Randomized trial of low-dose interleukin-2 vs cyclosporine A and interferon-gamma after high-dose chemotherapy with peripheral blood progenitor support in women with high-risk primary breast cancer.

High-risk primary breast cancer patients treated with high-dose chemotherapy (HDC) and stem cell support (SCS) have shown prolonged disease-free survival (DFS) in many studies; however, only one trial has demonstrated an overall survival benefit (OS). We hypothesize that the period following myeloablative therapy is ideal for immunologic manipulation and studied the effects of two different methods of immunotherapy following HDC with SCS aimed at the window of immune reconstitution. Seventy-two women with high-risk stage II or III breast cancer were randomized following HDC to receive either interleukin 2 (IL-2) at 1 million units/m(2) SQ daily for 28 days or combined cyclosporine A (CsA) at 1.25 mg/kg intravenously daily from day 0 to +28 and interferon gamma (IFN-gamma) 0.025 mg/m(2) SQ every 2 days from day +7 to +28. At a median follow-up of 67 months, no significant difference was observed in DFS or OS between the two treatment groups. The IL-2 arm had a 59% DFS (95% CI (0.45, 0.78)) and a 72% OS (95% CI (0.58, 0.88)) at 5 years. The CsA/INF-gamma arm had a similar outcome with a 55% DFS (95% CI (0.40, 0.76)) and a 78% OS (95% CI (0.65, 0.94)) at 5 years. Treatment was well tolerated, without increased toxicity.

Phase I/II study of tandem cycles of high-dose chemotherapy followed by autologous hematopoietic stem cell support in women with advanced ovarian cancer.

The objectives of this study were to investigate the tolerability of a novel high-dose chemotherapy (HDC) regimen with peripheral blood progenitor cell (PBPC) support in patients with pretreated advanced ovarian cancer and to determine the maximum-tolerated dose (MTD) of topotecan in this setting. Advanced ovarian cancer patients previously treated with platinum-based first-line therapy were enrolled. After PBPC mobilization and harvesting, patients received three consecutive cycles of HDC with PBPC support. Cycle 1 was carboplatin area under the concentration curve 20 and paclitaxel 250 mg/m(2). Cycle 2 was topotecan starting at 5 mg/m(2), dose escalated in 2 mg/m(2) increments, and etoposide 600 mg/m(2). Cycle 3 was thiotepa 500 mg/m(2). After each cycle, PBPCs were infused. Granulocyte colony stimulating factor (5 microg/kg/day) was administered until neutrophil recovery occurred. Seventeen patients were enrolled; all were safety evaluable. The most common nonhematologic toxicity was grade 3 mucositis (44%). Engraftment of PBPCs was successful in all patients after each cycle, and no treatment-related deaths occurred. Of 14 patients with measurable disease, 5 (36%) had complete responses, 2 (14%) had partial responses, and 4 (29%) had stable disease. The median progression-free and overall survivals were 7 and 18 months, respectively. The MTD of topotecan was not reached. The tolerability and activity of this regimen in patients with advanced ovarian cancer warrant further investigation.

Phase II trial of sequential high-dose chemotherapy with paclitaxel, melphalan and cyclophosphamide, thiotepa and carboplatin with peripheral blood progenitor support in women with responding metastatic breast cancer.

A single high-dose cycle of chemotherapy can produce response rates in excess of 50%. However, disease-free survival (DFS) is 15-20% at 5 years. The single most important predictor of prolonged DFS is achieving a complete response (CR). Increasing the proportion of patients who achieve a complete response may improve disease-free survival. Women with metastatic breast cancer and at least a partial response (PR) to induction chemotherapy received three separate high-dose cycles of chemotherapy with peripheral blood progenitor support and G-CSF. The first intensification was paclitaxel (825 mg/m(2)), the second melphalan (180 mg/m(2)) and the third consisted of cyclophosphamide 6000 mg/m(2) (1500 mg/m(2)/day x 4), thiotepa 500 mg/m(2) (125 mg/m(2)/day x 4) and carboplatin 800 mg/m(2) (200 mg/m(2)/day x 4) (CTCb). Sixty-one women were enrolled and 60 completed all three cycles. Following the paclitaxel infusion most patients developed a reversible, predominantly sensory polyneuropathy. Of the 30 patients with measurable disease, 12 converted to CR, nine converted to a PR*, and five had a further PR, giving an overall response rate of 87%. The toxic death rate was 5%. No patient progressed on study. Thirty percent are progression-free with a median follow-up of 31 months (range 1-43 months) and overall survival is 61%. Three sequential high-dose cycles of chemotherapy are feasible and resulted in a high response rate. The challenge continues to be maintenance of response and provides the opportunity to evaluate strategies for eliminating minimal residual disease.

