Weekly paclitaxel in advanced non-small cell lung cancer.

Paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) is one of the most commonly used agents in treating patients with locally advanced and metastatic non-small cell lung cancer (NSCLC). It is usually given once every 3 weeks. We have evaluated paclitaxel given once per week for 3 weeks every 4 weeks for patients with recurrent or metastatic NSCLC. Two consecutive studies using weekly paclitaxel were performed. The first study was a dose-escalation study with paclitaxel beginning at 50 mg/m(2) days 1, 8, and 15 every 4 weeks. Subsequent dose escalation was performed with 10 mg/m(2) increments per week. The second phase II study used paclitaxel at 80 mg/m(2) days 1, 8, and 15 every 4 weeks. The phase I study showed that the maximum tolerated dose was 90 mg/m(2)/wk for 3 weeks with 1 week off. The efficacy and side effects of both phase I and II were quite similar; therefore, the results were combined. Seventeen patients were in the phase I and 30 patients in the phase II study. The mean age was 72 years. Twenty-three patients had Eastern Cooperative Oncology Group performance status of 2 and 16 patients had received prior chemotherapy. One complete and 13 partial responses were observed with response duration ranging from 1 to 18+ months. Overall response rate was 30% (95% confidence interval, 18.5% to 42%). Overall median survival was 184 days. Grade 3/4 neutropenia was 8.5%, grade 3/4 infections was 6.4%, and grade 2 peripheral neuropathy was also 6.4%. Hyperglycemia with random blood sugar levels greater than 250 mg/dL was 6.4% and grade 3 fatigue was 4.3%. In general, treatment was well tolerated. In the best prognostic group of 16 patients without prior chemotherapy and with performance status 0 to 1, the response rate was 37.5% with a 1-year survival rate of 44% and median survival of 305 days. Prior chemotherapy, poor performance status, age higher than 70 years, and male gender carried a worse prognosis. In both phase I and II studies we observed limited myelosuppression, peripheral neuropathy, and constitutional symptoms. Weekly paclitaxel, delivered at our schedule, is an active and well-tolerated regimen. The role of weekly paclitaxel in NSCLC should be better defined in future randomized studies.

Treatment of squamous cell esophageal cancer with topotecan: an Eastern Cooperative Oncology Group Study (E2293).

Seventeen patients with enhanced measurable squamous cell carcinoma of the esophagus were treated with topotecan 1.5 mg/m2 daily for 5 days repeated every 21 days. Toxicity was severe, with 1 death from myelotoxicity and 10 patients with life-threatening myelotoxicity. Severe gastrointestinal toxicity consisting of vomiting was also seen in three patients. No response was seen in any of the patients in the study. Topotecan given in this manner has no activity in squamous cell carcinoma of the esophagus.

Ifosfamide, carboplatin and etoposide (ICE) in metastatic and refractory breast cancer.

Twenty-five patients with metastatic breast cancer were treated with ICE after failure of previous chemotherapy. Their median age was 50 years (range 36-73). All but 1 patient had multiple sites of metastases. Nineteen (76%) patients had undergone two or more chemotherapy regimens for metastatic disease prior to ICE. The performance status (PS) of the patients was Eastern Cooperative Oncology Group (ECOG) 0:6; 1:12; 2:5; 3:2. Ifosfamide 1.25 g/m(2) over 3 h D1-3 along with mesna, etoposide 80 mg/m(2) D1-3 and carboplatin 300 mg/m(2) D1 were given every 3 weeks. We observed a partial response in 10 patients (40%, 95% confidence interval 21-62%). The response duration ranged from 1 to 15 months with a median duration of 4.5 months. The survival of all 25 patients ranged from 10 days to 25 months, with a median of 9 months. All 25 patients were evaluable for toxicity. Thirteen patients (52%) experienced grade 4 hematological toxicity, which improved after growth factor support. Four patients had leukopenic fever, 1 had gram-negative sepsis, while 2 had Clostridium difficile enterocolitis and another had herpes zoster reactivation. Four patients (16%) experienced grade 3-4 gastrointestinal (G-I) toxicity. No hepatic or renal toxicity was observed (1 patient had microscopic hematuria). One patient died of G-I bleed, and another patient died at home of undetermined cause. We conclude that ICE is an effective salvage regimen in metastatic and refractory breast cancer, even in heavily pretreated patients, and is a tolerable treatment when used with growth factor.

