Phase II trial of paclitaxel, carboplatin, and concurrent radiation therapy for locally advanced non-small-cell lung cancer

We conducted a phase II trial to investigate the efficacy of concurrent chemoradiation in patients with stage III non-small-cell lung cancer (NSCLC). Thirty patients with inoperable NSCLC were enrolled onto a multicenter phase II trial of concurrent chemoradiation therapy. Patients received six weekly cycles of paclitaxel 45 mg/m(2) over 1 h; carboplatin at (area under the curve) AUC 2; and radiation therapy of 60 Gy. Radiation was administered to the primary tumor and regional lymph nodes (40 Gy over 4 weeks) followed by a boost to the primary tumor (20 Gy in 2 weeks). After the initial phase of concurrent chemoradiation, patients received an additional four cycles of paclitaxel 175 mg/m(2) over 3 h and carboplatin at AUC 6 every 3 weeks. The overall objective response rate of 30 assessable patients was 76.7%. At the median follow-up time of 13.1 months, the median survival time was 14.5 months (95% CI, 10.59-18.48). The median progression-free survival was 10.5 months (95% CI, 7.72-13.28). The major toxicity was hematologic. The incidence of grade 3 esophagitis was 10%. In conclusion, this chemoradiation regimen is well tolerated and shows significant clinical results for locally advanced NSCLC. Locoregional failure rate remains an important issue with this newer chemotherapeutic regimen. A novel chemotherapy and radiation therapy is clearly needed.     

A phase II trial of preoperative concurrent radiation therapy and weekly paclitaxel/carboplatin for patients with locally advanced non-small-cell lung cancer

This study was designed to evaluate the efficacy and toxicity of a novel preoperative combined-modality regimen in patients with locally advanced non-small-cell lung cancer (NSCLC). Patients with clinical stage IIB, IIIA, or IIIB NSCLC received preoperative combined-modality therapy with concurrent radiation therapy (RT) and weekly paclitaxel/carboplatin for 5 consecutive weeks. After this treatment, patients believed to have resectable disease by standard surgical criteria underwent thoracotomy. Patients whose disease remained unresectable after initial therapy received further RT with concurrent paclitaxel/carboplatin. Of 107 patients entered into this clinical trial, only 20 patients (19%) were considered to have surgically resectable disease at the time of study entry. Ninety-eight patients (92%) completed preoperative combined-modality therapy. Forty-nine patients (46%) underwent thoracotomy and 34 patients had definitive resection. Fourteen patients (13%) had pathologic complete response (pCR). Thirteen of 18 patients (72%) with clinical stage T3 N0 (IIB) tumors had definitive resections, and 33% had pCR. After a median follow-up of 32 months, the 1- and 2-year actuarial survival rates for the entire group are 64% and 42%, respectively. Favorable-prognosis subgroups included patients who had definitive resection and patients with clinical stage T3 N0 tumors (2-year survival rates of 67% for both subgroups). Preoperative therapy with RT and weekly paclitaxel/carboplatin showed activity in this patient population; however, disease in the majority of patients with extensive involvement of mediastinal nodes remained unresectable after this treatment. Results in patients who initially had unresectable disease do not appear different than results achieved with concurrent RT/chemotherapy approaches. Postoperative complications associated with this preoperative combined-modality regimen were more frequent than expected with resection alone.     

A randomized phase III trial of combined paclitaxel, carboplatin, and radiation therapy followed by weekly paclitaxel or observation for patients with locally advanced inoperable non-small-cell lung cancer

