Management of Advanced Germ Cell Tumors
▪ 34A Risk-Adapted Therapy of Metastatic Testis Cancer: Good-Risk Patients
Stefan Sleijfer
Ronald De Wit
INTRODUCTION
Before the introduction of cisplatin-based multidrug chemotherapy, the outcome of most patients with disseminated germ cell tumor was very poor. In the 1970s, Einhorn and Donohue developed a regimen consisting of cisplatin, vinblastine, and bleomycin (PVB), yielding impressive results (1). The durable disease-free survival (DFS) rate obtained with this regimen was a major breakthrough in the treatment of this tumor entity, and since then, germ cell tumor has become a model for curable diseases (2). In 1987, a randomized phase III trial comparing two cisplatin-based therapies was reported by Williams et al. (3). This study revealed that four cycles of the combination of bleomycin, etoposide, and cisplatin (BEP) had a favorable toxicity profile and improved activity compared with four cycles of PVB (3). Following the report of this study, four cycles of BEP has become the standard first-line chemotherapeutic regimen for patients with disseminated germ cell tumor.
Shortly after the introduction of cisplatin-based chemotherapy, it was recognized that patients could be categorized into groups with different prognoses. Various prognostic factors were identified, including the primary site (gonadal vs. extragonadal), seminoma or nonseminoma, extent of disease, localization of metastatic disease, and the level of the tumor markers a-fetoprotein (AFP), β-human chorionic gonadotropin (β-HCG), and lactate dehydrogenase (LDH). Combination of two or more of these factors resulted in a wide number of classifications. By using these differential prognostic categories, studies were initiated in separate groups. For patients with good prognostic features, studies were designed to find new regimens with reduced toxicity but with the same treatment efficacy, whereas for patients with poor risk, studies aimed at enhancing antitumor activity by intensifying treatment. However, because large institutions and groups, such as Memorial Sloan-Kettering Cancer Center (MSKCC) (4), Indiana University (5), Australian Germ Cell Trial Group (6), the European Organization for Research and Treatment of Cancer (EORTC) (7), and the Medical Research Council (MRC) (8), used their own criteria of disease extent and serum markers cut-off values for determining risk status, including or excluding patients affected the response rates obtained in the various regimens. For example, the EORTC criteria for good-prognosis nonseminomatous testicular cancer required that 90% of patients achieve a complete response rate with cisplatin-based therapy (7), whereas according to the early MSKCC criteria (4), good-risk patients only required a complete response rate probability of 50% or greater.
Because the diverse classification systems severely hampered intergroup study result comparisons, the International Germ Cell Cancer Collaborative Group (IGCCCG) was established in 1991 in order to develop a consensus classification. The IGCCCG system was formulated on the basis of the outcomes of almost 6,000 patients with disseminated germ cell tumor who were treated with cisplatin-based chemotherapy, and the system consisted of three groups with a good, an intermediate, and a poor prognosis (Table 34A.1). Because seminoma is more susceptible to chemotherapy than nonseminoma and because seminoma consequently possesses a more favorable prognosis, none of the patients with seminoma fulfills the criteria for poor risk. For patients with nonseminomatous cancer, the 5-year survival rates of the good-, intermediate-, and poor-risk groups are 92%, 80%, and 48%, respectively, whereas these rates for patients with seminoma are 86% for the good-prognosis and 72% for the intermediate-prognosis groups (9).
This chapter addresses the treatment of patients with germ cell tumor who belong to the good-risk metastatic disease group. In particular, it focuses on those trials that form the basis of the current standard treatment. However, it should be noted that all studies except one (10) in this particular subgroup were done before the introduction of the IGCCCG classification; therefore, the translation of the results of the individual chemotherapeutic regimens in the studies is hampered. This chapter also provides guidelines on how treatment may be adapted in situations where the scheduled treatment plan has to be changed because of encountered toxicity.
RESULTS OF FOUR CYCLES OF BLEOMYCIN, ETOPOSIDE, AND CISPLATIN IN GOODPROGNOSIS DISEASE
Following initial trial results showing the efficacy of cisplatinbased chemotherapy and the subsequent recognition of the efficacy of etoposide (3), four cycles of BEP became standard treatment for all patients regardless of the prognostic group. BEP consists of bleomycin (30 units) given weekly, etoposide (100 mg/m2) given daily for 5 days, and cisplatin (20 mg/m2) administered daily over a period of 5 days. Patients received these cycles at 3-week intervals. In Europe, initially, a lower dose of etoposide was given for a total dosage of 360 mg/m2/cycle.
Irrespective of the prognostic classification used, the longterm DFS rates by BEP chemotherapy are impressive in patients who had a good prognosis. The rate of patients achieving a no-evidence-of-disease (NED) state either by BEP alone or after adjunctive resection of postchemotherapeutic residual masses ranges from 90% to 95%. Relapses after obtaining the NED state occur in approximately 5% of patients, of which most relapses are encountered in the first 2 years after treatment (11). In addition, >50% of relapsing patients can be successfully treated by subsequent salvage chemotherapy. These favorable figures obtained by BEP are reflected in excellent long-term overall survival rates ranging from 90% to 95% (10,12,13,14,15).
TABLE 34A.1 THE INTERNATIONAL GERM CELL CONSENSUS CLASSIFICATION (IGCCCG) | |||||||||||||||
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SIDE EFFECTS OBTAINED WITH BLEOMYCIN, ETOPOSIDE, AND CISPLATIN
The impressive outcome of chemotherapeutic treatment with BEP, however, is sometimes at the expense of severe toxicity, both in the short term and in the long term. One of the most severe acute side effects of the use of bleomycin is the occurrence of bleomycin-induced pneumonitis (BIP). Clinically significant BIP occurs in approximately 10% of patients and has a fatal outcome in approximately 3% of all patients treated with bleomycin (16), thereby accounting for a substantial proportion of the total mortality in patients with good-prognosis disease. Several risk factors for the development of BIP have been identified, including the total bleomycin dose, renal dysfunction, age, extent of disease (17), smoking, and, probably, existing pulmonary comorbidity (16) (Table 34A.2). There are several indications that BIP develops through bleomycin-induced damage of the endothelium of the pulmonary vasculature. Another vascular side effect of bleomycin is the occurrence of Raynaudlike phenomenon, manifesting as painful digits and paresthesias, particularly following exposure to cold temperature (18). The reported incidence of this side effect, which may last for many years after completion of treatment, varies widely from 6% to up to 40% of the patients treated for testicular cancer, depending on the method of investigation (3,10,19). Other well-known side effects of bleomycin are fever, occurring several hours after infusion, and skin toxicity.
The characteristic side effect of the second compound of the BEP regimen, etoposide, is bone marrow depression. Severe myelosuppression, defined as neutropenia grade 4, neutropenic fever, and thrombopenia grade 4, occurs in about 20% of the patients at any point of time during treatment with four cycles of BEP (10). Late-term etoposide-related toxicity consists of an increased risk of acute leukemia (20). This risk is clearly dose related and is predominantly apparent at a total dose of >2 g/m2. In patients receiving a cumulative dose of <2 g/m2 of etoposide, this risk is still estimated to be increased 20-fold compared with the general population. However, because the risk of developing acute leukemia in the general population is rather small, the cumulative risk for patients treated with etoposide-based regimens is approximately 6% (21).
