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Long-term experience with carboplatin monotherapy for clinical stage I seminoma: a retrospective single-center study
ADULT UROLOGY
LONG-TERM EXPERIENCE WITH CARBOPLATIN MONOTHERAPY FOR CLINICAL STAGE I SEMINOMA: A RETROSPECTIVE SINGLE-CENTER STUDY ¨ LTL, WALTER WIRTENBERGER, ANDREAS P. BERGER, HANNES STEINER, LORENZ HO GEORG BARTSCH, AND ALFRED HOBISCH
ABSTRACT Objectives. To evaluate the long-term oncologic efficacy and morbidity of carboplatin monotherapy, which was introduced at our department 11 years ago for the treatment of Stage I seminoma. Radiotherapy is the standard treatment of patients with clinical Stage I seminoma. Carboplatin has been advocated as a treatment alternative to avoid the late side effects of radiotherapy and the high recurrence rate of surveillance strategies. Methods. From February 1990 until August 2001, 108 patients received two adjuvant cycles of single-agent carboplatin (400 mg/m2 body surface on days 1 and 22) 2 weeks after high inguinal orchiectomy. To assess for myelosuppression, complete blood counts were performed at least once a week until the nadir occurred after the second treatment cycle. Results. During a mean follow-up period of 59.8 months (range 6 to 134), 2 patients (1.85%) developed a recurrence (retroperitoneal tumor) within the first year. Both patients received cisplatin-based salvage chemotherapy. At last follow-up, all patients were alive without any evidence of disease. Carboplatin treatment was well tolerated by all patients and was associated with only mild gastrointestinal side effects. Leukopenia was noted in 32 patients (29.6%); 21 (19.4%) of these patients had World Health Organization (WHO) grade 1, 8 (7.4%) had grade 2, 3 (2.8%) had grade 3, and none had grade 4. No patient developed neutropenic fever. Thrombocytopenia was observed in 48 patients (44.4%); of these patients, 38 (35.2%) had WHO grade 1, 5 (4.6%) had grade 2, 2 (1.9%) had grade 3, and 3 (2.8%) had grade 4. Conclusions. From an oncologic standpoint, two cycles of carboplatin monotherapy was highly effective and very well tolerated by all patients. UROLOGY 60: 324–328, 2002. © 2002, Elsevier Science Inc.
R
adiotherapy after unilateral inguinal orchiectomy is still the standard treatment of patients with clinical Stage I seminoma.1,2 Irradiation to the para-aortic and ipsilateral pelvic lymph nodes (“dogleg”) has been favored for decades. On the basis of work performed by Fossa et al.,2 the radiation field was limited to the para-aortic lymph nodes, but had no impact on survival and recurrence rates. Although radiotherapy with 26 to 36 Gy is associated with relapse-free survival rates of more than 94% and cure rates greater than 98%,2–5 additional research into alternative treatment moFrom the Department of Urology, University of Innsbruck, Innsbruck, Austria Reprint requests: Hannes Steiner, M.D., Department of Urology, University of Innsbruck, Anichstrasse 35, Innsbruck 6020, Austria Submitted: January 3, 2002, accepted (with revisions): March 12, 2002
324
© 2002, ELSEVIER SCIENCE INC. ALL RIGHTS RESERVED
dalities is being performed in view of the well-documented late side effects, including second malignancies and gastrointestinal toxicity.6,7 Surveillance strategies, which provide another treatment option, are fraught with high recurrence rates (9% to 33%), which causes additional psychological stress and requires more intensive treatment in patients who have a relapse.8 To avoid the morbidity of radiotherapy, chemotherapy was added as a third treatment alternative, and previous studies have demonstrated good response rates to cisplatinbased chemotherapy in patients with advanced seminoma.9 Unfortunately, cisplatin-based chemotherapy is associated with severe side effects. Although cisplatin has only moderate bone marrow toxicity, it is associated with nephrotoxicity, ototoxicity, and neurotoxicity, as well as severe nausea and vomiting.10,11 However, carboplatin, a less toxic analog of cisplatin, that also was shown 0090-4295/02/$22.00 PII S0090-4295(02)01708-9
TABLE I. Hematologic toxicity in 108 patients treated with two cycles of carboplatin WHO Grade of Toxic Effects Leukocytes Platelets
G1
G2
G3
G4
21 (19.4) 38 (35.2)
8 (7.4) 5 (4.6)
3 (2.8) 2 (1.9)
0 (0.0) 3 (2.8)
KEY: WHO ⫽ World Health Organization. Data presented as the number of patients, with the percentage in parentheses.