A randomized Phase II study of interleukin-2 with and without beta-interferon for patients with advanced non-small cell lung cancer: an Eastern Cooperative Oncology Group study (PZ586).

Interleukin-2 (IL-2) and beta-interferon (beta-IFN) are biologic agents with antitumor activity observed in preclinical models. Some studies of patients with advanced non-small cell lung cancer treated with IL-2 report relatively long survival, despite low response rates. Seventy-six evaluable patients with stage IV non-small cell lung cancer were treated in a randomized Phase II study with either IL-2 alone or IL-2 plus beta-IFN. Patients received either IL-2 at 6 x 10(6) Cetus units/m2 3 days weekly or the combination of IL-2 at 5 x 10(6) Cetus units/m2 plus beta-IFN at 6 x 10(6) units/m2, both given 3 days weekly. Both biologic agents were administered by intravenous bolus injection on an outpatient basis. Objective responses were observed in 3/76 (4%)) patients. Grade 4 toxicity occurred in 3/39 patients treated with IL-2 alone, and in 4/37 patients treated with IL-2 plus beta-IFN. An additional lethal respiratory toxicity occurred in a patient who received IL-2 plus beta-IFN. The median survival of all patients treated on this study was 33 weeks. Despite producing only a 4% objective response rate. IL-2 appears to have a favorable impact on survival comparable to chemotherapy. The role for this immune therapy in the management of non-small cell lung cancer requires further study.

Phase II trial of trimetrexate for patients with advanced gastric carcinoma: an Eastern Cooperative Oncology Group study (E1287).

BACKGROUND: A Phase II study was conducted to evaluate the response, duration of response, and duration of survival of patients with measurable gastric carcinoma treated with trimetrexate (TMTX) who had not had prior chemotherapy. METHODS: Thirty-three patients with unresectable or metastatic gastric adenocarcinoma who had not received previous chemotherapy were treated with intravenous TMTX 12 mg/m(2) daily for 5 days. The dosage of TMTX was reduced to 8 mg/m(2) daily for 5 days for those who had received prior radiotherapy. The cycle was repeated every 3 weeks until disease progression or unacceptable toxicity occurred. RESULTS: Thirty-three patients could be analyzed with follow-up data. There was one Grade 5 (lethal) toxicity and four Grade 4 toxicities. Hematologic toxicity was the most common. The overall response rate was 21%, the overall median progression free survival was 2.7 months, and the overall median survival was 5.9 months for the entire cohort. No patients were alive at last follow-up. CONCLUSIONS: Though TMTX as a single agent has activity in gastric carcinoma with manageable toxicity, it cannot be recommended for routine use as a single agent due to the brief duration of response and median survival.

A phase II trial of homoharringtonine and caracemide in the treatment of patients with advanced large bowel cancer.

Twenty-four previously untreated, ambulatory patients with advanced colorectal carcinoma were treated with either caracemide (11 patients) or homoharringtonine (13 patients). No objective responses were observed in any of the treatment cohorts. Caracemide was well tolerated with the exception of one death due to sepsis. On the homoharringtonine arm one patient died of pulmonary sepsis, one patient experienced grade 4 leukopenia requiring more than 4 weeks of recovery, and an additional patient developed grade 4 renal failure. These severe and unexpected complications caused early termination of accrual to the homoharringtonine arm of the study. These agents have no activity in the treatment of advanced colorectal carcinoma.

Phase II protocol for the evaluation of new treatments in patients with advanced gastric carcinoma: results of ECOG 5282.

The study was a Phase II randomized study to evaluate the efficacy of new agents for the treatment of advanced gastric carcinoma. Patients were randomized to receive single agent chemotherapy with mitoxantrone, etoposide, aclacinomycin-A or spirogermanium. The patients were stratified by prior use of chemotherapy, prior doxorubicin use and ECOG performance status. Patients with a history of cardiac disease or prior doxorubicin exceeding a dose of 400 mg/m2 were restrictively randomized to sopirogermanium or etoposide only. One hundred and fourteen patients were registered for the study. Among 98 evaluable patients there were only two partial responses (both in the etoposide arm), and one complete response in the mitoxantrone arm. The median survival on the study was 3.3 months. One hundred and six patients were analyzable for toxicity. There were four treatment-related deaths and four life-threatening toxicities. Because of low response rates and relatively high toxicities the studied compounds were not deemed worth further investigation for advanced gastric cancer.

