Joan Jacob

High-Dose Cisplatin in Hypertonic Saline

To overcome the dose limiting toxicity of cisplatin we have administered high-dose cisplatin (200 mg/m2 body surface area in five divided daily doses with each dose administered in 250 mL of 3% saline) together with extensive hydration (250 mL/h normal saline with 20 meq KCI/L). In 17 previously untreated patients with poor prognosis nonseminomatous testicular cancer, 8 with tumor-associated obstructive uropathy, there was no statistically significant decrease in creatinine clearance or elevation of serum creatinine after three to four cycles of a high-dose cisplatin in combination chemotherapy regimen. High-dose cisplatin in combination with vinblastine, bleomycin, and VP-16 produced an 88% complete response rate in these high-risk patients who are characterized primarily by the presence of advanced bulky lung and abdominal disease. Six patients with ovarian cancer who had a relapse after treatment with standard dose cisplatin regimens were treated with high-dose cisplatin and three partial responses were seen. Four patients had no adverse effects on renal function whereas 2 patients had transient elevations in serum creatinine (4 to 5 mg/dL). Hypertonic saline did not provide protection against the nonrenal toxicities of cisplatin.

A randomized trial of standard chemotherapy v a high-dose chemotherapy regimen in the treatment of poor prognosis nonseminomatous germ-cell tumors.

We performed a prospective randomized trial of a high-dose chemotherapy regimen v standard cisplatin-based chemotherapy in poor prognosis nonseminomatous germ-cell cancer patients. The high-dose regimen consisting of twice the standard dose of cisplatin (P), along with vinblastine (Ve), bleomycin (B), and the epipodophylotoxin etoposide (VP-16) (V) (PVeBV) was compared to the classic regimen with normal dose cisplatin, vinblastine, and bleomycin (PVeB). Eligibility criteria included large abdominal masses, liver metastases, multiple pulmonary metastases, brain metastases, marked elevations in serum tumor markers (alpha-fetoprotein greater than 1,000 ng/mL or the beta-subunit of human chorionic gonadotropin greater than 10,000 mIU), unfavorable histology (pure choriocarcinoma), or extragonadal germ-cell tumors. Fifty-two consecutive patients with poor prognostic features were randomized to receive either PVeBV or PVeB. The median follow-up is 4 years. Treatment with the high-dose regimen increased the complete remission rate (88% v 67%, P = .14) and was associated with a lower relapse rate (17% v 41%, P = .2). The median survival of patients receiving standard therapy was 30 months, while the median survival for patients receiving the high-dose regimen has not been reached. Actuarial 5-year survival for patients treated with the high-dose regimen is 78%, compared with 48% for patients receiving standard therapy (two-sided Mantel-Cox test = .06). Disease-free survival was also superior for patients randomized to PVeBV (P = .03). Sixty-eight percent of patients (23 of 34) randomized to PVeBV are alive and continuously disease-free, compared with 33% (six of 18) for PVeB (P = .02). The major difference in toxicity between the high-dose regimen and standard therapy was the severity of myelosuppression and the incidence of severe hearing loss. Ninety-one percent of patients treated with PVeBV had a WBC count less than 1,000/microL, compared with 50% of patients receiving PVeB (P less than .05). Hearing aids were recommended for 12 patients who received PVeBV and two who received PVeB. The increased effectiveness of the PVeBV regimen in poor prognosis germ-cell cancer patients may relate to the double-dose cisplatin, the addition of VP-16, or to a synergistic effect of these two drugs.

Phase I study of taxol and granulocyte colony-stimulating factor in patients with refractory ovarian cancer.

PURPOSE To increase the taxol dose beyond the current standard dose intensity of 175 mg/m2 per 21 days in patients with refractory ovarian cancer. PATIENTS AND METHODS Fifteen patients who had platinum-refractory or recurrent advanced-stage ovarian cancer were treated with taxol in a phase I trial and were given granulocyte-colony stimulating factor (G-CSF). Taxol was administered at doses of 170, 200, 250, and 300 mg/m2 every 3 weeks. G-CSF was given as a daily subcutaneous injection that started 24 hours after the completion of the taxol infusion. RESULTS Four patients required either taxol dose reduction or delay. The dose-limiting toxicity (DLT) was peripheral neuropathy, and it occurred at 300 mg/m2. This toxicity was manifested clinically as a stocking-and-glove sensory disturbance that primarily affected proprioception, and was associated with objective changes on nerve conduction studies in affected individuals. Mucositis was rarely observed. Substantial myelosuppression was observed, but was not dose-limiting. Five of 14 assessable patients experienced an objective response to therapy, with another five individuals who experienced a 30% to 45% reduction in tumor mass. CONCLUSION Taxol can be safely administered in doses up to 250 mg/m2 with G-CSF support, which may make it possible to study taxol dose intensification.