to be effective in advanced seminoma, can be administered without significant nephrotoxicity, ototoxicity, or neurotoxicity.9,12,13 The dose-limiting side effect of carboplatin is bone marrow suppression, in particular, thrombocytopenia.9 In the present study, we retrospectively evaluated the long-term oncologic efficacy and morbidity of carboplatin monotherapy, which was introduced at our department 11 years ago. MATERIAL AND METHODS Patients with histologic evidence of pure clinical stage I seminoma and clear surgical margins were eligible for singleagent carboplatin chemotherapy. Staging was performed according to the criteria recommended by the “Workshop for Staging and Treatment of Testicular Cancer” (Lugano 1979). In addition, computed tomography of the thorax, abdomen, and pelvis, as well as blood chemistry, including alpha-fetoprotein, beta-human chorionic gonadotropin (HCG), and lactate dehydrogenase (LDH) determinations, were performed. All patients provided written informed consent before chemotherapy. From February 1990 until August 2001, 108 patients (mean age 35 years, range 21 to 64) received two adjuvant cycles of single-agent carboplatin (400 mg/m2 body surface) dissolved in 1000 mL of 5% dextrose solution approximately 2 weeks after high inguinal orchiectomy. On days 1 and 22, chemotherapy was given on an outpatient basis by infusion for 60 minutes using a peripheral venous line with hydration before and after (500 and 250 mL saline, respectively). In addition, ondansetron (8 mg) was administered as a prophylactic antiemetic. To assess for hematologic toxicity, complete blood counts were performed at least once a week until the nadir was reached after the second cycle of carboplatin. Follow-up investigations were performed at 3-month intervals for the first 2 years, every 6 months until the end of the fifth year, and annually thereafter. Each follow-up examination included a physical examination, complete blood count, and blood chemistry, including alpha-fetoprotein, beta-HCG, and LDH measurements. Computed tomography of the thorax, abdomen, and pelvis was performed twice in the first year; chest radiography and abdominal ultrasonography were performed at subsequent follow-up visits.
RESULTS The pathologic tumor stage in the 108 patients was pT1 in 88, pT2 in 16, and pT3 in 4 patients. Small vessel invasion occurred in 13 patients (12%). In 13 patients (12%), the tumor was more than 6 cm in size, and 95 patients had tumors 6 cm or less in size. At the time of orchiectomy, 49 patients (45.3%) were 34 years old or younger. Of the UROLOGY 60 (2), 2002
108 patients, 13 presented with preoperatively elevated beta-HCG levels; 10 patients had levels between 10 and 80 mU/mL and 3 patients had higher levels (250, 275, and 380 mU/mL, respectively). Before surgery, elevated LDH levels ranging between 290 and 700 U/L were found in 9 patients, and 1 patient had a preoperative LDH level of 1850 U/L. Alpha-fetoprotein was within normal limits in all patients. After semicastration, all markers returned to normal in accordance with their half-life periods. Chemotherapy was generally well tolerated, and patients experienced only mild nausea. Bone marrow suppression was not uncommon (Table I). A total of 32 patients (29.6%) developed leukopenia. In 3 patients, the leukocyte levels ranged between 1.5 ⫻ 109/L and 2.0 ⫻ 109/L; in all other leukopenic patients, the leukocyte levels were between 2.1 ⫻ 109/L and 4.0 ⫻ 109/L. None of the patients experienced neutropenic fever. Thrombocytopenia was observed in 48 patients (44.4%). After the second cycle of chemotherapy, 3 patients presented with platelet counts between 16 ⫻ 109/L and 20 ⫻ 109/L. Of these patients, one recovered without complications after receiving one therapeutic thrombocyte transfusion. Another patient received therapeutic thrombocyte transfusions on days 14 (platelet level 17 ⫻ 109/L) and 21 (platelet level 19 ⫻ 109/L) after the second cycle. At 9 months after chemotherapy, the patient’s thrombocyte and leukocyte levels were again within normal limits. In these 2 patients, thrombocytes were administered as a prophylactic measure. The third patient did not require any transfusions. During a mean follow-up period of 59.8 months (range 6 to 134; less than 12 months in 9 patients [8.3%]), 2 patients (1.85%) developed ipsilateral para-aortic recurrences within the first year after adjuvant treatment. One patient, a 26-year-old man with a preoperatively LDH-positive (1890 U/L) seminoma, developed a marker-negative enlarged lymph node (clinical Stage IIB) 10 months after treatment. The second recurrence was seen in a 30-year-old patient with a preoperatively betaHCG-positive (275 mU/mL) and LDH-negative seminoma. Nine months after chemotherapy, he 325
TABLE II. Surveillance after orchiectomy for clinical stage I seminoma; results of studies including >100 patients Investigator Duchesne et al.,15 1990 Horwich et al.,16 1992 von der Maase et al.,17 1993 Warde et al.,18 1997 Total
Patients (n) Mean Follow-up (mo) Recurrence (n) 113 103 261 201 678
30 62 48 73
13 17 49 31 110
(11.5) (16.5) (18.7) (15.4) (16.2)
Data in parentheses are percentages.