A phase II trial of amonafide in patients with endometrial cancer: a Gynecologic Oncology Group Study.

Twenty-nine evaluable patients with endometrial cancer were treated with amonafide 300 mg/m2 for 5 consecutive days every 3 weeks. Two partial responses (8%) were seen. Hematologic toxicity was severe or life-threatening in 13 patients occurring as follows: leukopenia in 13 patients (45%); thrombocytopenia in 10 patients (34%); granulocytopenia in 13 patients (45%); and anemia in four patients (14%). In view of the low response rate and high toxicity, this dose schedule of amonafide does not warrant further investigation in endometrial cancer.

A phase II trial of amonafide in patients with mixed mesodermal tumors of the uterus: a Gynecologic Oncology Group study.

Amonafide demonstrated a poor response rate and substantial toxicity in patients who had measurable, advanced mixed mesodermal tumors of the uterus. Amonafide-a drug that acts through intercalation of tumor DNA-was used to treat 16 patients who had measurable, advanced mixed mesodermal tumors of the uterus as part of a Gynecologic Oncology Group (GOG) Phase II study. The starting dose was 300 mg/m2 intravenously over 1 hour for 5 consecutive days every 3 weeks. Severe or life-threatening hematologic toxicity occurred in 50% of the patients. Two patients experienced vomiting requiring hospitalization. Other toxicities were not severe. One patient had a partial response and one had stable disease, each lasting 4 months. This dose schedule was associated with poor response rate and substantial toxicity.

Amonafide in patients with leiomyosarcoma of the uterus: a phase II Gynecologic Oncology Group study.

Twenty-six evaluable patients who had leiomyosarcoma of the uterus were treated with amonafide, 300 mg/m2, for 5 consecutive days every 3 weeks. One partial response (4%) resulted. Hematologic toxicity was substantial, with grade 3 or 4 events occurring as follows: leukopenia, 12 patients (46%); thrombocytopenia, 4 patients (15%); and granulocytopenia, 7 patients (27%). One patient had transient grade 4 renal failure. Considering the poor activity and substantial toxicity that was observed, no further studies are planned by the Gynecologic Oncology Group using amonafide at this dose schedule in leiomyosarcomas.

A phase II trial of amonafide in patients with nonsquamous cell carcinoma of the cervix. A Gynecologic Oncology Group study.

Twenty-seven patients with nonsquamous cell carcinoma of the cervix were entered into a Phase II study of amonatide; 24 patients were evaluable for toxicity, while 23 were evaluable for response. Patients received amonafide, 300 mg/m2, intravenously for 5 consecutive days every 3 weeks. The median age of patients was 45 years. All but two patients were completely ambulatory. Twelve patients had received prior chemotherapy, while 22 had been treated with radiation therapy. One of 27 (4.3%) patients had a partial response (PR) to this regimen and 13 (56.5%) had stable disease. Sixteen patients experienced a median white blood cell (WBC) nadir of 350/mm3, seven developed life-threatening thrombocytopenia, and one had severe anemia requiring transfusion. Nonhematologic toxicity was mild. Amonafide had insignificant activity in these patients with nonsquamous cell carcinoma of the cervix.

Dose-escalation study of weekly 1-hour paclitaxel administration in patients with refractory cancer.

