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PURPOSE The cisplatin-vinorelbine regimen has superior activity in advanced non-small-cell lung cancer (NSCLC). We conducted a phase I trial to identify the maximum-tolerated dose (MTD) and dose-limiting toxicities (DLTs) of this regimen with concomitant thoracic radiation (RT) in patients with advanced chest malignancies. PATIENTS AND METHODS Patients with advanced chest malignancies that required RT were enrolled onto this phase I study of standard chest radiation (30 daily 2-Gy fractions for a total of 60 Gy) and concurrent chemotherapy with cisplatin starting at 100 mg/m2 every 3 weeks and vinorelbine starting at 20 mg/m2/wk. RESULTS Thirty-seven patients were treated on this study. Two of three patients treated at the maximum-administered dose of cisplatin 100 mg/m2 per cycle and vinorelbine 25 mg/m2/wk experienced acute DLT (neutropenia), which required deescalation. The dose level of cisplatin 100 mg/m2 and vinorelbine 20 mg/m2/wk, although tolerated acutely, produced delayed esophagitis, which proved dose-limiting. The recommended phase II dose was cisplatin 80 mg/m2 every 3 weeks and vinorelbine 15 mg/m2 given 2 of every 3 weeks with concomitant chest RT. CONCLUSION Concomitant chemoradiotherapy with cisplatin and vinorelbine is feasible. The recommended phase II dose is cisplatin 80 mg/m2 every 3 weeks with vinorelbine 15 mg/m2 given twice over 3 weeks on a day 1/day 8 schedule. Esophagitis is the DLT, with neutropenia occurring at higher dose levels. A Cancer and Leukemia Group B (CALGB) phase II trial is currently underway to evaluate further the efficacy and toxicities of this regimen in unresectable stage III NSCLC.

PURPOSE We designed a phase I dose-escalation study of vinorelbine on a novel (daily-times-three) schedule with ifosfamide with granulocyte colony-stimulating factor (G-CSF) support to define the dose-limiting toxicity (DLT) and maximum-tolerated dose (MTD) of vinorelbine in this combination. PATIENTS AND METHODS Cohorts of patients with stage IIIB or IV non-small-cell lung cancer (NSCLC) and no prior chemotherapy received vinorelbine starting at 15 mg/m2 on days 1, 2, and 3, and ifosfamide starting at 2.0 g/m2 on days 1, 2, and 3 with G-CSF support for all patients. Cycles were repeated every 21 days. Plasma vinorelbine concentrations were also analyzed. RESULTS Forty-two patients were treated. The median age was 58 years (range, 34 to 75) and 41 had a performance status of 0 or 1. The DLT was neutropenia and sepsis at a maximum-administered vinorelbine dose of 35 mg/m2 for 3 days. The recommended phase II dose was vinorelbine 30 mg/m2 with ifosfamide 1.6 g/m2 both given on 3 consecutive days. The overall response rate was 40% (17 of 42; all partial responders). The median survival duration was 50 weeks, with a 1-year survival rate of 48%. Pharmacokinetic analysis showed that vinorelbine in this combination and on this schedule is cleared 1.5 to two times faster than in single-agent once-weekly studies. CONCLUSION Myelosuppression is the DLT of this regimen with no major subjective toxicities. With tolerable toxicity and an encouraging 1-year survival rate of 48%, further investigation of this new vinorelbine schedule is warranted in this and other combination regimens.

