Phase II trial of pembrolizumab in patients with platinum refractory germ-cell tumors: a Hoosier Cancer Research Network Study GU14-206.

Background: Despite remarkable results with salvage standard-dose or high-dose chemotherapy ∼15% of patients with relapsed germ-cell tumors (GCT) are incurable. Immune checkpoint inhibitors have produced significant remission in multiple tumor types. We report the first study of immunotherapy in patients with GCT. Patients and methods: Single arm phase II trial investigating pembrolizumab 200 mg i.v. Q3weeks until disease progression in patients with relapsed GCT and no curable options. Patients age ≥18 with GCT who progressed after first-line cisplatin-based chemotherapy and after at least one salvage regimen (high-dose or standard-dose chemotherapy) were eligible. Centrally assessed programmed death-ligand 1 (PD-L1) on tumor and infiltrating immune cells was scored. Primary end point was overall response rate using immune-related response criteria. Simon two-stage design with type I error 20% and power 80% was utilized. Results: Twelve male patients were enrolled. Median age was 38 years. All patients had nonseminoma. Primary site was testis (11) or mediastinum (1). Median AFP 615 (range 1-32, 760) and hCG 4 (range 0.6-37, 096). Six patients had late relapse (>2 years). Median number of previous chemotherapy regimens was 3. Six patients received prior high-dose chemotherapy. Two patients had positive PD-L1 staining (H-score 90 and 170). Median number of pembrolizumab doses was 2 (range 1-8). There were six grade 3 adverse events. No immune-related adverse events were reported. No partial or complete responses were observed. Two patients achieved radiographic stable disease for 28 and 19 weeks, respectively; both had continued rising AFP level despite radiographic stability and had negative PD-L1 staining. Conclusion: This is the first reported trial evaluating immune checkpoint inhibitors in GCT. Pembrolizumab is well tolerated but does not appear to have clinically meaningful single-agent activity in refractory GCT. Clinical trial information: NCT02499952.

Multidisciplinary clinic approach improves overall survival outcomes of patients with metastatic germ-cell tumors.

Background: To report our experience utilizing a multidisciplinary clinic (MDC) at Indiana University (IU) since the publication of the International Germ Cell Cancer Collaborative Group (IGCCCG), and to compare our overall survival (OS) to that of the National Cancer Institute (NCI) Surveillance, Epidemiology, and End Results (SEER) Program. Patients and methods: We conducted a retrospective analysis of all patients with metastatic germ-cell tumor (GCT) seen at IU from 1998 to 2014. A total of 1611 consecutive patients were identified, of whom 704 patients received an initial evaluation by our MDC (including medical oncology, pathology, urology and thoracic surgery) and started first-line chemotherapy at IU. These 704 patients were eligible for analysis. All patients in this cohort were treated with cisplatin-etoposide-based combination chemotherapy. We compared the progression-free survival (PFS) and OS of patients treated at IU with that of the published IGCCCG cohort. OS of the IU testis cancer primary cohort (n = 622) was further compared with the SEER data of 1283 patients labeled with 'distant' disease. The Kaplan-Meier method was used to estimate PFS and OS. Results: With a median follow-up of 4.4 years, patients with good, intermediate, and poor risk disease by IGCCCG criteria treated at IU had 5-year PFS of 90%, 84%, and 54% and 5-year OS of 97%, 92%, and 73%, respectively. The 5-year PFS for all patients in the IU cohort was 79% [95% confidence interval (CI) 76% to 82%]. The 5-year OS for the IU cohort was 90% (95% CI 87% to 92%). IU testis cohort had 5-year OS 94% (95% CI 91% to 96%) versus 75% (95% CI 73% to 78%) for the SEER 'distant' cohort between 2000 and 2014, P-value <0.0001. Conclusion: The MDC approach to GCT at high-volume cancer center associated with improved OS outcomes in this contemporary dataset. OS is significantly higher in the IU cohort compared with the IGCCCG and SEER 'distant' cohort.

Long-term toxicity of cisplatin in germ-cell tumor survivors.