BackgroundThis study was designed to determine the efficacy and safety of additional maintenance chemotherapy after standard induction chemotherapy/radiation therapy (XRT) in stage III non–small-cell lung cancer (NSCLC). The primary objective was to increase 1-year survival.Patients and MethodsEligible patients (N = 220) had confirmed stage IIIA or IIIB NSCLC, and an Eastern Cooperative Oncology Group (ECOG) performance status of 0-1. Patients received induction chemotherapy (paclitaxel 200 mg/m² + carboplatin AUC = 6/3 weeks) for 2 cycles, followed by paclitaxel 45 mg/m² + carboplatin AUC = 2 weekly ×7 and concurrent daily XRT (cumulative dose = 66.6 Gy in 37 fractions) and then observation or maintenance. Before randomization, 101 patients (46%) discontinued treatment due to progressive disease (n = 34), toxicity (n = 33), patient request (n = 13), death (n = 7), or other (n = 14). The remaining 119 patients were randomly assigned to either “observation” or “maintenance” (6 cycles of paclitaxel 70 mg/m²/wk [3 weeks on/1 week off]); a median of 5 of 6 planned cycles was delivered in the maintenance arm.ResultsFor the observation group vs. the maintenance group, the estimated 1- and 4-year survival rates were 77% vs. 66% and 38% vs. 17% (median, 26.9 months vs. 16.1 months, respectively [P = .07]); the estimated 1- and 4-year performance-free survival (PFS) were 46% vs. 24% and 25% vs. 13% (median, 10.2 months vs. 8.2 months, respectively [P = .04]). Common toxicities were neutropenia, thrombocytopenia, and fatigue.ConclusionMedian survival in both groups surpassed the standard, most notably the 26.9-month survival in the observation group. Maintenance chemotherapy, when added to a regimen of both induction and concurrent chemoradiotherapy, did not improve clinical outcomes, with endpoints favoring the standard arm.     

Paclitaxel and carboplatin in inoperable non-small-cell lung cancer: A phase II study

Background: Based on the high activity of single-agent paclitaxel and thesuperior one-year survival rates of patients with non-small-cell lung cancer(NSCLC) treated with carboplatin, a phase II trial was initiated using bothagents in patients with inoperable stages III and IV disease to investigatethe efficacy and toxicity of the combination.Patients and methods: Since July 1995, 60 patients fulfilling alleligibility criteria entered this study. All patients received paclitaxel 175mg/m² as a three-hour infusion, and carboplatin dosed to anarea under the concentration-time curve of seven, every three weeks. Nogranulocyte colony-stimulating factor was given. Of the 56 male and fourfemale patients, the median age was 57 years (range 29 to 75 years) and themedian Eastern Co-Operative Oncology Group performance status was one. Mostof the patients had stage IV (34) adenocarcinoma (31) with low differentiation(28). The median number of chemotherapy cycles was three, with a range of oneto eight.Results: Of 55 evaluable patients, 15 (27.3%) achieved partialresponses, 15 (27.3%) had stable disease, and 25 (45.4%) hadprogressive disease. The median survival was 8.95 months and 21.6% ofthe patients survived more than one year. Grade 2/3 nonhematologic toxicityincluded alopecia (59%), neurotoxicity (3%), andmyalgia/arthralgia (10%). Grade 2/3 neutropenia occurred in 14%of patients, whereas grade 3/4 thrombocytopenia was seen in only 4%.One patient died of complications of a severe allergic reaction.Conclusion: Combination treatment using paclitaxel and carboplatin isactive and well tolerated in patients with inoperable non-small-cell lungcancer. The dose-response relationship to paclitaxel and results of comparisonwith other platinum-based regimens remain to be determined.     

Combined chemoradiotherapy regimens of paclitaxel and carboplatin for locally advanced non-small-cell lung cancer: a randomized phase II locally advanced multi-modality protocol.

PURPOSE: This phase II noncomparative randomized trial was conducted to determine the optimal sequencing and integration of paclitaxel/carboplatin with standard daily thoracic radiation therapy (TRT), in patients with locally advanced unresected stage III non-small-cell lung cancer (NSCLC). Survival data were compared with historical standard sequential chemoradiotherapy data from the Radiation Therapy Oncology Group. PATIENTS AND METHODS: Patients with unresected stages IIIA and IIIB NSCLC, with Karnofsky performance status > or = 70% and weight loss < or = 10%, received two cycles of induction paclitaxel (200 mg/m2)/carboplatin (area under the plasma concentration time curve [AUC] = 6) followed by TRT 63.0 Gy (arm 1, sequential) or two cycles of induction paclitaxel (200 mg/m2)/carboplatin (AUC = 6) followed by weekly paclitaxel (45 mg/m2)/carboplatin (AUC = 2) with concurrent TRT 63.0 Gy (arm 2, induction/concurrent), or weekly paclitaxel (45 mg/m2)/carboplatin (AUC = 2)/TRT (63.0 Gy) followed by two cycles of paclitaxel (200 mg/m2)/carboplatin (AUC = 6; arm 3, concurrent/consolidation). RESULTS: With a median follow-up time of 39.6 months, median overall survival was 13.0, 12.7, and 16.3 months for arms 1, 2, and 3, respectively. During induction chemotherapy, grade 3/4 granulocytopenia occurred in 32% and 38% of patients on study arms 1 and 2, respectively. The most common locoregional grade 3/4 toxicity during and after TRT was esophagitis, which was more pronounced with the administration of concurrent chemoradiotherapy on study arms 2 and 3 (19% and 28%, respectively). CONCLUSION: Concurrent weekly paclitaxel, carboplatin, and TRT followed by consolidation seems to be associated with the best outcome, although this schedule was associated with greater toxicity.     