Concomitant chemoradiotherapy with cisplatin and combination chemotherapy in the neoadjuvant setting have both shown promising results.Purpose: To identify a locally and systemically active concomitant chemoradiotherapy regimen incorporating high-dose cisplatin, interferon alfa-2a (IFN), fluorouracil (5-FU), hydroxyurea (HU) and radiotherapy.Methods: Phase I cohort design establishing the maximal tolerated dose (MTD) of cisplatin with and without granulocyte colony stimulating factor (GCSF). For the first six dose levels, a 4-week cycle consisted of escalating doses of cisplatin during weeks 1 and 2, IFN (week 1), and 5-FU and HU (week 2) with single daily radiation fractions of 200 cGy during days 1–5 of weeks 1–3 and no treatment in week 4. When dose-limiting neutropenia was encountered, GCSF was added during weeks 1, 3, and 4. Finally, to decrease esophagitis, the radiotherapy schedule was altered to 150 cGy twice daily during weeks 1 and 2, followed by a 2-week break (level 7).Results: Forty-nine patients with refractory chest malignancies were treated. The MTD of this regimen without GCSF was cisplatin 50 mg/m2 in weeks 1 and 2, IFN 5 million Units (MU)/m2 per day on days 1–5 in week 1, 5-FU 800 mg/m2 per day for 5 days by continuous infusion, and HU 500 mg every 12 h for 11 doses during week 2. The addition of GCSF during weeks 1, 3, and 4 allowed for escalation of cisplatin to 100 mg/m2 during weeks 1 and 2, with a decreased dose of IFN at 2.5 MU/m2 per day to avoid renal toxicity. Dose-limiting toxicity (DLT) included severe neutropenia, thrombocytopenia, and esophagitis in 5 of 13 patients. Increased thrombocytopenia in patients receiving GCSF was not observed. During hyperfractionated radiotherapy (level 7) chemotherapy doses were as above except for a reduction of 5-FU to 600 mg/m2 per day. While severe esophagitis was reduced, grade 4 thrombocytopenia became more prevalent and was seen in 6 of 7 patients. In-field tumor responses were observed in 17 of 28 evaluated patients with non-small-cell lung cancer. The median times to progression and survival were 4 and 6 months, respectively. When only patients with all known disease confined to the radiotherapy field were considered the corresponding times were 6 and 15 months, respectively. Most treatment failures occurred outside of the irradiated field.Conclusions: (1) This intensive multimodality regimen can be given with aggressive supportive care incorporating GCSF. The recommended phase II doses for a 4-week cycle are cisplatin 50 mg/m2 week 1, and 100 mg/m2 week 2, IFN 2.5 MU, HU 500 mg every 12 h×11 and 5-FU 800 mg/m2 per day with single fraction radiotherapy during weeks 1–3 and GCSF during weeks 1, 3, and 4. (2) GCSF can be safely administered and provides effective support of neutrophils when administered simultaneously with IFN, cisplatin, and chest radiotherapy. (3) There is synergistic renal toxicity when high doses of IFN and cisplatin are given together. (4) Hyperfractionated radiotherapy decreases the severity of esophagitis but increases thrombocytopenia. (5) Although highly toxic, response rates, time to progression and survival figures with this regimen are encouraging and support its investigation in the phase II setting.

Background: We designed a trial of intensive multimodality therapy for carcinoma of the esophagus and gastroesophageal junction to assess tumor response and operability after neoadjuvant chemotherapy and to determine the impact of trimodality therapy on long-term survival. Methods: Thirty-two patients with resectable (clinical stage IIa, n=17; IIb, n=1; III, n=14) squamous cell cancer (n=15) or adenocarcinoma (n=17) were treated with neoadjuvant chemotherapy (cisplatin, 5-fluorouracil, leukovorin), resection, and postoperative chemoradiotherapy (hydroxyurea, 5-fluorouracil; 50–66 Gy). Results: Use of neoadjuvant chemotherapy yielded the following results: a measurable clinical response in 22 patients, stable disease in eight patients, disease progression in one patient, and death in one patient. Thirty-one patients underwent resection, with the following results: two operative deaths (6.5%) and nonfatal morbidity in 17 (59%); the median hospital stay was 13 days. Pathologic staging was stage 0, n=1; I, n=2; IIa, n=11; IIb, n=5; III, n=7; and IV, n=5. Postoperative chemoradiotherapy was completed in 23 patients with one death, for an overall treatment-related mortality rate of 12.5% (four of 32). At a mean follow-up of 22.5 months, median survival is 19.7 months and 14 patients are alive and disease free. Conclusions: Neoadjuvant therapy for cancer of the esophagus and cardia results in good tumor response. Esophagectomy in this setting can be accomplished with acceptable morbidity and mortality. Results of an interim analysis of survival are encouraging and suggest that further investigation of this regimen is warranted.

