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Biomedical subjects

R J Motzer

Publications and source records attributed to R J Motzer.

At least 73 records · Page 4Linked to original sources
PubMed1995

Etoposide and cisplatin adjuvant therapy for patients with pathologic stage II germ cell tumors.

PURPOSE: Two options cure nearly all patients with pathologic stage II nonseminomatous germ cell tumors (NSGCTs): two cycles of adjuvant chemotherapy with cisplatin, vinblastine, and bleomycin (PVB) or cisplatin, vinblastine, bleomycin, cyclophosphamide, and dactinomycin (VAB-6); or close observation with full treatment at relapse. Two cycles of etoposide plus cisplatin (EP) were given to selected patients with pathologic stage II NSGCT and high-volume nodal metastases. PATIENTS AND METHODS: All patients had pathologic stage II NSGCT with one or more of the following features found at retroperitoneal lymph node dissection (RPLND), suggesting a greater than 50% likelihood of relapse after observation alone: (1) any lymph node involved by tumor greater than 2 cm (stage N2b); (2) > or = six nodes involved with tumor (stage N2b); and (3) extranodal extension (stage N3). Two cycles of therapy were given at 21-day intervals; each cycle consisted of etoposide 100 mg/m2 plus cisplatin 20 mg/m2 per day given on days 1 to 5. RESULTS: Fifty patients were treated with two cycles of EP. Treatment was well tolerated; five patients (10%) were admitted for nadir fever and none had grade II or greater neurologic, renal, or pulmonary toxicity. All 50 patients are alive and relapse-free at a median follow-up time of 35 months (range, 12 to 72). The follow-up duration has been > or = 2 years for 42 patients. CONCLUSION: A treatment program that consists of two cycles of EP is effective in preventing relapses in patients with completely resected pathologic stage N2b and N3 NSGCT. The likelihood of relapse without adjuvant cisplatin-containing chemotherapy in this group has been shown to be greater than 50%. As has been demonstrated in patients with disseminated germ cell tumor (GCT), EP can be considered a therapeutic option in the adjuvant setting for completely resected N2b and N3 NSGCT.

Adolescent↗
PubMed1995

Interferon alfa-2a and 13-cis-retinoic acid in renal cell carcinoma: antitumor activity in a phase II trial and interactions in vitro.

PURPOSE: A phase II trial of interferon alfa-2a (IFN) and 13-cis-retinoic acid (CRA) was conducted in patients with renal cell carcinoma (RCC). In vitro studies were performed to investigate potential mechanisms of interaction. PATIENTS AND METHODS: Forty-four patients were treated. IFN was given daily at 3 MU and escalated to 6 and 9 MU if tolerated. The dose of CRA was 1 mg/kg/d. The effects of combining CRA and IFN on the proliferation of five RCC cell lines were examined, and retinoid sensitivity was correlated to the expression of retinoic acid receptors. RESULTS: Thirteen (30%) of 43 assessable patients achieved a major response (three complete and 10 partial). Responding sites included bone metastases and renal primary tumors. Seven responding patients remain progression-free at 10+ to 19+ months. The response proportion was higher than in our prior experience with IFN, which was 10% in 149 patients. Eleven of 12 renal cancer cell lines were resistant to CRA alone; one, SK-RC-06, showed 90% inhibition of cell growth. CRA augmented the antiproliferative effect of IFN in several IFN-sensitive cell lines, but not in IFN-resistant lines. Northern blot analysis showed that expression of retinoic acid receptor-beta (RAR-beta) was repressed and not induced by retinoic acid in retinoic acid-insensitive RCC lines. However, RAR-beta expression was induced by retinoic acid in SK-RC-06 cells. CONCLUSION: IFN and CRA showed antitumor activity in patients with advanced RCC, and the proportion and nature of response suggested CRA added therapeutic benefit to IFN. A phase III randomized trial of IFN plus CRA versus IFN alone and a phase II trial of single-agent CRA have been initiated.

Adolescent↗
PubMed1995

Phase I/II trial of dexverapamil plus vinblastine for patients with advanced renal cell carcinoma.

