSGCT of the testis are at a 1.5% to 5% risk of relapse. The 2 of 40 patients (5%) who had bilateral testis tumors in our study are within this range. Testicular tumors may also contain chemo-insensitive teratoma components that can spread to the retroperitoneum in 3% of patients with clinical stage I NSGCT.19 Teratoma may grow after chemotherapy but it should not present an immediate threat to the patient since it can be detected during followup. Resection is possible before it compresses neighboring structures and before it undergoes secondary malignant transformation. An often cited argument against adjuvant chemotherapy is the development of particularly aggressive late relapses resistant to salvage chemotherapy. However, such late relapses occur after high dose chemotherapy for bulky metastatic disease. To our knowledge late chemotherapy resistant relapses have not been reported to date in our setting of clinical stage I disease with low dose chemotherapy. Since almost all patients with NSGCT are young at presentation, special attention must be given to fertility after treatment. Only 30% to 55% of patients with stage I NSGCT have a normal pretreatment sperm count,8,11 while 46% on active surveillance father children. The impact of chemotherapy on spermatogenesis is clearly dose dependent but no
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CHEMOTHERAPY FOR NONSEMINOMATOUS GERM CELL TUMORS OF TESTIS
substantial changes in sperm quality are found following 2 cycles of BEP after a recovery time of at least 9 months.6,8,10 CONCLUSIONS One course of modified BEP chemotherapy shows excellent long-term results in patients with clinical stage I NSGCT at high risk for relapse. Our results are consistent with those achieved with current standard treatment options, including 2 courses of standard or modified BEP. Our protocol provides low toxicity and costs, and lessens the chance of overtreatment. Provided that other studies confirm our results, a single cycle of modified BEP chemotherapy could become standard treatment in patients with high risk clinical stage I NSGCT.
8.
9.
10.
11.
Abbreviations and Acronyms BEP CT EC NSGCT
⫽ ⫽ ⫽ ⫽
bleomycin, etoposide and cisplatin computerized tomography embryonal carcinoma nonseminomatous germ cell tumor of testis RPLND ⫽ retroperitoneal lymph node dissection VI ⫽ vascular invasion
12.
13.
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