Long-term survival with concurrent chemoradiation therapy followed by consolidation docetaxel in stage IIIB non-small-cell lung cancer: a phase II Southwest Oncology Group Study (S9504)

PURPOSE: Here we report 5-year survival data from S9504, a Southwest Oncology Group phase II trial evaluating consolidation docetaxel after concurrent cisplatin/etoposide and thoracic radiation therapy in patients with pathologically documented stage IIIB non-small-cell lung cancer. Survival outcomes were compared with a predecessor study (S9019) with identical eligibility, staging criteria, and treatment, excepting docetaxel consolidation. PATIENTS AND METHODS: Treatment consisted of cisplatin 50 mg/m(2) per day on days 1, 8, 29, and 36; etoposide 50 mg/m(2) per day on days 1-5 and 29-33; and concurrent thoracic radiation therapy (total dose, 61 Gy). Consolidation docetaxel (75 mg/m(2) initial dose) started 4-6 weeks after completion of chemotherapy. RESULTS: Concurrent chemotherapy was generally well tolerated, with a low level of radiation-related esophagitis; 2 patients died from pneumonitis. Grade 3/4 neutropenia during consolidation docetaxel was common. At a median follow-up of 71 months, median progression-free survival was 16 months; median survival 26 months; and 3-, 4-, and 5-year survival rates were 40%, 29%, and 29%, respectively. Brain metastasis was the most common site of failure. In the predecessor trial S9019, median survival was 15 months, and 3-, 4-, and 5-year survival rates were 17%, 17%, and 17%, respectively. CONCLUSION: The 5-year survival rate in S9540 of 29% compares favorably with the predecessor trial S9019 and other treatment approaches currently used in this patient population. A phase III trial designed to validate the concept of consolidation docetaxel is presently under way.     

Consolidation docetaxel after concurrent chemoradiotherapy in stage IIIB non-small-cell lung cancer: phase II Southwest Oncology Group Study S9504.

PURPOSE: To test the concept of taxane sequencing in combined-modality therapy, this phase II trial (S9504) evaluated consolidation docetaxel after concurrent chemoradiotherapy in patients with pathologically documented stage IIIB non-small-cell lung cancer (NSCLC). Results were compared with those of the predecessor study (S9019) with identical eligibility, staging criteria, and treatment, excepting docetaxel consolidation. PATIENTS AND METHODS: Treatment consisted of cisplatin 50 mg/m2 on days 1, 8, 29, and 36, etoposide 50 mg/m2 on days 1 through 5 and 29 through 33, and concurrent thoracic radiotherapy (total dose of 61 Gy). Consolidation docetaxel started 4 to 6 weeks after chemoradiotherapy at an initial dose of 75 mg/m2. RESULTS: Stage subsets (tumor-node-metastasis system) in 83 eligible patients were as follows: T4N0/1, 31 patients (37%); T4N2, 22 patients (27%), and T1-3N3, 30 patients (36%). Concurrent chemoradiotherapy was generally well tolerated, but two patients died from probable radiation-associated pneumonitis. Neutropenia during consolidation docetaxel was common (57% with grade 4) and most frequent during escalation to 100 mg/m2. Median progression-free survival was 16 months, median survival was 26 months, and 1-, 2-, and 3-year survival rates were 76%, 54%, and 37%, respectively. Brain metastasis was the most common site of failure. In S9019, median survival was 15 months and 1-, 2-, and 3-year survival rates were 58%, 34%, and 17%, respectively. CONCLUSION: Consolidation docetaxel after concurrent chemoradiotherapy in stage IIIB NSCLC is feasible and generally tolerable, and results compare favorably with the predecessor trial S9019. Nevertheless, this study remains hypothesis-generating and does not provide definitive evidence of the benefit of this approach. Phase III trials evaluating the S9504 regimen have been initiated to validate these results.     

Long-Term Survival with Concurrent Chemoradiation Therapy Followed by Consolidation Docetaxel in Stage IIIB Non–Small-Cell Lung Cancer: A Phase II Southwest Oncology Group Study (S9504)

PurposeHere we report 5-year survival data from S9504, a Southwest Oncology Group phase II trial evaluating consolidation docetaxel after concurrent cisplatin/etoposide and thoracic radiation therapy in patients with pathologically documented stage IIIB non–small-cell lung cancer. Survival outcomes were compared with a predecessor study (S9019) with identical eligibility, staging criteria, and treatment, excepting docetaxel consolidationg.Patients and MethodsTreatment consisted of cisplatin 50 mg/m² per day on days 1, 8, 29, and 36; etoposide 50 mg/m² per day on days 1–5 and 29–33; and concurrent thoracic radiation therapy (total dose, 61 Gy). Consolidation docetaxel (75 mg/m² initial dose) started 4–6 weeks after completion of chemotherapy.ResultsConcurrent chemotherapy was generally well tolerated, with a low level of radiationrelated esophagitis; 2 patients died from pneumonitis. Grade 3/4 neutropenia during consolidation docetaxel was common. At a median follow-up of 71 months, median progression-free survival was 16 months; median survival 26 months; and 3-, 4-, and 5-year survival rates were 40%, 29%, and 29%, respectively. Brain metastasis was the most common site of failure. In the predecessor trial S9019, median survival was 15 months, and 3-, 4-, and 5-year survival rates were 17%, 17%, and 17%, respectively.ConclusionThe 5-year survival rate in S9540 of 29% compares favorably with the predecessor trial S9019 and other treatment approaches currently used in this patient population. A phase III trial designed to validate the concept of consolidation docetaxel is presently under way.     