Phase II trial of oral altretamine for consolidation of clinical complete remission in women with stage III epithelial ovarian cancer: a Southwest Oncology Group trial (SWOG-9326).

OBJECTIVE: The aim of this study was to evaluate the 2-year survival rate in a group of women in complete clinical remission (cCR) from Stage III ovarian cancer following front-line therapy who were then treated with a 6-month course of altretamine. METHODS: Patients were documented to be in cCR by physical examination, computed tomography or magnetic resonance imaging scan, and serum CA-125. Treatment consisted of altretamine (Hexalen) 260 mg/m(2)/day po divided into four doses taken after meals and at bedtime for 14 of 28 days for six cycles. Based on previous experience in the Southwest Oncology Group, the treatment would be considered promising if the 2-year survival rate was > or = 65% as measured from study registration. RESULTS: From 9/1/93 and 7/1/97, 112 patients were registered and 97 were fully evaluable. The majority of patients had optimally debulked (< or = 1 cm: 63%), high-grade (Grade 3: 82%) tumors. The 2-year survival rate in this study was 75% (95% CI: 66-84%). For those patients with optimal disease, the 2-year survival rate was 82% (95% CI: 72-92%) and for those with suboptimal disease it was 64% (95% CI: 48-79%). Four patients (4%) experienced Grade 4 and 21 patients (22%) experienced Grade 3 toxicities consisting primarily of nausea/vomiting, neutropenia, fatigue, anxiety, and paresthesias. CONCLUSIONS: The 2-year survival rate in this study warrants further evaluation of consolidation therapy for women in clinical complete remission following front-line chemotherapy for Stage III ovarian cancer. Caution is advised in the interpretation of these data, however, because of the nonrandomized nature of the trial and the unknown contribution of front-line use of paclitaxel to the durability of clinical complete response.

Reduction of paclitaxel-induced peripheral neuropathy with glutamine.

PURPOSE: Dose-limiting toxicity of many newer chemotherapeutic agents is peripheral neuropathy. Prior attempts to reduce this side effect have been unsuccessful. We report on the possible successful reduction of peripheral neuropathy with glutamine administration after high-dose paclitaxel. EXPERIMENTAL DESIGN: Patients entered a high-dose chemotherapy protocol in which the first high-dose cycle was paclitaxel at 825 mg/m(2) given over 24 h. The first cohort of patients did not receive glutamine, and the second cohort of patients received glutamine at 10 g orally three times a day for 4 days starting 24 h after completion of paclitaxel. Neurological assessment was performed at baseline, and at least 2 weeks after paclitaxel, and consisted of a complete neurological exam and nerve conduction studies. RESULTS: There were paired pre- and post-paclitaxel evaluations on 33 patients who did not receive glutamine and 12 patients who did. The median interval between pre- and post-exams was 32 days. For patients who received glutamine, there was a statistically significant reduction in the severity of peripheral neuropathy as measured by development of moderate to severe dysesthesias and numbness in the fingers and toes (P < 0.05). The degree and incidence of motor weakness was reduced (56 versus 25%; P = 0.04) as well as deterioration in gait (85 versus 45%; P = 0.016) and interference with activities of daily living (85 versus 27%; P = 0.001). Moderate to severe paresthesias in the fingers and toes were also reduced (55 versus 42% and 64 versus 50%, respectively), although this value was not statistically significant. All of these toxicities were reversible over time. CONCLUSIONS: Glutamine may reduce the severity of peripheral neuropathy associated with high-dose paclitaxel; however, results from randomized, placebo-controlled clinical trials will be needed to fully assess its impact, if any. Trials are currently ongoing to assess its efficacy for standard-dose paclitaxel in breast cancer and other tumors for which peripheral neuropathy is the dose-limiting toxicity.

Phase I trial of sequential high-dose chemotherapy with escalating dose paclitaxel, melphalan, and cyclophosphamide, thiotepa, and carboplatin with peripheral blood progenitor support in women with responding metastatic breast cancer.