Summary Purpose: To define the activity and toxicity of preoperative chemotherapy and postoperative concomitant chemoradiotherapy in patients with carcinoma of the esophagus, and to determine the effect on survival in patients treated with this approach. Patients and methods: Patients were treated with two 21-day cycles of induction chemotherapy with cisplatin 100 mg/m 2 on day 1, 5-fluorouracil (5-FU) 800 mg/m 2 /day continuous infusion on days 1-5, and leucovorin 100 mg/m 2 every four hours on days 1-5. Surgical resection was performed if feasible (and could also be performed prior to chemotherapy). Patients then received radiotherapy (50 to 60 Gy) every other week x five to six weeks, concomitantly with 5-FU 800 mg/m 2 continuous infusion daily and hydroxyurea 1 g twice daily x five days. Results: Forty-six patients were treated. With a minimum follow-up of 58 months, the median survival for the entire group was 16 months; the median survivals for patients with squamous carcinoma and adenocarcinoma were 29 months and 12 months, respectively. Toxicities of induction chemotherapy were severe neutropenia and mucositis; there was one toxic death. Toxicities of concomitant chemoradiotherapy were neutropenia, mucositis and esophagitis. There were five cases of radiation pneumonitis, one fatal. Conclusion: Induction chemotherapy and postoperative concomitant chemoradiotherapy can be added to surgical resection for carcinoma of the esophagus. Combined modality therapy, as reported here, produces long-term survival benefit, particularly in patients with squamous carcinoma. However, similar outcome results have been reported with less toxic and shorter treatment regimens as tested in randomized studies.

Ifosfamide and vinorelbine have demonstrated single-agent activity against advanced non-small cell lung cancer. The dose-limiting toxicity of each agent is myelosuppression. Several trials have studied this combination to determine its toxicity and efficacy in non-small cell lung cancer. We conducted a dose-escalation study of vinorelbine in a novel (daily x 3) schedule with ifosfamide and granulocyte colony-stimulating factor support to define the dose-limiting toxicities and maximum tolerated dose of vinorelbine in this combination. Other investigators have studied this combination in the phase II setting. In our phase I study involving 42 patients, the recommended phase II dose was vinorelbine 30 mg/m2 with ifosfamide 1.6 g/m2, each given on 3 consecutive days, followed by granulocyte colony-stimulating factor. The overall response rate was 40%, with a median survival of 50 weeks. Myelosuppression proved to be dose limiting for this regimen, without other major toxicities. Other groups have studied the ifosfamide/vinorelbine combination, and studies adding cisplatin to this regimen have been conducted as well. Given the tolerable toxicity and encouraging response rates and 1-year survival rate seen with this regimen, further investigation of the ifosfamide/vinorelbine regimen has continued in a phase II Cancer and Leukemia Group B trial. Further study of the potential application of the combination as induction therapy for stage III disease is warranted.

Current clinical investigations in the palliative care setting for patients with non-small cell lung cancer are focused on new drugs and combinations. The goal of these studies is to identify more effective and/or less toxic therapy. At the University of Chicago, we have conducted phase I and II studies to integrate new single agents into novel combination chemotherapy regimens. Two such studies have combined the use of ifosfamide with either vinorelbine or paclitaxel. All these drugs have established single-agent activity in non-small cell lung cancer and a favorable toxicity spectrum. We describe the study rationale and design, and the preliminary data of these trials.