Results of a phase II concurrent chemoradiotherapy study using three-dimensional conformal radiotherapy with cisplatin and oral etoposide in stage III nonsmall-cell lung cancer

This phase II study was designed to utilize conformal radiation therapy with cisplatin and oral etoposide in patients with stage III or locally recurrent non-small-cell lung cancer to determine tolerance and toxicity of therapy. From April 1992-February 1996, 18 patients with pathologically confirmed stage IIIA, IIIB, or locally recurrent non-small-cell lung cancer (NSCLC) were entered on study. Metastatic workup included a CT scan of the thorax and upper abdomen as well as a bone scan. Chemotherapy consisted of IV cisplatin (100 mg/m2) with IV etoposide (25 mg/m2) on day 1; oral etoposide was given (50 mg/m2) days 2-14. Using three-dimensional planning, 40-45 Gy were delivered to the clinical target volume, followed by a boost to the gross tumor volume for a total of 70 Gy. Patients with recurrent disease received 40-50 Gy in total. Eighteen patients were enrolled: 16 patients were treated with curative intent and were evaluable for outcome. Two patients were treated for locally recurrent NSCLC and were not included in the outcome analysis. Stages included IIIA (44%) and stage IIIB (54%). Forty-four percent had T3/4 tumors, and 69% had N2/3 disease. Overall survival at 1 year was 64%, while 2-year overall survival was 50%. Distant metastasis-free survival at 1 year was 67%, and at 2 years 60%. The 1-year chest progression-free survival was 57%, and at 2 years 50%. Sixty-three percent required hospitalization for dehydration or neutropenia. Fifty-six percent developed leukopenia (<1,000 cells/microl) sometime during the therapy. We conclude that concurrent cisplatin and oral etoposide with conformal radiation therapy provide encouraging results in stage III lung cancer. The major toxicities of this therapy included leukopenia, thrombocytopenia, and mucosal esophagitis. Local progression of disease continues to be a problem with the current doses given. Future studies should evaluate dose escalation of radiation therapy with limited volumes, utilizing conformal radiation and chemotherapy to improve local control and potentially impact upon distant metastases.     

Five-year results of a phase II trial of hyperfractionated radiotherapy and concurrent daily cisplatin chemotherapy for stage III non-small-cell lung cancer

The purpose of this study was to evaluate the 5-year results for a phase II trial of hyperfractionated radiotherapy (RT) and concurrent daily cisplatin chemotherapy. Between August 1994 and December 1999, 63 patients with stage IIIA and stage IIIB non-small-cell lung cancer were treated with RT to a dose of 69.6 Gy at 1.2 Gy twice daily with daily cisplatin at 6 mg/m. Thirty-seven patients elected to receive consolidation carboplatin and paclitaxel chemotherapy. Recurrence and survival outcomes were evaluated by Kaplan-Meier analysis. Acute and late side effects were scored by the Radiation Therapy Oncology Group (RTOG) grading system. Radiographic complete or partial tumor response was achieved in 34 of 63 (54%) of cases. Median absolute survival was 20.1 months. Median time to local recurrence and distant metastases were 10.6 and 8.6 months, respectively. Overall survival rates were 57%, 35%, and 23% at 1, 3, and 5 years, respectively. Survival was significantly greater for patients receiving consolidation chemotherapy (50% versus 20% at 3 years). Only 5 patients (7%) experienced Grade 3 or 4 esophagitis. There were 16 cases of Grade 1 or 2 pneumonitis; steroid therapy resolved symptoms in 9 patients. This regimen of hyperfractionated RT and chemotherapy achieved significant response, and 5-year survival rates with acceptable toxicity.     

Long-term results of a phase III trial comparing once-daily radiotherapy with twice-daily radiotherapy in limited-stage small-cell lung cancer

