Biomedical subjects
Publications and source records attributed to R B Golbey.
Mediastinal germ cell tumors are rare, and in the past they were uniformly lethal. A high index of suspicion leading to early diagnosis combined with modern interdisciplinary management can now prolong comfortable survival and produce many cures. The development of Cis-Platinum based combination chemotherapy, and its early use, has been the major factor in the improvement of treatment results.
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The Testicular Cancer Intergroup Study was initiated to evaluate the efficacy of adjuvant chemotherapy in Stage II and salvage therapy in Stage I nonseminomatous testicular carcinoma. Chemotherapy regimens of cisplatin, vinblastine, and bleomycin (PVB) or the same drugs plus cyclophosphamide and dactinomycin (VAB) were used at institution or cooperative group preference. A comparison of the toxicities of these two regimens shows that VAB caused significantly more mucosal, dermatologic, and otologic toxicity than PVB, and PVB caused more leucopenia. Both regimens were equally effective in controlling cancer. Either regimen could be used as chemotherapy in testicular cancer, and the decision about which one to use could be based on their differences in toxicity and degree of patient convenience.
Standard chemotherapy for disseminated germ cell tumors (GCT) cures most patients but causes considerable acute toxicity, including treatment-related death due to septicemia during neutropenia and pulmonary fibrosis. In addition, chronic and delayed toxicities, particularly Raynaud's phenomenon, have been reported in 6% to 37% of treated patients. In an attempt to minimize the acute and chronic effects of treatment which are related primarily to vinblastine and bleomycin, a randomized trial comparing the efficacy and toxicity of vinblastine + bleomycin + cisplatin + cyclophosphamide + dactinomycin (VAB-6) and etoposide + cisplatin (EP) was conducted on 164 eligible patients with good-prognosis GCT. Seventy-nine of 82 (96%) patients receiving VAB-6 and 76/82 (93%) receiving EP achieved a complete remission (CR) with or without adjunctive surgery. Similar proportions of patients in both arms were found at surgery to have necrosis/fibrosis or mature teratoma. With a median follow-up of 24.4 months in the VAB-6 arm and 25.9 months in the EP arm, the total, relapse-free, and event-free survival distributions were similar in the two arms. Patients receiving EP experienced less emesis (P = .05), higher nadir WBC (P = .06) and platelet counts (P = .01), less magnesium wasting (P = .0001), less mucositis (P = .09), and no pulmonary toxicity. No treatment-related mortality was observed. EP is an efficacious and less toxic regimen and is recommended for good-prognosis patients with disseminated GCT.
One hundred sixty-six patients with germ-cell tumors (GCT) of the testis, retroperitoneum, and mediastinum were treated with cyclophosphamide, vinblastine, bleomycin, dactinomycin, and cisplatin (VAB-6), with and without maintenance chemotherapy. The overall complete response (CR) rate was 78%, 67% to chemotherapy alone, and 11% after chemotherapy and resection of viable residual cancer. The CR rate in all patients with seminoma was uniformly high, while the CR rate of patients with testicular nonseminomatous germ-cell tumors (79%) was superior to that of similar tumors of extragonadal origin (60%). The overall relapse rate was 12%, and was greater in tumors of extragonadal origin (21%) than in those of testicular origin (11%). Three relapses occurred after 2 years. Maintenance chemotherapy did not prolong either relapse-free or total survival. Toxicity was tolerable, and there were no treatment deaths. No Raynaud's phenomena have occurred, with a minimum duration since start of therapy of 36 months. VAB-6 is an effective chemotherapy regimen in patients with GCT with no treatment-related deaths and a majority of patients requiring only 3 months of treatment.
To determine the frequency and prognostic importance of pretreatment clinical characteristics in patients currently undergoing treatment for stage III non-small-cell lung cancer (NSCLC), data were collected on 378 patients receiving high-dose (120 mg/m2) cisplatin plus vinca alkaloid combination chemotherapy regimens since 1978. Variables analyzed included age, sex, weight loss, performance status, histologic subtype, presence of extrathoracic metastases, number of metastatic organ sites, presence of liver, bone, or brain involvement, prior radiation or surgery, and serum lactate dehydrogenase (LDH). The effect of a major response to chemotherapy on survival was also investigated. Using multivariable analyses, the following were found to be associated with outcome: initial performance status, with patients having a performance status of 80% to 100% having an increased major objective response rate and survival; bone metastases, which were adversely predictive of response rate and survival; elevated serum LDH and male sex, both of which were associated with shortened survival and remission duration; and the presence of two or more extrathoracic metastatic organ sites, which was associated with shorter survival. When major objective response with chemotherapy was included in a conditional multivariable analysis, it was strongly associated with longer median survival. Information from this analysis may be useful when comparing the response data of completed studies in similar patients, in designing future trials, and in the selection of cisplatin plus vinca alkaloid therapy for individual patients with advanced NSCLC.