PURPOSE: The reduced cardiac toxicity of the dextro-(d-) stereoisomer of verapamil (dexverapamil; Knoll Pharmaceuticals, Whippany, NJ) warrants its study as a potential multidrug-resistance (MDR) reversal agent. PATIENTS AND METHODS: Twenty-three patients with advanced renal cell carcinoma (RCC) were treated with vinblastine at a dose of 0.11 mg/kg intravenous (IV) bolus injection on days 1 and 2 every 21 days. Dexverapamil was added to subsequent cycles after resistance had been demonstrated. Dexverapamil treatment was begun 18 hours before day 1 of vinblastine administration and was given orally every 6 hours for 12 doses. Patients in group A were treated with a dose of 120 mg/m2, and those in group B were treated with 180 mg/m2 plus dexamethasone; plasma concentrations achieved in patients were correlated with in vitro effects. RESULTS: Toxicities included hypotension, asymptomatic bradycardia, and mild atrioventricular conduction delays, although one patient had dexverapamil discontinued for grade IV congestive heart failure. There were no partial or complete responses. The mean day-1 serum dexverapamil plus norverapamil plasma concentrations were 2,575 ng/mL (range, 697 to 6,015 ng/mL) for group A and 1,654 ng/mL (range, 710 to 4,132 ng/mL) for group B at the time of vinblastine administration. These concentrations were in the range of those that reversed vinblastine resistance in vitro. CONCLUSION: The advantage of dexverapamil as an MDR reversal agent is its potential for achieving desired blood levels with substantially less toxicity than the racemic mixture of verapamil. Based on tolerability, it is a suitable drug for further study in clinical trials of malignancies other than RCC that attempt to achieve MDR reversal. The dose of 120 mg/m2 given orally every 6 hours, with dose escalation based on individual tolerance, represents a feasible schedule to be considered for such studies.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1995

Paclitaxel in germ cell cancer.

The teratocarcinoma cell line 833K and its relatively cisplatin-resistant subline 833K/63CP 10 were used to assess the cytotoxicity of paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ), cisplatin, and 4-hydroxyperoxycyclophosphamide quantitatively. The results showed that paclitaxel had marked cytotoxicity against teratocarcinoma, particularly in the cells that were relatively cisplatin resistant. These studies suggested synergy in cytotoxicity for paclitaxel, cisplatin, and 4-hydroxyperoxycyclophosphamide. A phase II trial of paclitaxel was conducted in patients with previously treated germ cell tumors with restricted prior treatment. The paclitaxel dose was 250 mg/m2 given by 24-hour continuous infusion. In 31 patients treated with paclitaxel, eight (26%) achieved a major (complete or partial) response. The antitumor activity of paclitaxel in the phase II trial has led us to further study it as a part of combination therapy. Since the in vitro studies showed synergistic cytotoxicity, combination studies of paclitaxel, ifosfamide, and platinum are under way as salvage treatment for patients with germ cell tumors.

Adolescent↗
PubMed1994

Computerized quantitation of synergism and antagonism of taxol, topotecan, and cisplatin against human teratocarcinoma cell growth: a rational approach to clinical protocol design.

