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Current status and future perspectives in the treatment of advanced testicular cancer

2002; Wiley; Volume: 9; Issue: 1 Linguagem: Inglês

10.1046/j.1442-2042.2002.00407.x

1442-2042

Tsuneharu Miki, Masahiro Nakao,

Ovarian cancer diagnosis and treatment

Testicular cancer is a rare malignant neoplasm in Japan. It occurs mainly in young males and is one of the most aggressive solid tumors. Chemotherapy is highly effective in the treatment of testicular cancer, although surgery and radiation therapy also play important roles, and multidisciplinary strategy is important. As result of its clinical features, testicular cancer has evoked widespread interest among clinicians as a model for a curable malignant neoplasm.1,2 Seventy to 80% of patients with disseminated testicular cancer have been cured because of the current progress in cisplatin-based chemotherapy.2 However, the remaining cases have a poor prognosis as they do not respond to initial chemotherapy or they suffer a relapse of the disease. In this article, we review past studies on chemotherapy for advanced testicular cancer and discuss present issues and future perspectives in treatment. Testicular cancer is one of the most chemosensitive neoplasms and various kinds of chemotherapy regimen have been used in treatment.1 As for single anti-cancer agents, cyclophosphamide (CPM), vinblastine (VBL) and bleomycin (BLM) were proved to be effective in the treatment of advanced testicular cancer, with 12–22% complete response (CR) rates.3–5 A combination of VBL and BLM was recognized to act synergistically, with 30–39% CR rates.6,7 Wittes et al., at the Memorial Sloan-Kettering Cancer Center, developed original vinblastine, actinomycin D and bleomycin (VAB) therapy and achieved a 15% CR rate and a 34% overall response rate.8 Chemotherapy of testicular cancer made rapid progress due to the clinical use of cisplatin, which was discovered by Rosenberg and associates in 1965.9 Cisplatin was used in the treatment of advanced testicular cancer in the 1970s because of its high antitumor activity and relative lack of myelosuppression.1,10 Higby and colleagues treated 15 metastatic testicular cancer patients with cisplatin and reported that the CR and partial response (PR) rates were 46% and 20%, respectively.11 In 1974, Einhorn and co-workers at Indiana University started using cisplatin, vinblastine and bleomycin (PVB) therapy.1 In the early trial, PVB achieved a 70% CR rate and a 100% response rate. After reducing the dose of VBL (0.2 mg/kg for days 1 and 2 to 0.3 mg/kg for day 1) to improve the hematopoietic side-effects, PVB therapy was recognized to be one of the most useful chemotherapy regimens for advanced testicular cancer in the early 1980s.1 Researchers at the Memorial Sloan-Kettering Cancer Center (MSKCC) started original VAB therapy in 1972.8 Adding cisplatin to the VAB regimen (VAB-2 regimen), they reported a 50% CR rate and a 34% PR rate in 1974.12 After the VAB-3 to VAB-5 trials, the VAB-6 regimen was initiated in 1979.13–15 VAB-6 therapy achieved a 91% CR rate and was also shown, like PVB therapy, to be an excellent treatment modality for advanced testicular cancer.15 Etoposide (VP-16) was shown to have major activity in advanced testicular cancer. At first, etoposide was used in salvage chemotherapy for residual or recurrent cancer after cisplatin-based ordinary chemotherapy.16 Peckman and associates evaluated the usefulness of etoposide as a first line chemotherapy and found that it achieved a 83% cure rate.17 In 1981, the South-eastern Cancer Study Group started a randomized prospective trial comparing PVB to cisplatin, etoposide and bleomycin (BEP) as a first line chemotherapy. A total of 244 patients were used in this trial. Both chemotherapy regimens had almost the same CR rates. However, the disease-free rate of the patients treated with BEP therapy (83%) was higher compared with those treated with PVB therapy (74%).18 To date, BEP therapy is recognized as being superior to PVB therapy, and it is the standard first line chemotherapy for advanced testicular cancer.2 Cisplatin-based combination chemotherapy made a dramatic improvement in the treatment of advanced testicular cancer. However, approximately 20–30% of patients are cisplatin refractory or have a relapse after standard chemotherapy, and have a poor prognosis. Poor prognostic features include bulky tumor mass, extrapulmonary