was diagnosed with an LDH-positive (1640 U/L) and beta-HCG-negative retroperitoneal recurrence (clinical Stage IIB). Neither of the 2 patients had evidence of pulmonary metastases on computed tomography. Both patients were free of tumor after cisplatin-based salvage chemotherapy at a follow-up of 8.1 and 5.8 years, respectively. At last follow-up, all patients were alive with no evidence of disease. COMMENT Clinical Stage I seminoma is a highly curable disease with a very low death rate. With the abovementioned treatment strategies, the disease-specific survival rate approaches 100%.8 Postorchiectomy radiotherapy to the para-aortic and ipsilateral pelvic lymph nodes has been the reference standard adjuvant treatment for clinical Stage I seminoma in the past decades.1,8 The radiation field was recently restricted to the para-aortic lymph nodes, yielding equal results in terms of survival and recurrence rates.2 Treatment with 26 to 36 Gy produces moderate acute gastrointestinal side effects, with nausea and vomiting the most common. Fatigue is also a common side effect after radiotherapy. Despite the excellent cure rates, limited acute toxicity, and extensive experience with radiotherapy, the significant late side effects associated with this therapeutic approach (peptic ulcer disease, second malignancy, deep vein thrombosis, hepatitis, and myelitis) have prompted a search for alternative modalities.6,7 Apart from the high success rates, treatment modalities favored by patients should be associated with the least adverse effects on daily activities and lifestyle and minimal long-term toxicity. Surveillance protocols were devised in an attempt to reduce the morbidity. However, several surveillance studies have shown a 16% to 20% risk of recurrent disease (Table II), with recurrence rates of up to 33% in some cohorts.8,14 Surveillance protocols have demonstrated that the median time to recurrence ranges from 12 to 18 months and that 96% of relapses occur in the retroperitoneum. Because most (67% to 84%)8,14 –18 patients can be cured with orchiectomy alone, and cure rates in 326
the case of recurrence are high, a surveillance strategy may still be an option, but close observation and excellent patient compliance are mandatory for this treatment modality to be successful. There are no physical side effects and the quality of life is not impaired, except that frequent follow-up examinations are necessary, which include computed tomography. Nonetheless, this regimen causes considerable psychologic stress, since longterm follow-up is mandatory because of the risk of late recurrence.8,19 Furthermore, surveillance is not considered less costly than adjuvant therapy, particularly because cisplatin-based salvage chemotherapy and retroperitoneal lymph node dissection are required in 9% to 33% of patients.20,21 Chemotherapy as adjuvant therapy for clinical Stage I seminoma (Table III) provides an alternative to radiotherapy. A number of therapeutic regimens have been described that differ with regard to dosage22 and number of cycles (one or two). Recent work by Dieckmann et al.23 suggests that two cycles of carboplatin monotherapy is more effective than one cycle, which is associated with a recurrence rate (8.6%) almost as high as that observed in some surveillance studies (Table II). Although we are aware of the risk of relapse in 9 of our patients in whom the follow-up was shorter than 12 months, we believe that our retrospective analysis provides additional data that help assess the efficacy of adjuvant chemotherapy in patients with clinical Stage I seminoma. Previous studies have shown that only 2 of a total of 263 patients who were treated with two cycles of carboplatin had a relapse (Table III). Overall, the recurrence rate among all 371 patients was 1.07%, which indicates that better results can be achieved with carboplatin compared with adjuvant radiotherapy or surveillance strategies. Several studies have reported that chemotherapy yields higher cure rates in relapsed surveillance patients compared with those who underwent primary radiotherapy, reinforcing the value of adjuvant chemotherapy for Stage I seminoma.16,24 –26 The better response of metastatic lesions to primary chemotherapy— even single-agent cisplatin— compared with radioUROLOGY 60 (2), 2002