PURPOSE: This Phase III study was performed to determine whether twice-daily (b.i.d.) radiotherapy (RT) resulted in better survival than once-daily (q.d.) RT for patients with limited-stage small-cell lung cancer (LD-SCLC). METHODS AND MATERIALS: A total of 310 patients with LD-SCLC initially received three cycles of etoposide and cisplatin. Subsequently, the 261 patients without significant progression were randomized to two cycles of etoposide and cisplatin plus either q.d. RT (50.4 Gy in 28 fractions) or split-course b.i.d. RT (24 Gy in 16 fractions, a 2.5-week break, and 24 Gy in 16 fractions) to the chest. Patients then received a sixth cycle of etoposide and cisplatin followed by prophylactic cranial RT. RESULTS: Follow-up ranged from 4.6 to 11.9 years (median, 7.4 years). The median survival and 5-year survival rate from randomization was 20.6 months and 21% for patients who received q.d. RT compared with 20.6 months and 22% for those who received b.i.d. RT (p = 0.68), respectively. No statistically significant differences were found in the rates of progression (p = 0.68), intrathoracic failure (p = 0.45), in-field failure (p = 0.62), or distant failure (p = 0.82) between the two treatment arms. No statistically significant difference was found in the overall rate of Grade 3 or worse (p = 0.83) or Grade 4 or worse toxicity (p = 0.95). Grade 3 or worse esophagitis (p = 0.05) was more common in the b.i.d. arm. Grade 5 toxicity occurred in 4 (3%) of 130 patients who received b.i.d. RT compared with 0 (0%) of 131 who received q.d. RT (p = 0.04). CONCLUSION: Although this study did not demonstrate an advantage to split-course b.i.d. RT, the long-term survival was favorable, likely reflecting the positive influences of concurrent combined modality therapy and prophylactic cranial RT.     

Mature results from a phase II trial of accelerated induction chemoradiotherapy and surgery for poor prognosis stage III non-small-cell lung cancer.

Mature results are reported from a phase II trial of accelerated induction chemoradiotherapy and surgical resection for stage III non-small-cell lung cancer whose prognosis is poor. Surgically staged patients with poor prognosis stage III non-small-cell lung cancer were eligible for this study. Four-day continuous intravenous infusions of cisplatin 20 mg/m2/day, 5-fluorouracil 1,000 mg/m2/day, and etoposide 75 mg/m2/day were given concurrently with accelerated fractionation radiation therapy, 1.5 Gy twice a day, to a total dose of 27 Gy. Surgical resection followed in 4 weeks. Identical postoperative chemotherapy and concurrent radiation to a total dose of 40 to 63 Gy was subsequently given. Between February 1991 and June 1994, 42 eligible and evaluable patients, 23 with stage IIIA disease and 19 with stage IIIB disease, were entered in this trial. Treatment was well tolerated. The pathologic response rate was 40%. This response was complete in 5%. With a median follow-up of 54 months, the Kaplan-Meier 4-year survival estimate is 19%: 26% for stage IIIA and 11% for stage IIIB patients. Patients with a pathologic response, resectable disease, or pathologic downstaging to stage 0, I, or II had a better survival. The 4-year estimates of locoregional and distant disease control are 70% and 19%, respectively. It is concluded that although the ultimate role of concurrent chemoradiotherapy and surgery in stage III non-small-cell lung cancer must await the results of phase III clinical trials, survival and locoregional control in this study appear improved in comparison with historical experience. There is a subset of patients, able to undergo resection with pathologic downstaging, who have a projected survival equivalent to that of patients with more limited disease. Clinical or pathologic tools to identify these patients before treatment would be highly useful.     

Randomized phase III trial of sequential chemoradiotherapy compared with concurrent chemoradiotherapy in locally advanced non-small-cell lung cancer: Groupe Lyon-Saint-Etienne d'Oncologie Thoracique-Groupe Fran?ais de Pneumo-Cancérologie NPC 95-01 Study.

PURPOSE: We conducted a phase III study to compare the survival impact of concurrent versus sequential treatment with radiotherapy (RT) and chemotherapy (CT) in unresectable stage III non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Patients were randomly assigned to one of the two treatment arms. In the sequential arm, patients received induction CT with cisplatin (120 mg/m2) on days 1, 29, and 57, and vinorelbine (30 mg/m2/wk) from day 1 to day 78, followed by thoracic RT at a dose of 66 Gy in 33 fractions (2 Gy per fraction and 5 fractions per week). In the concurrent arm, the same RT was started on day 1 with two concurrent cycles of cisplatin 20 mg/m2/d and etoposide 50 mg/m2/d (days 1 to 5 and days 29 to 33); patients then received consolidation therapy with cisplatin 80 mg/m2 on days 78 and 106 and vinorelbine 30 mg/m2/wk from days 78 to 127. RESULTS: Two hundred five patients were randomly assigned. Pretreatment characteristics were well balanced between the two arms. There were six toxic deaths in the sequential arm and 10 in the concurrent arm. Median survival was 14.5 months in the sequential arm and 16.3 months in the concurrent arm (log-rank test P = .24). Two-, 3-, and 4-year survival rates were better in the concurrent arm (39%, 25%, and 21%, respectively) than in the sequential arm (26%, 19%, and 14%, respectively). Esophageal toxicity was significantly more frequent in the concurrent arm than in the sequential arm (32% v 3%). CONCLUSION: Although not statistically significant, clinically important differences in the median, 2-, 3-, and 4-year survival rates were observed, with a trend in favor of concurrent chemoradiation therapy, suggesting that is the optimal strategy for patients with locally advanced NSCLC.     

