Successful treatment of disseminated extragonadal germ cell cancer with intensive conventional chemotherapy after first-line high-dose chemotherapy

High-dose chemotherapy (HDCT) with peripheral blood stem cell (PBSC) support has been investigated as a first-line treatment in patients with poor risk germ cell cancer. However, effective management of patients with residual cancer after HDCT has not been well addressed, and the outcome in such patients is poor. Here, we report a case of disseminated germ cell cancer successfully treated with intensive conventional chemotherapy after HDCT. A 31-year-old man presented with a bulky mass at the retroperitoneum, which had invaded the lumbar and sacral vertebra, and multiple lung and liver metastases. The patient's serum beta subunit of human chorionic gonadotrophin (β-hCG) was elevated to 2600 IU (cut-off value <0.1 IU). At the time of diagnosis of poor risk germ cell cancer of extragonadal origin, he underwent two cycles of BEP (bleomycin, etoposide, and cisplatin) chemotherapy and PBSC harvest followed by three cycles of HDCT with PBSC transplantation. The liver metastases disappeared. The retroperitoneal bulky mass and multiple lung metastases shrank but were still present, and the serum β-hCG level was not completely normalized. An additional three courses of BEP and five courses of VIP (cisplatin, ifosfamide, etoposide) normalized the β-hCG level. Pathological evaluation of the residual masses revealed no viable cancer cells at either site. The patient is alive without disease recurrence 5 years after completion of chemotherapy.     

Cisplatin-based combination chemotherapy for disseminated germ cell tumors: long-term follow-up

A retrospective analysis of the initial 229 cases of disseminated germ cell tumors treated at Indiana University with cisplatin, vinblastine, and bleomycin (PVB), with or without doxorubicin revealed 146 patients who are alive and disease-free with a minimum follow-up of 6 years and a median follow-up of 8.5 years. At 12 years, the estimated probability of survival is 65.0%, and the estimated probability of relapse-free survival for complete responders is 83.5%. Long-term complications, such as clinically significant organ toxicity or therapy-related second malignancies, have not been observed. The functional status of survivors is maintained, with 95% returning to their pretherapy status, of which 88% are fully employed. Of patients receiving chemotherapy without abdominal surgery, 35% have fathered healthy children posttherapy. Achievement of complete remission (CR) in disseminated germ cell tumors with cisplatin-based combination chemotherapy translates to long-term disease-free survival and cure for the majority of patients, with preservation of functional status.     

A review of second-line chemotherapy and prognostic models for disseminated germ cell tumors

Despite an excellent prognosis even for patients with disseminated disease, about 20% to 30% of men with advanced germ cell tumors are refractory to first-line chemotherapy or experience disease recurrence after an initial remission with such treatment. Many of these are cured with conventional dose cisplatin/ifosfamide-based regimen or high-dose chemotherapy with stem cell rescue. Controversy exists regarding the optimal choice between these 2 second-line approaches, and available data for each is reviewed here. Clinical factors can help prognosticate patients, and recently an international effort developed a prognostic model for the second-line setting that can be universally applied in future studies.     

Thromboembolic events during chemotherapy for germ cell cancer: a cohort study and review of the literature.

PURPOSE: To evaluate the risk of major thromboembolic complications in male germ cell cancer patients receiving cisplatin-based chemotherapy and to review the literature on this subject. PATIENTS AND METHODS: One hundred seventy-nine germ cell cancer patients treated between January 1979 and May 1997 in our hospital were analyzed with respect to risk factors for developing thromboembolic events, such as baseline tumor characteristics, prior tumor therapy, administration of cytostatic agents, and the use of antiemetic drugs. The patients were treated with a variety of combination chemotherapy regimens, primarily cisplatin-containing combination regimens. RESULTS: Of the 179 patients, 15 patients (8.4%) were identified who developed a total of 18 major thromboembolic complications in the time period between the start of chemotherapy and 6 weeks after administration of the last cytostatic drug in first-line treatment. Of these 18 events, three (16.7%) were arterial events, including two cerebral ischemic strokes, and 15 (83. 3%) were venous thromboembolic events, including 11 pulmonary embolisms. One (5.6%) of the 18 events was fatal. Liver metastases (odds ratio, 4.9; 95% confidence interval, 1.1 to 20.8) and the administration of high doses of corticosteroids (>/= 80 mg dexamethasone per cycle; odds ratio, 3.5; 95% confidence interval, 1. 2 to 10.3) as antiemetic therapy were identified as risk factors for the development of major thromboembolic complications. CONCLUSION: Germ cell cancer patients who receive chemotherapy, in particular those who have liver metastases or receive high doses of corticosteroids, are at considerable risk of developing thromboembolic complications.     