CONTEXT: Testicular germ-cell tumors (GCT) are highly curable. A multidisciplinary approach, including cisplatin-based chemotherapy has resulted in cure in the majority of patients with GCT. Thus, the life expectancy of survivors will extend to many decades post-diagnosis. Late treatment toxicities associated with cisplatin-based chemotherapy may impact their future health. OBJECTIVE: To systematically evaluate evidence regarding the long-term toxicity of cisplatin in GCT survivors. EVIDENCE ACQUISITION: We carried out a critical review of PubMed/Medline in February 2017 according to the Preferred Reporting Items for Systematic Review and Meta-analysis (PRISMA) statement. Identified reports were reviewed according to the Consolidated Standards of Reporting Trials (CONSORT) criteria. Eighty-three publications were selected for inclusion in this analysis. EVIDENCE SYNTHESIS: Included reports evaluated long-term toxicities of cisplatin-based chemotherapy in GCT survivors. Studies reporting neuro- and ototoxicity, secondary malignancies, cardiovascular, renal and pulmonary toxicities, hypogonadism and infertility were found. Seven studies (8%) reported genetic underpinnings of long-term toxicities and 3 (4%) and 14 (19%) studies correlated long-term toxicities with circulating platinum levels and cumulative dose of cisplatin, respectively. Significant risks for long-term toxicities associated with cisplatin and platinum-based regimens were reported. The cumulative dose of cisplatin and circulating platinum were reported as risk factors. Several single-nucleotide polymorphisms identified patients susceptible to cisplatin compared with wild-type individuals. CONCLUSIONS: GCT survivors cured with cisplatin-based chemotherapy are at risk for long-term side-effects. Detection of single-nucleotide polymorphisms could be a valuable tool for predicting long-term toxicities. PATIENT SUMMARY: Herein, this article summarizes the available evidence of long-term toxicity of cisplatin-based chemotherapy in GCT survivors and provide insights from Indiana University.

Prognostic factors in patients with poor-risk germ-cell tumors: a retrospective analysis of the Indiana University experience from 1990 to 2014.

BACKGROUND: Based on the risk stratification from the International Germ Cell Cancer Collaborative Group (IGCCCG), only 14% of patients with metastatic germ-cell tumors (GCT) had poor-risk disease with a 5-year progression-free survival (PFS) rate of 41% and a 5-year overall survival (OS) rate of only 48%. This analysis attempts to identify prognostic factors for patients with poor-risk disease. PATIENTS AND METHODS: We conducted a retrospective analysis of all patients with GCT diagnosed and treated at Indiana University from 1990 to 2014. Clinical and pathological characteristics were available for all patients and all of them were treated with cisplatin-etoposide-based chemotherapy. Cox proportional hazards models were used to target significant predictors of disease progression and mortality. A significance level of 5% was used in the analysis. RESULTS: We identified 273 consecutive patients with poor-risk GCT (PRGCT). Median follow-up time was 8 years (range 0.03-24.5). The 5-year PFS and OS rates were 58% [95% confidence interval (CI) 51% to 63%] and 73% (95% CI 67% to 78%), respectively. In multivariate survival analyses, multiple risk factors were associated with disease progression, including liver metastasis, brain metastasis, primary mediastinal nonseminomatous GCT (PMNSGCT), and elevation in logarithmic ß-hCG. Significant predictors of mortality were PMNSGCT [hazard ratio (HR) 4.63, 95% CI 2.25-9.56; P < 0.001], brain metastasis (HR 3.30, 95% CI 1.74-6.23; P < 0.001), and increasing age (HR 1.03, 95% CI 1.01-1.06; P = 0.02). CONCLUSIONS: Patients with PMNSGCT, brain metastasis, or with increasing age are at higher risk of death than their counterparts. This contemporary cohort (1990-2014) of 273 patients with PRGCT had improved PFS and OS outcomes than those from the historical IGCCCG group of patients (1975-1990).

Utilization of sperm banking and barriers to its use in testicular cancer patients.

