Stephen D. Williams

Intraperitoneal cisplatin plus intravenous cyclophosphamide versus intravenous cisplatin plus intravenous cyclophosphamide for stage III ovarian cancer

BACKGROUND Intravenous platinum-based chemotherapy is the standard primary therapy for advanced ovarian cancer. We conducted a phase 3 trial to compare the effects of intraperitoneal and intravenous cisplatin on the survival of women with previously untreated, stage III, epithelial ovarian cancer. METHODS The patients underwent an initial exploratory laparotomy and resection of all tumor masses larger than 2 cm. Within four weeks after surgery, six courses of intravenous cyclophosphamide (600 mg per square meter of body-surface area per course) plus either intraperitoneal cisplatin (100 mg per square meter) or intravenous cisplatin (100 mg per square meter) were administered at three-week intervals. RESULTS Of 654 randomized patients, 546 were eligible for the study. The estimated median survival was significantly longer in the group receiving intraperitoneal cisplatin (49 months; 95 percent confidence interval, 42 to 56) than in the group receiving intravenous cisplatin (41 months; 95 percent confidence interval, 34 to 47). The risk of death was lower in the intraperitoneal group than in the intravenous group (hazard ratio, 0.76; 95 percent confidence interval, 0.61 to 0.96; P = 0.02). Moderate-to-severe tinnitus, clinical hearing loss, and neuromuscular toxic effects were significantly more frequent in the intravenous group. CONCLUSIONS As compared with intravenous cisplatin, intraperitoneal cisplatin significantly improves survival and has significantly fewer toxic effects in patients with stage III ovarian cancer and residual tumor masses of 2 cm or less.

Treatment of Disseminated Germ-Cell Tumors with Cisplatin, Bleomycin, and either Vinblastine or Etoposide

Standard chemotherapy for disseminated germ-cell tumors includes a combination of cisplatin, vinblastine, and bleomycin, but this regimen produces substantial neuromuscular toxicity. In a randomized clinical trial in 261 men with disseminated germ-cell tumors, we substituted etoposide for the vinblastine in this regimen in half the patients to compare the efficacy and toxicity of the two treatments. Among 244 patients who could be evaluated for a response, 74 percent of those receiving the regimen including vinblastine and 83 percent of those receiving the regimen including etoposide became disease-free with or without subsequent surgery (P not significant). Among the 157 patients with high tumor volume, 61 percent became disease-free on the regimen that included vinblastine, as compared with 77 percent on the regimen that included etoposide (P less than 0.05). Survival among the patients who received etoposide was higher (P = 0.048). The regimens were similar in terms of myelosuppressive effects and pulmonary toxicity. However, the etoposide regimen caused substantially fewer paresthesias (P = 0.02), abdominal cramps (P = 0.0008), and myalgias (P = 0.00002). We conclude that etoposide with cisplatin and bleomycin is superior to vinblastine with cisplatin and bleomycin in the treatment of disseminated germ-cell tumors because of diminished neuromuscular toxicity and, among patients with advanced disease, better efficacy.

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.

Immediate Adjuvant Chemotherapy versus Observation with Treatment at Relapse in Pathological Stage II Testicular Cancer

Between 1979 and 1984, 195 evaluable patients were entered in an international multicenter study comparing two regimens for patients with completely resected pathological Stage II testicular cancer (that is, with positive retroperitoneal lymph nodes). All patients had undergone orchiectomy and dissection of the retroperitoneal lymph nodes. They were randomly assigned to be treated with two cycles of immediate adjuvant cisplatin-based chemotherapy or to be observed monthly with treatment at relapse. The median follow-up period was four years. Of the 97 patients assigned to adjuvant chemotherapy, 6 (6 percent) had a recurrence; however, only 1 had received adjuvant chemotherapy before the recurrence. Three died (one of testicular cancer), and 94 of the 97 survived. Of the 98 patients who were observed, 48 (49 percent) had a relapse. However, almost all patients with relapses were effectively treated, and 93 of the 98 are alive and disease-free; 3 have died of testicular cancer. No identifiable factors were strongly associated with the risk of relapse. We conclude that two courses of cisplatin-based adjuvant chemotherapy will almost always prevent relapse in pathological Stage II testicular cancer treated with orchiectomy and retroperitoneal-lymph-node dissection. However, when surgery, follow-up, and chemotherapy are optimal, observation with chemotherapy only for relapse will lead to equivalent cure rates.