visceral metastases, marked elevation of serum markers and primary extragonadal germ cell tumors. According to these clinical features, several classifications of advanced testicular cancer were proposed to identify poor-prognostic patients and to enable the selection of a suitable treatment modality. In 1983, Bosl’s group at the MSKCC conducted a multivariate analysis of prognostic variables in patients with advanced testicular cancer and proposed a mathematical model based on the pretreatment level of lactic dehydrogenase (LDH) and human chorionic gonadotropin (HCG) and the total number of sites of metastases.19,20 In this model, the poor-risk group is defined as patients whose probability of a CR is less than 50%. In 1987, Stoter et al. of the European Organization for Research on Treatment of Cancer (EORTC) Genito-Urinary Tract Cancer Cooperative Group evaluated 214 patients with disseminated testicular cancer and divided them into four groups according to the complete responder rates of 100, 89, 41 and 18%, respectively.21 This classification was based on four prognostic factors: trophoblastic elements in the primary tumors, serum concentration of AFP and size and number of lung metastases. However, HCG-β, the single most important prognostic factor, was not included in the final model to estimate the possibility that a patient will have a CR. Birch and associates of the South-eastern Cancer Study Group proposed an original staging system which split disseminated testicular cancer into three groups (minimal, moderate and advanced disease), in which the observed proportion of favorable responders in each group were 99%, 90% and 58%, respectively.22 However, one major problem is that no tumor marker was included in this classification. The various staging systems have made it difficult to compare the results of each randomized and non-randomized trial because each trial has used different prognostic factors (Table 1).19–23 The International Germ Cell Cancer Collaborative Group (IGCCCG) from 10 countries proposed a simple, easily acceptable prognostic classification in 1997 (Table 2).23 Presently, the IGCCCG classification seems to be the most useful staging system for evaluating the outcome of clinical trials for disseminated testicular cancer. The purpose of chemotherapy trials in good-prognosis testicular cancer is to reduce the toxicity of treatment while preserving the treatment’s efficacy. As carboplatin is less toxic than cisplatin, Bajorin and associates compared the efficacy between etoposide plus carboplatin (EC) and etoposide plus cisplatin (EP) in the treatment of good-risk testicular cancer.24 The rate of incomplete response or relapse in patients treated with EC was higher than that in patients treated with EP. They concluded that the use of carboplatin in good-risk testicular cancer should be restricted. Elimination of BLM was also evaluated in several randomized clinical studies. Bosl and co-workers also conducted a randomized trial of EP versus VAB-6 in patients with good-risk germ cell tumors.25 The EP regimen, being as efficacious as VAB-6 but less toxic, was recommended for good-prognosis testicular cancer. The Australian Germ Cell Trial Group compared cisplatin and vinblastine (PV) with PVB in patients with good-prognosis germ cell carcinoma.26 Death from progressive malignancy occurred in 15% of the patients on PV and 5% of the patients on PVB. The authors concluded that the complete deletion of bleomycin compromises therapeutic efficacy. Loeher and colleagues compared three cycles of BEP and the same number of cycles of EP and stated that bleomycin was an essential component in the treatment of patients with favorable-prognosis testicular cancer.27 De Wit et al. of the EORTC Genitourinary Tract Cancer Cooperative Group also compared the use of BEP and EP in patients with good-prognosis testicular non-seminoma. BEP and EP achieved 95% and 87% CR rates, respectively.28 BEP seemed to be more effective than EP, although the dose of etoposide (360 mg/m2) was less than in the usual BEP regimen (500 mg/m2), and this might present a problem in comparing the treatment outcome with other trials. Saxman and co-workers at Indiana University reported the result of a long-term follow-up study of patients with favorable-prognosis germ cell tumors treated with three or four cycles of BEP.29 There was no statistically significant difference in survival between the two groups. They