PURPOSE: Testicular cancer is the most common carcinoma in 20- to 40-year-old men. Eighty percent of patients with metastases achieve disease-free status with chemotherapy with or without surgical resection. Standard first-line chemotherapy is bleomycin, etoposide, and cisplatin (BEP) for three to four courses or etoposide and cisplatin (EP) for four courses. Forty percent of patients receiving chemotherapy will have permanently reduced sperm counts impairing future fertility. Sperm banking is an effective method of maintaining fertility. This retrospective study was performed to assess utilization and results from sperm banking, as well as the barriers to its use. METHODS: Patients 18 and older who had received chemotherapy were given a five-item questionnaire on follow-up visit. This questionnaire included a mix of quantitative and qualitative questions. RESULTS: Two hundred patients enrolled in the study, and all 200 completed the questionnaire. Of the two hundred, 139 (70 %) patients chose not to bank sperm; 71 (51 %) of those were not interested, 25 (18 %) declined due to desire to start chemotherapy, 24 (17 %) were not offered, 12 (9 %) declined due to cost, and 7 (5 %) answered "other." The average age at cancer diagnosis of patients who banked sperm was 28.4 as opposed to 32.6 for patients who did not (p = 0.003). The percentage of patients that had children before their diagnosis was 21 % in the sperm banking group, and 50 % in the group that did not (p = 0.0002). Sixty-one (30 %) chose to bank sperm; 11 of 61 patients (18 %) utilized the banked sperm; 9 of 11 (82 %) patients that utilized were successful; and 3 of 9 (33 %) successes resulted in multiple gestations. CONCLUSIONS: Sperm banking provides the opportunity for paternity in testicular cancer patients with reduced sperm counts following treatment. However, the majority of these patients chose not to bank sperm or were not offered the opportunity. A range of factors such as time, emotional state, patient age, disease stage, prior children, institutional practices, and cost all influence whether banking is offered to patients and taken up. The authors provide recommendations to help clinicians overcome some of these barriers.

Outcome following resection for patients with primary mediastinal nonseminomatous germ-cell tumors and rising serum tumor markers post-chemotherapy.

BACKGROUND: To assess the outcome of surgical resection in patients with primary mediastinal nonseminomatous germ-cell tumors (PMNSGCT) with rising serum tumor markers (STM) following standard platinum-based chemotherapy. PATIENTS AND METHODS: A total of 158 consecutive patients with PMNSGCT who received platinum-based chemotherapy followed by complete surgical extirpation of residual disease at Indiana University from 1982 to 2007 were retrospectively reviewed. Thirty-five of these 158 patients had rising STM at time of resection. RESULTS: Thirty-five patients (34 males and 1 female) comprise the basis of this report. Three patients had rising human chorionic gonadotropin, and the remaining 32 patients had rising alpha-fetoprotein at the time of thoracic surgery. Twenty-four of the 35 (69%) pathologically demonstrated viable germ-cell tumor, while 8 patients had teratoma and 3 patients had necrosis only at time of resection, despite the presence of rising STM. Twenty-seven patients normalized their tumor markers postoperatively. Twenty-one of 35 died, 5 were lost to follow-up, and 9 are alive. Of the nine patients alive, seven are continuously disease free with median follow-up of 64 months (range 25-220 months). CONCLUSION: The presence of rising STM doesn't preclude successful therapy with surgical resection, especially if carried out by experienced thoracic surgical oncologists.

Outcome analysis of patients with transformed teratoma to primitive neuroectodermal tumor.