Phase II study of induction chemotherapy with gemcitabine and vinorelbine followed by concurrent chemoradiotherapy with oral etoposide and cisplatin in patients with inoperable stage III non-small-cell lung cancer

PURPOSE: For locoregionally advanced inoperable non-small-cell lung cancer (NSCLC), concurrent chemoradiotherapy has become a standard therapy. We conducted a Phase II trial to examine the efficacy and toxicity of adding gemcitabine and vinorelbine induction chemotherapy to concurrent chemoradiotherapy with oral etoposide and cisplatin. METHODS AND MATERIALS: Eligibility included inoperable clinical Stage III NSCLC without pleural effusion, ECOG performance status 0-1, and weight loss < or =5%. Induction chemotherapy consisted of three cycles of gemcitabine 1,000 mg/m2 and vinorelbine 30 mg/m2, each given i.v. on Days 1 and 8, every 3 weeks. During once-daily thoracic radiotherapy (1.8 Gy/day, total 63 Gy), two cycles of oral etoposide (100 mg on Days 1-5 and 8-12) plus cisplatin (50 mg/m2 on Days 1 and 8) were given concurrently 4 weeks apart. RESULTS: Between April 2002 and November 2003, 42 patients were enrolled and 40 were included in response and toxicity evaluation. The median age was 59 years and 13 patients had IIIA and 27 had IIIB; 24 had squamous ca, 12 had adenocarcinoma, and 4 had others. Objective tumor responses were obtained in 29 patients (72.5%), including 18 (45.0%) after induction chemotherapy. After a median follow-up of 23.8 months, the median survival time and progression-free survival was 23.2 months and 10.9 months, respectively, with 2-year survival rate of 43.9%. For the patients with supraclavicular nodal involvement, the median survival time was 11.8 months with 2-year survival rate of 16.7%, whereas the corresponding figures were 27.8 months and 52.0%, respectively, for those without supraclavicular nodal involvement. Toxicity of induction chemotherapy was mild and well tolerated. However, concurrent chemoradiotherapy was associated with G3/4 hematologic toxicity in 75.7%, G3 esophagitis in 24.2%, and two treatment-related deaths. There were nonlife-threatening late toxicities in additional 6 patients. CONCLUSIONS: Induction chemotherapy with gemcitabine and vinorelbine followed by concurrent chemoradiotherapy with etoposide and cisplatin showed very promising survival in patients with Stage III NSCLC, especially in those without supraclavicular nodal involvement, which warrants further evaluation.     

Effects of amifostine on acute toxicity from concurrent chemotherapy and radiotherapy for inoperable non-small-cell lung cancer: report of a randomized comparative trial

PURPOSE: To determine the ability of amifostine to reduce the severity and/or incidence of the acute toxicities of concurrent chemotherapy and radiotherapy (RT) for non-small-cell lung cancer. METHODS AND MATERIALS: Patients with inoperable, nonmetastatic non-small-cell lung cancer receiving concurrent chemoradiotherapy were randomized to one of two treatment groups. Arm 1 patients received thoracic RT (total dose, 69.6 Gy in 58 fractions of 1.2 Gy b.i.d. 5 d/wk), plus oral etoposide (50 mg b.i.d. 30 min before thoracic RT for 10 days, repeated on Day 29) and cisplatin (50 mg/m2 i.v. on Days 1, 8, 29, and 36). Arm 2 patients received the same treatment plus amifostine (500 mg i.v. 20-30 min before any treatment the first 2 days of each week). Acute effects were assessed using the National Cancer Institute Common Toxicity Criteria. RESULTS: Sixty-two patients were enrolled between November 1998 and January 2001. The minimal follow-up was 24 months, and the median follow-up of living patients was 31 months. The patient and tumor characteristics were equally distributed between the patients in the two arms. The median survival time was 20 months in Arm 1 patients and 19 months in Arm 2 patients. The maximal esophageal toxicity was mild (Grade 1) in 23%, moderate (Grade 2) in 42%, and severe (Grade 3-4) in 35% of patients in Arm 1; the corresponding rates for the Arm 2 patients were 48%, 35%, and 16% (p = 0.021). Severe pneumonitis occurred in 16% of the Arm 1 and none of the Arm 2 patients (p = 0.020, chi-square test). Neutropenic fever occurred in 39% of Arm 1 and 16% of Arm 2 patients (p = 0.046, chi-square test). Mild hypotension, dysgeusia, and sneezing were significantly more frequent among the patients in Arm 2. CONCLUSION: Amifostine reduced the severity and incidence of acute esophageal, pulmonary, and hematologic toxicity resulting from concurrent cisplatin-based chemotherapy and RT. Amifostine had no apparent effect on survival in these patients with unresectable non-small-cell lung cancer, suggesting that it does not have a tumor-protective effect.     

