Prospective randomised study of split-course radiotherapy versus cisplatin plus split-course radiotherapy in inoperable squamous cell carcinoma of the oesophagus

Between 1983 and 1989, 211 patients with inoperable squamous cell carcinoma of the oesophagus were randomised in a study comparing split-course irradiation (two courses of 20 Gy in five fractions of 4 Gy, separated by a rest of 2 weeks) (arm A) and the same split-course irradiation in combination with cisplatin (CDDP) (3-4 days before each of the two courses of radiotherapy, repeated every 3-4 weeks, for a total of six cycles) (arm B). The Cox's regression model with retrospective stratification was used to compare the two arms to correct for the imbalance at randomisation of the T classification. The median overall survival was 7.9 (95% confidence interval (CI) 7.3-9.4) months in arm A and 9.6 (95% CI 8-13.5) months in arm B. The difference in overall survival was only borderline significant (P=0.048) with a reduction of the instantaneous rate of death of 24%. The 1 and 2 year overall survival rate were respectively 29% (95% CI 21-37%) and 15% (95% CI 8-22%) in arm A and 45% (95% CI 36-54%) and 20% (95% CI 13-27%) in arm B; thereafter, the survival curves became similar. The median progression free survival (PFS) was 5.0 (95% CI 4.6-5.7) versus 6.9 (95% CI 5.3-8.7) months (P=0.028) and the median time to local progression was 6.2 (95% CI 5.1-7.6) months versus 10.9 (95% CI 8.1-15.5) months (P=0.018), respectively, in arms A and B. Haematological toxicities were slightly more commonly observed in the combined group (1% versus 6%). This study shows that split-course irradiation in combination with CDDP is very well tolerated and should be preferred to radiotherapy alone.     

Radiotherapy versus chemotherapy plus radiotherapy in surgically treated IIIA N2 non-small-cell lung cancer

Preoperative chemotherapy in patients with stage III non-small-cell lung cancer (NSCLC) remains controversial. Phase II trials utilizing preoperative chemotherapy in selected patients have achieved complete resection rates of 50%-70% with 3-5 year failure-free survival rates of 15%-33%. Between October 1992 and November 1994, 57 adults (50 of whom were evaluable) with surgically staged IIIA NSCLC and pathologically documented ipsilateral mediastinal nodal involvement (N2) were enrolled in a Cancer and Leukemia Group B randomized trial. Preoperative therapy was thought to be critical to facilitating surgical resectability. For patients randomized to the radiotherapy/surgery/radiotherapy (RSR) arm (n = 24), treatment consisted of preoperative radiation therapy (RT) at 40 Gy, surgery, and then additional RT at 14-20 Gy. For patients randomized to the chemotherapy/surgery/chemotherapy/radiotherapy (CSCR) arm (n = 26), treatment consisted of 2 cycles of cisplatin/etoposide with filgrastim support (PE) followed by surgery, 2 more cycles of PE, then RT 54-60 Gy. The total dose of RT on either arm was 54 Gy if completely resected or 60 Gy if incompletely resected or unresected. Clinical characteristics were well balanced between the two arms. Thoracotomy was performed in 42 patients (84%), 28 (67%) of whom had complete resection. The median failure-free and overall survival rates were 12 months (95% confidence interval [CI], 9-23 months) and 23 months (95% CI, 19 months-infinity) for the RSR arm and 11 months (95% CI, 5-20 months) and 18 months (95% CI, 12-32 months) for the CSCR arm. The rates of overall and complete surgical resection, downstaging of nodal involvement, and failure-free (P = 0.92) and overall survival (P = 0.41) did not differ between the two treatment arms. Moreover, in this trial, the chemotherapy regimen was sufficiently toxic to have had a lower completion rate of prescribed therapy in the CSCR arm than in the RSR arm.     

Randomized trial of postoperative adjuvant therapy in stage II and III rectal cancer to define the optimal sequence of chemotherapy and radiotherapy: a preliminary report.