concluded that three courses of BEP was the preferred regimen in good-prognosis testicular cancer. Xiao et al. also undertook a follow-up study of patients with good-prognosis germ cell tumor treated with EP.30 The survival rate of the patients treated with four cycles of EP was equivalent to that treated with BEP. According to these clinical studies, currently, three cycles of BEP and four cycles of EP are both standard options in the treatment of good-prognosis testicular cancer. A comparison of three cycles of BEP and four cycles of EP in a carefully controlled randomized study seems to be the next step. An intermediate prognosis group, a selection of patients whose 5 years survival rate is approximately 80%, was first introduced into the IGCCCG classification in 1997. Moderate disease on the Indiana classification is recognized as good-prognosis because the rate of favorable responders for chemotherapy is 90%. Researchers of the EORTC group compared four cycles of BEP and the same number of cycles of VIP (VP-16, IFM, CDDP) in patients with intermediate-prognosis metastatic testicular non-seminoma.31 The definition of intermediate-prognosis is not identical but similar to the IGCCCG classification. The CR rate and 5-year progression-free survival of both the BEP and VIP regimens were similar, although VIP was more toxic than BEP. BEP seemed to be the standard chemotherapy regimen for intermediate-prognosis testicular cancer. The researchers of the EORTC group have also started a randomized trial to compare BEP and BEP plus paclitaxel for intermediate- and poor-prognosis testicular cancer.32 All 7 patients with intermediate-prognosis disease receiving T-BEP (addition of paclitaxel to BEP) achieved a CR. Clinical trials have not been sufficient to decide the treatment strategy for patients with intermediate-prognosis disease. At present, this group should be treated with standard BEP therapy. The likelihood of cure with standard chemotherapy for patients with poor-prognosis disease is less than 50%. Efforts have been made to develop more effective therapy for poor-risk patients. At first, PVB therapy was recognized as the standard therapy for disseminated germ cell tumors. Then etoposide was introduced into first line chemotherapy and a trial comparing PVB and BEP in advanced germ cell tumors was undertaken.18 According to the subgroup analysis for the 72 patients with advanced stage disease, classified by the Indiana University staging system, the disease-free rate of the PVB regimen was 38% and that of the BEP regimen was 63%. The BEP regimen has since been recognized as the standard to evaluate the outcome of other chemotherapy trials for poor-prognosis testicular cancer. The dose intensity of cisplatin, the most active agent on testicular cancer, was evaluated to improve the cure rate of the treatment. Ozols and associates compared PVeBV (double dose CDDP, VP-16, BLM, VBL) and PVB (standard dose CDDP, VBL, BLM) in the treatment of poor-prognosis non-seminomatous germ cell tumors.33 PVeBV achieved a higher CR rate (88%) than PVB (67%). However, this trial was not compared with standard BEP therapy. Furthermore, the interpretation of results was also complicated by the inclusion of VP-16 only in the high-dose PVeBV regimen. Nichols and co-workers undertook a randomized trial comparing the BEP regimen with a double dose of CDDP and a standard dose of BEP.34 This dose intensity did not show a higher response rate or survival benefit. In fact, significantly increased neurotoxicity, ototoxicity, nausea and vomiting, and myelosuppression occurred. In conclusion, dose escalation of CDDP beyond the standard dose resulted in excess toxicity without the accompanying therapeutic efficacies. Ifosfamide (IFM), usually used in the salvage chemotherapy regimen, was applied to the first line therapy. Nichols’ group compared the standard BEP regimen and the experimental VIP (VP-16, IFM, CDDP).35 A total of 304 men were randomized to receive four courses of BEP or VIP. Overall the CR rate (VIP, 37%; BEP, 31%), favorable response rate (VIP, 63%; BEP, 60%), 2-year failure-free rate (VIP, 64%; BEP, 60%) and 2-year overall survival (VIP, 74%; BEP, 71%) were not significantly different between the two arms. However, hematologic and genitourinary toxicities were significantly frequent in patients treated with VIP. It was concluded that four courses of BEP should remain the standard therapy for disseminated