TABLE 34A.2 RISK FACTORS FOR DEVELOPMENT OF BLEOMYCIN-INDUCED PULMONARY TOXICITY | |||||||
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Cisplatin is regarded as the most active component of the BEP regimen. However, it is also one of the most emetogenic agents known. Nowadays, this disturbing side effect can be alleviated considerably by the introduction of the 5HT-antagonists and by the recent availability of the neurokinin-1-antagonist, aprepitant (22,23). Another serious side effect of cisplatin is nephrotoxicity. During cisplatin-based therapy, a median decrease of 20% in glomerular filtration rate (GFR) is observed. On long-term follow-up, a persistent impaired renal dysfunction defined as a GFR <70% of the lower normal range is found in 20% to 30% of the patients after receiving cisplatin-based treatment for germ cell tumor (25). Neurotoxicity manifesting as various forms, including peripheral sensory neuropathy, autonomic neuropathy, Lhermitte sign, and, sporadically, encephalopathy, is another side effect of cisplatin (26). The most predominant neuropathic symptom is paresthesia and is reported by approximately one half of the patients (27). The exact underlying mechanism is uncertain, but accumulation of cisplatin in neurons is the probable mechanism. Cisplatin-induced vasospasms account probably for additional neurotoxic symptoms such as focal seizures or transient blindness. Ototoxicity, another form of cisplatinmediated neurotoxicity, is caused by destruction of auditory neurons and outer hair cells in the organ of Corti. By pure-tone audiometry, disturbances at the higher frequencies are found in approximately 70% of patients treated with cisplatin-based chemotherapy for germ cell tumor (27). Fortunately, clinical neuropathy is, to a great extent, reversible and rarely impacts daily-life activities of the majority of patients.
In view of these severe treatment-related side effects and the excellent prognosis of patients with good-risk metastatic germ cell tumor, the trials carried out in this group aimed to reduce treatment toxicity without compromising efficacy. These studies focused particularly on elimination of bleomycin, substituting cisplatin by the less toxic component carboplatin, and reduction of the total drug dose by decreasing the number of cycles.
TRIALS STUDYING THE DELETION OF BLEOMYCIN FROM TREATMENT
Because of the severe side effects of bleomycin and doubts in the 1980s whether bleomycin provided a major contribution in cisplatin-based chemotherapy in germ cell tumor, several efforts have been made to find out if this component could be deleted from treatment. Three studies investigating this topic have been published.
In an Australian study, which was initiated before the superiority of etoposide over vinblastine was demonstrated by Williams et al. (3), 222 patients were randomized to receive treatment with cisplatin and vinblastine, 6 mg/m2 on day 1 and day 2 every 3 weeks (PV), with or without bleomycin 30 units weekly for a maximum of 12 weeks (PVB) (28). Patients were classified as having good prognosis according to criteria of the Australian Germ Cell Trial Group. In the 218 evaluable patients, tumor-related mortality was significantly increased in the PV arm compared with those assigned to receive PVB (16 patients vs. 6 patients). Because of this increase, it was concluded that bleomycin could not be deleted from this regimen. Patients allocated to PVB experienced considerably more toxicity, resulting in six toxic deaths compared with one in the PV arm. Overall survival was similar for both arms after a minimum follow-up of 4 years (28).
Loehrer et al. (15) reported an Eastern Cooperative Oncology Group study comparing three cycles of BEP with three cycles of EP in 171 patients deemed to have a favorable prognosis according to the Indiana staging system. In both groups, the rate of patients achieving NED status after chemotherapy with or without subsequent resection of residual mass was similar. However, the number of relapses after obtaining NED was greater in the EP arm, which was translated into a significantly decreased overall survival (95% vs. 86%). These results clearly show that three cycles of BEP is superior to three cycles of EP and that bleomycin cannot be eliminated from treatment when three cycles of BEP are given.
The largest study investigating whether bleomycin could be eliminated from therapy was an EORTC study randomly assigning 419 patients to four cycles of BEP or four cycles of EP (14). Patients enrolled in this study were categorized as good prognosis according to the EORTC criteria that were in use at that time (7). Etoposide was given at a slightly reduced dose of 360 mg/m2/cycle. The number of complete responses obtained by chemotherapy alone plus those achieving NED after additional surgery (95% vs. 87%) was clearly in favor of the BEP arm. The numbers of patients relapsing was identical in both arms. As expected, the toxicity in this study was more pronounced in the BEP arm, particularly for pulmonary toxicity; neurotoxicity and Raynaud-like phenomenon were also encountered more frequently. Because of the relatively low number of events, overall survival did not differ significantly. To place this study in full perspective, it must be noted that good-risk patients according to the EORTC classification (7) represents a group with an extremely good prognosis compared with other classification systems. Nevertheless, even in this group, the deletion of bleomycin resulted in a decrease in efficacy, underlining the importance of bleomycin in four cycles of BEP with etoposide at a dose of 360 mg/m2/cycle.
In view of the congruent results of these three studies, it can be firmly concluded that bleomycin cannot be omitted without attenuating treatment efficacy from the following regimens: three cycles of BEP, four cycles of PVB, or four cycles of BEP (with etoposide at a dose of 360 mg/m2/cycle). However, whether bleomycin can be deleted from four cycles of BEP, with etoposide dosed at 500 mg/m2/cycle, remains to be elucidated. By retrospectively analyzing two studies containing a treatment arm with four cycles of EP, Xiao et al. from MSKCC reported on the long-term efficacy of four cycles of EP in patients reclassified as having good prognosis according to IGCCCG classification (29). This update showing a 91% DFS indicated that four cycles of EP is a valid alternative.
Another strategy to circumvent bleomycin-mediated detrimental effects is by omitting this drug and by integrating another compound known to be active in germ cell malignancies. An example of such a drug is ifosfamide. Hinton et al. (30) reanalyzed an intergroup study in which patients with “advanced” metastatic disease, defined according to the Indiana staging system, were randomized to receive treatment with either four cycles of BEP or four cycles of ifosfamide, etoposide, and cisplatin (VIP). Applying the IGCCCG classification, 13.1% of the 286 evaluable patients enrolled belonged to the good-prognosis group. In this group, as in the other risk groups, VIP yielded equivalent antitumor efficacy compared with BEP, but at the cost of increased myelosuppression. These findings are consistent with the results from a study comparing VIP versus BEP in patients with intermediate-risk disease (31). Therefore, although ifosfamide yields comparable efficacy as bleomycin in combination with etoposide and cisplatin, on the basis of the observed significant increase in myelosuppression, VIP should not be recommended as initial treatment of patients presenting with good-risk disease.
TRIALS ESTABLISHING WHETHER CISPLATIN CAN BE SUBSTITUTED BY CARBOPLATIN
As previously mentioned, cisplatin accounts for a substantial part of the encountered toxicity during treatment with BEP. Carboplatin is another platinum analog with proven activity against germ cell tumor. Its toxicity profile is predominantly featured by the occurrence of myelosuppression, but carboplatin is less emetogenic and lacks cisplatin-mediated toxicities such as ototoxicity, neurotoxicity, and renal deterioration.