PURPOSE: We conducted a prospective randomized trial to define the optimal sequence of chemotherapy and radiotherapy of postoperative adjuvant treatment in stage II and III rectal cancer. PATIENTS AND METHODS: Three hundred eight patients were enrolled onto the study. We randomly assigned 155 to arm I (early radiotherapy group) and 153 to arm II (late radiotherapy group). Treatment included eight cycles of chemotherapy at 4-week intervals and pelvic radiotherapy of 45 Gy in 25 fractions. Radiotherapy started on day 1 of the first chemotherapy cycle in arm I and on day 1 of the third chemotherapy cycle in arm II. The chemotherapy regimen consisted of fluorouracil 375 mg/m(2)/d and leucovorin 20 mg/m(2)/d. Chemotherapy was administered for 3 days per cycle in two cycles during the period of radiotherapy and for 5 days per cycle in the remaining six cycles. RESULTS: Twenty patients in arm I and 14 in arm II were not eligible. We included 274 patients in the analysis. With a median follow-up of 37 months for surviving patients, disease-free survival was significantly prolonged in arm I compared with arm II (81% v. 70% at 4 years; P =.043). Twenty-three recurrences occurred in arm I and 38 in arm II (P =.047). Overall survival was not significantly different between arms I and II (84% v. 82% at 4 years; P =.387). CONCLUSION: Early radiotherapy with concurrent chemotherapy after resection of stage II and III rectal cancer demonstrated a statistically significant advantage for disease-free survival compared with late radiotherapy with chemotherapy.     

A randomised trial of high-dose chemotherapy in the salvage treatment of patients failing first-line platinum chemotherapy for advanced germ cell tumours.

BACKGROUND: Incomplete remission or relapse from first-line chemotherapy has poor prognosis in male germ cell tumour patients. This phase III randomised trial compares conventional salvage to high-dose-intensification chemotherapy. PATIENTS AND METHODS: Between February 1994 and September 2001, 280 patients from 43 institutions in 11 countries, were randomly assigned to receive either four cycles of cisplatin, ifosfamide and etoposide (or vinblastine) (arm A), or three such cycles followed by high-dose carboplatin, etoposide and cyclophosphamide (CarboPEC) with haematopoietic stem cell support (arm B). RESULTS: Similar complete and partial response rates were observed in both treatment arms (56%; 95% CI 50% to 62%). There were 3% and 7% toxic deaths in arms A and B, respectively. No significant improvements with CarboPEC were observed in either 3-year event-free survival (35% versus 42%, P=0.16) or overall survival (53%; 95% CI 46% to 59%). Complete responders with CarboPEC had a significant improvement in disease-free survival (55% versus 75% at 3 years, P <0.04). CONCLUSIONS: The single cycle of high-dose salvage chemotherapy after three cycles of standard dose chemotherapy had no effect on treatment outcomes. These results suggest that data from uncontrolled studies should not be used to justify routine use of a toxic and expensive treatment without confirmation in a randomised trial.     

Radiotherapy with concomitant weekly docetaxel for Stages III/IV oropharynx carcinoma. Results of the 98-02 GORTEC Phase II trial

PURPOSE: We designed a prospective Phase II clinical trial to evaluate the addition of weekly chemotherapy using Docetaxel during standard radiation therapy in patients with Stages III and IV oropharynx carcinoma. METHODS: A total of 63 patients have been entered in a Phase II multicenter trial. Radiotherapy delivered, with conventional fractionation, 70 Gy in 35 fractions. Patients received during the period of radiotherapy seven cycles of Docetaxel (20 mg/m2 each week). RESULTS: Radiotherapy compliance was good in respect to total dose, treatment duration, and treatment interruption. The rate of Grade 3 and 4 mucositis was 84%. Grade 3 and 4 skin toxicity occurred in 53% of the patients. Hematologic toxicity was infrequent, with only a 5% rate of Grade 3 or 4 neutropenia. Three-year overall actuarial survival and disease-free survival rates were, respectively, 47% (95% CI = 39-68%) and 39% (95% CI = 30-57%). The local and regional control rate was 64%. CONCLUSION: The adjunction of weekly Docetaxel to conventional radiotherapy is feasible. Mucositis and skin toxicity were the major acute toxic effects. Therapeutic results were similar to those observed with concomitant chemotherapy using platinum and/or 5-FU. Further trials using Docetaxel in combination with other cytotoxic agents are needed.     