Dose-intensive chemotherapy in refractory germ cell cancer--a phase I/II trial of high-dose carboplatin and etoposide with autologous bone marrow transplantation.

Between September 1986 and March 1988, 33 patients with refractory germ cell cancer were entered on a phase I/II trial of two courses of high-dose carboplatin plus etoposide with autologous bone marrow support. All patients had extensive prior treatment and had either cisplatin-refractory disease (67%) defined as progression within 4 weeks of the last cisplatin dose or failed at least two cisplatin-based regimens (35%) including a cisplatin-ifosfamide salvage regimen. Patients received a fixed total dose of etoposide of 1,200 mg/m2 with each cycle. The carboplatin dose ranged from 900 mg/m2 to 2,000 mg/m2. Twenty of the 33 patients received the second cycle of therapy. Despite extensive prior therapy with cisplatin, neurotoxicity, nephrotoxicity, or hearing impairment with high-dose carboplatin and etoposide was unusual. The most common nonhematologic toxicity was moderate enterocolitis. The hematologic toxicity of this regimen was substantial at each dose level. All 53 courses were accompanied by granulocytopenic fevers. Seven of the 33 patients (21%) died from treatment. All of these deaths occurred during the granulocyte nadir, and five were related to documented sepsis. Overall, 14 of 32 patients (44%) evaluable for response obtained an objective response, including eight complete remissions. Four patients remain in complete remission, with three patients being continuously free of disease in excess of 1 year. Eight responders (including four complete remissions) had progressed while receiving cisplatin. We conclude that carboplatin and etoposide can be administered in combination at high dosages and this regimen may have curative potential for patients with germ cell tumors resistant to conventional-dose cisplatin-based therapies.

Efficient retrovirus-mediated transfer of the multidrug resistance 1 gene into autologous human long-term repopulating hematopoietic stem cells

Pre-clinical studies indicate that efficient retrovirus-mediated gene transfer into hematopoietic stem cells and progenitor cells can be achieved by co-localizing retroviral particles and target cells on specific adhesion domains of fibronectin. In this pilot study, we used this technique to transfer the human multidrug resistance 1 gene into stem and progenitor cells of patients with germ cell tumors undergoing autologous transplantation. There was efficient gene transfer into stem and progenitor cells in the presence of recombinant fibronectin fragment CH-296. The infusion of these cells was associated with no harmful effects and led to prompt hematopoietic recovery. There was in vivo vector expression, but it may have been limited by the high rate of aberrant splicing of the multidrug resistance 1 gene in the vector. Gene marking has persisted more than a year at levels higher than previously reported in humans.

The development of non-germ cell malignancies within germ cell tumors. A clinicopathologic study of 11 cases

Eleven male patients had germ cell tumors of the testis (7), mediastinum (3), or retroperitoneum (1) in which non‐germ cell malignancies developed. Such malignant non‐germ cell elements were present in the primary excisions of five patients and were subsequently found in additional resected tissue in 10 of 11 patients. In the patients who had multiple pathology specimens examined, a progression from atypia to predominant non‐germ cell malignancy was often found. The authors believe these malignant elements arose within teratomatous foci, since eight of nine cases had teratoma in the primary tumor, and teratoma was found in subsequently resected tissue in one additional case. Cisplatin therapy frequently “unmasked” the non‐germ cell malignant elements by destroying the more chemosensitive germ cell cancers. The prognosis was worst for five patients who developed progressive embryonal rhabdomyosarcoma: two of these patients died of local spread of tumor, whereas a third died of metastatic sarcoma. Only one patient, who had total surgical excision of rhabdomyosarcoma, survived. Other forms of sarcoma that developed within germ cell tumors did not appear to adversely affect the prognosis beyond that of teratoma. It is currently recommended, when feasible, that patients with teratoma and sarcoma undergo total surgical excision. Further treatment with cisplatin regimens, after eradication of the germ cell component, has not been helpful. The role of other forms of chemotherapy remains speculative.