BACKGROUND: Cisplatin-based induction chemotherapy may achieve a complete response (i.e., no sign of tumor following treatment) in 70%-80% of patients with germ cell tumors. However, only a minority of patients in whom the firstline regimens fail are cured with the salvage regimens. PURPOSE: The aim of these studies was to identify new agents or new regimens for the treatment of germ cell tumors by carrying out quantitative assessment in vitro of two promising new antitumor agents (paclitaxel [Taxol] and topotecan) and three more established agents (cisplatin, vincristine, and etoposide). These agents were used singly or in two- and three-drug combinations and were selected because they represent five distinct categories of antineoplastic mechanisms. METHODS: The combination index-isobologram method, which is based on the median-effect principle developed by Chou and Talalay, was used for computerized data analysis. This method was selected because it takes into account both the potencies of each drug and combinations of these drugs and the shapes of their dose-effect curves. RESULTS: Synergism against the growth of teratocarcinoma cells resistant to cisplatin (833K/64CP10 cells) was greater than against the growth of parent 833K cells. The degrees of synergism were in the following order: cisplatin + topotecan > or = paclitaxel + cisplatin + topotecan > paclitaxel + topotecan > or = paclitaxel + etoposide > paclitaxel + cisplatin + etoposide > paclitaxel + cisplatin. All other combinations showed nearly additive effects or moderate antagonism. The degrees of antagonism were as follows: cisplatin + etoposide > or = paclitaxel + vincristine > paclitaxel + cisplatin + vincristine > cisplastin + vincristine. The combination of paclitaxel and cisplatin was synergistic against 833K/64CP10 cells and moderately antagonistic against 833K cells. Since the combination of paclitaxel, cisplatin, and topotecan and the two-component combinations of these drugs (cisplatin + topotecan and paclitaxel + topotecan) showed synergism stronger than that of other combinations, these three drugs were selected for illustrating detailed data analysis, using a computer software program developed in this institute. CONCLUSIONS AND IMPLICATIONS: Our findings suggest that, as a result of synergy, the doses of these agents needed to achieve an antitumor effect may be reduced by twofold to eightfold when these agents are given in combination. The present quantitative data analyses for synergism or antagonism provide a basis for a rational design of clinical protocols for combination chemotherapy in patients with advanced germ cell tumors.

Antineoplastic Agents↗
PubMed1994

Platinum-DNA adducts assayed in leukocytes of patients with germ cell tumors measured by atomic absorbance spectrometry and enzyme-linked immunosorbent assay.

BACKGROUND: Platinum-DNA adducts can be measured in peripheral blood cells, and high adduct levels have previously been correlated with favorable clinical response to platinum-based therapy in patients with germ cell tumors and ovarian cancer. METHODS: To evaluate the relationship between platinum-DNA adducts and clinical response to chemotherapy, 36 patients with germ cell tumors treated with cisplatin-based chemotherapy had platinum-DNA adducts assayed in leukocytes by atomic absorption spectrometry (AAS) and cisplatin-DNA enzyme-linked immunosorbent assay (ELISA). Three chemotherapy regimens were involved: cisplatin and etoposide (Regimen A); carboplatin and etoposide (Regimen B); and cyclophosphamide, vinblastine, dactinomycin, bleomycin, and cisplatin [VAB-6] with or without high dose carboplatin plus etoposide plus autologous bone marrow rescue (Regimen C). Blood samples were drawn before and after each cycle of chemotherapy. RESULTS: One hundred ninety-two blood samples were assayed by AAS and 137 by ELISA: DNA adducts measured by AAS and ELISA increased immediately after treatment and decreased during the intervening time before the next treatment. DNA adducts were measurable by both methods 4-8 weeks after the last cycle of therapy. The peak and mean adduct levels measured in samples drawn immediately after Cycles 1 and 2 and after all cycles were analyzed in terms of their relationship to clinical response. In contrast to numerous prior studies, a positive correlation was not observed between DNA adduct formation as determined by either AAS or ELISA and favorable clinical responses. CONCLUSIONS: This study demonstrated that peak and mean platinum-DNA adduct levels were influenced by the dose and schedule of the platinum analogue. For example, treatment with VAB-6 with or without high dose carboplatin and etoposide (Regimen C) resulted in significantly higher adduct levels when measured by AAS compared with Regimen A or B. Inconsistencies between studies regarding observed correlations of DNA adducts and treatment outcome may be attributable to differences in platinum analogue, dose, schedule, and timing of sample procurement. These factors must be considered in future studies.

Adolescent↗
PubMed1994

Serum tumor marker decline is an early predictor of treatment outcome in germ cell tumor patients treated with cisplatin and ifosfamide salvage chemotherapy.