Accelerated versus standard cyclophosphamide, epirubicin and 5-fluorouracil or cyclophosphamide, methotrexate and 5-fluorouracil: a randomized phase III trial in locally advanced breast cancer.

BACKGROUND: The purpose of this study was to evaluate the impact of a dose-dense primary chemotherapy on pathological response rate (pCR) in patients with locally advanced breast cancer (LABC) treated with combined modality therapy. PATIENTS AND METHODS: Stage IIIA/IIIB patients received three courses of induction chemotherapy (ICT) with cyclophosphamide, epirubicin and 5-fluorouracil (CEF) followed by local therapy (total mastectomy or segmental mastectomy with axillary nodes dissection) and adjuvant chemotherapy (ACT) with three courses of CEF alternated with three courses of cyclophosphamide, methotrexate, 5-fluorouracil (CMF). Patients were randomized to receive ICT and ACT every 3 weeks (arm A, 'standard treatment') or every 2 weeks with granulocyte-macrophage colony-stimulating factor (GM-CSF) support (arm B, 'dose-dense treatment'). In both arms radiotherapy was administered after the end of chemotherapy (in selected cases) and patients with hormonal receptor-positive tumors received tamoxifen for 5 years. RESULTS: A total of 150 patients were randomized (77 arm A and 73 arm B) and demographics were well balanced between the two arms. Compliance to treatment was excellent: 95% and 93% of patients in arms A and B, respectively, completed the treatment program with no modification or delay. Median duration of treatment (ICT+local+ACT) was 183 days (range 0-265) in arm A and 139 days (0-226) in arm B. The average relative dose intensity (ARDI) of chemotherapy was 1.3 with a 30% increase in the dose intensity in arm B in comparison with arm A. No difference in clinical [62%; 95% confidence interval (CI) 49% to 73.2%] and pathological response rates to ICT was observed between the two arms. Median follow-up was 5 years (range 1-96 months); median disease-free survivals were 4.8 years in arm A and 4.5 years in arm B. Median overall survival was 7.8 years in standard therapy: this figure has not yet been reached in the dose-dense treatment. CONCLUSIONS: In LABC a dose-dense regimen, while allowing a 30% increase in the dose intensity of chemotherapy, did not provide significant improvement in pathological response rates. However, accelerated chemotherapy reduced the duration of the combined-modality program (6.1 versus 4.6 months) with no additional toxicities.     

CODEL: phase III study of RT,RT + TMZ,or TMZ for newly diagnosed 1p/19q codeleted oligodendroglioma. Analysis from the initial study design

BackgroundWe report the analysis involving patients treated on the initial CODEL design.MethodsAdults (>18) with newly diagnosed 1p/19q World Health Organization (WHO) grade III oligodendroglioma were randomized to radiotherapy (RT; 5940 centigray ) alone (arm A); RT with concomitant and adjuvant temozolomide (TMZ) (arm B); or TMZ alone (arm C). Primary endpoint was overall survival (OS), arm A versus B. Secondary comparisons were performed for OS and progression-free survival (PFS), comparing pooled RT arms versus TMZ-alone arm.ResultsThirty-six patients were randomized equally. At median follow-up of 7.5 years, 83.3% (10/12) TMZ-alone patients progressed, versus 37.5% (9/24) on the RT arms. PFS was significantly shorter in TMZ-alone patients compared with RT patients (hazard ratio [HR] = 3.12; 95% CI: 1.26, 7.69; P = 0.014). Death from disease progression occurred in 3/12 (25%) of TMZ-alone patients and 4/24 (16.7%) on the RT arms. OS did not statistically differ between arms (comparison underpowered). After adjustment for isocitrate dehydrogenase (IDH) status (mutated/wildtype) in a Cox regression model utilizing IDH and RT treatment status as covariables (arm C vs pooled arms A + B), PFS remained shorter for patients not receiving RT (HR = 3.33; 95% CI: 1.31, 8.45; P = 0.011), but not OS ((HR = 2.78; 95% CI: 0.58, 13.22, P = 0.20). Grade 3+ adverse events occurred in 25%, 42%, and 33% of patients (arms A, B, and C). There were no differences between arms in neurocognitive decline comparing baseline to 3 months.ConclusionsTMZ-alone patients experienced significantly shorter PFS than patients treated on the RT arms. The ongoing CODEL trial has been redesigned to compare RT + PCV versus RT + TMZ.     