Human lymphoblastoid interferon treatment of Kaposi's sarcoma in the acquired immune deficiency syndrome. Clinical response and prognostic parameters

Thirty consecutive patients with the acquired immune deficiency syndrome were treated with intramuscular human lymphoblastoid interferon for Kaposis sarcoma. Patients were divided into three groups receiving 7.5 million units/m2 per day, 15 million units/m2 per day, or 25 million units/m2 per day for 28 days. Because of dose-limiting toxicity in the highest dose group, all patients received between 6 and 15 million units/m2 per day. There were three partial responses and four minor responses. The responses were not dependent on drug dose, but did correlate with higher total lymphocyte and OKT4-positive lymphocyte numbers and absence of prior opportunistic infection. Patients who had endogenous acid-labile alpha-interferon prior to therapy were more likely to have progressive disease during interferon administration.

Combination chemotherapy of disseminated kaposi's sarcoma in patients with the acquired immune deficiency syndrome

Two clinical trials were conducted to assess the efficacy and safety of a combination chemotherapy regimen for the treatment of Kaposis sarcoma in patients with the acquired immune deficiency syndrome (AIDS). Eighteen consecutive patients with disseminated Kaposis sarcoma were treated with a six-drug regimen of doxorubicin (Adriamycin), vinblastine, bleomycin/actinomycin D, vincristine, dacarbazine (ABV/ADV). A brief partial or complete response was achieved in 13 patients. Most patients died of opportunistic infections. Eighteen consecutive patients with disseminated Kaposis sarcoma were then randomly assigned to therapy with either recombinant alpha interferon or ABV/ADV. The treatment responses in these two groups were comparable to results of earlier trials, and the incidence of opportunistic infections during therapy did not differ between the two treatment arms. It is concluded that chemotherapy is effective and safe for use in palliative management of Kaposis sarcoma in patients with AIDS.

MALIGNANCIES IN THE AIDS PATIENT: NATURAL HISTORY, TREATMENT STRATEGIES, AND PRELIMINARY RESULTS

Almost 40% of the 3000 US patients with acquired immunodeficiency syndrome (AIDS) have a malignancy at the time of reporting, and the incidence of AIDS patients who develop a malignancy during the course of the disease may be 65-70%. 2 types of malignancies have been noted with increased frequency in AIDS victims: Kaposis sarcoma and malignant lymphomas. About 35% of all AIDS patients and 50% of homosexual or bisexual victims have developed Kaposis sarcoma, and those with coincident opportunistic infection have 2.5 times the mortality of those without such infection. There are 2 essential features to the histopathology of Kaposis sarcoma: 1) vascular proliferation and 2) spindle-shaped neoplastic cells in a network of reticulin fibers that appear to be of endothelial origin. The treatment of the epidemic form of Kaposis sarcoma has not been successful, and the projected 2-year survival is only 30%. The causes of death in the majority of such patients are overwhelming opportunistic infections, especially cytomegalovirus and Pneumocystis carinii, and irreversible cachexia and wasting. Interferon therapy has had a beneficial effect in patients with disease limited to skin, with T4/T8 ratios over 0.5, and without a prior history of opportunistic infection; however, there is no evidence that interferon exerts any beneficial effects on the underlying immune defects. An aggressive 6-drug combination chemotherapy regimen has been tried on patients whose tumors appeared to be life-threatening and was effective in controlling the Kaposis sarcoma, but again did not appreciably alter immune parameters. Several other approaches to the treatment of epidemic Kaposis sarcoma are under evaluation, including gamma interferon, interleukin-2, and plasmapheresis. Patients who develop malignant lymphomas require combined treatment with central nervous system radiation and systemic combination chemotherapy. There is no evidence that the antitumor responses obtained in AIDS-related malignancies translate into survival advantages to the AIDS victim.

Carboplatin and renal dysfunction.

Excerpt To the Editor:Carboplatin is a second-generation platinum analogue that has activity in refractory ovarian cancer similar to that of cisplatin (1). Carboplatin appears to have a spectrum of...