Forty-nine patients with metastatic germ cell tumors were treated with etoposide 100 mg/m2 and cisplatin 20 mg/m2 intravenously each day for five days as "salvage" chemotherapy. Forty-seven patients had received standard induction regimens for metastatic germ cell tumors before receiving etoposide and cisplatin. Four patients were treated after surgical resection of a single site of relapse (Group I). Forty-five patients had measurable or evaluable disease at the time of treatment. In 17 patients with evaluable disease who had either achieved a prior complete remission or received no prior cisplatin (Group II), eight (47 percent) complete and four (24 percent) partial remission were observed. In 28 patients who had never achieved a prior complete remission (Group III), no complete and five (18 percent) partial responses were observed. Seven of 21 patients in Groups I and II and none of 28 patients in Group III remain alive and free of disease. Assuming prior treatment with cisplatin-based chemotherapy, these data and a review of the published experience with similar salvage regimens for patients with relapsing or refractory germ cell tumors suggest that combination chemotherapy based on etoposide and cisplatin is effective primarily in those patients who achieved a prior complete remission. Such therapy is ineffective in the absence of a prior complete remission probably because the patients have tumors that are largely resistant to cisplatin. Observed responses are probably due to etoposide alone. Investigational therapies should be pursued in those patients whose disease is refractory to current induction regimens.
Thirty patients with advanced seminoma were treated with VAB-6. Eighteen patients were previously untreated, eight had relapsed after radiation therapy, and four had persistent disease following chemotherapy and radiation therapy. Two patients had received prior high-dose cisplatin. Twenty-four (86%) of 28 evaluable patients achieved a complete remission. Four patients had relapsed. The median disease-free follow-up of patients achieving complete remission was 32+ months. VAB-6 is effective treatment for patients with advanced seminoma, and chemotherapy is recommended as the initial therapy in all patients with stage II seminoma with disease larger than 5 cm, extragonadal seminoma, and stage III seminoma.
Thirty-eight patients with extragonadal germ-cell tumors treated at Memorial Sloan-Kettering Cancer Center (New York) between 1975 and 1982 received high-dose cisplatin-based chemotherapy. Complete response was achieved in 89% of patients with pure seminoma and all complete responders are alive without evidence of disease (median follow-up time, 29+ months). Complete response was achieved in only 41% (12 of 29) of patients with extragonadal nonseminomatous germ-cell tumors; only four patients are alive and free of disease (median survival time, 18 months). Although patients with extragonadal seminoma respond well with current cisplatin-based chemotherapy, minimal improvement in CR rates has been achieved in patients with extragonadal nonseminomatous tumors. Patients with extragonadal nonseminomatous germ-cell tumors have a relatively poor prognosis when compared to patients with primary testicular tumors and investigational trials of innovative therapy should be considered.
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In the United States, there are an estimated 5000 to 6000 new patients annually who might be candidates for major hepatic resection to treat their recurrent colon cancer. Since 1971, the program reported here has evaluated various factors that might influence the curative potential of such an approach. Sixty-five patients had a major hepatic resection from March 1971 through May 1982. Using a stepwise proportional hazard analysis, all data that had been stored in CLINFO (a data analysis system by Bolt, Beranek and Newman; Boston, MA) were evaluated for the effect of multiple variables on the survival of patients with resected hepatic metastases. Twenty-seven had a right hepatic lobectomy; 14 had extended right hepatectomy with one having the caudate lobe also removed; ten had left lobectomy, nine had left lateral segmentectomy; and five had a major hepatic resection with three-dimensional wedge excision of a metastatic deposit in the contralateral lobe. The 30-day operative mortality rate was 7% (4/58) for patients undergoing the standard major hepatic resection. It was 14% for seven patients in whom the isolation-hypothermic perfusion technique was used early in the series. In ten patients, wedge excision only was required to remove the tumor. Stage I disease is defined as tumor confined to the resected portion of the liver without invasion of major intrahepatic vessels or bile ducts. Stage II disease is regional spread and Stage III disease is metastasis to lymph nodes or extraregional sites. The 3-year survival estimate was 66% for the 37 patients with Stage I disease. The 3-year survival estimate for 13 patients with Stage II disease was 58%. Five of the nine patients with Stage III disease are presently alive from 3 to 23 months; one of the other four died at 35 months of disease. The stage of liver disease was the most significant variable in this survival analysis (p = 0.02); Dukes' classification of colorectal primary was significant at p less than 0.05. Those factors found not to be significant determinants of survival were: number of metastatic hepatic deposits, site of colon primary, age, sex, preoperative liver function tests, and CEA.