Hypofractionated accelerated radiotherapy with concurrent chemotherapy for locally advanced squamous cell carcinoma of the head and neck

PURPOSE: To investigate the tumor control rates in locally advanced head-and-neck cancer using accelerated hypofractionated radiotherapy with chemotherapy. METHODS AND MATERIALS: The data from patients with squamous cell cancer of the larynx, oropharynx, oral cavity, and hypopharynx (International Union Against Cancer Stage II-IV), who received accelerated hypofractionated radiotherapy with chemotherapy between January 1, 1998, and April 1, 2005, were retrospectively analyzed. Two different chemotherapy schedules were used, carboplatin and methotrexate, both single agents administered on an outpatient basis. The endpoints were overall survival, local control, and disease-free survival. RESULTS: A total of 81 patients were analyzed. The 2-year overall survival rate was 71.6% (95% confidence interval [CI], 61.5-81.8%). The 2-year disease-free survival rate was 68.6% (95% CI, 58.4-78.8%). The 2-year local control rate was 75.4% (95% CI, 65.6-85.1%). When excluding patients with Stage II oral cavity, larynx, and hypopharynx tumors, 68 patients remained. For these patients, the 2-year overall survival, local control, and disease-free survival rate was 67.6% (95% CI, 56.0-79.2%), 72.0% (95% CI, 61.0-83.0%), and 64.1% (95% CI, 52.6-75.7%), respectively. CONCLUSION: Accelerated hypofractionated radiotherapy and synchronous chemotherapy can achieve high tumor control rates while being resource sparing and should be the subject of prospective evaluation.     

The role of radiation therapy in the treatment of testicular germ cell tumors.

Infradiaphragmatic radiotherapy remains the treatment of choice for patients with stage I and II (small volume) testicular seminoma. With this approach, the disease-free survival rate exceeds 90% to 95%, and the ultimate disease-free survival rate (including salvage) is 95% to 100%. Initial therapy for patients with large-volume stage II, III, and IV disease should include multiagent systemic chemotherapy. Involved field radiotherapy is recommended for these patients following the chemotherapy, especially in patients with residual masses larger than a few centimeters. Although not used frequently in the United States, infradiaphragmatic radiotherapy is a viable treatment option for patients with clinical stage I testicular nonseminomas. Such therapy results in approximately an 85% to 90% relapse-free survival rate, with an ultimate survival rate (including salvage) approaching 100%. Initial therapy for patients with stage II or greater disease generally should include chemotherapy and/or surgery. Radiotherapy is often useful as post-chemotherapy consolidation, especially for unresectable masses. For extra-gonadal seminomas, radiotherapy is useful as definitive therapy for small-volume disease and as consolidative therapy (postchemotherapy) for more advanced disease.     