Ifosfamide, cisplatin and etoposide combination in locally advanced inoperable non-small-cell lung cancer: a phase II study

From March 1993 to February 1997, 43 eligible patients with inoperable stage IIIA (ten patients) and stage IIIB (33 patients), histologically confirmed NSCLC received 3 courses of the ICE combination (ifosfamide 1.5 g m(-2) and mesna 750 mg m(-2) two times a day, cisplatin 25 mg m(-2) and etoposide 100 mg m(-2), all administered intravenously (i.v.) on days 1-3 every 3 weeks) with G-CSF support. After three cycles, patients were submitted to radical surgery or received two additional courses of the ICE regimen and/or curative radiotherapy. Grade 3-4 neutropenia occurred in 21% of 114 evaluable courses, but was of short duration, leading to neutropenic fever in 5% of the courses. Severe thrombocytopenia and anaemia were observed in 13% and 3% of the courses respectively. Non-haematological toxicity was generally mild with only two episodes of reversible renal impairment. The overall response rate after three chemotherapy courses was 69% (28 partial responses, one complete response). Ten patients (8/10 patients in stage IIIA, 2/33 patients in stage IIIB) underwent radical surgery. Median TTP for patients not undergoing surgery (n = 33) was 8 months (range 3-34+); median DFS for patients rendered NED by surgery (n = 10) was 26 months (range 1-54+). Median OS for the entire group was 12.5 months (range 2-57+). The ICE regimen is active in locally advanced NSCLC with acceptable toxicity and warrants further exploration as induction chemotherapy in larger series.     

Phase II study of paclitaxel and carboplatin for advanced non-small-cell lung cancer

A prospective phase II study was conducted to determine the response, toxicity and survival rate of lung cancer patients treated with combination paclitaxel and carboplatin in stage IIIB and IV NSCLC. Eligible patients required measurable and/or evaluable diseases; performance status (ECOG) 0-2; no previous chemotherapy; adequate hepatic, renal and bone marrow function. Paclitaxel was administered at a dose of 200 mg/m2, 3 h infusion, followed by carboplatin at an AUC of 6. Treatment was repeated every 3 weeks for six courses. G-CSF 5 microgram/kg was subcutaneously injected during subsequent courses if there was grade 3-4 leucopenia or granulocytopenia in the previous course. From April 1996 through July 1997, 53 patients were enrolled; all are assessable for toxicity and response. The median age was 56 years (range, 20-77 years). Sixty four percent were male, 64% had adenocarcinoma and 62% had stage IV disease. Two hundred and seventy two courses were administered; 36 patients (68%) completed all six cycles. Two patients achieved a complete response (4%) and 27 patients achieved a partial response (51%), for an overall response rate of 55%. Sixteen patients had stable disease (30%) and 8 patients had progressive disease (15%). The median progression free survival time for all patients, stage IIIB and stage IV patients was 28 weeks (range, 18-37 weeks), 31 weeks (range 21-41 weeks) and 22 weeks (range 16-29 weeks), respectively. The median survival time and 1 year survival rate for all patients was 55 weeks (range, 51-59 weeks) and 55%, respectively. Stage IIIB patients had better median survival time and 1-year survival rate than stage IV patients (75 vs. 46 weeks, P = 0.007; 80% vs. 42%, P = 0.003). Grade 3 and 4 granulocytopenia, anemia and thrombocytopenia were observed in 25, 3, and 1%, respectively, of the 272 courses administered. G-CSF was required in 28% of the 272 courses. There were four episodes of febrile neutropenia (1.5%), three episodes of angina pectoris (1%) and one episode of anaphylaxis (0.4%). Other common toxicities, generally mild, included myalgia, arthralgia, peripheral neuropathy and asthenia. Most toxicities showed cumulative effect. Paclitaxel plus carboplatin is a moderately active regimen in advanced NSCLC. Toxicities of this regimen are well tolerated.     