One hundred and seventeen patients with colorectal hepatic metastases had insertion of catheters for infusional chemotherapy. The two-year survival estimate of patients with less than 50% hepatic replacement and no other adverse factors was 37%. Nine of 39 patients in this group are alive at 24 months. The catheters were placed into the hepatic artery (HA), 23; into the portal venous system (PV), 18; into both HA and PV, 64; or into an accessory HA following ligation, 12. Fifty-nine patients had ligation of the common HA also. The 30-day postoperative mortality rate was 1.7% (2/117) and morbidity was 37.6%. The majority of complications were related to fever (61%, 27/44). Over the past 2 years, 87% of patients have been discharged within 10 days following surgery. Preoperative CEA ranged from 0.5-12,150 ng/ml (median 165 ng/ml); 93% (78/84) had plasma CEA levels exceeding 5 ng/ml. All patients had careful intraoperative staging: per cent hepatic replacement (PHR) ranged from 5-95% (median 60%); portal, celiac, or periaortic lymph node metastases were observed in 31% (36/117). Initial intrahepatic chemotherapy programs consisted of either CAMF (9 patients), MAFL (60 patients), BFS (22 patients), continuous infusion FUDR (14 patients), or miscellaneous drugs (4 patients). Median survival time of 109 evaluable patients was 11.5 months. The effect of 20 variables on the observed survival time was analyzed using a multivariate proportional hazard model. Three variables were found to have influenced survival: PHR emerged as the most significant, p = 0.000001. Increased PHR was associated with decreased survival time. Lymph node metastases and prior chemotherapy were prognostic factors also, p = 0.0006 and p = 0.03, respectively. No patient with PHR greater than 80% lived more than 8 months. Utilization of these variables would appear to be necessary for accurate stratification and evaluation of future chemotherapy trials in patients with colorectal hepatic metastases.
Forty-five patients with clinical stage I nonseminomatous germ cell tumor of the testis (NSGCTT) were entered in a prospective clinical trial to receive no treatment other than orchiectomy until clinical evidence of relapse. Of this group, 36 patients (80%) have been continuously free of disease for a median duration of 19.5 months after orchiectomy. Nine patients (20%) have relapsed, eight within seven months of orchiectomy. Seven of nine relapsing patients have been rendered free of disease with chemotherapy and/or surgery for a median duration of seven months (range, one to 33 months) after completion of treatment; the other two patients are presently under treatment although one has progressive disease. The relapse rate was higher in patients with embryonal carcinoma than in those with teratocarcinoma, 57% versus 17%. These preliminary results imply that the omission of routine lymphadenectomy or lymph-node irradiation in clinical stage I NSGCTT deserves further trial.
Primary extragonadal seminoma (EGS) is a rare tumor of young adults that often presents with bulky primary tumors and metastatic disease. Long-term survival is inadequate with conventional therapy consisting of radiotherapy with or without surgery. The charts of 21 patients with EGS treated initially either with conventional therapy (group I) or with multimodality therapy including initial chemotherapy with high doses of cisplatin followed by either radiotherapy or surgery or both (group II) were reviewed. Five of the ten patients in group I developed recurrent disease and four of them eventually died of disease. Only one of 11 patients in group II died of metastatic disease and the remaining patients are free of disease with 19+ to 46+ months of follow-up. Of the six patients from group II who underwent surgical resection of apparently residual disease after chemotherapy but prior to radiotherapy, five were found to have completely necrotic tumor and one had microscopic disease on histologic examination, proving the efficacy of chemotherapy. Combined modality therapy including initial chemotherapy containing high doses of cisplatin provided rapid reduction in tumor burden and the results appeared superior to treatment that did not include initial chemotherapy.