Two studies were performed to determine the maximum tolerated dose (MTD) of paclitaxel and vinorelbine, respectively, in combination with a fixed dose of ifosfamide in previously untreated patients with stage IIIB or IV non-small cell lung cancer. Response rate and survival were also assessed. Both regimens were given with mesna and granulocyte colony-stimulating factor support. The maximum tolerated dose of paclitaxel in combination with 1.6 g/m2/d X 3 ifosfamide was 300 mg/m2, and the recommended dose for phase II study is 250 mg/m2. Among 31 patients treated with ifosfamide/paclitaxel, there were seven partial responses; additionally, 10 patients had either minor regression or stable disease. The maximum tolerated dose of vinorelbine in combination with 1.6 g/m2/d X 3 ifosfamide was 35 mg/m2/d X 3, and the recommended dose for phase II study is 30 mg/m2/d X 3. Among 42 patients treated with ifosfamide/vinorelbine, responses have been encouraging, and final analysis is pending. The dose-limiting toxicity for both regimens was neutropenia. These findings indicate that ifosfamide-containing combination chemotherapy regimens have activity in advanced non-small cell lung cancer and are well tolerated when administered with granulocyte colony-stimulating factor.

Most patients with advanced solid tumors of the chest will have local and/or distant disease progression despite standard therapy. Vinorelbine (Navelbine; Burroughs Wellcome Co, Research Triangle Park, NC; Pierre Fabre Medicament, Paris, France) is a new semisynthetic vinca alkaloid with single-agent activity in lung cancer that recently also has been shown to act as a radiosensitizer in vitro. This study aims to define the maximum tolerated dose and dose-limiting toxicity when vinorelbine is given with cisplatin and concomitant radiation therapy. To date, 25 patients with advanced malignancies of the chest have been treated in a dose-escalation trial of vinorelbine administered once weekly with cisplatin (100 mg/m2 every 21 days) and concomitant thoracic radiation therapy (2 Gy/d x 30 fractions for 60 Gy). Vinorelbine was initially given at 20 and 25 mg/m2/wk. Acute dose-limiting toxicity was myelosuppression, which was seen at a vinorelbine dose of 25/mg/m2/wk, with grade 4 neutropenia in two of three patients and one treatment-related death from neutropenic sepsis. At vinorelbine 20/mg/m2/wk, no acute dose-limiting toxicity was seen, but grade 3 or 4 esophagitis developed in three of six patients near the end or after completion of radiation therapy. We subsequently decreased the administration of vinorelbine to weeks 1, 2, 4, and 5. Tolerance appears to be greater with this schedule; however, severe or life-threatening esophagitis at the completion of therapy continues to be observed. Given these preliminary results, it appears feasible to treat patients with advanced chest malignancies with concomitant cisplatin, vinorelbine, and radiation therapy. The significant dose reduction of vinorelbine that is necessary with concomitant radiation therapy provides the first in vivo evidence of a strong radiosensitizing effect of vinorelbine. The schedule is currently being modified to reduce the incidence of esophagitis.

Vinorelbine (Navelbine; Burroughs Wellcome Co, Research Triangle Park, NC; Pierre Fabre Medicament, Paris, France), a semisynthetic vinca alkaloid, and ifosfamide have each shown activity as a single agent and in various combination-chemotherapy regimens against non-small cell lung cancer. Vinorelbine usually has been given on a once-weekly schedule. We designed a phase I study adding escalating doses of vinorelbine on a novel schedule of 3 consecutive days to ifosfamide in a dose-intensive regimen with granulocyte colony-stimulating factor. The goals were to define the dose-limiting toxicity and maximum tolerated dose of vinorelbine and to document the toxicity profile and the overall response and survival rates observed. Eligibility criteria included histologically or cytologically documented stage IIIB or stage IV non-small cell lung cancer, measurable or evaluable disease, and no prior chemotherapy. Treatment consisted of escalating doses of vinorelbine (starting at 15 mg/m2) on days 1, 2, and 3 and ifosfamide at 2 g/m2 and decreased to 1.6 g/m2 on days 1, 2, and 3. Granulocyte colony-stimulating factor was administered subcutaneously at 5 micrograms/kg on days 5 through 11 in all patients. Cycles were repeated every 21 days. Forty-two patients were treated. The median age was 58 years (age range, 34 to 75 years); 41 patients had a performance status of 0 or 1. Dose-limiting neutropenia was observed in two of three patients at the initial dose level of ifosfamide 2 g/m2 and vinorelbine 15 mg/m2. Ifosfamide was therefore decreased to 1.6 g/m2, and vinorelbine was subsequently escalated, with a maximum administered dose of 35 mg/m2. The recommended phase II dose was ifosfamide 1.6 g/m2 on days 1, 2, and 3 with vinorelbine 30 mg/m2 on days 1, 2, and 3, given with granulocyte colony-stimulating factor support, on a 21-day cycle. At the recommended phase II dose myelosuppression remained the most common toxic effect, with grade 3 or 4 neutropenia of brief duration occurring in 20 patients. Final analysis has not yet been completed, but responses have been observed at several dose levels. The maximum tolerated dose of vinorelbine given on days 1, 2, and 3 is 30 mg/m2 when given with ifosfamide at 1.6 g/m2 on days 1, 2, and 3 and granulocyte colony-stimulating factor support. Myelosuppression is the dose-limiting toxic effect. Future analyses of the data will report the overall response and survival rates in these patients.