At MSKCC, a trial was conducted that randomized 270 patients to receive four cycles of etoposide with either cisplatin (EP) or carboplatin (EC) (32). The dose of etoposide was 500 mg/m2/cycle in both regimens, and carboplatin was administrated as a fixed dose of 500 mg/m2. EP was given at 3-week interval, whereas EC was administered at 4-week interval because of the anticipation of more severe myelosuppression. The rate of complete responses obtained did not differ, but more patients assigned to EC experienced a relapse (12% vs. 3%). An unfavorable outcome defined as an incomplete response or relapse occurred in 24% in patients receiving EC, compared with 13% in those allocated to EP. In addition, the patients treated with EC were more frequently admitted because of neutropenic fever and encountered more thrombocytopenia (33). Because of successful salvage therapy in patients relapsing after EC, there was no difference in overall survival (32).
The largest study investigating whether cisplatin could be substituted by carboplatin is a collaborative study of the MRC and EORTC (34). In this study, 598 patients with nonseminoma were randomly allocated between either BEP or bleomycin, etoposide, and carboplatin (BEC). In both regimens, etoposide was administered at 360 mg/m2. Bleomycin was given at 3-week interval. Carboplatin was dosed at an area under the curve dosage of 5 mg/mL/min. A status of NED was achieved in more patients in the BEP group (94.4%) than in the BEC group (87.3%). In addition, there were more relapses on BEC, resulting in a significant difference in DFS in favor of the patients allocated to BEP. As expected, deterioration in renal function
and audiometry was more pronounced in the BEP group. Myelosuppression, on the other hand, particularly thrombocytopenia, was more frequent in the patients receiving carboplatin. Most importantly, overall survival was significantly greater for the BEP group, with 3-year overall survival rates of 97% and 90% for patients receiving BEP and BEC, respectively.
and audiometry was more pronounced in the BEP group. Myelosuppression, on the other hand, particularly thrombocytopenia, was more frequent in the patients receiving carboplatin. Most importantly, overall survival was significantly greater for the BEP group, with 3-year overall survival rates of 97% and 90% for patients receiving BEP and BEC, respectively.
Taken together, the data obtained by these two studies conclusively indicate that carboplatin cannot replace cisplatin with the used drugs and schedules for the treatment of patients with good-prognosis nonseminoma. Obviously, the application of carboplatin results in an inferior outcome in this patient group compared with cisplatin-based regimens.
TRIALS INVESTIGATING THE FEASIBILITY OF REDUCING THE NUMBER OF CYCLES
Because many of the side effects associated with BEP are dose related, reduction in total drug dose is an important objective. The most straightforward manner to achieve this purpose is by reducing the number of cycles from four to three.
The first to do so were Einhorn et al. (12) for the Southeastern Cancer Study Group, which compared the efficacy of three versus four cycles of BEP in 184 patients with minimal and moderate disease according to the Indiana staging system. At a median follow-up of 19 months, it appeared that the antitumor efficacy of both schedules was similar in terms of achieved complete response rate, relapse rate, and DFS. Toxicity clearly favored the three cycles of BEP group. At a longer follow-up, a median of 10.1 years, both strategies exhibited comparable efficacy in terms of overall survival and DFS (13).
However, because this study was designed to detect a response rate difference >10%, a difference of anything <10% could not be excluded. Of note, in the clinical practice, a difference between 5% and 10% would be considered unacceptable, because it may considerably increase the risk of failure to first-line chemotherapy and thereby the ultimate outcome. Therefore, a subsequent trial performed by the EORTC and MRC was designed to exclude a difference of 5% or more in 2-year progression-free survival (PFS) between three and four cycles of BEP (10). For patients allocated to four cycles, the final cycle was without bleomycin. This study, which began in 1995, is the only trial in which patients were entered with good-prognosis disease, according to the IGCCCG system. In this large trial, 812 patients were randomized to receive three or four cycles of BEP. The primary endpoint, 2-year PFS was equivalent at 90.7% (95% CI, 87.8%-93.6%) and 89.1% (95% CI, 85.9%-92.3%) for three and four cycles, respectively. The achieved response rate and overall survival at 2 years, 97.0% versus 97.1% for three and four cycles, respectively, were identical as well, indicating that in terms of efficacy, these two regimens are equivalent. The large size of the trial allowed another question to be answered—whether a “condensed” 3-day regimen was equivalent to a 5-day regimen. By using a 2 × 2 factorial study design and a second randomization, therapeutic similarity between a condensed 3-day regimen and the conventional schedule was also assessed. Of the 812 patients entered on the study, 681 patients were also randomized for this purpose. The condensed 3-day BEP consisted of bleomycin, 30 units weekly for 9 weeks; etoposide, 165 mg/m2 on days 1 through 3; and cisplatin, 50 mg/m2 on days 1 and 2. The 5-day regimen comprised bleomycin, 30 units weekly for 9 weeks; etoposide, 100 mg/m2 on days 1 through 5; and cisplatin, 20 mg/m2 on days 1 through 5. Hence, the total doses administered per cycle were similar for both schedules. The two study arms yielded identical 2-year PFS, 89.5% (95% CI, 86.1%-92.9%) for the 3-day schedule and 89% (95% CI, 85.5%-92.5%) for the 5-day schedule, demonstrating equivalent efficacy for this comparison as well. In the patients assigned to the 5-day schedule, postponement of the next cycle and dose reduction of etoposide due to hematologic adverse events were more common, whereas nausea and late ototoxicity occurred more frequently in the 3-day arm. A second report on this study (35) described the quality of life in 666 participating patients. On the basis of questionnaire-based assessments, it was concluded that three cycles of either the 3- or the 5-day schedule of BEP were associated with acceptable toxicities. However, when four cycles were given, the 5-day schedule should be preferred over a 3-day schedule because of gastrointestinal toxicity and long-term risk for tinnitus with the 3-day schedule.
A third study aiming to establish the feasibility of dose reduction was conducted by Toner et al. (36) for the Australian and New Zealand Germ Cell Trial Group. In this study, three cycles of BEP (30 units bleomycin on days 1, 8, and 15; 100 mg/m2 etoposide on days 1 to 5; 20 mg/m2 cisplatin on days 1 to 5, given at 3-week interval) were compared with four cycles of BEP (30 units bleomycin on day 1; 120 mg/m2 etoposide on days 1 to 3; 100 mg/m2 cisplatin on day 1, at 3-week interval). Hence, the cumulative doses and dose intensities of the applied agents differ considerably between these two regimens. In total, 166 patients were enrolled. The study was terminated prematurely when an interim analysis revealed an inferior overall survival rate for those allocated to four cycles of BEP at a median follow-up of 33 months. These findings suggest that increasing the total dose of cisplatin does not compensate for lowering the total doses and dose intensities of bleomycin and etoposide. Drawing firm conclusions from this study, however, is hampered because of the multiple differences between the two regimens.
On the basis of the studies described in the preceding text, three cycles of BEP, with bleomycin given weekly and etoposide at a dose of 500 mg/m2/cycle, is equivalent to four cycles of BEP for good-risk patients and is accompanied by a more acceptable toxicity profile, more convenience for the patients, and reduced costs. Therefore, three cycles of BEP is recommended as standard therapy for patients with good-prognosis disease.