BACKGROUND: Serum tumor marker regression (alpha-fetoprotein [AFP] and human chorionic gonadotrophin [hCG]) was studied in patients treated with ifosfamide-based chemotherapy for cisplatin-resistant germ cell tumors (GCT) to investigate the role of marker regression as a predictor of treatment outcome. METHODS: Fifty-four patients treated with cisplatin and ifosfamide-containing therapy were the subject of this retrospective analysis. The serum tumor marker half-life (T1/2) for the first two cycles of therapy was calculated for each patient using all marker values Day 7 through the end of the second treatment cycle. A calculated T1/2 for hCG of less than or equal to 3 days or a calculated T1/2 for AFP of less than or equal to 7 days was defined as appropriate marker regression; any T1/2 greater than these values was considered prolonged. A variable designated "marker decline" was defined to indicate whether the serum tumor marker half-life of AFP and/or hCG was satisfactory or unsatisfactory for each individual patient. Both univariate and multivariate analyses were conducted to investigate "marker decline" as a predictor for response, event-free survival (time to death or relapse), and overall survival. RESULTS: Satisfactory marker decline predicted an improved event-free survival and overall survival. The median event-free survival for patients with an unsatisfactory marker decline was 5.8 months versus 20.7 months for patients with a satisfactory marker decline. Survival for patients with an unsatisfactory marker decline was 6.3 months versus 20.7 months for those patients with a satisfactory marker decline. Further evaluation demonstrated that hCG decline was a stronger predictor for improved survival than AFP decline. A multivariate analysis performed on selected clinical variables using a Cox regression model demonstrated that marker decline, pretreatment hCG, and primary site were independent predictors for event-free and overall survival. CONCLUSIONS: The rate of serum AFP and/or hCG decline during the first two cycles of therapy was predictive for event-free and overall survival in GCT patients treated with ifosfamide-based salvage therapy. Those patients with an appropriate serum tumor marker decline had a longer event-free and overall survival. When evaluated separately, the rate of hCG decline was more predictive of treatment outcome than decline of AFP. The rate of serum tumor marker regression during the first two cycles of therapy is a clinically useful tool in assessing treatment outcome at an early point in therapy and may thereby identify patients who could benefit from a change to more intensive therapy.

Biomarkers, Tumor↗
PubMed1994

Hormonal ablation as effective therapy for carcinomatous meningitis from prostatic carcinoma.

BACKGROUND: Metastases to the meninges from prostatic cancer are rare, accounting for less than 0.5% of all solid tumor cases. Management for patients with leptomeningeal metastases of various histologic types includes intrathecal chemotherapy and radiation therapy, but the prognosis is poor. Therefore, the identification of selected patients for whom effective therapy exists is of paramount importance. METHODS: A patient with adenocarcinoma of the prostate presented with leptomeningeal metastases as his first manifestation of metastatic disease. RESULTS: Androgen blockade was initiated with flutamide and ketoconazole. After 5 days of therapy, leuprolide acetate depot was substituted for ketoconazole. The patient responded to therapy and remained asymptomatic with a normal serum prostate-specific antigen levels at 16-plus months with no further evidence of malignant cells in spinal fluid from repeated lumbar punctures. CONCLUSION: Patients with hormone-naive metastatic prostatic carcinoma manifested as carcinomatous meningitis should be considered for hormonal ablative therapy. This is preferred to the use of intrathecal chemotherapy, which has limited efficacy.

Adenocarcinoma↗
PubMed1994

Clinical relevance of the i(12p) marker chromosome in germ cell tumors.