A single high-dose cycle of chemotherapy with stem cell support can produce disease-free survival of 15-20% for at least 3 years in women with responding stage IV breast cancer. North American Autologous Bone Marrow Transplant Registry data suggest that a complete response (CR) is the single most important prognostic factor associated with prolonged disease-free survival. Therefore, if sequential high-dose chemotherapy can increase the CR rate, then perhaps an increased proportion of patients will remain disease free. Women with at least a partial response (PR) to induction chemotherapy received three separate high-dose cycles of chemotherapy with peripheral blood progenitor support and granulocyte colony-stimulating factor. The first intensification was a dose escalation of paclitaxel (400-825 mg/ m2), the second intensification was melphalan (180 mg/m2), and the third intensification consisted of 6000 mg/m2 cyclophosphamide (1500 mg/m2/day), 500 mg/m2 thiotepa (125 mg/m2/day), and 800 mg/m2 carboplatin (200 mg/m2/day; CTCb). Thirty-six women were enrolled and 31 completed all three cycles. After the paclitaxel infusion most patients developed reversible predominantly sensory neuropathy. Of the 19 patients with measurable disease, 6 converted to CR, 7 converted to a PR* (the complete resolution of all soft tissue or visceral disease with sclerosis of prior lytic bone lesions), and 2 had a further PR for an overall response rate of 79%. Two patients had no further response and disease in two patients progressed, and thus they were taken off the study before CTCb. Seventy-eight percent are progression-free at a median follow-up of 14 months (range, 3-24+). Three sequential cycles of high-dose chemotherapy are feasible and were administered in this study with no mortality. Single agent paclitaxel at doses up to 825 mg/m2 were well tolerated with moderate reversible toxicity.

Influence of inflammatory bowel disease on the ability of patients to tolerate systemic fluorouracil-based chemotherapy.

PURPOSE: To evaluate the safety of administering fluorouracil (5FU)-based chemotherapy to cancer patients with inflammatory bowel disease (IBD). PATIENTS AND METHODS: We retrospectively reviewed all patients entered into the Memorial Sloan-Kettering Cancer Center clinical data base from 1985 through 1995 who had a diagnosis of IBD, had a gastrointestinal malignancy, and were treated with systemic 5FU-based chemotherapy. A total of 19 patient charts were identified and reviewed. RESULTS: Fifty-three percent of patients reviewed experienced severe (grade III/IV) diarrhea on treatment. Sixty percent of patients with a history of active IBD and 40% of patients with a history of inactive IBD experienced severe diarrhea on treatment. The incidence of severe diarrhea did not appear to be substantially influenced by age, schedule of 5FU administration, concurrent radiation, or type of IBD. CONCLUSION: While there does appear to be an increased risk of diarrhea exacerbation in IBD patients treated with 5FU, a substantial number of patients tolerate chemotherapy without increased difficulty. The degree of IBD activity or other clinical parameters can not be used to predict accurately the likelihood of toxicity.

Rapidly cycled courses of high-dose alkylating agents supported by filgrastim and peripheral blood progenitor cells in patients with metastatic breast cancer.

Our purpose was to determine the feasibility of a regimen of multiple, rapidly cycled courses of high-dose alkylating agents, including paired courses of escalating doses of thiotepa, supported by peripheral blood progenitor cells and filgrastim, in patients with responding stage IV breast cancer. The regimen consisted of two courses of cyclophosphamide (3.0 g/m2/course) followed by two courses of thiotepa (500-700 mg/m2/course). All courses were supported by filgrastim. Leukaphereses were performed after each cyclophosphamide course to harvest peripheral blood progenitors (PBPs) for use as rescue following thiotepa administration. The planned interval for all courses was 14 days. Forty-two patients were enrolled. Thirty-eight received all four courses, and four did not receive the second thiotepa cycle due to poor PBP mobilization. The maximum dose of thiotepa that was administered was 700 mg/m2 x 2. At this dose, one patient developed encephalopathy, which resolved over several weeks. The median number of days to an absolute neutrophil count of 0.5 x 10(9)/liter after PBP reinfusion for cycles 1 and 2 of thiotepa were 9 (range, 7-16) and 9 (range, 8-13) days, respectively. The corresponding values for platelet recovery to >20 x 10(9)/liter were 11 (range, 8-39) and 12 (range, 10-28) days, respectively. There were no treatment-related deaths. Hospitalization was required following 28 of 84 cyclophosphamide courses and 76 of 80 thiotepa courses. Four patients developed grade III-IV mucositis. The median interval between courses of treatment was 15 (range, 13-29) days. Of 19 patients who entered the protocol with measurable disease in partial response from prior therapy, 8 (42%) achieved complete response following the high-dose therapy. Nine (21%) of 42 remain progression free at a median follow-up of 28 (range, 20-32) months. Therefore, we concluded that the administration of multiple, rapidly cycled courses of high-dose alkylating agents is feasible.