EFFICACY OF FOUR CYCLES OF ETOPOSIDE WITH CISPLATIN
The recommended standard regimen of three cycles of BEP is relatively contraindicated for patients at increased risk to develop bleomycin-related toxicities. For these patients, a regimen lacking bleomycin is warranted. In a retrospective analysis, Xiao et al. (29) reported the outcomes of four cycles of EP with etoposide at 500 mg/m2/cycle in good-risk patients, according to the MSKCC classification, on two randomized trials. One of these trials compared four cycles of EP with a regimen that was predominantly used as standard treatment at MSKCC, comprising cisplatin, vinblastine, bleomycin, dactinomycin, and cyclophosphamide (VAB-6) (37). This study revealed that EP was therapeutically equivalent but less toxic (37). The second study was a randomized comparison between etoposide with either cisplatin (EP) or carboplatin (EC) (32). In the long-term follow-up report of the 214 patients who had received EP in these two trials, a status of NED was achieved in 91%, whereas 86% were alive at a median follow-up of 7.6 years. Reclassification using the IGCCCG criteria showed that 148 (69%) of the patients belong to the good-prognosis group. Outcome in this particular group was excellent, with 96% reaching complete response and 5% experiencing a relapse (29). In the light of these data, four cycles EP with etoposide given at 500 mg/m2/cycle is a valid alternative
in patients for whom there is concern for the risk to develop bleomycin-mediated side effects (Table 34A.3).
in patients for whom there is concern for the risk to develop bleomycin-mediated side effects (Table 34A.3).
TABLE 34A.3 REPORTED DURABLE DFS OR PFS RATES OBTAINED IN PATIENTS WITH GOOD-PROGNOSIS DISEASE | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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The only randomized trial to directly compare 3BEP and 4EP was conducted by the French Federation of Cancer Centers Genito-Urinary Group with a total of 270 patients (38). The study was originally designed to test for therapeutical equivalence, with an expected favorable response of 90% and not more than a 10% difference in the response proportions between the two treatment arms. In view of the curative potential of chemotherapy in testicular cancer, a difference between 5% and 9% would have been more appropriate. To rule out a difference of 5% in the 2 or 3 year PFS rate would have required 800 patients. In the alternative case that a difference in efficacy between the treatment groups would be observed and the investigators would change their objective by aiming to detect a difference of 10%, a total of 61 events would be required, translating into a total of 408 patients needed. Hence, the 270 patients recruited and 257 evaluable for the efficacy analysis were insufficient numbers to detect either superiority of one regimen or noninferiority. When the eventual 4-year event-free-survival rates are added to those previously reported results by 3BEP and 4EP (Table 34A.3), there is no indication that there are clinically meaningful differences in the efficacy of the two regimens (39).
Although the study was underpowered to detect superiority of one regimen over the other, the sample size did allow to observe differences in toxicity. There was an unexpected difference in neurological toxicity (any grade) in favor of 4EP; 16% on BEP versus 5% on EP, (p = 0.006). Three cycles of BEP also resulted in significantly greater frequency of Raynaud phenomenon, 29% versus 8% (p = 0.0001). Pulmonary toxicity was observed in 9% of patients on 3BEP, mostly grade 1 and 6% on 4EP, which was not significant. No toxic deaths occurred. These observations provide important information. First, the data on minor pulmonary toxicity add to other recent data that three cycles of BEP, with a cumulative dose of bleomycin of 270 mg, bear a minor risk of bleomycin-induced pneumonitis and the risk of bleomycin-associated death has become less than 0.2% (10). Second, this direct randomized study of 3BEP versus 4EP provides the important information that the addition of bleomycin to 3EP causes greater incremental neurological toxicity than the addition of a fourth cycle of EP in the EP regimen. Of equal importance is the significant greater skin toxicity of bleomycin. The difference in toxicity is similar to that observed in the study of the EORTC of 4BEP versus 4EP that showed skin toxicity (any grade) in 39% of patients receiving BEP versus 5% on EP (p < 0.001), and late Raynaud phenomenon in 8% versus 0%, respectively, (p < 0.001) (14). Hence, it is clear that bleomycin clinically significantly contributes to the chemotherapy toxicity. Raynaud phenomenon is considered to reflect vascular damage. Arteriograms have documented diffuse narrowing in the hands of these patients. Also, late cardiovascular toxicity appears to be associated with the development of Raynaud phenomenon. Late cardiovascular disease is well documented in testis cancer survivors after platinum-based chemotherapy. Most of the patients in these studies have been treated with cisplatin, vilblastine, and bleomycin or BEP; thus the combined use of bleomycin and cisplatin. Databases on platinum-based chemotherapy without bleomycin are too small to detect meaningful differences in the occurrence of late cardiovascular toxicity.
For the time being, 3BEP and 4EP can still be considered standard regimens, which yield excellent long-term efficacy results in IGCCC good-risk germ cell cancer. However, there may very well be differences in acute and late toxicity inflicted by this chemotherapy that eventually identifies a winner.
TREATMENT OF SEMINOMA VERSUS NONSEMINOMA
Because most studies conducted in disseminated germ cell tumor accrued patients with both nonseminomatous and seminomatous cancer, treatment of patients with pure seminoma does not differ from that of patients with nonseminoma from the same prognosis group. However, regarding the toxicity of BEP and the fact that patients with seminoma are generally 10 to 20 years older than patients with nonseminoma having more comorbidity, reduction of treatment-induced toxicity is especially important for these patients. The slightly greater chemosensitivity of seminoma over nonseminoma enables the assessment of potentially less toxic schedules. As a consequence, studies have been done focusing on patients with seminoma. However, most trials performed in patients with seminomatous cancer have been phase II because of the rarity of this disease; randomized data are therefore scarce. More than 90% of patients presenting with “advanced” seminoma are still categorized into the good-risk group according to the IGCCCG classification. The only randomized trial in this patient group published as a full paper is a study by Horwich et al. comparing four cycles EP with etoposide at a dose of 360 mg m2/cycle to four cycles single-agent carboplatin,
400 mg m2/cycle, adjusted to renal function (40). This study was intended to show equivalence for both schedules, but following publications that revealed inferiority of carboplatin-based schedules in patients with nonseminoma (32,34), enrollment declined considerably, so the study was terminated early, when 130 patients were entered in total. After a median follow-up of 4.5 years, the disease-free and overall survival at 3 years were in favor for those assigned EP, although these differences were not statistically significant. In view of the low power of this study because of the relatively small number of patients accrued, this outcome should not be regarded as an indication for similar efficacy between both regimens.
400 mg m2/cycle, adjusted to renal function (40). This study was intended to show equivalence for both schedules, but following publications that revealed inferiority of carboplatin-based schedules in patients with nonseminoma (32,34), enrollment declined considerably, so the study was terminated early, when 130 patients were entered in total. After a median follow-up of 4.5 years, the disease-free and overall survival at 3 years were in favor for those assigned EP, although these differences were not statistically significant. In view of the low power of this study because of the relatively small number of patients accrued, this outcome should not be regarded as an indication for similar efficacy between both regimens.