BACKGROUND: Germ cell tumors in men are curable at all stages and are among the most sensitive of all cancers to chemotherapy. An isochromosome of the short arm of chromosome 12, i(12p), has been reported to be a frequent marker of these tumors and to have diagnostic and prognostic significance. PURPOSE: We evaluated the possible association between this cytogenetic marker and clinical outcome for men with germ cell tumors. METHODS: One hundred seventy-eight germ cell tumor samples from 150 men were studied using conventional and molecular cytogenetic techniques. Of these samples, 171 were evaluable. Patient characteristics, disease stage, treatment outcome, and disease status were correlated with the observed cytogenetic changes. In addition, 28 biopsy specimens obtained from 28 patients with tumors of uncertain histogenesis were evaluated to determine whether the presence of i(12p) could serve as a diagnostic marker of a germ cell origin for these tumors. RESULTS: Of the 171 evaluable tumor accessions, 101 (59%) yielded abnormal karyotypes. i(12p) was determined to be present in 79 of the 101 (79%) abnormal karyotypes, which were derived from all cell types and primary sites. An abnormal karyotype was more frequently obtained from nonseminomatous tumors (91/137 [81%]) than from seminomas (10/34 [30%] [P < .001]). Tumors resulting in a cytogenetic failure were more likely to respond completely to chemotherapy than tumors with an abnormal karyotype (P = .004). i(12)p copy number was not associated with response or survival. Fluorescence in situ hybridization using a chromosome 12 centromere-specific probe detected i(12p) in 47 of 47 tumors (100%) already shown to have i(12p) by cytogenetic analysis and in 13 of 49 tumors (27%) exhibiting either an abnormal karyotype or a cytogenetic failure. One or more copies of i(12p), excess 12p copy number, or a deletion on the long arm of chromosome 12 was found in seven of 28 (25%) midline tumors of uncertain histogenesis, thus establishing a diagnosis of a germ cell tumor in these patients. One partial and five complete responses were observed in these seven patients. Only two partial responses were seen in the 17 patients who had no detectable germ cell tumor-related cytogenetic marker (P = .009). CONCLUSIONS: i(12p) is a highly nonrandom chromosomal marker seen in about 80% of male germ cell tumors with evaluable cytogenetic abnormalities. The presence of this isochromosome has diagnostic and possibly prognostic importance for patients with these tumors. IMPLICATIONS: Cytogenetic studies of germ cell tumors in prospective clinical treatment trials are warranted to define more precisely the relationship between histologic subtype, serum tumor marker production, and prognosis.

Adolescent↗
PubMed1994

Phase II trial of liposomal encapsulated doxorubicin in patients with advanced renal cell carcinoma.

Fourteen patients with advanced renal cell carcinoma were treated on a phase II trial with liposomal encapsulated doxorubicin (Lipodox, LED). None of the fourteen evaluable patients achieved a complete or partial response. Myelosuppression was the most common toxicity and no cardiac toxicity was evident. Seventy-nine percent (11 of 14) of patients experienced grade III or IV neutropenia. In summary, LED did not show antitumor activity in the treatment of advanced renal cell carcinoma.

Aged↗
PubMed1994

Phase II trial of topotecan in patients with advanced renal cell carcinoma.

Fifteen patients with advanced renal cell carcinoma were treated on a phase II trial with topotecan. None of the fourteen evaluable patients achieved a complete or partial response. Myelosuppression was the most common toxicity. Eighty percent (12 of 15) of patients experienced grade III or IV neutropenia and/or anemia. Topotecan is not efficacious in the treatment of advanced renal cell carcinoma.

Adult↗
PubMed1994

Advanced seminoma: treatment results, survival, and prognostic factors in 142 patients.

PURPOSE: To investigate the efficacy of chemotherapy and to assess the relationship between selected pretreatment characteristics and survival in patients with advanced seminoma. PATIENTS AND METHODS: One hundred forty-two patients with advanced seminoma treated with platinum-based chemotherapy were the subject of this study. Treatment regimens included cisplatin, vinblastine, bleomycin, cyclophosphamide, and dactinomycin (VAB-6) (45 patients), a six-cycle regimen of VAB-6 alternating with etoposide and cisplatin (two patients), cisplatin and etoposide (60 patients), and etoposide and carboplatin (35 patients). RESULTS: One hundred thirty of 140 (93%) assessable patients treated with platinum-based therapy achieved a favorable response (complete response or a partial response with negative serum tumor markers). One hundred twenty-five patients (88%) are alive and 120 (86%) remain progression-free at a median follow-up duration of 43 months. Fifty-seven of 60 patients (95%) who were treated with cisplatin and etoposide achieved a favorable response; 55 (92%) remain progression-free. The relative risks of death or of an event (death or relapse) related to human chorionic gonadotropin (HCG) elevation were 1.8 (P = .04) and 1.96 (P = .001), respectively. The relative risks of death or of an event associated with lactate dehydrogenase (LDH) elevation were 2.6 (P = .05) and 2.7 (P = .02), respectively. All 19 patients with a mediastinal primary tumor site achieved a complete response, and 18 of 19 (95%) remain progression-free. CONCLUSION: Four cycles of cisplatin and etoposide is highly effective therapy for seminoma and is the standard therapy at our center. Elevation of the serum markers HCG and LDH were of prognostic significance, while an extragonadal primary tumor site was not associated with an adverse prognosis. Studies of tumor biology, including genetic analysis, are ongoing to determine other parameters that may correlate with response and survival.