To evaluate the safety and efficacy of weekly low-dose paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) in patients with refractory cancer, participating subjects received standard prophylactic medication followed by intravenous paclitaxel once a week for 3 weeks every 4 weeks. The 50-mg/m2 starting dose was increased by 10 mg/m2 for every five patients, as long as no dose-limiting toxicity had occurred in more than two of five patients treated at the preceding level. Eligibility criteria included metastatic and refractory malignant disease; an Eastern Cooperative Oncology Group performance status of 0, 1, or 2; and adequate hematologic, hepatic, and renal functions. Of 30 patients treated and evaluable for toxicity, 25 were evaluable for response. The majority of patients tolerated the treatment very well. In a total of 114 cycles, the worst toxicities observed were leukopenia (one grade 4, two grade 3), granulocytopenia (one grade 3, one grade 4), anemia (one grade 3, two grade 2), and infection (one grade 5, one grade 3). Three patients had grade 2 gastrointestinal toxicity and three had grade 1 peripheral neuropathy. Only one dose-limiting toxicity, at 100 mg/m2, has occurred. This patient died of bilateral pneumonia with neutropenia. We have observed partial responses in seven of 12 patients with breast cancer and three of eight with non-small cell lung cancer. The study remains open at the current dose level of 100 mg/m2/wk. Weekly low-dose paclitaxel is well tolerated and efficacious. Further phase II studies are warranted, to continue evaluation of this schedule of paclitaxel either alone or in combination with other drugs active in paclitaxel-responsive diseases.

A phase I study of weekly cisplatin and whole abdominal radiation for the treatment of stage III and IV endometrial carcinoma: a Gynecologic Oncology Group pilot study.

A Gynecologic Oncology Group Phase I study was designed to evaluate the toxicity of whole abdominal radiation therapy with concurrent weekly cisplatin in patients with surgical International Federation of Gynaecology and Obstetrics (FIGO) Stage III and IV endometrial carcinoma. Cisplatin 15 mg/m2 was given once weekly during radiation therapy to the whole abdomen with a pelvic boost and optional para-aortic radiation. All eight patients received the prescribed dose of radiation therapy. Cisplatin chemotherapy was halted in one patient due to increased serum creatinine after three cycles. Acute adverse effects were within acceptable limits, with one patient admitted to the hospital after completion of treatment for diarrhea. Hematopoietic toxicity was clinically unimportant. Serious late toxicities included one radiation enteritis requiring a bowel resection and chylous ascites in one patient. There was no late renal damage reported. This regimen appears to be tolerated acutely and the late toxicities were similar to those seen with whole abdominal radiation therapy alone.

A phase II trail of aminothiadiazole in patients with mixed mesodermal tumors of the uterine corpus: a Gynecologic Oncology Group study.

Aminothiadiazole (NSC 4728) is an analog of the thiadiazoles, a group of drugs that stimulated interest because they do not cause significant myelosuppression and have a unique ability to increase uric acid production unrelated to tissue damage. Previous articles have reported results in ovarian cancer, squamous cell cervical cancer, nonsquamous cell cervical cancer, and endometrial cancer. The Gynecologic Oncology Group chose to study aminothiadiazole in patients with mixed mesodermal tumors of the uterus refractory to prior chemotherapy. Twenty-two patients were entered into this study. Eligibility required that patients had histologically confirmed measurable malignancy. All patients received a starting dose of aminothiadiazole of 125 mg/m2 intravenously (30-45 min infusion) repeated at weekly intervals. All patients also took allopurinol, 300 mg orally per day, to prevent hyperuricemia. Subsequent therapy was not given unless the white blood cell count was > 3,000/microliters and platelets were > 100,000/microliters prior to treatment. One patient (5%) in this study had a partial response, which lasted only 1.2 months. The site of this response was a mesenteric mass. Most patients in this study had no toxicity whatsoever, and no life-threatening toxicity was seen. There were no complete responses. Aminothiadiazole in this dose schedule appears to have no utility in previously treated patients with mixed mesodermal tumors of the uterus.

Ifosfamide, carboplatin, etoposide, and paclitaxel chemotherapy: a dose-escalation study.