A phase II study of weekly paclitaxel and carboplatin in previously untreated patients with advanced non-small-cell lung cancer

Purpose: Both paclitaxel (P) and carboplatin (C) have a significant activity in non-small cell lung cancer (NSCLC). Weekly administration of P is active, is dose intense, and has a favorable toxicity profile. To evaluate the efficacy and toxicity of weekly P and C in advanced-stage NSCLC, we initiated this phase II study in patients with advanced NSCLC (III B with pleural effusion and stage IV). Patients and Methods: Eligible patients were treated with paclitaxel 100 mg/m² intravenously (iv) over 1 h followed by carboplatin AUC 2 iv over 30 min. This treatment was administered weekly for 3 of every 4 wk until disease progression or intolerable toxicities. Results: Of the 30 patients enrolled in the study, one patient did not meet the eligibility criteria. Of the remaining 29 patients, 6 did not complete at least two cycles of treatment and hence were not assessable for response. The overall response rate was 43.5% (10/23) (all partial responses). An additional 43.5% had stable disease. The median time to progression was 162 d and the median duration of response was 169 d. Overall survival at 1 yr on intent-to-treat analyses was 44% and median survival was 10.8 mo. We observed the following grade 3/4 toxicities: hypersensitivity to paclitaxel (13%), hypersensitivity to carboplatin (3%), neutropenia (31%), thrombocytopenia (7%); 31% experienced grade 1 neuropathy and 17% experienced grade 2 neuropathy. Conclusions: We conclude that weekly paclitaxel and carboplatin is active and very well tolerated in patients with advanced NSCLC.     

Phase I/II study of daily carboplatin, 5-fluorouracil and concurrent radiation therapy for locally advanced non-small-cell lung cancer

A study was undertaken to determine the maximum tolerated dose, the dose-limiting toxicities and the response rate of carboplatin and 5-fluorouracil administered daily with concurrent thoracic radiation therapy in patients with locally advanced non-small-cell lung cancer. In a phase I/II clinical trial, patients with histologically documented, unresectable stage IIIA or IIIB non-small-cell lung cancer (NSCLC) were enrolled. Carboplatin (20-40 mg m(-2) 2-h infusion, daily) and 5-fluorouracil (200 mg m(-2) 24-h continuous infusion, daily) were administered concurrently with radiotherapy on days 1-33. Radiotherapy, with a total dose of 60 Gy, was delivered in 30 fractions on days 1-40. In the phase I portion, the daily dose of carboplatin was escalated from 20 to 40 mg m(-2). Once the maximum tolerated dose (MTD) and recommended dose (RD) of carboplatin was determined, the study entered the phase II portion. In the phase I portion, the daily MTD and RD of carboplatin were 40 and 35 mg m(-2), respectively. The dose-limiting toxicity was neutropenia. In the following phase II study, 30 patients were entered and the objective response rate was 76.7% (95% CI, 62-92%) and the local control rate was 85.7%. The median survival time was 19.8 months, with a survival rate of 70% at 1 year, 36.7% at 2 years. The major toxicities of treatment were neutropenia (>or=grade 3, 87.9%) and thrombocytopenia (>or=grade 3, 23.3%). This combined therapy for locally advanced non-small-cell lung cancer is promising and shows acceptable toxicity.     

Phase II study of carboplatin in untreated,inoperable non-small-cell lung cancer

Summary A total of 51 previously untreated patients with non-small-cell lung cancer (NSCLC) were treated with 130 mg/m² carboplatin given every 4 weeks as an i. v. infusion on days 1, 3, and 5. Ten patients achieved a partial response and five, a minor response. The overall response rate was 20% (95% confidence limits, 8%–32%). The median duration of response was 3 months and the median overall survival was 4.5 months. Leucopenia, thrombocytopenia and anemia of WHO grade 3 occurred in 4%–6% of patients and grade 3 nausea and vomiting was observed in 8% of our subjects. Grade 4 thrombocytopenia occurred in 3 (6%) patients. Apart from nausea and vomiting, nonhematologic toxicities above grade 2 were not observed. Further trials using carboplatin in NSCLC as a single agent or in combination with other chemotherapeutic agents or radiation are warranted.     