germ cell tumors. Alternating cycles of various regimens were administered to compare their efficacies in the treatment of poor-risk testicular germ cell tumors. Bosl and colleagues evaluated the effectiveness of alternating cycles of EP (VP-16, CDDP) and VAB-6.36 This trial was not a prospective randomized trial. The result did not exceed the response and survival rate of the patients treated with VAB-6 alone. Investigators of the EORTC group undertook a trial comparing four cycles of BEP to an alternating regimen of PVB and BEP on patients with poor-prognosis testicular non-seminoma.37 There was no significant difference in the CR rate, relapse rate and disease-free and overall survival between the two regimens. Kaye and associates compared two sequential chemotherapy regimens, BOP (BML, VCR, CDDP)/VIP-B (VP-16, IFM, CDDP, BLM) and BEP/EP.38 BOP/VIP-B consisted of three cycles of BOP followed by three cycles of VIP-B. BEP/EP consisted of four cycles of BEP and two subsequent cycles of EP. This trial is useful because the results are broadly comparable with those of many other trials using the standard BEP regimen. However, the intensive BOP/VIP-B was associated with more toxicity and showed no improvement in response rate or survival compared with BEP/EP. Alternative cycles of different regimen did appear to have any advantage when compared with standard BEP for poor-prognostic cases. Therefore, four cycles of BEP remains the standard regimen for these patients. In recent years, high-dose chemotherapy followed by autologous bone marrow transplantation (AuBMT) or peripheral blood stem cell transplantation (PBSCT) has been applied to both the salvage treatment for refractory testicular cancer and the first-line treatment for poor-risk disease. Morris and Bosl summarized the trials using high dose chemotherapy in the first line setting conducted at the MSKCC and compared them with standard VAB-6 and VAB-6/EP.39 Patients with poor-risk disease defined by MSKCC criteria, who were being treated with two cycles of VAB-6 or VIP and who had tumor markers which failed to decline according to the predicted half-life, were switched to high-dose CE (CBDCA, etoposide) therapy with AuBMT or CEC (CBDCA, etoposide, CPM) therapy with AuBMT. The rates of the surviving patients with no evidence of disease (NED) treated with VAB-6, VAB-6/EP, VAB-6±CE, VIP±CEC were 17%, 31%, 50% and 50%, respectively. Bokemeyer et al. conducted a matched-pair analysis of the patients with poor-risk disease treated with high-dose or standard dose chemotherapy.40 The high-dose group consisted of the patients treated with high-dose VIP followed by PBSCT within the German multicenter trials. The standard dose group were the patients treated with standard BEP or VIP at Indiana University. The IGCCCG classification and the Indiana staging system were used to define the clinical features of poor-risk disease. Two-year progression-free survival (75%vs 59%) and overall survival (82%vs 71%) were significantly prolonged in the high dose chemotherapy group. Data obtained from these retrospective studies suggest that high-dose chemotherapy with bone marrow rescue in the first line setting may improve the survival of patients with poor-prognosis testicular cancer. Thus, we keenly await the results of currently ongoing prospective randomized trials.39,40 A treatment strategy for patients with refractory testicular cancer who failed in the initial therapy has not yet been established. About 70–80% of patients with advanced testicular cancer attained a CR with standard first-line BEP therapy alone or with the following salvage surgery.2 Patients who fail to achieve a CR or have recurrences during the follow-up period, will be candidates for salvage chemotherapy. Podophyllins, etoposide (VP-16) and teniposide, were recognized as active anti-cancer agents for patients being refractory for cisplatin-based combination chemotherapy.41 However, to date, etoposide is included in the induction chemotherapy regimen.16 Ifosfamide was also conceded to be active for cisplatin-refractory testicular cancer. Wheeler and associates treated 30 patients with ifosfamide who had previously been treated with BEP and etoposide.42 There were six PRs and one CR for an overall response rate of 23%. Ifosfamide was thus used in combination chemotherapies such as VIP (VP-16, IFM, CDDP) and VeIP (VBL, IFM, CDDP). According to several trials, ifosfamide and cisplatin-containing