Phase II study of three-dimensional conformal radiotherapy and concurrent mitomycin-C,vinblastine, and cisplatin chemotherapy for Stage III locally advanced,unresectable, non-small-cell lung cancer

PURPOSE: To evaluate the feasibility, treatment outcome, and toxicity of hyperfractionated three-dimensional conformal radiotherapy (CRT) and concurrent mitomycin-C, vinblastine, and cisplatin (MVP) chemotherapy in locally advanced, unresectable, Stage III non-small-cell lung cancer (NSCLC). METHODS AND MATERIALS: Between August 1993 and December 1996, 161 patients with unresectable Stage III NSCLC were entered into this trial, and 146 (91%) completed the treatment. Hyperfractionated RT was given to a total dose of 64.8-70 Gy (1.2 Gy/fraction, b.i.d.) with two cycles of concurrent MVP chemotherapy (mitomycin-C 6 mg/m(2) on Days 2 and 29, vinblastine 6 mg/m(2) on Days 2 and 29, and cisplatin 60 mg/m(2) on Days 1 and 28). Of the 146 patients who completed the treatment, 78 received noncoplanar three-dimensional CRT using 4-6 fields and 17 received coplanar-segmented CRT. The clinical tumor response was assessed 1 month after RT completion by CT. Toxicity was graded using the Southwestern Oncology Group criteria. The normal tissue complication probability for the lung was calculated to determine the correlation with radiation pneumonitis, if any. Nineteen (13%) had Stage IIIA and 127 (87%) had IIIB disease, including 16 patients with pleural effusion and 20 with supraclavicular lymph node metastasis. RESULTS: The response rate was 75%, composed of 22% complete responders and 53% partial responders. With a minimal follow-up of 45 months, the overall survival rate was 51.2% at 1 year, 25.1% at 2 years, and 14.8% at 5 years; the median survival was 12 months. Patients achieving a complete response (n = 32) had a 2-year overall survival rate of 49.8% and a 5-year survival rate of 39.2% compared with 22.5% and 11.4%, respectively, for the partial responders (n = 78; p = 0.0001). The actuarial local progression-free survival rate for all patients was 65.4% at 1 year, 42.1% at 2 years, and 36.3% at 4 years, and the actuarial distant-free survival rate was 65.4% at 1 year, 42.1% at 2 years, and 36.2% at 5 years. Severe weight loss (>10%) occurred in 20 (13.7%) of the 146 patients during treatment, 42 patients (29%) developed radiation pneumonitis (29 Grade 1 and 13 Grade 2). The average normal tissue complication probability value of the patients who had radiation pneumonitis was significantly greater than that of patients without pneumonitis (66.0% vs. 26.4%). Four patients died of treatment-related toxicity. CONCLUSION: Hyperfractionated three-dimensional CRT and concurrent chemotherapy, as described here, is a well-tolerated regimen with acceptable toxicity. More effective treatment schemes are required to improve local disease control and overall survival.     

Induction chemotherapy with carboplatin/paclitaxel followed by surgery or standard radiotherapy and concurrent daily low-dose cisplatin for locally advanced non-small cell lung cancer (NSCLC)

Five-year survival in patients with unresectable non-small-cell lung cancer (NSCLC) is less than 10%. In the present phase II study, 43 patients with locally advanced stage IIIA or selected IIIB NSCLC were given four courses of carboplatin AUC = 6 and paclitaxel 200 mg/m2 (3-hour infusion), every 3 weeks. Responsive patients, when possible, underwent surgery followed by standard radiotherapy (50 Gy) or radiotherapy (60 Gy), with concurrent cisplatin as intravenous continuous infusion of 4 mg/m2/d. Sixteen of the 42 evaluable patients achieved partial response (38%) and 3 complete response (CR) (7%) for an overall response rate of 45% (95% CI 30.1-60.2). R0 resectability rate was 29%, with 21% of pathologic CRs. Three more CRs were achieved with concurrent chemoradiotherapy in responsive but unresected patients. Grade III/IV hematologic toxicity was 9%, while one perioperative death occurred. The median duration of response was 14 months (range: 3-44+); median survival was 15 months (range: 9-47+). One-year and 2-year survival rates were 51% and 22%, respectively. The median survival in the responsive resected patients was 26 months, with 2-year survival of 57%. Carboplatin/paclitaxel represents an effective and well-tolerated induction therapy, suggesting its possible role in combination with radiotherapy as neoadjuvant treatment in locally advanced NSCLC in alternative to cisplatin-based regimens.     

Organ preservation in patients with invasive bladder cancer: initial results of an intensified protocol of transurethral surgery and radiation therapy plus concurrent cisplatin and 5-fluorouracil

To assess safety, tolerance, and disease control of transurethral resection of the bladder tumor (TURB) plus concurrent cisplatin, 5-fluorouracil (5-FU), and radiation therapy (RT) with selective organ preservation in patients with bladder cancer.

Forty-five patients with muscle-invading or high-risk T1 (G3, associated carcinoma in situ, multifocality, >5 cm) bladder cancer were entered into a protocol of TURB followed by concurrent cisplatin (20 mg/m²/day, 20-min infusion) and 5-FU (600 mg/m²/day, 120-hour continuous infusion), administered on Day 1–5 and 29–33 of RT (single dose 1.8 Gy, total dose to the bladder 54–59.4 Gy). Response was evaluated by restaging TURB 6 weeks later. In case of invasive residual or recurrent tumor, salvage cystectomy was recommended. Median follow-up was 35 months (range: 8–80 months).

