L. C. Drinkard

Phase I study of vinorelbine, cisplatin, and concomitant thoracic radiation in the treatment of advanced chest malignancies.

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.

Phase I study of vinorelbine and ifosfamide in advanced non-small-cell lung cancer.

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.

A phase I trial of concomitant chemoradiotherapy with cisplatin dose intensification and granulocyte-colony stimulating factor support for advanced malignancies of the chest

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.

Intensive multimodality therapy for carcinoma of the esophagus and gastroesophageal junction.

AbstractBackground: 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.

Induction chemotherapy, surgery, and concomitant chemoradiotherapy for carcinoma of the esophagus: A long-term analysis

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/m2 on day 1, 5-fluorouracil (5-FU) 800 mg/m2/day continuous infusion on days 1-5, and leucovorin 100 mg/m2 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/m2 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.

Induction chemotherapy, surgery and concomitant chemoradiotherapy for carcinoma of the esophagus

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.

Intensive multimodality therapy for carcinoma of the esophagus and gastroesophageal junction

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.