A number of phase II trials examining regimens yielding outcomes comparable to BEP have been published. Several of these were carboplatin-based multidrug regimens such as ifosfamide and carboplatin (41) and cyclophosphamide, vincristine, and carboplatin (42), the latter regimen with the advantage that it enables administration in an outpatient setting. Other regimens showing good efficacy in disseminated seminoma are four cycles of EP (43), cyclophosphamide and cisplatin (44), and cisplatin, vincristine, and ifosfamide that was, however, accompanied with severe toxicity, primarily hematologic (45). It should be emphasized, though, that none of these regimens have been compared with three cycles of BEP. Therefore, to date, either 3 × BEP or 4 × EP should be regarded standard treatment for these patients.
ADJUSTING SCHEDULED TREATMENT PLAN BECAUSE OF TOXICITY
Treatment with BEP can be complicated by the occurrence of severe toxicity precluding further treatment according to the standard treatment plan. In such cases, it is warranted to adjust the chemotherapeutic treatment without seriously attenuating the ultimate outcome.
If bleomycin-related toxicities including severe skin reactions or pulmonary toxicity occur, further bleomycin administration is contraindicated. Also, the development of renal dysfunction, for example, by the coadministration of cisplatin, can be a reason to stop further bleomycin therapy, as renal deterioration renders patients at greater risk for bleomycinmediated side effects. This is underscored by the observation that patients with a compromised creatinine clearance <80 mL/min at the first bleomycin administration have a four times increased risk to develop bleomycin-induced pulmonary toxicity compared with patients with a normal renal function (17). Because bleomycin, as reported earlier in this chapter, is an essential component of the curative chemotherapy, withholding bleomycin treatment may compromise efficacy. However, the minimum dose of bleomycin remains to be established. Because, as discussed previously, three cycles of EP are inferior compared with three cycles of BEP with a cumulative dose of 270 units bleomycin (15), the critical minimum dose of bleomycin is unknown but lies somewhere between 30 and 270 units bleomycin. Should further bleomycin administration be contraindicated in the individual patient, there are several options. The first is simply to accept the omittance of the remaining bleomycin doses when most of the intended cumulative dose of bleomycin has been given, for example, more than 180 units. In such a case, it is mandatory that both etoposide and cisplatin be administered full dose and on time for the full three cycles. This approach, however, adds some risk for attenuation of antitumor activity. On the basis of the outcomes obtained with four cycles of EP (29), probably the safest option is to continue with EP and to add an extra (fourth) cycle. An alternative strategy is to replace BEP with VIP during the remaining cycles. BEP and VIP are therapeutically equivalent, as has been shown in patients with disseminated disease, including a small group of patients with good prognosis features (30,31). This approach, however, is accompanied by more toxicity, in particular hematologic toxicity.
Another commonly occurring event during BEP is myelosuppression, predominantly because of the use of etoposide. Severe neutropenia with neutrophils <0.5 × 109 per L or platelets <100 × 109 per L may necessitate postponement of a subsequent cycle. Treatment delay should preferably not exceed 3 to 7 days, and treatment should be continued at full dose following recovery above these values. To avoid further treatment delays in subsequent cycles, patients should be treated with granulocyte colony-stimulating factor (G-CSF) following any previous dose delays for reasons of prolonged neutropenia. The occurrence of neutropenic complications, such as neutropenic fever or sepsis, should also warrant the use of G-CSF rather than attenuation of etoposide dose and schedule adherence.
The most worrisome cisplatin-induced side effect hindering administration of chemotherapy according to appropriate guidelines is the development of renal dysfunction, which considerably decreases the clearance of both cisplatin and bleomycin. In fact, cisplatin is advised not to be given in the face of a creatinine clearance of <40 to 50 per mL. If the creatinine clearance begins to decrease, vigorous hydration measures should be used to avoid further deterioration of renal function. Only if forced by persistent severe renal dysfunction, the substitution of cisplatin for carboplatin may be considered. In view of the slightly higher chemosensitivity of seminoma, the use of carboplatin in elderly patients with seminoma who have worsening renal function during cisplatin-containing treatment may be of slightly lesser concern, whereas for patients with nonseminoma, the use of carboplatin-based regimens should be postponed whenever possible.
EMERGENCE OF A PREVIOUSLY UNDERESTIMATED LONG-TERM SIDE EFFECT
In addition to the long-term and well-known side effects associated with BEP, such as acute leukemia and second solid malignicies, ototoxicity, neurotoxicity, decline of renal function, and infertility, evidence is recently mounting that patients are also at a significant risk to experience cardiovascular events (46,47). This risk is now estimated to be two- to threefold greater than in the general population several years after treatment (48,49,50). In view of the considerable incidence of cardiovascular events in the general population, the risk for cardiovascular sequelae in the long term exceeds the risk for relapse or leukemia. The underlying responsible mechanisms have not been elucidated yet, but effects on the endothelium (possibly by cisplatin, or by bleomicin, or the particular combination of these agents) exerted by chemotherapy may be involved. Additionally, in patients chemotherapeutically treated for germ cell tumor, the rate of cardiovascular risk factors such as hypertension, hypercholesterolemia, insulin resistance, overweight, and hypogonadism is increased compared with patients with stage I disease (48). Therefore, physicians involved in the follow-up of these patients should regularly screen for cardiovascular risk factors and treat accordingly.
Because it is currently unclear as to which exact treatment component is the main cause for this detrimental effect, further investigation is warranted in order to elucidate the responsible treatment compounds and to find means to circumvent this side effect. Until then, it remains uncertain as to which of the two recommended treatment options, three cycles of BEP or four cycles of EP, should be preferred over the other in view of the late-term cardiovascular risk.
CONCLUSION
The successful treatment of disseminated germ cell tumor has been a major challenge since the implementation of cisplatinbased multidrug chemotherapy. The subsequent recognition that patients can be classified into groups with different prognosis status has prompted investigators to develop regimens according to risk status. For patients with good-risk features, the aim of such trials is to design regimens with an improved toxicity profile while maintaining efficacy. As a consequence of this goal, standard chemotherapy has been narrowed from four cycles of BEP to three cycles of BEP. A valid alternative option is treatment with four cycles of EP, in particular, for those patients at increased risk to develop bleomycin-related side effects (Table 34A.2). In case of side effects necessitating adjustment of treatment, several strategies are available without comprising treatment efficacy.
Because it became clear that the risk for cardiovascular events presents the greatest long-term threat for patients cured from disseminated germ cell tumor, it is important to gain more insight into the underlying pathogenesis and exact cause of this particular adverse effect. This may enable further attenuation of treatment toxicity in the future. Therefore, efforts to minimize treatment-related toxicity without sacrificing the chance for cure should continue for patients with good-risk disease.
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▪ 34B Management of Advanced Germ Cell Tumors: IGCCC Intermediate- and Poor-Risk Patients
Peter S. Grimison
Guy C. Toner
INTRODUCTION
Patients with advanced germ cell tumors can be cured in 70% to 80% of cases with first-line chemotherapy and surgery (1). Despite these excellent outcomes, approximately 20% of patients with advanced disease die due to complications of the cancer or its treatment. The majority of patients with incurable disease can be identified before treatment based on defined clinical characteristics.