Induction therapy with paclitaxel and carboplatin followed by hyperfractionated radiotherapy plus weekly concurrent chemotherapy and subsequent consolidation therapy in unresectable locally advanced non-small-cell lung cancer

AIMS AND BACKGROUND: The purpose of this pilot study was to determine the safety and feasibility of a complete integrated approach, including induction chemotherapy with carboplatin/paclitaxel followed by accelerated hyperfractionated radiotherapy with concurrent chemotherapy, and then by consolidation chemotherapy for locally advanced stage III non-small cell lung carcinoma. METHODS: Systemic doses of carboplatin AUC 6 and paclitaxel (200 mg/m2), 3 weeks out of 4, were planned as induction and consolidation chemotherapy. Weekly carboplatin AUC of 2 plus paclitaxel (50 mg/m2) were given during thoracic radiotherapy. RESULTS: Eighteen patients were enrolled: 10 were evaluated at the end of chemoradiation and 8 received consolidation chemotherapy. On an intent-to-treat basis, 55% of patients achieved a response after induction therapy, whereas chemoradiation and consolidation therapy increased the response rate by 33% and 16%, respectively. No patient experienced grade > 3 acute hematologic toxicity during systemic-dose chemotherapy. With the exception of one episode of a severe cardiac adverse event, non-hematologic toxicity was similarly tolerable. Severe acute adverse events observed during concurrent chemoradiation were mainly represented by esophagitis, resulting in interruption of the radiotherapy in 25% of patients. More notably, only one patient experienced serious non-hematologic late toxicity. CONCLUSIONS: Although the present approach seemed feasible, our data did not support any possible advantage in favor of this three-phase integrated treatment, and therefore the design will not be investigated in a subsequent phase II study.     

Results of a preliminary study using hypofractionated involved-field radiation therapy and concurrent carboplatin/paclitaxel in the treatment of locally advanced non-small-cell lung cancer

Background

We aimed to evaluate the feasibility and efficacy of hypofractionated involved-field radiation therapy (IFRT) omitting elective nodal irradiation (ENI) with concurrent chemotherapy for locally advanced non-small-cell lung cancer (NSCLC).

Methods

Between July 2004 and July 2006, ten patients with locally advanced NSCLC were included in this study. One had stage IIIA and 9 had stage IIIB disease. The treatment consisted of IFRT in fractions of 2.5 Gy and weekly carboplatin (CBDCA)/paclitaxel (PTX). Hypofractionated IFRT with a median total dose of 65 Gy with median percent total lung volume exceeding 20 Gy (V20) of 20.2%, and a median of five courses of chemotherapy with weekly CBDCA (area under the curve, 1.5?2.0)/PTX (30?35 mg/m²) were given to all patients.

Results

The median survival time and the 1-, 2-, and 3-year overall survival rates were 29.5 months and 90.0%, 58.3%, and 43.8%, respectively. No elective nodal failure was encountered during the median follow up of 18.2 months. No acute or late toxicities of grade 3 or worse were observed. No in-field recurrence occurred in the group with a total dose of 67.5 Gy or more, but there was such recurrence in 83.3% of those in the group with less than 67.5 Gy.

Conclusion

Hypofractionated IFRT with weekly CBDCA/PTX was a feasible treatment regimen. Hypofractionated IFRT with a total dose of 67.5 Gy or more could be a promising modality to improve the treatment results in patients with locally advanced NSCLC.     

Randomized phase II trial comparing bevacizumab plus carboplatin and paclitaxel with carboplatin and paclitaxel alone in previously untreated locally advanced or metastatic non-small-cell lung cancer.