Ifosfamide, carboplatin, cisplatin, etoposide, and paclitaxel are chemotherapeutic agents active in treating many malignant diseases. The ICE combination (ifosfamide/carboplatin [or cisplatin]/etoposide) has been studied in breast cancer, small cell and non-small cell lung cancer, testicular cancer, lymphoma, and other malignancies with promising results. We conducted a dose-escalation study of paclitaxel in combination with ICE (ICE-T) to evaluate the toxicity and define the maximum tolerated dose of paclitaxel. To date, 24 patients have been treated with ICE-T. Patients had to have no or minimal prior chemotherapy, an Eastern Cooperative Oncology Group performance status of 0 or 1, and adequate bone marrow, liver, and kidney function. The doses of ICE were as follows: ifosfamide 1.25 g/m2/d days 1 to 3, carboplatin 300 mg/m2 day 1, and etoposide 80 mg/m2/d days 1 to 3. Paclitaxel was given at a dose of 120 mg/m2 to five patients, 135 mg/m2 to five patients, 150 mg/m2 to three patients, and 175 mg/m2 to 11 patients. All patients received granulocyte colony-stimulating factor support. The most common side effect was neutropenia. Grade 4 neutropenia and thrombocytopenia occurred during 34% and 20% of 94 cycles, respectively, with leukopenic fever occurring during 14% of cycles. No treatment-related death or sepsis occurred due to brief nadir durations of 3.5 days for neutropenia and thrombocytopenia. Other toxicities were mostly mild to moderate and did not require dose modification, although alopecia was universal. Nine patients (100%) with metastatic breast cancer and four (67%) with soft tissue sarcoma have attained documented objective responses with four complete remissions (one breast cancer and three sarcoma patients). The maximum tolerated dose of paclitaxel has not yet been defined, and the study is ongoing. In conclusion, this pilot study showed that ICE-T is safe and tolerable. The response to ICE-T is encouraging and warrants further study with this regimen.

Aminothiadiazole in the treatment of advanced leiomyosarcoma of the uterine corpus. A Gynecologic Oncology Group study.

Aminothiadiazole was used to treat 21 patients with metastatic or recurrent leiomyosarcoma of the uterus. All patients received a starting dose of aminothiadiazole of 125 mg/m2 intravenously (30-to-45-minute infusion), which was repeated at weekly intervals. All patients also took allopurinol 300 mg per day orally to prevent hyperuricemia, a side effect of aminothiadiazole. Five patients (25%) had stable disease but there were no objective responses. Toxicity was generally mild with this regimen. There was no life-threatening toxicity and only three episodes of severe toxicity. One patient experienced both grade 3 leukopenia and thrombocytopenia, while another patient had grade 3 nausea and vomiting. Further studies in this disease are not planned.

Phase I study of escalating doses of paclitaxel (Taxol) with fixed doses of ifosfamide, carboplatin, and etoposide.

The combination of ifosfamide (with mesna uroprotection), carboplatin, and etoposide (ICE) has demonstrated activity in a variety of cancers. Paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ), a dipertene compound extracted from the Pacific yew Taxus brevifolia, appeared a good candidate for study as an addition to the ICE regimen (ICE-T) because of its broad antitumor activity, its unique mechanism of action, and its toxicity profile, which was not expected to impact the ICE regimen adversely. In a phase I study, we evaluated the impact of adding escalating doses of paclitaxel (120 mg/m2, 135 mg/m2, 150 mg/m2, and 175 mg/m2) to the ICE regimen in 13 previously untreated (with two exceptions) patients with breast cancer, sarcoma, lung cancer, and adenoid cystic carcinoma. In general, ICE-T was well tolerated with some myelosuppression observed. Responses were seen at all dose levels. To date, the maximal tolerated dose of paclitaxel has not been reached; we are currently administering 175 mg/m2.

Ifosfamide/carboplatin/etoposide chemotherapy in patients with metastatic non-small cell lung cancer.

We have evaluated the combination of ifosfamide, carboplatin, and etoposide (ICE) along with mesna in 46 patients with stage IV non-small cell lung cancer. Treatment consisted of ifosfamide (1.25 g/m2/d with mesna) and etoposide (80 mg/m2/d) given intravenously on days 1 to 3 and carboplatin (300 mg/m2) given intravenously on day 1 every 4 weeks. Eligibility criteria included measurable disease; adequate hematologic, hepatic, and renal functions; no prior chemotherapy; and an Eastern Cooperative Oncology Group performance status (PS) of 0 to 3. Two patients were lost to follow-up and one had received prior chemotherapy, leaving 43 patients evaluable for response and toxicities. There were 27 male and 16 female patients. Twenty-three patients had a PS of 0 or 1 and 20 had a PS of 2 or 3. Eighteen patients had received prior radiotherapy. There were two complete responses and nine partial responses. The response rate was 35% in PS 0 or 1 patients and 15% in PS 2 or 3 patients. The most frequent toxicity was myelosuppression; 44% of patients experienced grade 3 or 4 leukopenia and 14%, grade 3 or 4 thrombocytopenia. Patients receiving prior radiation were significantly more prone to develop leukopenia (P = .01). Five patients developed leukopenic fever, and three died of sepsis. Gastrointestinal toxicities were mostly mild. No neurologic or genitourinary toxicities were observed. The median length of survival was 209 days for patients with a PS of 0 or 1 and 123 days for the entire group. The 1-year survival rate was 22% and 19%, respectively, in these two patient subgroups. ICE is an active regimen in patients with metastatic non-small cell lung cancer and a good PS. Myelosuppression is the major dose-limiting toxicity. Hematopoietic growth factors may be indicated in subsequent studies, especially in patients who had prior radiation therapy. The therapeutic effect of ICE on patients with a poor PS remains unsatisfactory and requires further investigation.