Chemotherapy of disseminated germ cell tumors

The success of management of germ cell tumors puts an extraordinary burden on the physician and health care system to assure that cure is achieved in all patients except the small proportion that present with advanced refractory disease. New prognostic systems can define groups of patients who have excellent outcomes with treatment and a group of patients for whom treatment less reliably results in cure. Good risk disseminated disease should be treated with three cycles of bleomycin, etoposide, and cisplatin, whereas those with more advanced disease should receive four cycles. Postchemotherapy resection of residual disease is commonly required. In patients who recur after primary chemotherapy, salvage treatments can result in cure in 30% to 40% of patients.     

Combination chemotherapy with newly-developed cytostatics for disseminated small cell lung cancer

The paper discusses the results of phase II clinical trials of chemotherapy regimens using newly-developed cytostatics for disseminated small cell lung cancer. Taxotere (docetaxel)/cisplatin and campto(irinotecan)/cisplatin were investigated as first-line treatment. Doxorubicin and vincristine in combinations with a novel antitumor cytostatic aranoza were studied for application as second-line treatment. Safety and immediate- and end results were reviewed. Taxotere (docetaxel)/cisplatin and campto(irinotecan)/cisplatin regimens were compared.     

Dose intensive chemotherapy in small cell lung cancer

The rationale for treatment intensification is to overcome the occurrence of drug resistance and to improve the outcome in SCLC. Several different approaches have been tested in the past two decades. Increasing the dose of conventional chemotherapy has failed to improve survival in extensive stage. In limited stage patients one randomized trial demonstrated a significant survival advantage by a 20% increase of the dose of cisplatin and cyclophosphamide given during the first cycle of chemotherapy. Shortening treatment intervals is achievable by weekly chemotherapy or by use of hematopoietic growth factors. Neither weekly chemotherapy, tested in four randomized trials, nor the application of hematopoietic growth factors significantly improved survival. However, two studies described a better survival for patients receiving chemotherapy in shorter treatment intervals. In one trial a 3-week interval was superior to a 4-week interval, and in a second one a 2-week interval superior to a 3-week interval. One smaller study, comparing a 4-week interval with a 2-week interval with stem cell augmentation by whole blood, revealed no difference in survival between both groups. A randomized trial comparing chemotherapy in intervals as short as possible with or without growth factor application showed no difference for the two groups. Thus, growth factor application seems not to be essential for treatment in short intervals and was not associated with superior survival in randomized trials. To achieve a more than two-fold increase in dose intensity some kind of stem cell support is mandatory. Several phase II trials with small patient numbers tested the concept of late intensification with bone marrow support in the 1980s. These trials did not show any convincing benefit. There is one randomized trial available testing the late intensification approach in which a superior progression free survival and a trend for better survival was demonstrated, but this difference was not statistically significant due to a high mortality rate and a substantial number of local relapses in the high dose arm. Newer concepts involving high dose therapy are combining high dose strategies with approaches for better local tumor control, administer high dose regimens earlier in the treatment course, or use multiple sequential high dose cycles. With these approaches 3-year survival rates of up to 40% have been reported. So up to date, the superiority of an intensified treatment strategy has not been demonstrated in a convincing way and further controlled trials will be necessary to clarify the role of dose intense chemotherapy in SCLC.     

Nonseminomatous germ cell cancer of the testis. Reducing treatment-related morbidity in patients with disseminated disease

Fourteen previously untreated patients with metastatic nonseminomatous germ cell cancer of the testis (NSGC) were treated with a modified VAB-4 regimen which was designed to reduce treatment-related morbidity. Nine of 10 patients with minimal disease and the only patient with advanced pulmonary disease achieved a complete response (CR) with chemotherapy alone. Two of three partial responders with advanced abdominal disease were converted to CR status with radiotherapy and/or surgery. None of the 12 CRs have relapsed (median duration of follow-up, 28+ months). We observed no granulocytopenic fever or permanent renal insufficiency. These results indicate that NSGC patients with a low tumor burden can be spared substantial toxicity without adversely affecting complete response rates.     