The Scottish and Manchester randomised trial of neo-adjuvant chemotherapy for advanced cervical cancer

204 eligible patients were entered into a multicentre randomised trial of neo-adjuvant chemotherapy prior to radical radiotherapy. The aim of this study was to assess whether there was any survival advantage in patients undergoing chemotherapy and radiotherapy compared with those given radiotherapy alone. Patients were aged up to 70 years, performance status 0-1/2, with bulky stage IIb, stage III or stage IVa squamous or adenosquamous carcinoma. Three cycles of methotrexate 100 mg/m2 and cisplatin 50 mg/m2 were given at 2-weekly intervals before radical radiotherapy. 104 eligible patients received the combination treatment and 100 radiotherapy only. The two arms of the study were well balanced for tumour and patient characteristics. The response rate to chemotherapy was 49%, 33% of patients in the radiotherapy (XRT) alone arm and 45% of the combination arm were clinically free of tumour at the end of treatment. The median follow-up for surviving patients is 5.4 years (range: 11 months-8 years) and 84% have been followed-up for more than 4 years. 134 patients have died (68 XRT only, 66 combined arm). The median survival RT alone was 111 weeks (95% confidence interval (CI) 72-151 weeks), combination arm 125 weeks (95% CI 79-170 weeks). The estimated death ratio is 0.79 (P = 0.19, 95% CI 0.56-1.12). The estimated 3-year survival is 40% (95% CI 30-50%) RT only compared with 47% (95% CI 37-57%) in the combination arm. Acute and late toxicity of radiotherapy was not increased by the addition of chemotherapy.     

Phase III trial comparing a defined duration of therapy versus continuous therapy followed by second-line therapy in advanced-stage IIIB/IV non-small-cell lung cancer.

PURPOSE: To compare four cycles of therapy versus continuous therapy to determine the optimal duration of chemotherapy in advanced non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Stage IIIB/IV NSCLC patients were randomized to arm A (four cycles of carboplatin at an area under the curve of 6 and paclitaxel 200 mg/m(2) every 21 days) or arm B (continuous treatment with carboplatin/paclitaxel until progression). At progression, all patients on both arms were to receive second-line weekly paclitaxel at 80 mg/m(2)/wk. The primary end points were survival and quality of life (QOL). RESULTS: Two hundred thirty patients were randomized. Fifty-seven percent of arm A patients completed four courses of therapy. In the 116 arm B patients, the median number of cycles delivered was four (range, zero to 19 cycles). Forty-two percent received five or more cycles; 18% received eight or more cycles. Overall response rates were 22% and 24% for arms A and B, respectively (P =.80). Median survival time and 1-year survival rates were 6.6 months and 28% for arm A and 8.5 months and 34% for arm B, respectively (log-rank P =.63). Rates of hematologic and nonhematologic toxicity were similar between the two arms, except for neuropathy. The rate of grade 2 to 4 neuropathy increased from 19.9% (95% confidence interval [CI], 13.6% to 26.2%) at cycle 4 to 43% (95% CI, 28.6% to 57.4%) at cycle 8. There were no differences in QOL. Only 45% of patients received second-line therapy (42% in arm A v 47% in arm B, P =.42). CONCLUSION: This study shows no overall benefit in survival, response rates, or QOL to continuing treatment with carboplatin/paclitaxel beyond four cycles in advanced NSCLC.     

Long-term results of conventional radiotherapy versus accelerated hyperfractionated radiotherapy versus concomitant radiotherapy and chemotherapy in locoregionally advanced carcinoma of the oropharynx