Adolescent↗
PubMed1994

Phase II trial of paclitaxel shows antitumor activity in patients with previously treated germ cell tumors.

PURPOSE: A trial of paclitaxel was conducted in patients with previously treated germ cell tumors (GCT). As the identification of new agents in GCT may be compromised by restricting entry criteria to heavily pretreated patients, an alternative trial design was used in which eligibility was restricted to patients with limited prior therapy. PATIENTS AND METHODS: Patients were eligible if their prior therapy was limited to one cisplatin-based regimen or < or = six cycles of prior cisplatin-based therapy. Paclitaxel 250 mg/m2 was administered by continuous infusion over 24 hours every 21 days. The dose of paclitaxel was modified for each patient based on toxicity. Granulocyte colony-stimulating factor (G-CSF) 5 micrograms/kg/d was administered during nadir periods. RESULTS: Thirty-one patients were treated; eight patients (26%) achieved a partial (n = 5) or a complete (n = 3) response. Responses were achieved in patients who had failed to respond to treatment with cisplatin, ifosfamide, and etoposide, and in patients with poor prognostic features, ie, mediastinal primary tumor site and patients with a best prior response of an incomplete response to cisplatin therapy. One complete responder remains continuously free of disease at 13+ months and one of the five patients who achieved a partial response remains progression-free at 14+ months. CONCLUSION: Paclitaxel has antitumor activity in GCT and warrants continued study in combination chemotherapy. Phase I/II trials will address its role in combination with cisplatin and ifosfamide and as a part of dose-intensive therapy. Furthermore, the study showed that a trial design in which eligibility criteria limits prior therapy was feasible, resulted in the identification of antitumor activity in a new agent, and may be considered in future trials for other promising new agents in GCT.

Adolescent↗
PubMed1994

The management of patients with advanced germ cell tumors. Seminoma and nonseminoma.

Treatment strategies for germ cell tumors have evolved substantially during the last decade and are directed by pretreatment prognostic factors that include histology (seminoma versus nonseminoma), primary site of disease, serum concentrations of lactate dehydrogenase and human chorionic gonadotropin, and the number of metastatic sites of disease. Patients with a high likelihood of achieving a complete response to therapy (CR0.5) are considered "good risk" and receive three or four cycles of cisplatin-based chemotherapy. Patients with a low likelihood of achieving a complete response (CR0.5) are considered "poor risk" and should be considered for innovative treatment strategies with the intent of increasing the proportion of patients who are cured. One approach in patients with "poor risk" disease uses early treatment with high-dose chemotherapy and autologous bone marrow transplantation. In addition, effective salvage regimens are available for those patients who fail first-line therapy.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1993

Suramin for germ cell tumors. In vitro growth inhibition and results of a phase II trial.