TABLE III. Carboplatin monotherapy as adjuvant treatment of clinical stage I seminoma Patients (n)
Cycles (n)
Mean Follow-up (mo)
Recurrence (%)
Oliver et al.,24 1994 Krege et al.,28 1997 Germa-Lluch et al.,27 1998 Dieckmann et al.,23 2000 Reiter et al.,29 2001 Total
53 43 28 32 107 263
2 2 2 2 2
44 28 14 48 74
1 0 1 0 0 2 (0.8)
Oliver et al.,24 1994 Dieckmann et al.,23 2000 Total
25 93 118
1 1
44 48
0 8 8 (6.8)
Investigator
therapy also underscores the role of first-line adjuvant chemotherapy.24 In fact, several Phase III trials are currently underway that compare chemotherapy and radiotherapy in this clinical setting.8,14 These trials will help assess the effectiveness of carboplatin monotherapy. Although evidence of a better treatment outcome compared with other modalities is increasing, we will have to wait for the results of these trials before carboplatin monotherapy can be recommended as the first-line adjuvant treatment of clinical Stage I seminoma. Similar to other studies23,24,27–29 we mainly observed mild side effects. The only difference in terms of toxicity between these reports and our results was the increased incidence of thrombocytopenia in our patients, which should be addressed in future studies. Furthermore, it will be important to investigate the potential long-term toxicity of this therapeutic regimen, although carboplatin therapy can be expected to be associated with only minimal long-term toxicity. An additional benefit for the patient is the mode of carboplatin administration. Although irradiation must be delivered daily in specialized centers during a period of 13 to 15 days, carboplatin monotherapy can be safely administered on an outpatient basis, which significantly improves the patient’s quality of life. In addition, the reduction of treatment to only 2 days also has favorable economic implications. CONCLUSIONS Overall, the results of our study confirm several published reports that in patients with clinical Stage I seminoma of the testis, two cycles of carboplatin monotherapy is an oncologically effective and well-tolerated treatment modality associated with very low morbidity. REFERENCES 1. Tjan-Heijnen VC, Oosterhof GO, de Wit R, et al: Treatment in germ cell tumours: state of the art. Eur J Surg Oncol 23: 110 –117, 1997. UROLOGY 60 (2), 2002
2. Fossa SD, Horwich A, Russell JM, et al, for the Medical Research Council Testicular Tumor Working Group: Optimal planning target volume for stage I testicular seminoma: a Medical Research Council randomized trial. J Clin Oncol 17: 1146 –1154, 1999. 3. Bamberg M, Schmidberger H, Meisner C, et al: Radiotherapy for stages I and IIA/B testicular seminoma. Int J Cancer 83: 823– 827, 1999. 4. Bauman GS, Venkatesan VM, Ago CT, et al: Postoperative radiotherapy for stage I/II seminoma: results for 212 patients. Int J Radiat Oncol Biol Phys 42: 313–317, 1998. 5. Taylor MB, Carrington BM, Livsey JE, et al: The effect of radiotherapy treatment changes on sites of relapse in stage I testicular seminoma. Clin Radiol 56: 116 –119, 2001. 6. Grossfeld GD, and Small EJ: Long-term side effects of treatment for testis cancer. Urol Clin North Am 25: 503–515, 1998. 7. Ruther U, Dieckmann K, Bussar-Maatz R, et al: Second malignancies following pure seminoma. Oncology 58: 75– 82, 2000. 8. Bayley AWP, Milosevic M, and Gospodarowicz M: Surveillance for stage I testicular seminoma: a review. Urol Oncol 6: 139 –143, 2001. 9. Horwich A, Mason M, and Dearnaley DP: Use of carboplatin in germ cell tumors of the testis. Semin Oncol 19: 72– 77, 1992. 10. Mollman JE: Cisplatin neurotoxicity. N Engl J Med 322: 126 –127, 1990. 11. Stuart NS, Woodroffe CM, Grundy R, et al: Long-term toxicity of chemotherapy for testicular cancer—the cost of cure. Br J Cancer 61: 479 – 484, 1990. 12. Horwich A, Dearnaley DP, Duchesne GM, et al: Simple nontoxic treatment of advanced metastatic seminoma with carboplatin. J Clin Oncol 7: 1150 –1156, 1989. 13. Horwich A, Oliver RT, Wilkinson PM, et al, for the MRC Testicular Tumour Working Party: A medical research council randomized trial of single agent carboplatin versus etoposide and cisplatin for advanced metastatic seminoma. Br J Cancer 83: 1623–1629, 2000. 14. Albers P, Perabo FG, Melchior D, et al: Adjuvant chemotherapy in stage I and stage II testicular cancer. World J Urol 19: 76 – 81, 2001. 15. Duchesne GM, Horwich A, Dearnaley DP, et al: Orchidectomy alone for stage I seminoma of the testis. Cancer 65: 1115–1158, 1990. 16. Horwich A, Alsanjari N, A’Hern R, et al: Surveillance following orchidectomy for stage I testicular seminoma. Br J Cancer 65: 775–778, 1992. 17. von der Maase H, Specht L, Jacobsen GK, et al: Surveil327