The combination of cisplatin, 5-fluorouracil, and leucovorin (PFL) has been reported to have a 29% response rate in advanced non-small cell lung cancer. Vinorelbine, a semi-synthetic vinca alkaloid, has also been reported to have single-agent activity in this disease. We designed a phase I-II study in which escalating doses of vinorelbine were added to PFL to define the dose-limiting toxicity and maximum tolerated dose of vinorelbine, and to determine the response rate and survival at the recommended phase II dose.This study enrolled patients between December 1991 and August 1993. Eligibility criteria included histologically or cytologically documented stage III or IV non-small cell lung cancer, measurable or evaluable disease, and no prior chemotherapy. Treatment consisted of escalating doses of vinorelbine (starting at 20 mg/m2) on days 1 and 6, cisplatin 100 mg/m2 on day 2, and 5-fluorouracil as a continuous infusion at 800 mg/m2/day for 4 days (days 2-5) with leucovorin 100 mg orally every 4 hours on days 1 through 5. Cycles were repeated every 21 days.Forty patients were treated during the study. The median age of the patients was 58 (range, 33-75) and 36 patients had a performance status of 0 or 1. Dose-limiting neutropenia was observed in both patients treated with vinorelbine at 25 mg/m2. At the recommended phase II vinorelbine dose of 20 mg/m2 on days 1 and 6, myelosuppression remained the most common toxicity, with 22 patients (55%) having grade 4 neutropenia. Fifteen patients (38%) required hospital admission for neutropenic fever; two died of neutropenic sepsis. Of 33 patients evaluated, 2 patients achieved a complete response and 10 patients achieved a partial response (overall response rate, 30%; 36% of the evaluated patients). Median survival was 10.4 months for the entire cohort (16.4 months for those with stage III disease and 9.6 months for patients with stage IV disease) and 1-year survival was 45%. The overall median time to progression was 8.1 months.The maximum tolerated dose of vinorelbine given on days 1 and 6 with PFL is 20 mg/m2; myelosuppression is the dose-limited factor. The response rate is similar to rates observed in prior studies of combination chemotherapy, but the median survival of patients with stage IV disease exceeds that of many other regimens.

Both paclitaxel and ifosfamide have significant single-agent activity in non-small cell lung cancer. We designed a phase I study combining escalating doses of paclitaxel, administered by 24-hour infusion, with ifosfamide given at a dose of 1.6 g/m2 daily x 3. Paclitaxel dose levels were 135, 170, 200, 250, and 300 mg/m2. The goal of the study was to determine the maximum tolerated dose and dose-limiting toxicities of paclitaxel when used in this combination. Dose escalation was possible because of the use of filgrastim, a granulocyte colony-stimulating factor. Twenty-five patients at three institutions were treated. The dose-limiting toxicity of the combination was granulocytopenia, with other toxicities being generally mild to moderate. The maximum tolerated dose of paclitaxel was 300 mg/m2, and the recommended phase II dose is 250 mg/m2. There was a suggestion of a dose-response curve with paclitaxel as all three partial responses were seen at the 250 mg/m2 dose level. An additional II patients had objective regression or stable disease lasting for 9 to 30 weeks. A phase II study of this combination is currently being planned by the Cancer and Leukemia Group B.