Phase II trial of paclitaxel by 3-hour infusion as initial and salvage chemotherapy for metastatic breast cancer.

PURPOSE: To evaluate the efficacy and safety of paclitaxel administered by 3-hour infusion as initial and salvage chemotherapy for metastatic breast cancer. PATIENTS AND METHODS: Forty-nine patients with metastatic breast cancer received paclitaxel via 3-hour intravenous infusion after standard premedication. Prophylactic granulocyte colony-stimulating factor (G-CSF) was not used, and chemotherapy was cycled every 3 weeks. For 25 patients who received paclitaxel as initial therapy (group I), the starting dose was 250 mg/m2. Twenty-four patients who had received two or more prior regimens, including an anthracycline (group II), started at 175 mg/m2. Paclitaxel pharmacokinetics were evaluated in 23 patients in group I. RESULTS: Grade 3 and 4 toxicities included (groups I/II) neutropenia (36%/33%), thrombocytopenia (0%/8%), anemia (0%/13%), neuropathy (8%/0%), arthralgia/myalgia (16%/4%), and mucositis (4%/4%). No significant hypersensitivity-type reactions or cardiac arrhythmias were seen. Six patients who received paclitaxel at > or = 250 mg/m2 experienced transient photopsia, without apparent chronic neuro-ophthalmologic sequelae. The mean peak plasma paclitaxel concentration was 5.87 mumol/L (range, 1.99 to 7.89) for these patients, and 6.08 mumol/L (range, 0.81 to 13.81) for 17 of 19 patients who did not experience visual symptoms. In 25 assessable patients in group I at a median follow-up time of 12 months, one complete response (CR) and seven partial responses (PRs) have been observed, for a total response rate of 32% (95% confidence interval [CI], 15% to 53%). In group II, five PRs were noted in 24 assessable patients (20.8%; 95% CI, 7% to 42%). Median response durations were 7 months for group I and 4 months for group II. CONCLUSION: Paclitaxel via 3-hour infusion, without prophylactic G-CSF, is active and safe as initial and subsequent therapy for metastatic breast cancer. The transient visual symptoms noted at higher doses seem unrelated to peak plasma paclitaxel concentration. Further studies that compare 3- and 24 hour (or other) infusion schedules are necessary to determine the optimal administration of paclitaxel in metastatic breast cancer.

Acute hypertensive crisis following octreotide administration in a patient with malignant pheochromocytoma.

A patient with a known history of resected pheochromocytoma was evaluated for recurrent paroxysmal hypertension. The recurrent tumor was localized by magnetic resonance imaging and by somatostatin receptor scintigraphy. Since this scintigraphy demonstrated the presence of somatostatin receptors, empiric treatment with the somatostatin analogue octreotide was initiated in an attempt to stabilize catecholamine secretion prior to attempted surgical resection. The patient experienced a paradoxical reaction manifested by an acute hypertensive crisis which was rapidly responsive to intravenous nicardipine. Stimulation of such a hypertensive crisis by octreotide has not previously been reported. The etiology of this reaction is unclear. We conclude that octreotide and other somatostatin analogues should be administered with extreme caution to patients with known or suspected pheochromocytomas.

Prospective follow-up for malignant melanoma in patients with atypical-mole (dysplastic-nevus) syndrome.

A total of 357 white patients who had melanocytic nevi that fulfilled the clinical criteria for the "classic" atypical-mole (dysplastic-nevus) syndrome (100 or more melanocytic nevi; one or more melanocytic nevi 8 mm or larger in diameter; and, one or more melanocytic nevi with atypical features) were followed for the development of cutaneous malignant melanomas. Seventeen patients (4.8%) developed malignant melanomas during an average follow-up period of 49 months. One patient developed two malignant melanomas. Eight of the malignant melanomas detected were in situ and ten were invasive melanomas (less than 0.86 mm in Breslow thickness), implying an excellent prognosis. The number of malignant melanomas detected in these patients exceeded significantly the number expected to occur in age- and sex-matched white controls. All groups were shown to have an increased risk for the development of malignant melanomas. Total-body photographs were helpful in detecting changes in size, shape, and color that led to the diagnosis of malignant melanoma. These data support the concept that patients with this readily regionalized clinical presentation of classic atypical-mole syndrome are at an increased risk for malignant melanomas and, therefore, should be examined regularly.