Patients who relapse or fail to adequately respond to firstline therapy can still potentially be cured with salvage therapy, but less than half achieve prolonged survival. Patients with disease refractory to initial chemotherapy have a worse outlook (2,3). The limited success of salvage therapy dictates that initial treatment choices and their skilled implementation by a multidisciplinary team are vital. Clinicians managing patients with advanced germ cell tumors need to be familiar with treatment regimens, able to identify patients at risk of refractory disease or relapse, and be experienced in their challenging management.
DEFINITION OF RISK GROUP AND PROGNOSTIC FACTORS
Determination of treatment based on pretreatment clinical characteristics was proposed early in the development of effective chemotherapy (4). In the 1980s, several major groups identified factors predictive of a poor outcome, including tumor marker elevation, extent or bulk of metastatic disease, visceral organ involvement, histopathology, and extragonadal primary site (5,6,7,8,9,10). Mediastinal primary nonseminomas were noted to have distinct clinical characteristics and respond poorly to treatment, with very poor outcomes (11,12,13). Although most analyses identified similar factors, unfortunately, many trial groups or individual centers produced their own prognostic classification systems and used them exclusively in the design and reporting of clinical trials. All of these analyses and classifications were open to criticism for their small numbers, exclusion of certain variables found important by other groups, and lack of consensus.
Bajorin et al. (14) demonstrated the impact of differences in prognostic classification on clinical trials in poor-prognosis disease. The inclusion of patients based on less stringent criteria could make the results of a treatment seem better than an equally effective alternative used in a more stringently selected patient population. This study demonstrated the need for uniform criteria for prognostic classification in clinical trial design and demonstrated clearly the problems of comparison of small phase II trials using differing patient selection criteria.
The International Germ Cell Consensus Classification
The International Germ Cell Cancer Collaborative Group (IGCCCG) developed a prognostic factor-based staging system in 1997, based on pooled data from almost 6,000 cases of advanced germ cell tumors treated with chemotherapy between 1975 and 1990 (15). Patients with nonseminoma and seminoma histologies arising from testicular and extragonadal primary sites were included. Three groups of patients with advanced germ cell tumors are defined by the IGCCC with good, intermediate, and poor prognoses (Table 34B.1). The intermediate-prognosis group included 26% of patients and achieved 79% overall survival at 5 years. The poor-prognosis group included 14% of patients and achieved 48% overall survival at 5 years.
The IGCCC staging system is now widely accepted. IGCCC groupings should be used to determine prognosis, select the most appropriate treatment for patients requiring chemotherapy, and determine eligibility for clinical trials (16). This use promises to allow better analysis of results and comparability between studies. All clinical trial results should be reported using the IGCCC criteria unless an improved and widely accepted classification is developed.
A recent meta-analysis of 1,775 patients included in published studies between 1989 and 2001 has reported improvement in treatment outcomes, particularly for patients with the worst prognosis. The 5-year survival for patients with good-, intermediate-, and poor-prognosis nonseminoma were 94%, 83%, and 71%, respectively (17). These improvements likely reflect advances in first-line chemotherapy and subsequent management, potential stage migration within prognostic categories, and improved outcomes from the establishment of experienced multidisciplinary management teams in specialized treatment centers.
TABLE 34B.1 DEFINITION OF INTERMEDIATE- AND POOR-RISK CATEGORIES ACCORDING TO THE IGCCC | ||||||||||||||||||
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Clinical characteristics predicting worse outcomes have been identified within the IGCCC poor-prognosis group (18,19) and in patients who commonly have a poor prognosis such as extragonadal germ cell tumors (11,13). Worst outcomes occur in patients classified as poor prognosis because of mediastinal primary site who have nonseminoma histology and metastases. Best outcomes occur in patients classified as poor prognosis because of very high tumor markers, who have testis or retroperitoneal primary site and no visceral metastases other than lung metastases (18). An international analysis of 635 patients with extragonadal germ cell tumors confirmed the findings of the IGCCC. Extragonadal seminomas of both mediastinal and retroperitoneal primary site had good outcomes. Mediastinal nonseminoma clearly had the worst outcomes (13).
Serum Tumor Marker Decline During Chemotherapy
A slower-than-expected decline of serum tumor markers during first-line chemotherapy has been associated with worse outcomes for patients with poor prognosis in a recently published prospective Intergroup trial (20) and a large retrospective French study (21). Similar results were found in two retrospective studies by investigators at the Memorial Sloan Kettering Cancer Center (MSKCC) for patients receiving firstline chemotherapy for good or poor-prognosis disease (22), and patients receiving salvage chemotherapy (23). A surge in tumor marker levels after initiation of chemotherapy was also found to be prognostic in one study (24). Marker decline has been assessed by other investigators with variable results (25). Slow decline of markers has been used in clinical trials at MSKCC to identify patients for early crossover to high-dose chemotherapy with bone marrow transplant (26). An ongoing French randomized trial is assessing the value of changing chemotherapy in patients with a predicted slow marker normalization (21). Although there is increasing evidence of the potential value of assessing the pattern of change of serum tumor markers, there remains no consensus as to the most appropriate methodology. At present, it should remain an investigational tool and awaits confirmation in prospective studies (22,23,25,27).
DEVELOPMENT OF EFFECTIVE SYSTEMIC THERAPY
Establishing the Current Standard of Four Cycles of BEP Chemotherapy
The proportion of patients with advanced germ cell tumors who could be cured increased dramatically in the late 1970s and early 1980s with the introduction of cisplatin-based chemotherapy (28). Subsequently, investigators at Indiana University performed a randomized trial in unselected patients that compared cisplatin, vinblastine, and bleomycin (PVB) with cisplatin, etoposide, and bleomycin (BEP) (29). There was no significant difference in cure rates among the 244 unselected evaluable cases. However, in the 72 patients considered to have a poor prognosis by Indiana University criteria, substantially more patients allocated to BEP achieved disease-free status (63% vs. 38%, p = 0.06). Rates of myelosuppression and pulmonary toxicity were similar but the etoposide arm produced less neurological toxicity. As a result of this trial, four cycles of BEP chemotherapy has been the standard therapy for patients who have intermediate- and poor-prognosis germ cell tumors for over 25 years, as recommended in international guidelines (27,30,31).
Multiple studies have been performed attempting to improve on the results with standard BEP. These have generally focused on increased dose intensity, the use of alternate or additional chemotherapy agents, strategies of alternating or sequential chemotherapy regimens, and high-dose chemotherapy with autologous stem cell rescue. Only some of these strategies have been tested adequately in randomized trials. The results of completed randomized trials are summarized in Table 34B.2 and are discussed below. Selected promising results from nonrandomized studies are also discussed.