Thirty-nine patients (87%) had no detectable tumor at restaging TURB; 29 patients (64%) have been continuously free of tumor in their bladders. A superficial relapse occurred in 4 patients, a muscle-invasive relapse in 6 patients. Overall survival and survival with preserved bladder was 67% and 54%, respectively, at 5 years. Hematologic Grade 3/4 toxicity occurred in 10%/4%; Grade 3 diarrhea occurred in 9%. Thirty-four patients (76%) completed the protocol as scheduled or with only minor deviations. One patient required salvage cystectomy because of a shrinking bladder.

Conclusion: This protocol of concurrent cisplatin/5-FU and RT has been associated with acceptable toxicity. The complete response rate of 87% and the 5-year survival with intact bladder of 54% are encouraging and compare favorably with our historical control series using RT with carboplatin and cisplatin alone.     

Prospective trial of concurrent chemoradiotherapy with protracted infusion of 5-fluorouracil and cisplatin for T4 esophageal cancer with or without fistula

PURPOSE: A prospective trial of concurrent chemoradiotherapy (CT-RT) with a protracted infusion of 5-fluorouracil and cisplatin was performed to evaluate the safety and efficacy of this protocol for T4 esophageal cancer (UICC 1997). METHODS AND MATERIALS: Between 1998 and 2000, 28 patients with T4 esophageal squamous cell carcinomas were treated with concurrent CT-RT. Of the 28 patients, 15 had Stage III, 5 Stage IVA, and 8 Stage IV disease. Five of the T4 tumors had evidence of fistula before treatment. Patients received a protracted infusion of 5-fluorouracil 300 mg/m(2)/24 h on Days 1-14, a 1-h infusion of cisplatin 10 mg/body on Days 1-5 and 8-12, and concurrent radiation at a dose of 30 Gy in 15 fractions during 3 weeks. This schedule was repeated twice, with a 1-week split, for a total RT dose of 60 Gy during 7 weeks for 25 patients. For the remaining 3 patients, 30 Gy of preoperative CT-RT was administered. RESULTS: Of the 25 patients who were treated with the full dose of CT-RT, 14 (56%) completed the two courses of the CT-RT protocol, and 8 patients (32%) received the full dose of RT but a reduced dose of chemotherapy. Eight (32%) of the 25 tumors showed complete regression. Although Grade 3 hematologic toxicities were frequently noted, Grade 4 or more hematologic toxicities were few. Of the 5 T4 fistulous tumors, 2 demonstrated the disappearance of the fistula after CT-RT. However, the worsening or development of an esophageal fistula was noted in 5 patients. The 2-year survival rate for patients with Stage III was 27%, and the median survival time for those with Stage III and Stage IVA+IV was 12 and 5 months, respectively. CONCLUSION: Despite its significant toxicity for esophageal fistula, this concurrent CT-RT protocol of protracted 5-fluorouracil infusion and cisplatin appears feasible and effective for T4 esophageal cancer with or without fistulas.     

Using treatment interruptions to palliate the toxicity from concurrent chemoradiation for limited small cell lung cancer decreases survival and disease control

BACKGROUND AND PURPOSE: We analyzed the impact on survival outcomes of treatment interruptions due to toxicity arising during the concurrent phase of chemotherapy/radiotherapy (ChT/RT) for our limited-stage small-cell cancer (LSCLC) population over the past 10 years. MATERIALS AND METHODS: From 1989 to 1999, 215 patients received treatment for LSCLC, consisting of six cycles of alternating cyclophosphamide/doxorubicin or epirubicin/vincristine (CAV; CEV) and etoposide/cisplatin (EP). Thoracic RT was started with EP at either the second or third cycle (85% of patients). RT dose was either 40 Gy in 15 fractions over 3 weeks or 50 Gy in 25 fractions over 5 weeks, delivered to a target volume encompassing gross disease and suspected microscopic disease with a 2 cm margin. Treatment breaks arising during concurrent ChT+RT were used to manage severe symptomatic or hematologic toxicities. We used the interruptions in thoracic RT as the 'marker' for any concurrent break and measured 'break duration' by the total length of time (in days) RT was interrupted, since that also signaled that ChT could be re-initiated. Patient results were analyzed for the impact of interruptions/treatment prolongation on overall and disease-free survival. RESULTS: For all patients, 2-year and 5-year overall and disease-specific survivals were 22.7 and 7.2, 27.6 and 9.3%, respectively; overall and disease-specific median survivals were 14.7 months each. A total of 56 patients (26%) had treatment breaks due to toxicity. Hematologic depression caused the majority of breaks (88%). The median duration of breaks was 5 days (range 1-18). Patients with and without interruptions were compared for a range of prognostic factors and were not found to have any significant differences. Comparing interrupted/uninterrupted courses, median survivals were 13.8 versus 15.6 months, respectively, and 5-year overall survivals were 4.2 versus 8.3%, respectively. There was a statistical difference between overall survival curves which favored the uninterrupted group (P=0.01). When comparing a series of prognostic variables, multivariable analysis found that the most significant factor influencing survival in the present study was the presence of treatment breaks (P=0.006). There was a trend for development of any recurrence in the patients with breaks (P=0.08). When controlling for the use of prophylactic cranial irradiation (PCI) in the two groups, the rate of failure in the chest was higher in the patients with RT breaks (58 vs. 33%). The rate of failure in the brain was dependent on the use of PCI only. CONCLUSIONS: Interruptions in treatment to palliate the toxicity from concurrent chemoradiation result in poorer local control and decreased survival.     