Paclitaxel by 3-hour infusion followed by 96-hour infusion on failure in patients with refractory malignant disease.

To explore the potential therapeutic differences between 3- and 96-hour infusions of paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) in patients with refractory malignant diseases, we conducted a phase II study in which patients were treated first with paclitaxel 135 mg/m2 by 3-hour infusion. If patients did not respond or relapsed after response, they were then treated by 96-hour infusion of paclitaxel at the same dose. Patients with metastatic or incurable breast, ovarian, lung, head/neck carcinomas, and lymphoma were eligible. They were required to have an Eastern Cooperative Oncology Group performance status of 2 or better and adequate hematologic, hepatic, and renal functions. In 22 patients entered thus far, we have observed one partial response in 10 lung cancer patients treated by 3-hour paclitaxel and one partial response in six patients treated by 96-hour infusion. Four partial responses were observed with 3-hour paclitaxel alone in nine breast cancer patients, while three partial responses occurred in five patients with 96-hour infusion after the 3-hour infusion failed. Nonhematologic toxicities such as fatigue, peripheral neuropathy, and mucositis occurred more commonly in the 96-hour infusion group. Our preliminary results suggest (1) that 3-hour infusion of paclitaxel is active against refractory breast cancer, (2) that 96-hour infusion of paclitaxel can induce partial response in breast cancer that was refractory to 3-hour treatment of paclitaxel, and (3) that more studies are needed to define the optimal treatment schedule of paclitaxel.

Phase II study of ifosfamide, carboplatin, and etoposide in patients with advanced non-small cell lung cancer.

This study was to define the efficacy of ifosfamide, mesna, carboplatin, and etoposide (ICE) in patients with metastatic non-small cell lung cancer (NSCLC). From September 1990 to October 1991, 33 patients were treated with ifosfamide/mesna 1.25 g/m2/day and etoposide 80 mg/m2/day intravenously from days 1 to 3, and carboplatin 300 mg/m2 on day 1 every 4 weeks. There were 20 male patients and 13 females. The median age was 65 (range: 38-79). Seventeen patients had a performance status (PS) of 0 or 1, and 16 had a PS of 2 or 3. All had measurable diseases. Nine had initial treatment for localized disease with concurrent radiation, 5-fluorouracil, and interferon-alpha 2b and four had radiation only. None had received chemotherapy for metastatic disease. There were nine partial responses (PR) (27.3%, 9/33) with a median response duration of 8 months (range: 2-16 months). Five patients had stable diseases (SD), which lasted for 3, 6+, 7+, 10+, or 13.4 months. The median survival was 8 months for PR and SD and 4 months for the entire group. Patients with PS of 2 or 3 were less likely to respond (18.8% vs 35.3%) and had a shorter median survival (2.7 months vs 6 months) than patients with better PS. Dose-limiting toxicity was myelosuppression. Seventeen (51.5%, 17/33) patients developed grade III-IV leukopenia with four septic episodes and three septic deaths. Grade III or IV thrombocytopenia was seen in five patients. Patients with prior radiation were significantly more prone to develop leukopenia (P < .005). Gastrointestinal toxicity was mostly mild. No neurologic or genitourinary toxicity was observed. In conclusion, ICE is active in patients with advanced NSCLC and good PS. Besides myelosuppression, it is well tolerated. Further study is indicated to evaluate if granulocyte-colony stimulating factor can reduce myelosuppression from ICE in good PS patients.