Increasing Cisplatin Dose
Preclinical models and clinical trials (32) suggest a dose-response relationship for cisplatin. A small randomized trial at the National Cancer Institute compared standard PVB to a regimen that included cisplatin 200 mg/m2/cycle and etoposide
(33). The higher dose of cisplatin was associated with a higher response rate and less frequent relapses. However, the apparent superiority of this arm may have been due to factors other than the cisplatin dose, including the addition of etoposide. A subsequent randomized phase III trial by the Southeastern Cancer Study Group compared standard BEP with cisplatin 100 mg/m2/cycle or the same treatment but with cisplatin 200 mg/m2/cycle (34). There were no significant differences in proportions of complete response, disease-free survival, or overall survival. The higher dose of cisplatin was associated with significantly greater ototoxicity, neurotoxicity, emesis, and myelosuppression. This trial demonstrated that there was no advantage to doubling the standard dose of cisplatin.
(33). The higher dose of cisplatin was associated with a higher response rate and less frequent relapses. However, the apparent superiority of this arm may have been due to factors other than the cisplatin dose, including the addition of etoposide. A subsequent randomized phase III trial by the Southeastern Cancer Study Group compared standard BEP with cisplatin 100 mg/m2/cycle or the same treatment but with cisplatin 200 mg/m2/cycle (34). There were no significant differences in proportions of complete response, disease-free survival, or overall survival. The higher dose of cisplatin was associated with significantly greater ototoxicity, neurotoxicity, emesis, and myelosuppression. This trial demonstrated that there was no advantage to doubling the standard dose of cisplatin.
TABLE 34B.2 RANDOMIZED TRIALS OF FIRST-LINE CHEMOTHERAPY FOR INTERMEDIATE-AND POOR-RISK ADVANCED GERM CELL TUMORS | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Use of Alternative or Additional Chemotherapy Agents
Drugs that have shown activity in relapsed germ cell tumors continue to be tested in randomized trials in the first-line setting (see Table 34B.2).
Ifosfamide in combination with cisplatin and etoposide demonstrated significant activity after failure of first-line therapy (35). The Eastern Cooperative Oncology Group performed a randomized trial that compared cisplatin, etoposide, and either ifosfamide (VIP) or bleomycin (BEP) (36). VIP was found to be more toxic without improvement in cure rates. An updated analysis confirmed no significant difference in overall survival at a median follow-up of 7.3 years (37). Therefore, BEP was recommended as standard therapy, except for patients at increased risk of bleomycin pulmonary toxicity. The European Organisation for Research and Treatment of Cancer (EORTC) performed a randomized trial of VIP versus BEP for intermediate-risk patients that was ceased prematurely after recruitment of 86 patients when data became available from the above study. This study also found that VIP was more toxic without improvement in cure rates (38).
Paclitaxel has demonstrated activity in relapsed germ cell tumors as a single agent (39,40) and in combination with ifosfamide and cisplatin (TIP) (41). A Dutch phase I/II study including 13 evaluable patients with intermediate- and poorrisk germ cell tumors demonstrated the feasibility and activity of adding paclitaxel to BEP (T-BEP) in the first-line setting (42). A randomized phase III trial conducted by the EORTC is comparing T-BEP to BEP, and is currently closed to recruitment with results awaited.
Alternating or Sequential Chemotherapy Regimens
Alternating and sequential chemotherapy regimens could decrease chemotherapy-resistant disease and improve cure rates. This strategy has been tested in a number of randomized trials (see Table 34B.2).
The EORTC tested alternating vinblastine and etoposide in a randomized trial that compared four cycles of BEP to alternating cycles of BEP and PVB (43). There was no advantage to the alternating regimen. The Medical Research Council (MRC) and EORTC developed a novel regimen composed of initial intensive induction therapy with cisplatin, bleomycin, and vincristine (BOP) followed sequentially by three cycles of a modified VIP regimen with bleomycin. Initial results of BOP/VIP-B in a large phase II study were encouraging (44), but a randomized comparison to a BEP regimen demonstrated increased toxicity without improvement in response rates or survival (45). A regimen composed of alternating cycles of cyclophosphamide, doxorubicin, and cisplatin (CISCA) with vinblastine and bleomycin (VB) was developed at the University of Texas M.D. Anderson Cancer Center with promising activity (46). The French Groupe d’Etude des Tumeurs Uro-Génitales (GETUG) compared four cycles of BEP to four to six cycles of alternating CISCA/VB in a randomized trial for intermediate- and poor-risk patients. CISCA/VB was associated with worse toxicity, but no improvement in response rates or survival between the two arms, even when analysis was restricted to patients with a poor prognosis by IGCCCG criteria (47).
Nonrandomized Trials
Some treatment regimens that have only been tested in nonrandomized trials are relevant. Since the publication of the IGCCC classification, some groups have retrospectively reanalyzed results of older trials (48,49,50,51,52,53). Several nonrandomized studies have also been performed that have prospectively used the IGCCC intermediate- and poor-prognosis criteria (54,55,56,57). Selected trials are summarized in Table 34B.3. Results have generally been promising compared with historical data, but cannot be considered to indicate the superiority of these regimens over standard BEP. Other potential explanations for improved outcomes include era of treatment, expertise of the treatment center, referral bias, and stage migration within the poor-prognosis subgroup. Therefore, these data are inadequate to determine a change in treatment outside a clinical trial. The most promising regimens should be considered for assessment in randomized trials.
One of the most promising regimens that uses additional chemotherapy agents and alternating chemotherapy regimens is C-BOP-BEP. This regimen has been studied prospectively by several groups with encouraging results (52,55) and is currently the subject of a randomized trial in the United Kingdom.
Two groups have recently reported preliminary results demonstrating the feasibility of accelerated delivery of BEP by repeating treatment every 2 weeks rather than the usual 3 weeks (58,59). Accelerated chemotherapy has improved outcomes in other chemosensitive cancers when other approaches have failed. For example, CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisolone) chemotherapy remained the standard of care for diffuse large cell non-Hodgkins lymphoma for over 25 years. More complex and intensive regimens were tested but none proved superior. Randomized trials demonstrated that cure rates and overall survival were improved by accelerating CHOP, cycling it 2-weekly rather than 3-weekly (60,61). There is current international interest in a randomized trial comparing accelerated BEP with standard BEP chemotherapy.
High-dose Chemotherapy Supported by Autologous Stem Cell Rescue
High-dose chemotherapy with reinfusion of autologous hemopoietic stem cells has been tested in the first-line setting for patients with poor-prognosis disease in a number of nonrandomized and randomized trials. The high-dose regimens have generally incorporated one or more cycles of carboplatin and etoposide with or without cyclophosphamide or ifosfamide. The morbidity and mortality of high-dose chemotherapy has been reduced by technological improvements, including the use of mobilized peripheral stem cells rather than autologous bone marrow transplantation (62), better supportive care, and increased physician expertise (63). Following the success of high-dose chemotherapy in the salvage setting, in which a proportion of patients refractory to conventional chemotherapy achieve prolonged survival (26,64,65,66,67,68), highdose chemotherapy has been investigated as part of first-line therapy for patients with poor prognosis.