BACKGROUND: The emergence of a primitive neuroectodermal tumor (PNET) within a germ-cell tumor (GCT) is rare. We assess the prognosis and response to treatment. PATIENTS AND METHODS: Eighty-one patients were identified. Selected patients were treated with cyclophosphamide 1200 mg/m(2), doxorubicin 75 mg/m(2), and vincristine 2 mg i.v. alternating with ifosfamide 1.8 g/m(2) x 5 days plus etoposide 100 mg/m(2) x 5 days (CAV/IE). Ewing's sarcoma (EWS) translocation was assessed using a FISH-based method. RESULTS: Median follow-up was 41 months. Seventy-six patients had PNET in the primary tumor or in initial metastasis. Five harbored PNET only at relapse. Twenty-six of 76 underwent primary retroperitoneal lymph node dissection, 13 of whom had retroperitoneal PNET and four are dead of disease (DOD). Fifty of 76 were initially treated with GCT chemotherapy (n = 49) or CAV/IE (n = 1). Twenty-seven of these 50 underwent complete postchemotherapy resection of residual PNET and 17 are DOD. Ten patients received CAV/IE. Eight achieved an objective response, and five are currently alive. One of the 14 specimens examined carried the EWS translocation. CONCLUSIONS: PNET of GCT origin is associated with an adverse outcome. For low-volume disease, surgery is the optimal initial therapy. CAV/IE may have a role in patients with unresectable disease.

Salvage chemotherapy with high-dose carboplatin plus etoposide and autologous peripheral blood stem cell transplant in male pure choriocarcinoma: a retrospective analysis of 13 cases.

Choriocarcinoma of testes is a very rare tumor with poor prognosis, usually presenting with high serum level of human chorionic gonadotropin (hCG>50,000 mIU/ml) and advanced hematogenous metastases. Data with salvage chemotherapy has been sparse, with few long-term survivors. Between April 1996 and October 2004, 184 patients with germ cell tumor were treated at Indiana University with salvage high-dose chemotherapy (HDCT) with autologous peripheral blood stem cell transplant. Thirteen had pure choriocarcinoma or choriocarcinoma syndrome (normal testes by palpation and ultrasound, normal serum alpha-fetoprotein, advanced hematogenous metastases and high level hCG). All patients had progressed following one or two lines of cisplatin combination therapy. HDCT regimen was carboplatin 700 mg/m(2) and etoposide 750 mg/m(2) intravenously given for 3 consecutive days. A second course was given after hematopoietic recovery, usually 3-4 weeks later. The median survival was 19 months (range 5-90). Six patients (46%) are alive and continuously disease free (cNED) at a median follow-up of 37 months (range 19-75). One additional patient who relapsed after HDCT and was treated with third line chemotherapy followed by two surgical resections of choriocarcinoma is currently alive NED at +90 months from HDCT. Long-term disease-free survival and potential cure is possible with HDCT in choriocarcinoma patients that progressed after standard cisplatin combination therapy.

Gefitinib in patients with chemo-sensitive and chemo-refractory relapsed small cell cancers: a Hoosier Oncology Group phase II trial.

BACKGROUND: Gefitinib has demonstrated activity in patients with non-small cell lung cancer (NSCLC). Clinical trials have not demonstrated a relationship between response to gefitinib and over-expression of the epidermal growth factor receptor (EGFR). Although, EGFR is not over-expressed in small cell lung cancer (SCLC), we postulated that gefitinib might affect tumor growth through other mechanisms. Agents that are active in NSCLC usually are also effective in SCLC. METHODS: The primary objective was to assess the clinical control rate: complete response (CR) partial response (PR) and stable disease (SD > 90 days), of gefitinib in patients with chemo-resistant and chemo-sensitive small cell cancers. Eligibility criteria included pathologic proof of a neuroendocrine tumor, especially small cell cancer, Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0-2, prior treatment with one or two prior chemotherapy regimens and adequate end-organ function. Patients received gefitinib, 250 mg p.o. daily until disease progression or intolerable side effects. RESULTS: From April 2003 to March 2004, 19 patients were enrolled. Small cell lung cancer accounted for 18 of the 19 patients and one patient had metastatic Merkel cell carcinoma. Twelve patients (63%) had chemo-sensitive disease, defined as progression greater than three months from completion of prior chemotherapy; 7 (37%) had chemo-refractory disease; 13 (68%) had one prior chemotherapy regimen. Other patient characteristics: mean age 64 years (range 52-79 years); ECOG PS 0/1/2 = 7/9/3, M:F = 9:10. Grade 3 toxicities included: fatigue in three patients (15.8%), pulmonary toxicities in three (15.8%) and one patient (5.3%) each with hyperglycemia or pain. Four patients had grade four toxicities: one patient (5.3%) with fatigue and three patients (15.8%) with dyspnea. There were no patients with grade 3 or 4 rash or diarrhea. Two patients had stable disease (<90 days) and 17 had progressive disease as their best response. This study was a two-stage design and because the continuing criterion for stage one was not met, stage 2 was not performed. Median time to progression (TTP) was 50 days (95% CI = 21-58 days). One year overall survival (OS) was 21% (95% CI = 6-45.6%). CONCLUSION: Although gefitinib has activity in select patients with NSCLC, this study failed to demonstrate benefit in patients with small cell lung cancer.