A phase I trial of a combination of vinorelbine (Navelbine; Burroughs Wellcome Co, Research Triangle Park, NC; Pierre Fabre Médicament, Paris, France) and ifosfamide given on a novel schedule on 3 consecutive days with granulocyte colony-stimulating factor was conducted to establish the maximum tolerated dose of vinorelbine and the dose-limiting toxicities of this regimen. Doses of vinorelbine were escalated in cohorts of patients. Of the 29 patients enrolled at the time of data analysis, 26 were evaluable for toxicity. At the first dose level (ifosfamide 2.0 g/m2 days 1, 2, and 3; vinorelbine 15 mg/m2 days 1, 2, and 3), two of three patients had dose-limiting toxicities. The dose of ifosfamide was decreased by 20%, and dose escalation of vinorelbine was restarted. At the vinorelbine dose level of 35 mg/m2/d for 3 days, three of four patients had dose-limiting toxicities. The recommended phase II doses were established as 1.6 g/m2/d ifosfamide for 3 days and 30 mg/m2/d vinorelbine for 3 days. This study established that granulocyte colony-stimulating factor was needed for approximately 8 days. We are currently examining the feasibility of two dose levels of vinorelbine (25 mg/m2 and 30 mg/m2/d for 3 days) in combination with ifosfamide (1.6 g/m2/d) given every 2 weeks.

In a randomized phase II study by the Cancer and Leukemia Group B, the cisplatin/5-fluorouracil/leucovorin (PFL) combination produced a 29% response rate in advanced, unresectable non-small cell lung cancer. Vinorelbine (Navelbine; Burroughs Wellcome, Co, Research Triangle Park, NC; Pierre Fabre Médicament, Paris, France), a semisynthetic vinca alkaloid, has also demonstrated single-agent activity in this disease. Therefore, a phase I-II study was designed to investigate the addition of vinorelbine in escalating doses to the PFL combination. The objectives of this study were to establish the maximum tolerated dose of vinorelbine in combination with PFL, and to define the overall response rate in a cohort of patients treated with the maximum tolerated dose. The regimen consisted of vinorelbine in escalating doses starting at 20 mg/m2/d intravenously on days 1 and 5, followed by leucovorin 100 mg orally every 4 hours on days 1 to 5,5-fluorouracil 800 mg/m2/d intravenous continuous infusion days 2 to 5 (96 hours), and cisplatin 100 mg/m2 intravenously 12 to 24 hours after administration of the first dose of vinorelbine. Cycles were repeated every 3 weeks. No dose-limiting toxicity was observed in the first five patients treated with the initial vinorelbine dose. Increasing the dose of vinorelbine to 25 mg/m2 in a second cohort of two patients, however, resulted in grade 4 granulocytopenia in both, and grade 4 diarrhea in one. It was concluded that this dose level was not feasible. During a preliminary analysis, one complete response and three partial responses were observed in 16 patients evaluated; one of these patients had a pathologic complete remission. This early analysis indicates activity for the regimen.

In an effort to combine the 3 major cancer treatment modalities against esophageal cancer, we designed a study building on our institution’s interest in 5-Fluorouracil modulation and concomitant chemoradiotherapy. From 1989 through 1992, we entered 41 patients with carcinoma of the esophagus into a study using induction chemotherapy, surgical resection, and concomitant chemoradiotherapy. Patients had to have no known distant metastases, a calculated creatinine clearance of ≥ 50 ml/hr, and a good performance status (Cancer and Leukemia Group B 0,1, or 2). Patients with adenocarcinoma and squamous cell carcinoma were eligible. Written informed consent was required.