Prognostic factors for favorable outcome in disseminated germ cell tumors

Between 1978 and 1982, 180 patients from Indiana University (Indianapolis) were entered on the Southeastern Cancer Study Group (SECSG) protocol 78 GU 240, a randomized comparison of cisplatin, vinblastine, and bleomycin (PVB) v PVB plus doxorubicin induction chemotherapy regimens, with a second randomization to maintenance vinblastine v no further therapy. One hundred forty-eight of these patients obtained a favorable response to chemotherapy, defined as a complete response (CR) or a surgical resection of teratoma. The prognostic significance of various patient characteristics was investigated using the logistic regression model. Two classifications for the extent of disease were considered: the Indiana staging system and the M.D. Anderson (MDA) staging system. The Indiana staging system had the greater prognostic significance. This staging system allowed the population to be split into three groups (minimal, moderate, advanced disease) in which the observed proportions of favorable responders were 99%, 90%, and 58%, respectively. Within the advanced group, the number of elevated tumor markers subdivided these patients into three groups, with the observed proportions of favorable responders being 73%, 65%, and 45%. The Indiana and MDA staging systems were subsequently prospectively used in SECSG protocol GU 81 332, a study randomizing patients to remission induction therapy with PVB v cisplatin, VP-16, and bleomycin. The prognostic value of the Indiana staging system was prospectively validated in this study.     

Cytotoxicity of Clostridium difficile toxin A for human colonic and pancreatic carcinoma cell lines.

The use of bacterial exotoxins may constitute novel adjuncts to treatment of gastrointestinal tract malignancies. Clostridium difficile toxin A was evaluated for its cytotoxic effect in vitro on 24 human cell lines and strains including carcinomas of the colon, pancreas, prostate, lung, breast, and lymphoid malignancies, as well as nonmalignant tissues. All nine colon and five pancreas cell lines were extraordinarily sensitive to the cytotoxic effect of Clostridium difficile toxin A at very low concentrations. This effect, which occurred rapidly and was dose dependent, was observed in all cells of seven colon and two pancreas cell lines at concentrations as low as 1-5 ng/ml (10(-12) to 10(-11) M), whereas cells derived from other sites required 60 to greater than 500 ng/ml to achieve an equivalent effect. The data suggest that Clostridium difficile toxin A may have potential therapeutic value in the treatment of some gastrointestinal tract cancers.     

Dose-dependent impairment of testicular function in patients treated with cisplatin-based chemotherapy for germ cell cancer

BACKGROUND:: The enormous differences in semen quality following cisplatin-basedcombination chemotherapy reported in previous studies may becaused by differences in the cisplatin dosages. PATIENTS AND METHODS:: We examined thirty-three patients treated with conventional-dosePEB (cisplatin 20 mg/m² x 5, q3w, etoposide 100 mg/m² x 5 q3wand bleomycin 15 mg/m² q1w) and 21 patients treated with high-dosePEB (cisplatin 40 mg/m² x 5 q3w, etoposide 200 mg/m² x 5 q3wand bleomycin 15 mg/m² qlw). RESULTS:: The sperm density was significantly higher (median 5.83 mill/ml)in the conventionally-treated group than in the group of high-dose-treatedpatients (median 0.005 mill/ml) (p = 0.008). Azoospermia waspresent in 19% of the conventionally- and in 47% of the high-dose-treatedpatients. All patients treated with a cumulative cisplatin doseabove 600 mg/m² had severe oligospermia or azoospermia. Serumvalues of basal follicle-stimulating hormone (FSH) (median 27.2iu/l vs. 15.2 iu/l) and stimulated FSH (median 57.7 iu/l vs.28.4 iu/l) were significantly higher in the high-dose groupthan in the conventionally-treated group. No differences couldbe detected in basal or stimulated testosterone or in luteinizinghormone in serum. CONCLUSION:: In patients treated with PEB for testicular cancer, we foundstrong evidence that the impairment of spermatogenesis is dose-dependent. cytotoxic agents, fertility, spermatogenesis, Leydig cell function, testicular cancer     