lance following orchidectomy for stage I seminoma of the testis. Eur J Cancer 14: 1931–1934, 1993. 18. Warde P, Gospodarowicz MK, Banerjee D, et al: Prognostic factors for relapse in stage I testicular seminoma treated with surveillance. J Urol 157: 1705–1710, 1997. 19. Blanke CD, Delgalvis SC, and Nichols GR: Late recurrence of seminoma. South Med J 90: 653– 655, 1997. 20. Buchholz TA, Walden TL, and Prestidge BR: Cost-effectiveness of posttreatment surveillance after radiation therapy for early stage seminoma. Cancer 82: 1126 –1133, 1998. 21. Warde P, Gospodarowicz MK, Panzarella T, et al: Longterm outcome and cost in the management of stage I testicular seminoma. Can J Urol 7: 967–973, 2000. 22. Calvert AH, Newell DR, Gumbrell LA, et al: Carboplatin dosage: prospective evaluation of a simple formula based on renal function. J Clin Oncol 7: 1748 –1756, 1989. 23. Dieckmann KP, Bruggeboes B, Pichlmeier U, et al: Adjuvant treatment of clinical stage I seminoma: is a single course of carboplatin sufficient? Urology 55: 102–106, 2000.
328
24. Oliver RT, Edmonds PM, Ong JY, et al: Pilot studies of 2 and 1 course carboplatin as adjuvant for stage I seminoma: should it be tested in a randomized trial against radiotherapy? Int J Radiat Oncol Biol Phys 29: 3– 8, 1994. 25. Oliver RT: Limitations to the use of surveillance as an option in the management of stage I seminoma. Int J Androl 10: 263–268, 1987. 26. Thomas GM, Sturgeon JF, Alison R, et al: A study of post-orchiectomy surveillance in stage I testicular seminoma. J Urol 142: 313–316, 1989. 27. Germa-Lluch JR: Germ cell tumours IV. London, Libbey, 1998, pp 139 –142. 28. Krege S, Kalund G, Otto T, et al: Phase II study: adjuvant single-agent carboplatin therapy for clinical stage I seminoma. Eur Urol 31: 405– 407, 1997. 29. Reiter WJ, Brodowicz T, Alavi S, et al: Twelve-year experience with two courses of adjuvant single-agent carboplatin therapy for clinical stage I seminoma. J Clin Oncol 19: 101–104, 2001.
UROLOGY 60 (2), 2002
LONG-TERM EXPERIENCE WITH CARBOPLATIN MONOTHERAPY FOR CLINICAL STAGE I SEMINOMA: A RETROSPECTIVE SINGLE-CENTER STUDY ¨ LTL, WALTER WIRTENBERGER, ANDREAS P. BERGER, HANNES STEINER, LORENZ HO GEORG BARTSCH, AND ALFRED HOBISCH
ABSTRACT Objectives. To evaluate the long-term oncologic efficacy and morbidity of carboplatin monotherapy, which was introduced at our department 11 years ago for the treatment of Stage I seminoma. Radiotherapy is the standard treatment of patients with clinical Stage I seminoma. Carboplatin has been advocated as a treatment alternative to avoid the late side effects of radiotherapy and the high recurrence rate of surveillance strategies. Methods. From February 1990 until August 2001, 108 patients received two adjuvant cycles of single-agent carboplatin (400 mg/m2 body surface on days 1 and 22) 2 weeks after high inguinal orchiectomy. To assess for myelosuppression, complete blood counts were performed at least once a week until the nadir occurred after the second treatment cycle. Results. During a mean follow-up period of 59.8 months (range 6 to 134), 2 patients (1.85%) developed a recurrence (retroperitoneal tumor) within the first year. Both patients received cisplatin-based salvage chemotherapy. At last follow-up, all patients were alive without any evidence of disease. Carboplatin treatment was well tolerated by all patients and was associated with only mild gastrointestinal side effects. Leukopenia was noted in 32 patients (29.6%); 21 (19.4%) of these patients had World Health Organization (WHO) grade 1, 8 (7.4%) had grade 2, 3 (2.8%) had grade 3, and none had grade 4. No patient developed neutropenic fever. Thrombocytopenia was observed in 48 patients (44.4%); of these patients, 38 (35.2%) had WHO grade 1, 5 (4.6%) had grade 2, 2 (1.9%) had grade 3, and 3 (2.8%) had grade 4. Conclusions. From an oncologic standpoint, two cycles of carboplatin monotherapy was highly effective and very well tolerated by all patients. UROLOGY 60: 324–328, 2002. © 2002, Elsevier Science Inc.