Randomized study of cisplatin dose intensity in poor-risk germ cell tumors: a Southeastern Cancer Study Group and Southwest Oncology Group protocol.

Between 1984 and 1989, 159 patients presenting with advanced germ cell cancer were entered on a randomized clinical trial comparing the efficacy and toxicity of etoposide and bleomycin and either standard-dose cisplatin (20 mg/m2 daily for 5 days) or high-dose cisplatin (40 mg/m2 daily for 5 days). Of the 159 patients, 153 were assessable for toxicity and response. As expected, patients receiving the high-dose cisplatin regimen experienced significantly more neurotoxicity, ototoxicity, nausea and vomiting, and myelo-suppression. Four patients (3%) died related to therapy. Despite the toxicity encountered, dose intensity was maintained. Overall, 84% of patients in the high-dose arm received 80% or more of the projected dose of cisplatin, etoposide, and bleomycin; and 90% of patients on the standard-dose arm received 80% or more of the projected dose. Of the 76 eligible patients randomized to receive the high-dose cisplatin regimen, 52 (68%) became disease-free with chemotherapy alone or with subsequent resection of residual teratoma or cancer. Of the 77 patients randomized to the standard-dose arm, 56 (73%) became disease-free with chemotherapy alone or with surgery. Median follow-up is now 24 months. Eleven patients (three high-dose and eight standard-dose) relapsed from disease-free status. Overall, 74% of patients receiving the high-dose cisplatin regimen are alive, and 63% are continuously free of disease. Of the patients receiving the standard-dose cisplatin regimen, 74% are alive, and 61% are continuously free of disease. This randomized prospective trial in advanced germ cell cancer achieved dose intensity of the most active single agent in this disease. This dose intensity did not translate into an improved survival or cure. We conclude that dose escalation of cisplatin beyond standard doses results in excess toxicity with no accompanying therapeutic benefit.

Long term effect of Cis‐Diamminedichloride platinum (CDDP) on renal function and structure in man

To examine CDDP induced nephrotoxicity in patients with testicular carcinoma, we measured renal function prior to therapy and at six month intervals for twelve months in fifteen patients and twenty‐four months in seven patients. CDDP was given iv at 20 mg/M2 per day for five days at three week intervals. Eight patients received three courses, four received four courses and three received more than four courses. The mean creatinine clearance ± SD prior to treatment was 112 ± 12 ml/min. By six months, it had decreased to 68.5 ± ml/min (p < 0.01) and it remained at that level. Plasma creatinine and blood urea nitrogen increased significantly. Subjects receiving other potential nephrotoxins in addition to CDDP developed a greater decrease in creatinine clearance (p < 0.05). Proteinuria and functional tubular disturbances were not observed. Microscopic features were characterized by hydropic degeneration of the renal tubular epithelium, thickened tubular basement membranes and mild interstitial fibrosis. Electron microscopy revealed phagolysosomes filled with flocculent material. CDDP resulted in a permanent, nonspecific renal injury in our patients. Although the renal injury has remained subclinical, future courses of CDDP may lead to clinically important chronic renal failure.

Fertility after chemotherapy for testicular cancer.

Sixty-nine patients with disseminated testicular cancer and no prior retroperitoneal lymphadenectomy treated with cisplatin, vinblastine, and bleomycin with or without doxorubicin were evaluated for semen analysis, serum gonadotropins, and testosterone. Since 1979, 41 men have been prospectively studied. Before treatment 77% were oligospermic, 17% were azoospermic, and only 6.6% could meet requirements for sperm banking. After 2 mo of therapy, 96% were azoospermic. A group of 28 patients treated between 1975 and 1979 were retrospectively evaluated. Normal sperm counts were found in 46% of those studied. Only 17% were azoospermic. Thirty-two percent have impregnated their wives, resulting in 5 healthy babies, 1 spontaneous abortion, and 3 ongoing pregnancies. These results show that (1) significant impairment of spermatogenesis exists before therapy, precluding the possibility of sperm banking in most patients, (2) combination chemotherapy in testicular cancer has substantial effects on gonadal function, rendering almost all patients azoospermic, and (3) a high degree of recovery of spermatogenesis occurs sometime after 2-3 yr from the initiation of treatment.