BACKGROUND: Several studies have indicated a role for specific growth factors in the differentiation or deregulated growth of germ cell cancers. One proposed mechanism of antitumor activity for suramin is the inhibition of these tumor-derived growth factors. METHODS: Based on these data, the effects of suramin were studied on the growth of a monolayer culture of two human teratocarcinoma cell lines, NT2/D1 and N2102ep. These represented one cell line that was sensitive (NT2/D1) and one that was resistant (N2102ep) to the differentiation agent retinoic acid. These studies were followed by a Phase II trial of suramin in patients with germ cell tumors. Patients were treated with a continuous infusion of suramin. Dosing was determined by a nomogram based on weekly serum concentrations. RESULTS: Suramin inhibited the growth of both cell types in a dose-dependent fashion at a concentration attainable in patient plasma. This provided the rationale for a clinical trial of suramin in patients with cisplatin-refractory germ cell tumors. Fourteen patients were treated, and no complete or partial responses were observed. One patient achieved a prolonged decline in serum alpha-fetoprotein level without change in the size of a bidimensionally measurable retroperitoneal mass for more than 11 months. CONCLUSIONS: Despite the results of the in vitro studies, a Phase II trial failed to demonstrate significant antitumor activity for suramin in patients with cisplatin-refractory germ cell tumors. Although the dosing of suramin by the nomogram was not associated with neurotoxicity, the time needed to achieve therapeutic levels was lengthy, and the levels, once achieved, were of short duration. Thus, an alternative means of administration, i.e., by intermittent bolus administration, is being investigated in trials for patients with prostatic carcinoma. The lack of definitive efficacy for suramin in this trial has led the authors to consider other agents in Phase II trials for cisplatin-refractory germ cell tumor.

Adult↗
PubMed1993

Phase II trial of high-dose carboplatin and etoposide with autologous bone marrow transplantation in first-line therapy for patients with poor-risk germ cell tumors.

BACKGROUND: Between 20% and 30% of patients with advanced germ cell tumors (GCTs) fail to have durable complete response to conventional cisplatin-based induction chemotherapy. However, third-line therapy with high-dose carboplatin and etoposide plus autologous bone marrow transplantation (AuBMT) has induced durable complete response in 10%-20% of patients with cisplatin-resistant GCT. PURPOSE: We conducted a phase II trial of first-line therapy that included high-dose carboplatin and etoposide plus AuBMT in untreated men with advanced GCTs and unfavorable prognosis (i.e., "poor-risk" patients). METHODS: Twenty-eight patients were treated with a conventional-dose, cisplatin-containing regimen (VAB-6 [cisplatin, vinblastine, bleomycin, cyclophosphamide, dactinomycin]) with or without high-dose carboplatin (1500 mg/m2) and etoposide (1200 mg/m2) plus AuBMT. Twenty-two of these patients were selected for treatment with two cycles of high-dose carboplatin and etoposide plus AuBMT when reduced clearance of serum tumor markers (alpha-fetoprotein [AFP] or human chorionic gonadotropin [HCG]), as evidenced by prolonged half-life (> 7 days for AFP and > 3 days for HCG), was observed after two cycles of conventional treatment. RESULTS: Fifteen (56%) of 27 patients considered assessable for response achieved a complete response (12 treated with high-dose chemotherapy plus AuBMT). Sixteen (57%) are alive; 13 (46%) are free of disease at a median follow-up of 31.2 months. For 36 cycles of high-dose chemotherapy, the median duration from bone marrow infusion until a granulocyte count of 0.5/mm3 and a platelet count of 50,000/mm3 was 16 days (range, 7-41 days and 8-30 days, respectively). Analysis showed a trend toward improved survival (P = .07) in patients treated with high-dose chemotherapy in this study, compared with 68 poor-risk patients with GCT treated with conventional-dose therapy alone in two earlier studies. Toxicity was not cumulative, and recovery of blood counts after AuBMT was generally rapid. CONCLUSIONS: Inclusion of high-dose carboplatin-containing chemotherapy in treatment of poor-risk GCT patients is feasible when serum tumor marker half-life is used to predict resistance to standard cisplatin-based therapy. High-dose therapy in this setting was well tolerated. IMPLICATIONS: Early use of a dose-intensive regimen may increase survival compared with conventional-dose therapy alone. Further studies with standard induction therapy and intensive high-dose therapy using hematopoietic growth factor support are warranted, followed by a randomized trial comparing this strategy with standard therapy.

Adolescent↗