Results of treatment of 255 patients with metastatic renal cell carcinoma who received high-dose recombinant interleukin-2 therapy.

PURPOSE: To determine the efficacy and toxicity of a high-dose interleukin-2 (IL-2) regimen in patients with metastatic renal cell carcinoma. PATIENTS AND METHODS: Two hundred fifty-five assessable patients were entered onto seven phase II clinical trials. Proleukin (aldesleukin; Chiron Corp, Emeryville, CA) 600,000 or 720,000 IU/kg was administered by 15-minute intravenous (i.v.) infusion every 8 hours for up to 14 consecutive doses over 5 days as clinically tolerated with maximum support, including pressors. A second identical cycle of treatment was scheduled following 5 to 9 days of rest, and courses could be repeated every 6 to 12 weeks in stable or responding patients. RESULTS: The overall objective response rate was 14% (90% confidence interval [CI], 10% to 19%), with 12 (5%) complete responses (CRs) and 24 (9%) partial responses (PRs). Responses occurred in all sites of disease, including bone, intact primary tumors, and visceral metastases, and in patients with large tumor burdens or bulky individual lesions. The median response duration for patients who achieved a CR has not been reached, but was 19.0 months for those who achieved a PR. Baseline Eastern Cooperative Oncology Group (ECOG) performance status (PS) was the only predictive prognostic factor for response to IL-2. While treatment was associated with severe acute toxicities, these generally reversed rapidly after therapy was completed. However, 4% of patients died of adverse events judged to be possibly or probably treatment-related. CONCLUSION: High-dose IL-2 appears to benefit some patients with metastatic renal cell carcinoma by producing durable CRs or PRs. Despite severe acute treatment-associated toxicities, IL-2 should be considered for initial therapy of patients with appropriately selected metastatic renal cell carcinoma.

Surgical resection following interleukin 2 therapy for metastatic renal cell carcinoma prolongs remission.

Records of 399 patients with metastatic renal cell carcinoma treated with interleukin 2 with or without lymphokine-activated killer cell immunotherapy enrolled in 14 separate clinical trials from multiple institutions were reviewed to determine whether patients with a partial response to interleukin 2 therapy would benefit from surgical resection of residual tumor. Sixty-two patients demonstrated objective responses (15.5%), 18 (4.5%) complete and 44 (11.0%) partial. Eleven patients underwent resection of residual tumor in the lung, kidney, retroperitoneum, or pelvis so that they had "surgically no evidence of disease" (SNED). Of these, 10 had partial responses, and one patient with progressive disease had a complete response. Comparison of response duration showed no difference between the complete response and SNED groups, but there was a significant difference between each of these groups and the partial response group. At this writing, all 11 patients in the SNED group remained alive without evidence of disease (median follow-up, 21 months). In contrast, only 14 patients (76%) with complete responses and 15 patients (35%) with partial responses remained free of disease progression. Enhanced survival of the complete response and SNED groups compared with the partial response group borders on significance and awaits longer follow-up. These data suggest that surgical resection, if technically feasible, may benefit patients who show a partial response to interleukin 2 treatment for metastatic renal cell carcinoma.

Pharmacokinetics of CPX-351; a nano-scale liposomal fixed molar ratio formulation of cytarabine:daunorubicin, in patients with advanced leukemia.

Forty-eight patients received CPX-351 (liposome-encapsulated cytarabine:daunorubicin at a 5:1 molar ratio) every other day for 3 doses at 10 dose levels. Pharmacokinetic parameters were dose-independent and exhibited low inter-patient variability. CPX-351 showed a negligible distribution phase and prolonged mono-exponential first-order plasma elimination (t(1/2)∼24 h). The plasma ratio of 5:1 was maintained at all dose levels. Nearly all of the detectable cytarabine and daunorubicin in circulation following CPX-351 administration was in the form of liposome encapsulated drug. Dose-dependent hematopoietic effects had early onset with cytopenias at 12 units/m(2), and a gradual increase in frequency and severity, until single induction complete response was achieved at 43 units/m(2). Non-hematologic effects had onset by 24 units/m(2) with shallow dose-response until maximum frequency and severity were observed at the 101-134 units/m(2) dose levels. Single induction response occurred over a 2.3-fold range of doses indicating that CPX-351 may be useful at high doses for patients suitable for intensive chemotherapy and at reduced doses for patients at increased risk of treatment-related mortality. The unique pharmacologic features of CPX-351 contribute to its promising antileukemic efficacy.

Skin rash following therapy with mitomycin C.

A 39-year-old man developed a widespread pruritic vesicular rash 1 week following the second course of treatment with mitomycin C plus doxorubicin for carcinoma of unknown origin. Skin rash is an uncommon complication of treatment with mitomycin C, and the frequency of its occurrence may be increased when the drug is given in combination with other cytotoxic agents.

Effective adjuvant treatments. A brief review of U.S. clinical trials.

A variety of adjuvant trials performed in the United States for osteogenic sarcoma, breast, lung, and colon cancer have achieved encouraging results and are briefly summarized. Trials in osteogenic sarcoma are reporting 2-year disease-free survival rates of 50%. However, they have only been evaluated against historical controls and there is some evidence that other factors might have greatly improved the disease-free survival in the absence of adjuvant therapy. The NSABP breast cancer trial only shows significant improvement for women under 50 years of age with 1 to 3 positive axillary nodes. A very promising trial using intrapleural BCG immunotherapy for squamous cell lung cancer is described. Also, two trials of 5-fluorouracil for colo-rectal cancer, both showing trends suggesting slight improvement among treated patients, are presented. Proper care in the design of adjuvant trials with sufficient attention paid to prognostic variables is urged.

Current trends and prospects in surgical adjuvant trials.

New concepts and treatments currently available for adjuvant studies are illustrated by a review of ongoing studies sponsored by the National Cancer Institute. More thorough information is needed on immunotherapeutic agents to allow more rationale in the use of these agents. Solid bases to properly select drugs or drug combinations for adjuvant purposes are being established. However, dose-schedule and duration of treatment are still to be defined. Strategies directed at prolonging the benefit of surgical adjuvant chemotherapy remain to be planned. Progress continuously achieved with immunotherapy and chemotherapy should rapidly broaden the spectrum of tumour types to be included in adjuvant studies.

Follow-up observations on the effect of human leukocyte interferon in non-Hodgkin's lymphoma.

Follow-up data for 11 patients with non-Hodgkin's lymphoma treated with partially purified human leukocyte interferon is presented. The interferon preparation used was 0.1% pure and treatment consisted of 5 x 10(6) U given intramuscularly twice daily for 60 injections. One complete, three partial, and three minimal responses were observed in five of seven evaluable patients with nodular non-Hodgkin's lymphoma. Duration of response appears to be from 6 to 12 mo. One patient achieved a second partial response on retreatment with interferon in spite of having received chemotherapy in the interval between interferon treatments. No responses were seen in three patients with rapidly progressive diffuse histiocytic lymphoma. Dose-limiting toxicity is leukopenia, which necessitated modification or cessation of treatment in three patients. Nonhematologic toxicities consisted of fever, malaise, arthralgia, and loss of appetite. In conclusion, interferon has activity against non-Hodgkin's lymphoma, and prior treatment with chemotherapy does not preclude a response to interferon.