salvage chemotherapy could achieve a 20–30% cure rate (Table 3).43–47 High-dose chemotherapy followed by AuMBT or PBSCT is applied to the treatment of patients with cisplatin-refractory or recurrent testicular cancer because of the poor efficacy of the standard dose salvage chemotherapy regimens such as VIP and VeIP. According to several trials, CR and disease-free rates of high-dose salvage chemotherapy with/without salvage surgery are 10–40% and 20–80%, respectively (Table 4).48–52 In the United States and western European countries, it is generally accepted that the VIP regimen is the second-line and high-dose chemotherapy is the third-line treatment for cisplatin-refractory or recurrent testicular cancer.53 A prospective randomized trial comparing VIP plus high-dose chemotherapy to VIP alone is under way in Europe.54 We also founded the Japan Blood Cell Transplantation Study Group and started a multicenter trial of high-dose chemotherapy in patients with advanced refractory testicular cancer to the standard BEP regimen in 1996.48,55 The results of these trials will define the role of high-dose chemotherapy in the salvage treatment of advanced testicular cancer. Those in whom VIP therapy or high-dose therapy cannot achieve a CR will be candidates for a chemotherapy with novel anti-cancer agents such as paclitaxel, docetaxel, gemcitabine and irinotecan hydrochloride (CPT-11).56–69 Paclitaxel was shown to be effective for previously treated testicular cancer because of its unique mechanism of antitumor activity and the premature stabilization of the microtubules assembly, which is different from that of DNA-damaging agents such as cisplatin and ifosfamide. The first trial of paclitaxel in pretreated germ cell tumors was undertaken by Motzer et al.56 The effective rate of paclitaxel in the salvage treatment of refractory testicular cancer ranged from 11 to 26% (Table 5).56–69 More recently, high effective rates (68% and 80%) of a combination chemotherapy with paclitaxel, ifosfamide and cisplatin (TIP) in the treatment of refractory disease were reported by Beyer et al. and Motzer et al.60,61 The results reported by Motzer et al. showed a high response rate to the TIP regimen in patients with relapsed testicular cancer after conventional dose first-line chemotherapy.61 Motzer and associates also reported the result of dose-intensive salvage therapy with paclitaxel, ifosfamide, carboplatin and etoposide (PICP) for cisplatin-resistant germ cell tumor patients with unfavorable prognostic features, achieving a 57% CR rate.62 Paclitaxel-based combination chemotherapy seems to be more effective than high dose chemotherapy for recurrent or cisplatin-resistant germ cell tumors.61,62 Gemcitabine, a novel pyrimidine anti-metabolite, was proved to be effective in the treatment of cisplatin-resistant ovarian germ cell cancer and applied to the treatment of testicular cancer.64 Two studies evaluating the efficacy of gemcitabine in heavily pretreated testicular cancer were reported (Table 5).65,66 These trials indicate the activity of gemcitabine in intensely pretreated testicular germ cell tumor. Einhorn et al. mentioned an ongoing trial of a combination of paclitaxel and gemcitabine in refractory testicular cancer,66 and we are awaiting the results. Irinotecan hydrochloride (CPT-11), a water-soluble derivative of camptothecin, was originally developed in Japan. Blocking the function of DNA topoisomerase I, irinotecan hydrochloride shows an antitumor activity against various kinds of malignant tumors. Miki and associates found an increased activity of irinotecan hydrochloride in combination with cisplatin or nedaplatin (254-s) according to a basic study using heterotransplanted human testicular cancer xerografts in nude mice.67,68 In recent years, we reported the results of salvage chemotherapy with a combination of irinotecan hydrochloride and cisplatin or nedaplatin for refractory testicular cancer.69 Six of the 14 patients (42.9%) treated with irinotecan-based combination chemotherapy achieved NED with/without following surgery. Due to the small number of patients, multi-institutional clinical trials are needed to define the role of novel anti-cancer agents in the treatment strategy for refractory testicular cancer. The role of salvage surgery for post-chemotherapy residual mass in patients with non-seminomatous germ cell tumors is well established. Histopathologic examination of residual tumors