Late cardiovascular toxicity following chemotherapy for germ cell tumors

The introduction of cisplatin-based chemotherapy has transformed germ cell tumors (GCTs), the most common malignancy to affect young adult men, into a highly curable cancer, even in the setting of advanced disease. However, over the past decade, the success of these chemotherapy regimens in curing GCTs has been temporized by an increasing recognition of their important late toxicities, such as cardiovascular disease. The relative risk of coronary artery disease in this population is particularly elevated within the first 10 years of follow-up, when patients are still in their 30s and 40s, which are age groups often considered too young to experience cardiovascular events. Two hypotheses have been proposed to explain the association between chemotherapy and cardiovascular disease in this population. The direct hypothesis asserts that chemotherapy causes diffuse endothelial damage, including in the coronary arteries, gradually leading to cardiovascular disease. In contrast, the indirect hypothesis proposes that chemotherapy leads to an increased incidence of cardiovascular disease risk factors, such as hypertension, hyperlipidemia, and the metabolic syndrome, which in turn enhance the risk of cardiovascular disease. This article summarizes the data on the association between chemotherapy (predominantly cisplatin-based) and the development of cardiovascular disease among GCT survivors, and reviews the evidence supporting both mechanistic hypotheses. In addition, recommendations are provided for the management of GCT survivors who received cisplatin-based chemotherapy and are therefore at risk for cardiovascular toxicity.     

Long-term effects of intravenous hyperalimentation administered during intensive chemotherapy for small cell bronchogenic carcinoma

Sixty-five patients with small cell bronchogenic carcinoma received their first two of three courses of intensive induction chemotherapy with (30 patients) or without (35 patients) intravenous hyperalimentation (IVH). Patients predominantly had extensive disease (55%), Zubrod's performance status 0 to 2 (63%) and less than or equal to 6% pretreatment weight loss (68%). Both treatment arms were comparable by prognostic factors. The chemotherapy included six remission induction courses of ECHO chemotherapy (E: epipodophyllotoxin VP-16-213; C: cyclophosphamide; H: hydroxydaunorubicin; O: oncovin [vincristine]) followed by six courses of maintenance with PRIME (PR: procarbazine; I: ifosfamide; ME: methotrexate). Prophylactic brain irradiation was given to all patients. Patients with limited disease received chest irradiation at the completion of ECHO. Fifty of 52 (96%) evaluable patients responded with a complete (56%) or partial (40%) remission. The complete remission (CR) rate was higher in the control arm (66% versus 43%; P = 0.11). Response duration and survival of patients was similar for both treatment arms. Combined median survival duration for all patients with limited and extensive disease was 15.75 and 11.50 months, respectively. Combined median survival duration for CR patients with limited and extensive disease was 25 and 13 months, respectively. Administration of IVH did not ameliorate the hematologic, gastrointestinal and infectious morbidity of ECHO chemotherapy. The IVH was effective in preserving body weight and improving delayed hypersensitivity reaction to a battery of skin test antigens. Administration of intensive ECHO chemotherapy to patients with small cell bronchogenic carcinoma resulted in high response rates, acceptable toxicities and improved survival. Administration of IVH did not improve the short- and long-term results of chemotherapy, and did not ameliorate its morbidity. Nutritional support, however, was helpful in preventing patient's weight loss.     

Primary chemotherapy for intracranial nongerminomatous germ cell tumors: results of the second international CNS germ cell study group protocol.