PURPOSE: To investigate the efficacy and safety of bevacizumab plus carboplatin and paclitaxel in patients with advanced or recurrent non-small-cell lung cancer. PATIENTS AND METHODS: In a phase II trial, 99 patients were randomly assigned to bevacizumab 7.5 (n = 32) or 15 mg/kg (n = 35) plus carboplatin (area under the curve = 6) and paclitaxel (200 mg/m(2)) every 3 weeks or carboplatin and paclitaxel alone (n = 32). Primary efficacy end points were time to disease progression and best confirmed response rate. On disease progression, patients in the control arm had the option to receive single-agent bevacizumab 15 mg/kg every 3 weeks. RESULTS: Compared with the control arm, treatment with carboplatin and paclitaxel plus bevacizumab (15 mg/kg) resulted in a higher response rate (31.5% v 18.8%), longer median time to progression (7.4 v 4.2 months) and a modest increase in survival (17.7 v 14.9 months). Of the 19 control patients that crossed over to single-agent bevacizumab, five experienced stable disease, and 1-year survival was 47%. Bleeding was the most prominent adverse event and was manifested in two distinct clinical patterns; minor mucocutaneous hemorrhage and major hemoptysis. Major hemoptysis was associated with squamous cell histology, tumor necrosis and cavitation, and disease location close to major blood vessels. CONCLUSION: Bevacizumab in combination with carboplatin and paclitaxel improved overall response and time to progression in patients with advanced or recurrent non-small-cell lung cancer. Patients with nonsquamous cell histology appear to be a subpopulation with improved outcome and acceptable safety risks.     

Long-term outcomes with concurrent carboplatin, paclitaxel and radiation therapy for locally advanced, inoperable head and neck cancer.

BACKGROUND: Our goal was to evaluate long-term efficacy outcomes of patients with squamous cell carcinoma of the head and neck (SCCHN) treated with carboplatin, paclitaxel (Taxol) and radiotherapy. PATIENTS AND METHODS: We conducted a phase II trial in inoperable patients with locally advanced SCCHN. Carboplatin 100 mg/m(2) and paclitaxel 40 mg/m(2) were administered i.v. once a week during external beam radiation therapy (180 cGy per fraction) for 6-7 weeks. Interstitial brachytherapy was used as a boost in selected patients with primary malignancies of the oral cavity and the oropharynx. RESULTS: Fifty-five patients were enrolled. Fifty-two patients (95%) had stage IV and 51 (93%) had technically unresectable disease; 62% had an oropharyngeal primary site. Twenty-one patients underwent brachytherapy boost. Grade 3 or 4 mucositis occurred in 30% of patients. One death occurred during treatment that was related to complications of gastrostomy tube placement. Forty of 50 assessable patients (80%) had an objective response, with a complete response rate of 52%. With a median follow-up of 69 months for surviving patients, the 5-year progression-free survival was 36% and the 5-year overall survival was 35%. Two of the 18 long-term survivors of >50 months were gastrostomy tube feeding dependent. Patients undergoing brachytherapy boost (n = 21) had similar outcomes compared with the rest of the patients. In multivariate analysis, baseline hemoglobin levels and N stage were predictive of survival. CONCLUSION: Treatment with concurrent carboplatin, paclitaxel and radiation is safe and offers curative potential for poor prognosis patients with locally advanced SCCHN.     

A phase II study of cisplatin and 5-fluorouracil with concurrent hyperfractionated thoracic radiation for locally advanced non-small-cell lung cancer: a preliminary report from the Okayama Lung Cancer Study Group

A recent meta-analysis and randomized studies have demonstrated that combined chemoradiotherapy is associated with a survival advantage for selected patients with locally advanced unresectable non-small-cell lung cancer (NSCLC). We conducted a phase II study of combined chemoradiotherapy to find a more effective combination of drugs and radiation than those previously reported for such patients. Between January 1994 and November 1996, 50 previously untreated patients with locally advanced unresectable NSCLC (stage IIIA with N2 or IIIB disease) were entered in this study. Patients were required to have Eastern Cooperative Oncology Group performance status < or = 2, age < or = 75 years and adequate organ function. Treatment consisted of three cycles of cisplatin (20 mg m(-2), days 1-5) and 5-fluorouracil (5-FU) (500 mg m(-2), days 1-5) every 4 weeks, and concurrent hyperfractionated thoracic radiation (1.25 Gy twice daily, with a 6-h interfraction interval; total radiation dose, 62.5-70 Gy). Of the 50 patients entered, 37 (74%) responded to this chemoradiotherapy, including two (4%) with complete response. By a median follow-up time of 41.0 months, 35 patients had died and 15 were still alive. The median time to progression for responding patients was 14.1 months (range, 2.6-51.3+ months). The median survival time was 18.7 months, with a survival rate of 66.0% at 1 year, 46.0% at 2 years and 27.6% at 3 years. Survival outcome was strongly affected by the extent of nodal involvement (median survival time, 27.4 months for N0-2 disease (n = 37) vs 10.7 months for N3 disease (n = 13); P = 0.007). The major toxicities of treatment were leukopenia and neutropenia (> or = Grade 3, 58% and 60% respectively). Other toxicities of > or = Grade 3 included thrombocytopenia (26%), anaemia (26%), nausea/vomiting (16%) and radiation oesophagitis (6%). Treatment-related death occurred for one patient. Our findings suggest that cisplatin and 5-FU in combination with concurrent hyperfractionated thoracic radiation is effective and feasible for the treatment of locally advanced unresectable NSCLC. The short-term survival in this study appeared to be more encouraging than those of similar chemoradiation trials. A randomized trial will be needed to compare the combination of cisplatin and 5-FU with other platinum-based regimens together with concurrent hyperfractionated thoracic radiation. In addition, in future studies, inclusion criteria for N3 disease with or without supraclavicular involvement should be reconsidered to correctly evaluate the effect of combined chemoradiotherapy for locally advanced unresectable NSCLC.     