R
adiotherapy after unilateral inguinal orchiectomy is still the standard treatment of patients with clinical Stage I seminoma.1,2 Irradiation to the para-aortic and ipsilateral pelvic lymph nodes (“dogleg”) has been favored for decades. On the basis of work performed by Fossa et al.,2 the radiation field was limited to the para-aortic lymph nodes, but had no impact on survival and recurrence rates. Although radiotherapy with 26 to 36 Gy is associated with relapse-free survival rates of more than 94% and cure rates greater than 98%,2–5 additional research into alternative treatment moFrom the Department of Urology, University of Innsbruck, Innsbruck, Austria Reprint requests: Hannes Steiner, M.D., Department of Urology, University of Innsbruck, Anichstrasse 35, Innsbruck 6020, Austria Submitted: January 3, 2002, accepted (with revisions): March 12, 2002
324
© 2002, ELSEVIER SCIENCE INC. ALL RIGHTS RESERVED
dalities is being performed in view of the well-documented late side effects, including second malignancies and gastrointestinal toxicity.6,7 Surveillance strategies, which provide another treatment option, are fraught with high recurrence rates (9% to 33%), which causes additional psychological stress and requires more intensive treatment in patients who have a relapse.8 To avoid the morbidity of radiotherapy, chemotherapy was added as a third treatment alternative, and previous studies have demonstrated good response rates to cisplatinbased chemotherapy in patients with advanced seminoma.9 Unfortunately, cisplatin-based chemotherapy is associated with severe side effects. Although cisplatin has only moderate bone marrow toxicity, it is associated with nephrotoxicity, ototoxicity, and neurotoxicity, as well as severe nausea and vomiting.10,11 However, carboplatin, a less toxic analog of cisplatin, that also was shown 0090-4295/02/$22.00 PII S0090-4295(02)01708-9
TABLE I. Hematologic toxicity in 108 patients treated with two cycles of carboplatin WHO Grade of Toxic Effects Leukocytes Platelets
G1
G2
G3
G4
21 (19.4) 38 (35.2)
8 (7.4) 5 (4.6)
3 (2.8) 2 (1.9)
0 (0.0) 3 (2.8)
KEY: WHO ⫽ World Health Organization. Data presented as the number of patients, with the percentage in parentheses.
to be effective in advanced seminoma, can be administered without significant nephrotoxicity, ototoxicity, or neurotoxicity.9,12,13 The dose-limiting side effect of carboplatin is bone marrow suppression, in particular, thrombocytopenia.9 In the present study, we retrospectively evaluated the long-term oncologic efficacy and morbidity of carboplatin monotherapy, which was introduced at our department 11 years ago. MATERIAL AND METHODS Patients with histologic evidence of pure clinical stage I seminoma and clear surgical margins were eligible for singleagent carboplatin chemotherapy. Staging was performed according to the criteria recommended by the “Workshop for Staging and Treatment of Testicular Cancer” (Lugano 1979). In addition, computed tomography of the thorax, abdomen, and pelvis, as well as blood chemistry, including alpha-fetoprotein, beta-human chorionic gonadotropin (HCG), and lactate dehydrogenase (LDH) determinations, were performed. All patients provided written informed consent before chemotherapy. From February 1990 until August 2001, 108 patients (mean age 35 years, range 21 to 64) received two adjuvant cycles of single-agent carboplatin (400 mg/m2 body surface) dissolved in 1000 mL of 5% dextrose solution approximately 2 weeks after high inguinal orchiectomy. On days 1 and 22, chemotherapy was given on an outpatient basis by infusion for 60 minutes using a peripheral venous line with hydration before and after (500 and 250 mL saline, respectively). In addition, ondansetron (8 mg) was administered as a prophylactic antiemetic. To assess for hematologic toxicity, complete blood counts were performed at least once a week until the nadir was reached after the second cycle of carboplatin. Follow-up investigations were performed at 3-month intervals for the first 2 years, every 6 months until the end of the fifth year, and annually thereafter. Each follow-up examination included a physical examination, complete blood count, and blood chemistry, including alpha-fetoprotein, beta-HCG, and LDH measurements. Computed tomography of the thorax, abdomen, and pelvis was performed twice in the first year; chest radiography and abdominal ultrasonography were performed at subsequent follow-up visits.