Testicular cancer: the quest continues.

Treatment for testicular cancer has dramatically improved during the last 15 years. Much of this success has come about because of improved staging and operative techniques but, most importantly, through the introduction of successful systemic chemotherapy. Nonetheless, relevant issues still remain to be addressed in regard to the optimal therapy for patients with germ cell neoplasms. Included in these issues is delineating the most effective but minimally morbid treatment for patients with early-stage and low-volume metastatic disease while continuing to create innovative treatment approaches for poor-risk patients with metastatic disease. The unique association of primary mediastinal germ cell neoplasms with the development of non-germ cell cancers and Klinefelter's syndrome may provide some early clues for the determination of factors controlling differentiation. These observations issue a challenge to both clinical and preclinical researchers involved in the study of this neoplasm.

Secondary leukemia associated with a conventional dose of etoposide: review of serial germ cell tumor protocols.

BACKGROUND: Case reports have suggested that treatment with high-dose etoposide can result in development of a unique secondary leukemia. PURPOSE: This study was designed to estimate the risk of developing leukemia for patients receiving conventional doses of etoposide along with cisplatin and bleomycin. METHODS: We reviewed the records at Indiana University of all untreated patients entering clinical trials using etoposide at conventional doses (cumulative dose, 2000 mg/m2 or less) for germ cell cancer between 1982 and 1991. The records of all patients who received a chemotherapy regimen containing etoposide, ifosfamide, or cisplatin after failing to respond to primary chemotherapy were also reviewed. RESULTS: Between 1982 and 1991, 538 patients entered serial clinical trials with planned cumulative etoposide doses of 1500-2000 mg/m2 in combination with cisplatin plus either ifosfamide or bleomycin. Of these 538 patients, 348 received an etoposide combination as initial chemotherapy and 190 received etoposide as part of salvage treatment. To date, 315 patients are alive, with median follow-up of 4.9 years, and 337 patients have had follow-up beyond 2 years. Two patients (0.37%) developed leukemia. One developed acute undifferentiated leukemia with a t(4;11) (q21;q23) cytogenetic abnormality 2.0 years after starting etoposide-based therapy, and one developed acute myelomonoblastic leukemia with no chromosome abnormalities 2.3 years after beginning chemotherapy. During this period, several hundred patients were treated with etoposide-based chemotherapy and did not enter clinical trials. Three of these patients are known to have developed hematologic abnormalities, including one patient with acute monoblastic leukemia with a t(11;19)(q13;p13) abnormality. CONCLUSIONS: Secondary leukemia after treatment with a conventional dose of etoposide does occur, but the low incidence does not alter the risk-to-benefit ratio of etoposide-based chemotherapy in germ cell cancer. IMPLICATIONS: The reports of leukemia associated with high doses of etoposide emphasize the need for diligent follow-up of patients and make careful risk-to-benefit analysis imperative.

Testicular cancer as a model for a curable neoplasm: The Richard and Hinda Rosenthal Foundation Award Lecture.