A phase I trial of outpatient weekly docetaxel and concurrent radiation therapy for stage III unresectable non small-cell lung cancer: a Vanderbilt Cancer Center Affiliate Network (VCCAN) Trial

Docetaxel has demonstrated activity as a radiosensitizer in numerous preclinical studies, probably due to its role as a cell cycle synchronizer for the G2/M radiosensitive phase of the cell cycle. We conducted a phase I trial to determine the maximum-tolerated dose (MTD) and dose-limiting toxicities (DLT) of docetaxel with concurrent thoracic radiation therapy (TRT) to patients with unresectable stage III non small-cell lung cancer (NSCLC). Fifteen patients were entered into this study. Docetaxel was administered as a 1-hour intravenous (I.V.) infusion, repeated every week for 6 weeks with starting dose of 20 mg/m2. Doses were escalated in 10 mg/m2 increments in successive cohorts of three new patients, if tolerated. Unacceptable toxicity was defined as grade = 3 nonhematologic or hematologic toxicity according to Eastern Cooperative Oncology Group (ECOG) toxicity criteria. TRT was administered to the primary tumor and regional lymph nodes (40 Gy) followed by a boost to the tumor (20 Gy). At the first dose level (20 mg/m2/week), one patient developed grade 4 hyperglycemia and accrual was expanded to five patients. At the second level (30 mg/m2/week), two out of six patients developed grade 3 esophagitis. At the third level (40 mg/m2/week), two out of four patients developed grade 3 esophagitis and one patient developed grade 3 pulmonary toxicity. The weekly docetaxel MTD with concurrent radiation therapy (RT) was found to be 30 mg/m2. The DLT was esophagitis and pulmonary toxicity. Other toxicities encountered included skin reaction, nausea and vomiting, as well as diarrhea. Additionally, there were no treatment-related mortalities or late-occurring toxicities. Esophagitis was the principal DLT of concurrent weekly docetaxel and thoracic radiation in the outpatient setting. The MTD of concurrent weekly docetaxel with TRT is 30 mg/m2 weekly for 6 weeks. This study is still open to accrual with weekly docetaxel and TRT in locally advanced NSCLC patients.     

Escalated hyperfractionated accelerated radiation therapy for locally advanced non-small cell lung cancer: a clinical phase II trial.