Phase II study of radiotherapy with three-dimensional conformal boost concurrent with paclitaxel and cisplatin for Stage IIIB non-small-cell lung cancer

PURPOSE: To evaluate the efficacy and toxicity of concurrent chemoradiotherapy with paclitaxel/cisplatin for Stage IIIB locally advanced non-small-cell lung cancer (NSCLC). METHODS AND MATERIALS: Radiotherapy was administered to a total dose of 70.2 Gy (daily fraction of 1.8 Gy, 5 days/wk), over an 8-week period, combined with chemotherapy. The chemotherapy consisted of weekly 40 mg/m2 of paclitaxel plus 20 mg/m2 of cisplatin for 8 consecutive weeks. All patients received three-dimensional conformal radiotherapy (3D-CRT), based on computed tomography simulated planning after 41.4 Gy. The median follow-up period of survivors was 24 months. RESULTS: Between January 2000 and October 2002, 135 patients with a median age of 60 years were enrolled and analyzed in this prospective trial. The overall response rate was 75% including 2 cases of complete response. The major patterns of failure were local failure and distant metastasis. The 2-year overall and progression-free survival rates were 37% and 18%, respectively. The median overall and progression-free survival times were 17 months and 9 months, respectively. Hematologic toxicity >Grade 2 was observed in 19% of patients and severe non-hematologic toxicity was infrequent. CONCLUSIONS: Three-dimensional conformal radiotherapy, combined with paclitaxel and cisplatin chemotherapy, was associated with a satisfactory outcome with manageable toxicity. Further investigations are needed to improve the local control.     

Concurrent hyperfractionated radiotherapy and low-dose daily carboplatin/paclitaxel in patients with early-stage (I/II) non-small-cell lung cancer: long-term results of a phase II study.

PURPOSE: Feasibility and activity of concurrent hyperfractionated radiotherapy (Hfx RT) and low-dose, daily carboplatin and paclitaxel were investigated in patients with early-stage (I/II) non-small-cell lung cancer in a phase II study. PATIENTS AND METHODS: Fifty-six patients started their treatment on day 1 with 30 mg/m2 of paclitaxel. Hfx RT using 1.3 Gy bid to a total dose of 67.6 Gy and concurrent low-dose daily carboplatin 25 mg/m2 and paclitaxel 10 mg/m2, both given Mondays through Fridays during the RT course, started from the second day. RESULTS: There were 29 complete responses (52%) and 15 partial responses (27%), and 12 patients (21%), experienced stable disease. The median survival time was 35 months, and 3- and 5-year survival rates were 50% and 36%, respectively. The median time to local progression has not been achieved, but 3- and 5-year local progression-free survival rates were 56% and 54%, respectively. The median time to distant metastasis has not been achieved, but 3- and 5- year distant metastasis-free survival rates were 61% and 61%, respectively. The median and 5-year cause-specific survivals were 39 months and 43%, respectively. Acute high-grade (> 3) toxicity was hematologic (22%), esophageal (7%), or bronchopulmonary (7%). No grade 5 toxicity was observed. Late high-grade toxicity was rarely observed (total, 10%). CONCLUSION: Hfx RT and concurrent low-dose daily carboplatin/paclitaxel was feasible with low toxicity and effective in patients with stage I/II non-small-cell lung cancer. It should continue to be investigated for this disease.     

Twice-daily radiotherapy as concurrent boost technique during two chemotherapy cycles in neoadjuvant chemoradiotherapy for resectable esophageal carcinoma: mature results of phase II study

PURPOSE: To determine the toxicities of neoadjuvant chemoradiotherapy using a three-drug regimen (cisplatin, 5-fluorouracil, and paclitaxel) and a conventional radiotherapy (RT) schedule combined with a concurrent boost technique during chemotherapy cycles, and to determine the rate of tumor response, overall survival, and impact of pathologic tumor response on survival. METHODS AND MATERIALS: The eligibility criteria included resectable adenocarcinoma or squamous cell carcinoma (T2-T3N0-N1M0), performance score < or =2, and no significant comorbidities for trimodality therapy. Chemotherapy consisted of two cycles of cisplatin, 5-fluorouracil, and paclitaxel. A concurrent boost technique was used in RT for 2 levels of radiation doses: 58.5 Gy in 34 fractions within 5 weeks to the gross tumor volume and 45 Gy in 25 fractions within 5 weeks to the clinical target volume by administering a boost dose of 13.5 Gy in 9 fractions, 1.5 Gy/fraction, as a second daily fraction for 9 days on Days 1-5 and 29-32 of the chemotherapy cycles. RESULTS: We enrolled 46 patients in the study. The paclitaxel dose was started at 75 mg/m(2) (n = 7) and escalated to 125 mg/m(2) (n = 5), at which point, dose-limiting toxicities occurred. Thereafter, paclitaxel at 100 mg/m(2) was used for an additional 34 patients. Toxicities included Grade 4 neutropenia (22%), febrile neutropenia requiring hospital admission (20%), Grade 3 (48%) and Grade 4 (7%) acute esophagitis, and paclitaxel-associated anaphylaxis (4%). Of the 46 patients, 3 (6.5%) died of treatment-related complications, 1 of pneumonia during induction therapy and 2 of postoperative complications (5% of the 40 patients who underwent resection). The histopathologic tumor response was a pathologic complete response (pT0N0) in 18 (45%) of 40 patients who underwent resection and 18 (39%) of all 46 registered patients. Minimal residual disease (pT1N0) at the primary site was present in 5 (11%) and residual disease in 23 (50%) of all 46 patients. The minimal follow-up for all long-term survivors (n = 16) was 5.5 years. The median survival time was 34 months, and the overall survival rate was 57%, 50%, and 37% at 2, 3, and 5 years, respectively. The 5-year overall survival (56% vs. 24%, p = 0.0214) and disease-free survival (48% vs. 6%) were significantly better statistically for patients with a pathologic complete response and minimal residual disease than for those with residual disease. All long-term survivors beyond 5.5 years without recurrence accrued from patient cohorts with a pathologic complete response or minimal residual disease. CONCLUSION: An incorporation of twice-daily RT as a concurrent boost to the conventional daily RT schedule during chemotherapy cycles is feasible and warrants additional study for radiation dose intensification. Such research would be prudent for both improved long-term survival and organ preservation in esophageal carcinoma.     