Possible relationships between histopathologic cell type and several clinical variables were examined in 253 patients with Stage III nonseminomatous germ cell tumors of the testis. No statistically significant associations were found between cell type and either the side of primary tumor or cryptorchidism. The presence of elements of choriocarcinoma was associated with the presence of retroperitoneal tumor (P less than 0.03) but no other association between cell type and site of metastasis was encountered. Elevated serum levels of human chorionic gonadotropin were found in patients with elements of choriocarcinoma but serum levels of alphafetoprotein, lactate dehydrogenase and carcinoembryonic antigen were not correlated with a specific cell type. No statistically significant association was found between cell type and either complete response to combined modality therapy or survival. These results would indicate that cell type is probably not an important prognostic variable in patients with Stage III nonseminomatous tumors of the testis.
Forty-four patients with nonseminomatous germ cell tumors with "poor prognostic features" were entered on the VAB-5 regimen and 38 are evaluable. VAB-5 represents an intensified version of the VAB-4 protocol. Poor prognostic features were considered to be bulky metastases ( greater than 5 cm in diameter), palpable retroperitoneal disease, liver metastases, brain metastases, involvement of two or more parenchymal organs, pure choriocarcinoma, alpha fetoprotein or human chorionic gonadotropin serum levels over 1000 ng/ml, lactic acid dehydrogenase serum levels over 400 mg/dl, and failure to prior chemotherapy. Eighteen of 38 evaluable patients became free of neoplasm, 11 with chemotherapy alone, and seven with combined chemotherapy and surgery. Fourteen of 18 complete responders remain alive and free of disease with a median follow-up of 50 months. Complete remission with testis tumor occurred in 13/15 without and 5/15 with prior chemotherapy and in none of eight patients with primary extragonadal germ cell tumors. Thirty-one patients received antibiotics when they developed fever during myelosuppression. Ten patients developed transient serum creatinine levels over 2 mg/dl after cis-platinum and one required hemodialysis with subsequent recovery. All patients had severe mucositis after induction. An apparent improvement of results over prior VAB protocols in patients with poor prognostic features was compromised by significant increases in toxicity and such patients require special study to improve cure rates.
The clinical records and histologic material of 48 patients with extraosseous osteogenic sarcoma were reviewed. Most patients developed their tumors in the fifth or sixth decades of life. Five patients (10%) developed neoplasms in an area of prior radiation therapy, a median of 15 years after their exposure. Six patients (13%) related a history of trauma to the area where their extraosseous osteogenic sarcoma developed. The course of most patients was that of multiple local recurrences (69%) followed by pulmonary metastases (80%) and death (76%). Amputation or wide resection followed by irradiation appeared to be the most effective types of therapy, with median survivals greater than 60 months for patients receiving these treatments, compared to 28 months for patients initially treated with resection alone. Chemotherapy was not effective for patients with advanced disease; however, adjuvant chemotherapy after surgery may have been of value. Four of five patients who received adjuvant chemotherapy after surgery are alive and disease-free; the only two survivors after development of pulmonary metastases received adjuvant chemotherapy after surgical resection of visible pulmonary metastases.
Thirty-six men with Stage III or bulky Stage II malignant germ cell tumors of the testis who received no prior chemotherapy were treated with the VAB-6 protocol without maintenance and 34 were evaluable. The VAB-6 regimen is a 3-4 month program beginning with successive inductions at 3-4 week intervals: day 1, cyclophosphamide 600 mg/m2 of body surface, bleomycin 30 mg, vinblastine 4 mg/m2 and dactinomycin 1 mg/m2 intravenously; days 1-3, bleomycin 20 mg/m2/day X 3 by continuous 24-hour intravenous infusion; and day 4, cis-platinum 120 mg/m2 intravenously. Complete responders receive a fourth induction and are followed thereafter without further chemotherapy. Incomplete responders have resection of residual disease one month after the third induction. If the resected specimen contains malignant tissue, an additional two inductions are given. Thirty-one of 34 (91%) evaluable patients achieved complete remission and 28 remain in complete remission with median follow up of 24+ months. Chemotherapy alone was most effective in patients with minimal metastatic disease, with no teratoma in primary tumor, and with pure seminoma. Patients with advanced metastatic deposits or with teratoma in the primary tumor frequently required combined chemotherapy and surgery to achieve disease free status. Myelosuppression was the principal potentially serious toxicity. With effective induction, maintenance chemotherapy is not necessary.