RESULTS The pathologic tumor stage in the 108 patients was pT1 in 88, pT2 in 16, and pT3 in 4 patients. Small vessel invasion occurred in 13 patients (12%). In 13 patients (12%), the tumor was more than 6 cm in size, and 95 patients had tumors 6 cm or less in size. At the time of orchiectomy, 49 patients (45.3%) were 34 years old or younger. Of the UROLOGY 60 (2), 2002
108 patients, 13 presented with preoperatively elevated beta-HCG levels; 10 patients had levels between 10 and 80 mU/mL and 3 patients had higher levels (250, 275, and 380 mU/mL, respectively). Before surgery, elevated LDH levels ranging between 290 and 700 U/L were found in 9 patients, and 1 patient had a preoperative LDH level of 1850 U/L. Alpha-fetoprotein was within normal limits in all patients. After semicastration, all markers returned to normal in accordance with their half-life periods. Chemotherapy was generally well tolerated, and patients experienced only mild nausea. Bone marrow suppression was not uncommon (Table I). A total of 32 patients (29.6%) developed leukopenia. In 3 patients, the leukocyte levels ranged between 1.5 ⫻ 109/L and 2.0 ⫻ 109/L; in all other leukopenic patients, the leukocyte levels were between 2.1 ⫻ 109/L and 4.0 ⫻ 109/L. None of the patients experienced neutropenic fever. Thrombocytopenia was observed in 48 patients (44.4%). After the second cycle of chemotherapy, 3 patients presented with platelet counts between 16 ⫻ 109/L and 20 ⫻ 109/L. Of these patients, one recovered without complications after receiving one therapeutic thrombocyte transfusion. Another patient received therapeutic thrombocyte transfusions on days 14 (platelet level 17 ⫻ 109/L) and 21 (platelet level 19 ⫻ 109/L) after the second cycle. At 9 months after chemotherapy, the patient’s thrombocyte and leukocyte levels were again within normal limits. In these 2 patients, thrombocytes were administered as a prophylactic measure. The third patient did not require any transfusions. During a mean follow-up period of 59.8 months (range 6 to 134; less than 12 months in 9 patients [8.3%]), 2 patients (1.85%) developed ipsilateral para-aortic recurrences within the first year after adjuvant treatment. One patient, a 26-year-old man with a preoperatively LDH-positive (1890 U/L) seminoma, developed a marker-negative enlarged lymph node (clinical Stage IIB) 10 months after treatment. The second recurrence was seen in a 30-year-old patient with a preoperatively betaHCG-positive (275 mU/mL) and LDH-negative seminoma. Nine months after chemotherapy, he 325
TABLE II. Surveillance after orchiectomy for clinical stage I seminoma; results of studies including >100 patients Investigator Duchesne et al.,15 1990 Horwich et al.,16 1992 von der Maase et al.,17 1993 Warde et al.,18 1997 Total
Patients (n) Mean Follow-up (mo) Recurrence (n) 113 103 261 201 678
30 62 48 73
13 17 49 31 110
(11.5) (16.5) (18.7) (15.4) (16.2)
Data in parentheses are percentages.
was diagnosed with an LDH-positive (1640 U/L) and beta-HCG-negative retroperitoneal recurrence (clinical Stage IIB). Neither of the 2 patients had evidence of pulmonary metastases on computed tomography. Both patients were free of tumor after cisplatin-based salvage chemotherapy at a follow-up of 8.1 and 5.8 years, respectively. At last follow-up, all patients were alive with no evidence of disease. COMMENT Clinical Stage I seminoma is a highly curable disease with a very low death rate. With the abovementioned treatment strategies, the disease-specific survival rate approaches 100%.8 Postorchiectomy radiotherapy to the para-aortic and ipsilateral pelvic lymph nodes has been the reference standard adjuvant treatment for clinical Stage I seminoma in the past decades.1,8 The radiation field was recently restricted to the para-aortic lymph nodes, yielding equal results in terms of survival and recurrence rates.2 Treatment with 26 to 36 Gy produces moderate acute gastrointestinal side effects, with nausea and vomiting the most common. Fatigue is also a common side effect after radiotherapy. Despite the excellent cure rates, limited acute toxicity, and extensive experience with radiotherapy, the significant late side effects associated with this therapeutic approach (peptic ulcer disease, second malignancy, deep vein thrombosis, hepatitis, and myelitis) have prompted a search for alternative modalities.6,7 Apart from the high success rates, treatment modalities favored by patients should be associated with the least adverse effects on daily activities and lifestyle and minimal long-term toxicity. Surveillance protocols were devised in an attempt to reduce the morbidity. However, several surveillance studies have shown a 16% to 20% risk of recurrent disease (Table II), with recurrence rates of up to 33% in some cohorts.8,14 Surveillance protocols have demonstrated that the median time to recurrence ranges from 12 to 18 months and that 96% of relapses occur in the retroperitoneum. Because most (67% to 84%)8,14 –18 patients can be cured with orchiectomy alone, and cure rates in 326