Split-course versus continuous thoracic radiation therapy for limited-stage small-cell lung cancer: final report of a randomized phase III trial

The optimal integration of radiation and chemotherapy for limited-stage small-cell lung cancer (SCLC) remains unclear. This phase III trial was conducted to determine whether chemotherapy plus interdigitating split-course thoracic radiation therapy (RT) improved survival compared with standard-dose continuous thoracic RT. One hundred fourteen patients were randomized to receive 50 Gy thoracic RT delivered in 2.0-Gy fractions given continuously (5 weeks) concurrent with the first 2 cycles of chemotherapy (arm A) or 50 Gy delivered via an interdigitating split course in 2.5-Gy fractions (8 weeks) concurrent with the first 3 cycles of chemotherapy (arm B). During the split-course RT, once-daily radiation was delivered on days 8-17 of each of the first two 21-day cycles and days 8-11 of the third 21-day cycle. All patients received the following chemotherapy: cisplatin/etoposide on cycles 1, 2, and 5 and cyclophosphamide/vincristine/doxorubicin on cycles 3, 4, and 6. Prophylactic cranial irradiation was recommended after a complete response to all therapy. One hundred ten eligible patients were randomized. Grade 3/4 esophagitis was reported in 9% of patients receiving continuous thoracic RT versus 4% of patients receiving split-course RT. Grade 3/4 hematologic toxicity was common in both treatment arms. Complete/partial response was observed in 80% of patients on arm A versus 84% on arm B. Overall survival rates at 5 years were 18% and 17% for arms A and B, respectively. Interdigitating split-course thoracic RT delivered in 2.5-Gy fractions was tolerable in patients with limited-stage SCLC but did not provide a survival advantage.     

Induction chemotherapy followed by concurrent chemotherapy and definitive high-dose radiotherapy for patients with locally advanced non-small-cell lung cancer (stages IIIa/IIIb): a pilot phase I/II trial.

BACKGROUND: Overall prognosis of patients with locally advanced non-small-cell lung cancer (LAD-NSCLC) is still unfavourable. Different attempts to improve treatment results have been made using combinations of chemotherapy and radiotherapy. The aim of this pilot phase I/II investigation was to test the feasibility and toxicity of a definitive multimodality protocol in patients with irresectable NSCLC stages IIIA (N2) and IIIB. PATIENTS AND METHODS: Thirty LAD-NSCLC patients (stages IIIA/IIIB: 3/27; median age: 54 years, range 34-70; male/female: 17/13) who were consecutively enrolled onto our ongoing neoadjuvant multimodality protocol from October 1996 to February 1999 remained inoperable after induction treatment. Three cycles of cisplatin/etoposide (PE) were followed by hyperfractionated accelerated radiotherapy (HF-RTx: 1.5 Gy bid up to a total dose of 45 Gy in 3 weeks) concurrent with one cycle of PE. Definitive local treatment was completed with a small volume boost of 20 Gy (qd), adding up to a total dose of 65 Gy to the primary. Patients were routinely offered prophylactic cranial irradiation (PCI; 30 Gy; 2 Gy qd). RESULTS: Overall toxicity of the definitive CTx/RTx protocol-the main endpoint of this investigation-turned out to be acceptable (oesophagitis grade 3/4: 6/4 patients; pneumonitis grade 3/4: 0/1 patients; no treatment-related deaths). Actuarial survival at 2 years was 31% with a loco-regional control rate of 21%. CONCLUSIONS: This regimen turned out to be feasible with acceptable toxicity and will serve as a reference arm in a planned randomised trial in stage IIIB NSCLC, testing the value of surgery in this setting: preoperative induction CTx/RTx followed by surgery versus definitive CTx/RTx.