PURPOSE: The optimum therapy for intracranial nongerminomatous germ cell tumors (NGGCT) remains controversial. The primary objective of this study was to determine whether intensive cisplatin and cyclophosphamide-based combination chemotherapy was effective in patients with intracranial NGGCT. PATIENTS AND METHODS: Twenty patients were enrolled, aged 5 to 41 years (median, 13 years). Initial therapy included two courses of Regimen A (cisplatin, etoposide, cyclophosphamide, and bleomycin). Patients achieving a complete remission (CR) then received two courses of Regimen B (carboplatin, etoposide, and bleomycin). Those in CR after four courses of treatment received one additional course of Regimen A and Regimen B, while those not in CR after four treatment courses underwent second-look surgery and/or irradiation. RESULTS: Sixteen of 17 patients assessable for response after two courses of treatment achieved a CR or partial response (CR + partial response, 0.94; 95% CI, 0.73 to 1.0). With a median follow-up of 6.3 years, 14 of 20 patients are alive without disease; eight patients were without relapse or progression, of whom three received local irradiation in first complete remission in violation of protocol, and six patients were in durable second or third complete remission after further chemotherapy and/or irradiation. The 5-year overall survival and event-free survival were 0.75 (95% CI, 0.56 to 0.94) and 0.36 (95% CI, 0.13 to 0.59), respectively. CONCLUSION: Intensive chemotherapy was effective in one-third of patients in this study. Salvage therapy, including irradiation, was feasible in patients with recurrent disease.     

Evaluation of optimal duration of chemotherapy in favorable-prognosis disseminated germ cell tumors: a Southeastern Cancer Study Group protocol

Four courses of PVP16B (cisplatin plus etoposide [VP-16] plus bleomycin) has been standard chemotherapy for disseminated germ cell tumors at Indiana University and the Southeastern Cancer Study Group (SECSG) since 1984. We began a random prospective phase III study in patients with favorable-prognosis (minimal and moderate extent) disseminated germ cell tumors comparing four courses of PVP16B over 12 weeks to the identical dose PVP16B administered in three courses over 9 weeks. The categories of minimal and moderate disease constitute approximately two thirds of all disseminated germ cell tumors that require chemotherapy. One hundred eighty-four patients entered this trial, and all patients have a minimal follow-up of 1 year. Overall, 106 of 107 (99%) minimal extent and 73 of 77 moderate patients (95%) achieved an initial disease-free status (NED), confirming the favorable prognostic categories. Eighty-six of 88 patients (98%) randomized to three courses and 93 of 96 randomized to four courses (97%) of PVP16B achieved disease-free status. There have been ten relapses (5%), with five on each arm. Currently, 81 of 88 (92%) and 88 of 96 (92%) patients randomized to three v four courses of PVP16B are continuously disease-free. This study confirms the high cure rate with PVP16B in favorable-prognosis germ cell tumors. The deletion of the fourth course of PVP16B significantly reduces the toxicity, cost, and inconvenience of this curative regimen. We conclude that three courses of PVP16B is the preferred regimen for favorable-prognosis germ cell tumors.     

Induction chemotherapy followed by low-dose involved-field radiotherapy for intracranial germ cell tumors.

PURPOSE: To investigate the efficacy of chemotherapy followed by low-dose involved-field radiotherapy for the treatment of intracranial germ cell tumors (GCTs). PATIENTS AND METHODS: Thirty-three patients with GCTs, including 16 pure germinomas, 11 human chorionic gonadotropin-beta (HCG-beta)-secreting germinomas, three mixed GCTs composed of immature teratomas plus germinomas (IMT/G), and three highly malignant mixed GCTs, were treated. Etoposide and cisplatin (EP) were used for the treatment of solitary pure germinomas, and ifosfamide, cisplatin, and etoposide (ICE) were used for the treatment of other GCTs. The dose schedule was 24 Gy for germinomas and 40 to 54 Gy for other GCTs. An involved-field set-up was used except for highly malignant GCTs, in which craniospinal irradiation was used. The median follow-up was 58 months (range, 18 to 102 months). RESULTS: Disease-related, overall, and relapse-free survival rates at 5 years were 100%, 93%, and 69% for all patients, 100%, 100%, and 86% for patients with pure germinomas, and 100%, 75%, and 44% for patients with HCG-beta-secreting germinomas, respectively. All six patients with nongerminomatous GCTs were alive at the last follow-up. All eight relapses (one pure germinoma, five HCG-beta-secreting germinomas, and two IMT/G), except one in a course of salvage treatment, were salvaged and free of disease at the last follow-up. No decline was observed in the full-scale, verbal, or performance intelligence quotient at 12 to 51 months after the treatment in 11 patients. CONCLUSION: Our results support an excellent prognosis after EP and ICE regimens followed by radiotherapy. Dose and volume can be reduced to 24 Gy in 12 fractions and involve a field set-up after EP chemotherapy for the treatment of pure germinomas.