BACKGROUND AND PURPOSE: To evaluate the feasibility, toxicity and the efficacy for locally advanced non-small cell lung cancer (NSCLC) treated with escalated hyperfractionated accelerated radiation therapy (EHART) combined with chemotherapy. PATIENTS AND METHODS: The EHART consisted of irradiation delivered twice per day with >6-h interval and five treatment days per week. In the first and second weeks, 1.2 Gy/fraction b.i.d, was given, and then 1. /fraction b.i.d in the third week; 1.4 Gy/fraction b.i.d in the fourth week; and 1. /fraction b.i.d in the fifth week, respectively. The total tumor dose delivered was 66 Gy/50 fractions/5 weeks. All patients received neoadjuvant and adjuvant chemotherapy. The chemotherapeutic regimen used was either MVP (mitomycin C, vindesine, cis-platinum), or EP (etoposide and cis-platinum). RESULTS: From February 1997 to February 1999, 73 eligible patients were registered. All were in stage IIIb with median age of 60 years (33-70). Of the 73 patients, 12 cases were withdrawn from the study due to Grade (Gr) III acute complications, distant metastases, or intercurrent diseases. Sixty-one patients completed the combined treatment as planned. A median of 4 cycles of chemotherapy (1-7) was administered and 66 Gy/50 fractions/36 days was delivered finally. The most common acute complication was radiation esophagitis, which occurred in 56 cases (77%), with Gr III in 11 cases (15%). Twenty-nine patients (40%) had acute pulmonary toxicity; with Gr III in 6 cases (8%). The median survival time was 13 months for the entire group. The 1-year and 2-year survival rates were 51 and 10%, respectively. Of the 61 patients who finished EHART, 34 were found to have locoregional progression. Thirty-two patients failed inside radiation fields, and 2 patients, outside radiation fields. The 1-year and 2-year locoregional progression-free rates were 71 and 34%, respectively. The 1-year and 2-year distant metastasis rates were 57 and 84%, respectively. CONCLUSIONS: EHART combined with chemotherapy could be tolerated by most of the stage IIIb NSCLC patients with acceptable complications. Locoregional control was improved, but the long survival was not prolonged significantly predominantly due to distant metastases.     

A phase II trial of induction chemotherapy followed by continuous hyperfractionated accelerated radiotherapy in locally advanced non-small-cell lung cancer

Background and purpose

We conducted a phase II study combining induction chemotherapy with continuous hyperfractionated accelerated radiotherapy (CHART) in locally advanced non-small-cell lung cancer (NSCLC).

Materials and methods

A total of 40 patients with stage III NSCLC were enrolled. All patients received 3 cycles of chemotherapy followed by CHART (56 Gy in 36 fractions over 12 days). The primary outcome measure was radiation toxicity. Secondary endpoints were response rate, overall survival, disease-free survival and loco-regional progression-free survival.

Results

Acute radiation toxicity was minimal and there were no significant late toxicities. The response rate after completion of chemoradiation was 65%. The median and 2-year overall survival, progression-free survival and loco-regional progression-free survivals were 15.7 months, 28%; 12.1 months, 23%; and 26.4 months, 51%, respectively.

Conclusions

Induction chemotherapy can be safely combined with CHART. The survival results are consistent with previous studies of chemotherapy followed by accelerated radiotherapy. This approach should be compared with synchronous chemoradiation to determine if it represents a less toxic alternative.     

Neoadjuvant chemotherapy followed by late-course accelerated hyperfractionated radiation therapy for locally advanced non-small-cell lung cancer: long-term results of a phase I/II clinical trial

Toxicity, response, and long-term results of a definitive chemotherapy/radiation therapy (RT) protocol in patients with unresectable stage III non-small-cell lung cancer (NSCLC) were evaluated. Two cycles of cisplatin-based chemotherapy were delivered before RT, and another 2 cycles were added for patients who responded to the first 2 cycles of chemotherapy. The first course of radiation covered the primary lesion and elective nodal regions, given in 2 Gy per fraction, 5 days a week for a dose of 40 Gy. Late-course hyperfractionated accelerated RT was delivered to the gross tumor twice a day for an additional 27 Gy within 2 weeks, using 1.5 Gy per fraction. Fifty-three patients with unresectable stage IIIA (N2) and IIIB NSCLC were eligible for analysis. Twelve patients developed grade 3 neutropenia, and 3 patients developed grade 4 neutropenia. Grade 2 or 3 esophagitis was observed in 14 and 2 patients, respectively, and grade 2 or 3 pneumonitis was observed in 9 and 1 patient, respectively. Six patients developed grade 2 and 1 patient developed grade 3 late lung toxicity. The median survival time was 15.5 months. Twenty-six of 53 patients (49%) have died of locoregional progression inside the thorax. The distant metastasis rate was 59.5% (22 of 37 patients) for those who did not respond to chemotherapy and 18.8% (3 of 16 patients) for those who responded to chemotherapy (P = 0.006). Late-course hyperfractionated accelerated RT combined with induction chemotherapy was well tolerated and yielded long-term results that compare favorably with those of studies using 2 cycles of induction chemotherapy and conventional fractionated RT. However, local control was still discouraging.