High-dose carboplatin and recombinant granulocyte-macrophage colony-stimulating factor in advanced-stage recurrent ovarian cancer.

PURPOSE We investigated whether carboplatin myelosuppression could be favorably modulated by the administration of recombinant granulocyte-macrophage colony-stimulating factor (rGM-CSF) in patients with advanced-stage ovarian cancer. PATIENTS AND METHODS Thirty-four patients with advanced-stage recurrent ovarian cancer were treated with high-dose carboplatin (800 mg/m2 per 35-day cycle) and rGM-CSF. rGM-CSF was administered as a daily subcutaneous injection starting 72 hours after the carboplatin dose and continuing until 7 days beyond the WBC nadir. rGM-CSF was administered in a phase I fashion. Seven patients were treated at an rGM-CSF dose of 3 micrograms/kg, 11 at 5 micrograms/kg, 10 at 10 micrograms/kg, and six at 20 micrograms/kg. RESULTS rGM-CSF-related toxicities that were not dose-related included nonneutropenic fever, rib pain, acute hypersensitivity reaction, and pericarditis. At the rGM-CSF dose of 20 micrograms/kg, debilitating malaise was seen in four of six patients and this was the dose-limiting toxicity. Patient tolerance of the 3-micrograms/kg and 5-micrograms/kg doses was good, but tolerance was limited for the 10-micrograms/kg dose. Febrile neutropenia was seen in four of seven patients at 3 micrograms/kg, two of 11 at 5 micrograms/kg, two of 10 at 10 micrograms/kg, and one of six at 20 micrograms/kg. Cumulative carboplatin myelotoxicity was blunted only in respect to WBC count, and not for platelets or RBCs. Gastrointestinal bleeding was seen in seven patients. The administered dose-intensity of carboplatin averaged 134 mg/m2/wk for the cohort, or 670 mg/m2 per 35-day cycle. There were two clinical complete responses and eleven partial responses, for a response rate of 38%. CONCLUSION rGM-CSF appears to be effective and tolerable at 5 micrograms/kg/d administered subcutaneously, if given with carboplatin doses up to approximately 600 mg/m2 over 35 days. The use of rGM-CSF with high-dose carboplatin is associated with a substantial response rate in poor-prognosis ovarian cancer patients.

5-fluorouracil (5-FU) and leucovorin in platinum-refractory advanced stage ovarian carcinoma

Twenty-nine patients with recurrent advanced stage ovarian cancer were treated with 5-fluorouracil (5-FU) and leucovorin by intravenous bolus on 5 consecutive days, repeated every 3 weeks. Twenty-one of these patients had experienced disease progression while receiving a cisplatin- or carboplatin-based regimen. There were 2 clinical complete responders and 1 partial responder to therapy (10% response rate; 95% confidence interval, 2 to 27%) and 11 individuals who experienced stable disease for periods ranging from 5 to 27 months. Of 204 cycles of therapy administered, 9 cycles were associated with hospitalization. These occurred in the more heavily pretreated members of the cohort. 5-FU and leucovorin appear to have activity in platinum-refractory ovarian cancer and form a well-tolerated regimen in most patients.

Activation of monocyte-mediated tumoricidal activity in patients with acquired immunodeficiency syndrome.

The purpose of these studies was to determine whether peripheral blood monocytes from acquired immunodeficiency syndrome (AIDS) patients with Kaposis sarcoma could be activated to lyse human tumor target cells in vitro. Monocytes were isolated and incubated for 24 hours in vitro with either medium (control), a crude mitogen-induced lymphokine preparation (MAF), or endotoxin before the addition of [125I]IUdR-labeled A375 melanoma target cells. Cytolysis was determined 72 hours later. Twelve (100%) of 12 patients tested had monocyte-mediated cytotoxicity values that were comparable to those of normal individuals. Recombinant human gamma interferon (IFN gamma) activated both normal and AIDS monocyte-mediated tumoricidal function only when combined with lypopolysaccharide (LPS). In addition, mononuclear cells from ten AIDS patients were also tested for their ability to secrete MAF and IFN gamma in response to a mitogenic stimulus. Lymphokines generated from all ten patients contained substantial amounts of IFN gamma (100 to 2,500 U/mL); however, three of these ten lymphokine preparations failed to activate normal monocytes to lyse tumor cells. These results suggest that monocyte-mediated tumoricidal function of AIDS patients is intact and thus suggest new approaches for the therapy of AIDS.