revealed necrosis or fibrosis in 40% of the cases, teratoma in 40% and carcinoma in 20%.1,70 The presence of viable cancer cells in the residual mass after chemotherapy is associated with the poor relapse-free survival rate. Residual teratoma can also grow and might transform and develop into carcinomatous or sarcomatous tissue. Patients with necrosis or teratoma that is completely resected have a good prognosis without further therapy, although additional chemotherapy is necessary for the cases with residual cancer.71–73 Due to the difficulty of predicting the probability of teratoma or carcinoma of the residual tumors with imaging studies, salvage surgery is mandatory for patients with a normal serum level of tumor markers and radiologically recognized residual masses in order to decide further treatment strategy.72 Surgical resection is not indicated for patients with elevated tumor markers, which means that viable malignant components remain.74 Some investigators recommended surgery for patients with initial masses of 3 cm or larger and showing normal CT scan after chemotherapy.74 However, this management is not accepted universally. The approach for patients with advanced seminoma and post-chemotherapy residual mass is still controversial. Between 80 and 85% of residual masses represent fibrosis and necrosis, while others contain viable cancer cells. The three options, close observation, radiation therapy and surgery, are acceptable in the treatment of residual tumors after chemotherapy for advanced seminoma. Herr and associates analyzed a total of 55 patients with advanced seminoma who had undergone surgical exploration of a mass seen on CT after chemotherapy. Of the 27 patients with a post-chemotherapy 3 cm or larger mass on CT, eight (30%) had residual tumors (seminoma in six patients and teratoma in two patients), whereas necrotic tissue was found in the other 28 patients with a mass smaller than 3 cm.75 It was concluded that patients with a residual mass smaller than 3 cm after chemotherapy did not benefit from surgery and patients with a residual tumor 3 cm or larger should undergo surgical resection. On the other hand, Schultz et al. undertook a follow-up study of 21 patients with seminoma with residual mass after chemotherapy and reported that 19 patients (90%) showed no evidence of disease for longer than 2 years.70 It was mentioned that observation is a viable option even when the residual tumor is larger than 3 cm. The optimal management for advanced seminoma patients with persistent radiographic mass after chemotherapy is unresolved and further investigations are necessary. Recently, the extent of salvage surgery after chemotherapy has been one of the main subjects of ongoing discussions. Residual teratoma or viable tumor cells seem to be located within the area of modified retroperitoneal lymph node dissection in advanced stage testicular cancer patients. Furthermore, teratoma or viable cancer cells are rarely identified outside the residual masses. As for retroperitoneal lymph node dissection, resection of the residual tumors or modified retroperitoneal lymph node dissection seems to be used for the majority of patients with disseminated testicular cancer after chemotherapy.76,77 As for thoracotomy, Steyerberg et al. reported that 48 of 54 patients (89%) with necrosis of retroperitoneal lymph nodes after chemotherapy had necrosis of the metastatic lung tumors, 7% had teratoma and 4% had cancer cells.78 The necessity of second surgery seems to be low for patients with necrotic retroperitoneal lymph nodes and careful follow-up of radiographical abnormalities may be acceptable. However, other researchers recommended the complete resection of all anatomical masses, if technically possible.79,80 Cisplatin-based combination chemotherapy can achieve a disease-free rate of approximately 70–80%. To date, the treatment of patients, refractory or recurrent after standard chemotherapy, is the most important issue for discussion concerning advanced testicular cancer. Three novel anti-cancer agents, paclitaxel, gemcitabine and irinotecan hydrochloride, were shown to have an activity in refractory testicular cancer. Applying these drugs as an early line therapy or in concomitant use with cisplatin or its derivatives should be investigated.81 Persistent efforts will achieve the development of a more effective treatment strategy in patients with poor-prognostic or refractory testicular cancer.