The combination of platinum, vinblastine, and bleomycin was first used at Indiana University in 1974. Thirty of 47 patients (64%) survived for 5 years, and 27 (57%) are currently disease free (NED) and cured of their neoplasm. From 1976 to 1978, 78 consecutive patients were entered on a random prospective study that indicated that equal therapeutic results could be achieved with a lower dosage (0.3 mg/kg) of vinblastine. Fifty-two (67%) patients are continuously NED, and 57 (73%) are currently NED for 2 or more years. Our third-generation study, done in conjunction with the Southeastern Cancer Study Group, tested the hypothesis of whether maintenance vinblastine was necessary to ensure optimal cure rates in disseminated testicular cancer. One hundred thirteen patients entered this maintenance study, and the results demonstrated that cure in a far-advanced cancer could be achieved with only 12 weeks of therapy (remission induction) because the relapse rate in such patients was only 7%. The cure rate for patients presenting with locoregional disease (Stages A and B) should approach 100%. Platinum, vinblastine, and bleomycin will regularly produce a 70% complete remission rate, and a further 10% of patients will be rendered NED with surgical resection of residual disease. The relapse rate with four courses of remission induction therapy in a large cooperative group study (Southeastern Cancer Study Group) was only 7%. The high success rate in disseminated disease has allowed the option of high cure rate in Stage B disease (positive retroperitoneal nodes) with or without adjuvant chemotherapy. At Indiana University, 137 patients have been followed with Stage A and B nonseminomatous testicular cancer from 1973 to 1979 with a minimum follow-up of 2 years, and currently 135 are alive and well. Successful treatment strategies in testicular cancer have yielded a cure rate unparalleled in cancer treatment.

Relation of proliferative activity to survival in patients with advanced germ cell cancer.

Patients with advanced disseminated germ cell tumors of the testis, retroperitoneum, and mediastinum have impaired survival compared to other patients with disseminated germ cell tumors having less bulky metastatic disease. Among patients with advanced disseminated germ cell tumors, we currently lack adequate predictors of long-term survival. Flow cytometric analysis of the paraffin-embedded, formalin-fixed tumor blocks of 50 of these patients suggests that proliferative activity is significantly correlated with survival (p less than 0.001) in multivariate analysis. Log (beta-human chorionic gonadotropin) is the only other useful predictor of long-term survival in multivariate analysis of prognostic factors in this group of patients. Flow cytometric DNA analysis may be useful in predicting survival in patients with advanced disseminated germ cell tumors.

Altered expression of Ape1/ref-1 in germ cell tumors and overexpression in NT2 cells confers resistance to bleomycin and radiation.

The human AP endonuclease (Ape1 or ref-1) DNA base excision repair (BER) enzyme is a multifunctional protein that has an impact on a wide variety of important cellular functions including oxidative signaling, transcription factor regulation, and cell cycle control. It acts on mutagenic AP (baseless) sites in DNA as a critical member of the DNA BER repair pathway. Moreover, Ape1/ref-1 stimulates the DNA-binding activity of transcription factors (Fos-Jun, nuclear factor-kappaB, Myb, ATF/cyclic AMP-responsive element binding protein family, HIF-1alpha, HLF, PAX, and p53) through a redox mechanism and thus represents a novel component of signal transduction processes that regulate eukaryotic gene expression. Ape1/ref-1 has also been shown to be closely linked to apoptosis associated with thioredoxin, and altered levels of Ape1/ref-1 have been found in some cancers. In a pilot study, we have examined Ape1/ref-1 expression by immunohistochemistry in sections of germ cell tumors (GCTs) from 10 patients with testicular cancer of various histologies including seminomas, yolk sac tumors, and malignant teratomas. Ape1/ref-1 was expressed at relatively high levels in the tumor cells of nearly all sections. We hypothesized that elevated expression of Ape1/ref-1 is responsible in part for the resistance to therapeutic agents. To answer this hypothesis, we overexpressed the Ape1/ref-1 cDNA in the GCT cell line NT2/D1 using retroviral gene transduction with the vector LAPESN. Using an oligonucleotide cleavage assay and immunohistochemistry to assess Ape1/ref-1 repair activity and expression, respectively, we found that the repair activity and relative Ape1/ref-1 expression in GCT cell lines are directly related. NT2/D1 cells transduced with Ape1/ref-1 exhibited 2-fold higher AP endonuclease activity in the oligonucleotide cleavage assay, and this was reflected in a 2-3-fold increase in protection against bleomycin. Lesser protection was observed with gamma-irradiation. We conclude that: (a) Ape1/ref-1 is expressed at relatively high levels in some GCTs; (b) elevated expression of Ape1/ref-1 in testicular cancer cell lines results in resistance to certain therapeutic agents; and (c) Ape1/ref-1 expression in GCT cell lines determined by immunohistochemistry and repair activity assays parallels the level of protection from bleomycin. We further hypothesize that elevated Ape1/ref-1 levels observed in human testicular cancer may be related to their relative resistance to therapy and may serve as a diagnostic marker for refractory disease. To our knowledge, this is the first example of overexpressing Ape1/ref-1 in a mammalian system resulting in enhanced protection to DNA-damaging agents.