the case of recurrence are high, a surveillance strategy may still be an option, but close observation and excellent patient compliance are mandatory for this treatment modality to be successful. There are no physical side effects and the quality of life is not impaired, except that frequent follow-up examinations are necessary, which include computed tomography. Nonetheless, this regimen causes considerable psychologic stress, since longterm follow-up is mandatory because of the risk of late recurrence.8,19 Furthermore, surveillance is not considered less costly than adjuvant therapy, particularly because cisplatin-based salvage chemotherapy and retroperitoneal lymph node dissection are required in 9% to 33% of patients.20,21 Chemotherapy as adjuvant therapy for clinical Stage I seminoma (Table III) provides an alternative to radiotherapy. A number of therapeutic regimens have been described that differ with regard to dosage22 and number of cycles (one or two). Recent work by Dieckmann et al.23 suggests that two cycles of carboplatin monotherapy is more effective than one cycle, which is associated with a recurrence rate (8.6%) almost as high as that observed in some surveillance studies (Table II). Although we are aware of the risk of relapse in 9 of our patients in whom the follow-up was shorter than 12 months, we believe that our retrospective analysis provides additional data that help assess the efficacy of adjuvant chemotherapy in patients with clinical Stage I seminoma. Previous studies have shown that only 2 of a total of 263 patients who were treated with two cycles of carboplatin had a relapse (Table III). Overall, the recurrence rate among all 371 patients was 1.07%, which indicates that better results can be achieved with carboplatin compared with adjuvant radiotherapy or surveillance strategies. Several studies have reported that chemotherapy yields higher cure rates in relapsed surveillance patients compared with those who underwent primary radiotherapy, reinforcing the value of adjuvant chemotherapy for Stage I seminoma.16,24 –26 The better response of metastatic lesions to primary chemotherapy— even single-agent cisplatin— compared with radioUROLOGY 60 (2), 2002
TABLE III. Carboplatin monotherapy as adjuvant treatment of clinical stage I seminoma Patients (n)
Cycles (n)
Mean Follow-up (mo)
Recurrence (%)
Oliver et al.,24 1994 Krege et al.,28 1997 Germa-Lluch et al.,27 1998 Dieckmann et al.,23 2000 Reiter et al.,29 2001 Total
53 43 28 32 107 263
2 2 2 2 2
44 28 14 48 74
1 0 1 0 0 2 (0.8)
Oliver et al.,24 1994 Dieckmann et al.,23 2000 Total
25 93 118
1 1
44 48
0 8 8 (6.8)
Investigator
therapy also underscores the role of first-line adjuvant chemotherapy.24 In fact, several Phase III trials are currently underway that compare chemotherapy and radiotherapy in this clinical setting.8,14 These trials will help assess the effectiveness of carboplatin monotherapy. Although evidence of a better treatment outcome compared with other modalities is increasing, we will have to wait for the results of these trials before carboplatin monotherapy can be recommended as the first-line adjuvant treatment of clinical Stage I seminoma. Similar to other studies23,24,27–29 we mainly observed mild side effects. The only difference in terms of toxicity between these reports and our results was the increased incidence of thrombocytopenia in our patients, which should be addressed in future studies. Furthermore, it will be important to investigate the potential long-term toxicity of this therapeutic regimen, although carboplatin therapy can be expected to be associated with only minimal long-term toxicity. An additional benefit for the patient is the mode of carboplatin administration. Although irradiation must be delivered daily in specialized centers during a period of 13 to 15 days, carboplatin monotherapy can be safely administered on an outpatient basis, which significantly improves the patient’s quality of life. In addition, the reduction of treatment to only 2 days also has favorable economic implications. CONCLUSIONS Overall, the results of our study confirm several published reports that in patients with clinical Stage I seminoma of the testis, two cycles of carboplatin monotherapy is an oncologically effective and well-tolerated treatment modality associated with very low morbidity. REFERENCES 1. Tjan-Heijnen VC, Oosterhof GO, de Wit R, et al: Treatment in germ cell tumours: state of the art. Eur J Surg Oncol 23: 110 –117, 1997. UROLOGY 60 (2), 2002
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