The GETUG group conducted an early randomized trial that compared intensive standard-dose chemotherapy with
double-dose cisplatin, vinblastine, bleomycin, and etoposide (P200VBE) to two cycles of P200VBE followed by a single highdose cycle of cisplatin, etoposide, and cyclophosphamide with autologous bone marrow transplantation (69). There was no significant improvement in cure rates or overall survival for high-dose chemotherapy (see Table 34B.2). Limitations of this study included the lower dose intensity of cisplatin in the highdose arm, and delays before the high-dose therapy was implemented. Many investigators believed that the role of high-dose chemotherapy was not answered by this trial given these limitations and subsequent improvements in techniques for highdose chemotherapy and support.
double-dose cisplatin, vinblastine, bleomycin, and etoposide (P200VBE) to two cycles of P200VBE followed by a single highdose cycle of cisplatin, etoposide, and cyclophosphamide with autologous bone marrow transplantation (69). There was no significant improvement in cure rates or overall survival for high-dose chemotherapy (see Table 34B.2). Limitations of this study included the lower dose intensity of cisplatin in the highdose arm, and delays before the high-dose therapy was implemented. Many investigators believed that the role of high-dose chemotherapy was not answered by this trial given these limitations and subsequent improvements in techniques for highdose chemotherapy and support.
TABLE 34B.3 SELECTED NONRANDOMIZED SERIES OF FIRST-LINE CHEMOTHERAPY FOR INTERMEDIATE- AND POOR-RISK ADVANCED GERM CELL TUMORS | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Investigators at MSKCC conducted two nonrandomized studies using two cycles of high-dose carboplatin and etoposide with or without cyclophosphamide, followed by autologous bone marrow transplantation. Eligible patients had a poor prognosis and slow rate of decline of tumor markers after two cycles of conventional chemotherapy (26, 65). The regimens were shown to be feasible and associated with improved survival compared with historical controls. A subsequent Intergroup randomized trial compared four cycles of BEP to two cycles of BEP followed by two cycles of high-dose carboplatin, etoposide, and cyclophosphamide supported by peripheral stem cells. Patients were eligible if they had poor prognosis or intermediate prognosis with LDH > 3 × normal by IGCCCG criteria. High-dose chemotherapy was associated with worse toxicity, but no improvement in durable response rates or overall survival (see Table 34B.2) (20). A subgroup analysis, restricted to patients who had a slow marker decline, showed improved durable response rates with high-dose chemotherapy. This result has not been confirmed in other studies.
The German Testicular Cancer Study Group developed a regimen using escalating doses of cisplatin, etoposide, and ifosfamide (VIP) supported by hemopoietic growth factor and peripheral stem cell support. The regimen delivered high-dose therapy upfront, rather than as consolidation after standard chemotherapy. This approach potentially allows increased dose and dose intensity from an earlier stage in treatment. The regimen was shown to be feasible in a nonrandomized trial (56). A subsequent phase III trial conducted by the EORTC compared four cycles of BEP to one cycle of VIP followed by three cycles of high-dose VIP with peripheral stem cell support in poor-prognosis patients. Unfortunately this trial closed prematurely due to inadequate recruitment. Initial results are awaited.
STANDARD TREATMENT
The IGCCC staging system should be used to determine prognosis for selection of treatment and reporting outcomes of treatment. The standard of care for patients who have intermediate-and poor-risk germ cell tumors remains four cycles
of bleomycin, etoposide, and cisplatin (BEP), according to the regimen developed at Indiana University (29,70). followed by surgical resection of all residual masses. No other chemotherapy regimen has been demonstrated to be superior in randomized trials. The VIP regimen, composed of cisplatin, etoposide, and ifosfamide, had similar efficacy but was more toxic in a randomized comparison to BEP. VIP may be appropriate for highly selected patients in whom bleomycin is contraindicated. Patients who are at risk of fatal toxicity from initial chemotherapy due to critical circumstances such as overwhelming tumor burden may benefit from a brief course of low-dose induction chemotherapy prior to standard chemotherapy (71,72). However, this approach has not been proven to be superior to initial BEP. The unsatisfactory results of current therapy stress the need for participation in clinical trials. All eligible patients should be encouraged to enter clinical trials of promising new therapies.
of bleomycin, etoposide, and cisplatin (BEP), according to the regimen developed at Indiana University (29,70). followed by surgical resection of all residual masses. No other chemotherapy regimen has been demonstrated to be superior in randomized trials. The VIP regimen, composed of cisplatin, etoposide, and ifosfamide, had similar efficacy but was more toxic in a randomized comparison to BEP. VIP may be appropriate for highly selected patients in whom bleomycin is contraindicated. Patients who are at risk of fatal toxicity from initial chemotherapy due to critical circumstances such as overwhelming tumor burden may benefit from a brief course of low-dose induction chemotherapy prior to standard chemotherapy (71,72). However, this approach has not been proven to be superior to initial BEP. The unsatisfactory results of current therapy stress the need for participation in clinical trials. All eligible patients should be encouraged to enter clinical trials of promising new therapies.
It is essential that an uncompromised course of chemotherapy is delivered. In general, the doses of chemotherapy agents should be calculated according to actual body weight and not adjusted down by artificially capping body weight or body surface area. Every attempt should be made to deliver chemotherapy according to the planned dose and schedule with as few treatment delays as possible. The use of granulocyte colony-stimulating factors (73) and prophylactic antibiotics (74) can facilitate effective delivery of chemotherapy by allowing avoidance of dose reductions or delays. Dose adjustments for toxicity should rarely be required, other than the potential need to cease bleomycin for pulmonary toxicity. In this situation, it is reasonable to substitute ifosfamide for the bleomycin, given the results of a randomized trial demonstrating equivalent efficacy (36).
The resection of residual masses at sites of metastatic disease is part of the standard of care for all patients with nonseminoma following normalization of tumor markers. Surgery probably plays a more important role in curing patients with poor-risk disease, because these patients are more likely to have persistent neoplasia in residual masses. The results of surgery in the salvage setting emphasize that resection of viable malignancy and teratoma is curative in some cases (75). An additional advantage of an aggressive surgical approach is that it allows identification of those patients who have persisting malignancy, who may benefit from further chemotherapy. The indications and type of retroperitoneal lymph node dissection vary considerably internationally. For patients with poor-prognosis nonseminoma, a bilateral template dissection should be performed after chemotherapy, and the threshold for undertaking surgery at any site with radiological evidence of residual disease should be low.
Impact of the Treating Institution on Outcome
A number of studies have identified an association between better outcomes and the management of patients with a poor prognosis in centers that treat larger numbers of cases. An analysis of a randomized trial conducted by the EORTC/MRC for poor-prognosis patients (45) found poorer survival in those institutions that recruited fewer than five patients compared to those that recruited more than five patients (76). Rates of 2-year overall survival (77% vs. 62%, p = 0.006), progression-free survival (73% vs. 55%, p = 0.006), and postoperative mortality were substantially better for patients who were treated in larger institutions. The authors concluded that specialist centers demonstrate superior results to nonspecialist centers (76). This conclusion is echoed by MSKCC data showing their results to be superior at all stages of the disease to the SEER database results (77). The Swedish Norwegian testicular cancer project found that patients with large-volume testicular cancer who were treated at large oncology centers compared to nonspecialist centers had improved 3-year survival (84% vs. 60%, p = 0.01) (78). These figures should be interpreted with some caution because the results are subject to many biases. However, it is appropriate to recommend referral to specialist units for treatment of germ cell tumors, particularly for patients who have an intermediate or poor prognosis at presentation.
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