Treatment of testicular cancer: a new and improved model.

Testicular cancer has become a model for a curable neoplasm. Prior to the advent of cisplatin combination chemotherapy, standard chemotherapy consisted of dactinomycin, alone or in combination with chlorambucil and methotrexate. Disseminated germ cell tumors were chemosensitive to these older regimens, with a 50% objective response rate and a 10% to 20% complete remission rate; however, the cure rate was only 5% to 10%. In 1974, we began our initial cisplatin plus vinblastine plus bleomycin (PVB) chemotherapy. Thirty-three of 47 patients with disseminated germ cell tumors treated from 1974 to 1976 achieved a complete remission (CR), and an additional five (11%) were rendered disease-free with post-PVB resection of teratoma or carcinoma. Twenty-seven (57%) of these patients are continuously disease-free with a minimal follow-up of 13 + years. Thus, cisplatin-based chemotherapy produced a one-log increase in the cure rate compared with dactinomycin. A subsequent phase III study performed from 1976 to 1978 demonstrated that the vinblastine dosage could be reduced 25% from 0.4 mg/kg to 0.3 mg/kg with a reduction in toxicity but without any decrement in therapeutic efficacy. A third-generation PVB study from 1978 to 1981 documented that optimal cure rates were achieved with 12 weeks of induction therapy with PVB and that long-term maintenance therapy with vinblastine was unnecessary. In 1978, we initiated salvage therapy with cisplatin plus etoposide (VP-16) in patients not cured with PVB, and 25% of these patients were subsequently cured with this regimen. This represented the first time an adult solid tumor had been cured with a second-line regimen. In 1983, we began studies with third-line therapy with cisplatin plus ifosfamide combination chemotherapy, and even in this refractory setting, approximately 20% of patients are curable. From 1981 to 1984, we compared cisplatin plus VP-16 plus bleomycin (PVP16B) with PVB as first-line chemotherapy. There was a significant reduction in neuromuscular toxicity favoring the VP-16 arm, and furthermore, 78% of these patients were continuously disease-free compared with 66% with PVB. Approximately 75% of patients with disseminated germ cell tumors will be cured with PVP16B, and an additional 10% are curable with salvage chemotherapy. This represents the highest cure rate in any adult malignancy.

Gallium scans in the evaluation of residual masses after chemotherapy for seminoma.

PURPOSE: To assess the ability of gallium scans to determine whether residual masses consist of viable tumor or necrotic fibrous tissue after chemotherapy for seminoma. PATIENTS AND METHODS: Thirty-two patients were enrolled and 27 were assessable. Patients receiving first-line or salvage chemotherapy had gallium scans performed during their first and last scheduled course of chemotherapy and results were compared with restaging computed tomographic (CT) scans and subsequent clinical outcome. RESULTS: Of 27 assessable patients, 22 received first-line chemotherapy (group A) and five salvage chemotherapy (group B). Eight patients were not gallium-avid before chemotherapy despite obvious clinical and radiographic evidence of metastatic seminoma. Eighteen of 19 gallium-positive patients had a persistent mass postchemotherapy on abdominal CT. Of 16 patients in group A whose tumors were gallium-avid, all 16 had normalized gallium scans after chemotherapy. However, two of these 16 patients recurred in their original disease site. In group B, there were three patients with gallium-avid tumors and all three had normalized scans postchemotherapy. Two patients who were not gallium-avid (one each in group A and B) also developed recurrent disease. Twenty-four of 27 patients are alive with no evidence of active disease at a median follow-up time of 18 months, including 20 with more than 1 year of follow-up data. CONCLUSION: Eight of 27 patients had false-negative gallium scans at the time of diagnosis. All nineteen gallium scans that were initially positive reverted to normal after chemotherapy. Two of 19 patients' follow-up gallium scans were false-negative. We therefore feel that gallium scans have minimal value in the prechemotherapy or postchemotherapy evaluation of metastatic seminoma.

Maintenance chemotherapy with daily oral etoposide following salvage therapy in patients with germ cell tumors.

PURPOSE: To evaluate the role of maintenance daily oral etoposide (VP-16) chemotherapy for germ cell patients who had a response to salvage therapy. PATIENTS AND METHODS: Thirty-seven patients were entered onto this trial, and 34 were fully assessable. This was as heavily pretreated patient population, with a median of two prior salvage regimens. The salvage treatment that immediately preceded oral VP-16 consisted of autologous bone marrow transplantation in 14 patients (41%), surgery in 10 (29%), and standard-dose salvage chemotherapy in 10 (29%). Daily oral VP-16 was administered at a dose of 50 mg/m2 for 21 consecutive days every 4 weeks for three cycles. RESULTS: The major toxicity with daily oral VP-16 was leukopenia. Three patients had grade III and two grade IV leukopenia. Two of these patients had granulocytopenic fever. Other grade III toxicities included thrombocytopenia (n = 1) and mucositis (n = 2). Twenty-three patients started daily oral VP-16 while in complete remission (CR) following salvage therapy. Seventeen (74%) remain continuously disease-free, with a median follow-up time of 36 months (range, 26 to 49) from initiation of daily oral VP-16. Eleven patients started daily oral VP-16 while in partial remission (PR) following salvage therapy. Three of these 11 patients converted to CR, but all three subsequently relapsed. CONCLUSION: Maintenance oral VP-16 was well tolerated in this heavily treated patient population. Results in this poor-risk population were encouraging.

Management strategies and outcomes of germ cell tumor patients with very high human chorionic gonadotropin levels.

PURPOSE: To determine the therapeutic results in advanced germ cell tumor (GCT) patients with initial human chorionic gonadotropin (hCG) elevation greater than 50,000 mIU/mL and to document the levels of hCG decline and subsequent plateau and outcome of this patient population. PATIENTS AND METHODS: We conducted a retrospective review of 41 patients who presented to Indiana University (IU) with hCG levels greater than 50,000 mIU/mL between December 1976 and August 1996. All patients had received cisplatin-containing regimens and were monitored with serial hCG levels. RESULTS: Twenty-two of 41 (53.7%) patients continuously show no evidence of disease (NED) and eight additional patients (19.5%) are currently NED with salvage therapy. Only two of 41 patients had a normal hCG level at the start of the fourth and final course of cisplatin combination chemotherapy. Eight additional patients showed normalized hCG levels 1 month later. Seven of these 10 are continuously NED and three are currently NED with salvage therapy. Thirty-one patients had an abnormal hCG greater than 1 month after they completed primary chemotherapy; 15 of these patients (48%) are continuously NED despite no further therapy and five additional patients (16%) are currently NED with salvage therapy. Overall, there was an initial rapid decline in hCG followed by a plateau after the first two courses of therapy. CONCLUSION: Less than 10% of patients who present with hCG levels greater than 50,000 mIU/mL will have a normal hCG at the institution of the fourth and final course of chemotherapy. However, 22 of 41 (53.7%) are continuously NED despite no further therapy. We feel that the optimal strategy for such patients is monthly observation with initiation of salvage therapy if and when there is serologic progression.