AIMS AND BACKGROUND: To compare conventional fractionation (CF) radiation therapy (RT), arm A, versus a split-course accelerated hyperfractionated schedule (S-AHF), arm B, versus CFRT plus concomitant chemotherapy (CT), arm C, in terms of five-year survival and toxicity for squamous cell tumors of the oropharynx. METHODS AND STUDY DESIGN: Between January 1993 and June 1998, 192 previously untreated patients with stage III and IV oropharyngeal carcinoma (excluding T1N1 and T2N1) were enrolled in a multicenter randomized phase III trial (ORO 93-01). In arms A and C, 66 to 70 Gy in 33 to 35 fractions was administered five days a week for six and a half to seven weeks. In arm B, the dose delivered was 64 to 67.2 Gy in two fractions of 1.6 Gy every day, five days a week, with a planned two-week split at 38.4 Gy. In arm C the CT regimen consisted of three cycles of carboplatin and 5-fluorouracil (CBDCA 75 mg/m2 on days 1 to 4 and 5-FU 1000 mg/m2 i.v. on days 1 to 4 every 28 days). RESULTS: No statistically significant difference was found in five-year overall survival (P = 0.39): 21% for arm A, 21% for arm B, and 40% for arm C. Similarly, there was no statistically significant difference in terms of five-year relapse-free survival: 15% for arm A, 17% for arm B, and 36% for arm C. There was a slight trend towards better five-year locoregional control (P = 0.07) for the combined arm: patients without locoregional relapse were 48% in arm C, 21% in arm A and 18% in arm B. Locoregional control was significantly better when arm C was compared with arms A and B combined (P = 0.02; arm A+B 20%; arm C 48%). Distant metastases were fairly balanced in the three arms (A: 14; B: 9; C: 11), with a tendency towards more frequent isolated distant metastasis development in arm C (8 of 11 [72%] versus 7 of 23 [30%] in arms A+B). Five-year second-tumor-free survival was 85%. The 13 second tumors were equally distributed and were mainly correlated with tobacco and alcohol consumption (five lung, two esophagus, two oral cavity, one larynx, one pancreas, one hepatocarcinoma, one myeloma). Arm C showed slightly more G3+ late side effects involving subcutaneous tissues and mucosa, although significant late sequelae were relatively uncommon and the mucosal side effects were mostly transient. The occurrence of persistent G3 xerostomia was comparable in the three treatment arms. CONCLUSIONS: The results obtained with the combination of CT and RT compared with RT alone did not reach statistical significance, but combined treatment almost doubled the five-year overall survival, relapse-free survival and locoregional control rate. Patients with advanced squamous cell carcinomas of the oropharynx who are medically suitable for the combined approach should be treated with a combination of radiotherapy and chemotherapy. The occurrence of second tumors is relatively common in these patients and may contribute substantially to the causes of death.     

Effects of different chemotherapy regimens on survival for advanced cervical cancer: systematic review and meta-analysis

BACKGROUND: A large number of trials have assessed various chemotherapy regimens for the treatment of advanced cervical cancer, but there is uncertainty about the magnitude of survival benefits. METHODS: We searched (last update January 2006) for trials in women with locally advanced or disseminated cervical cancer that compared neo-adjuvant or concurrent chemotherapy plus radiotherapy versus radiotherapy alone; or different chemotherapy regimens among themselves (with or without background radiotherapy in both arms). Sixty-five trials were identified with survival data on 11,180 women. Results for survival were combined with fixed and random effects models and between-study heterogeneity was estimated. Separate results were obtained for different regimens, cycle length, and type of chemotherapy (neo-adjuvant, concurrent, without radiotherapy). RESULTS: Twenty two comparisons had survival data on 3837 women randomized to receive chemotherapy plus radiotherapy versus radiotherapy alone; the summary relative hazard for mortality was 0.95, 95% CI, 0.83-1.08. Modest between-study heterogeneity (I2=38%) seemed to be due to contradictory results in early trials; trials published in the last decade had a summary relative hazard 0.89 (95% CI, 0.78-1.02) and no between-study heterogeneity (I2=0%). Results were similar for neo-adjuvant chemotherapy and for concurrent chemo-radiotherapy. Cisplatin or cisplatin-based combinations had no significant benefit overall, but a potential benefit was seen with short-length cycles (14 days) and a marginally significant harm with longer-length cycles (summary relative hazards 0.80, 95% CI, 0.66-0.99 and 1.18, 95% CI, 1.02-1.38, respectively). The summary relative hazard was 1.02, (95% CI, 0.84-1.24) for trials using neo-adjuvant chemotherapy and 0.85 (95% CI, 0.73-1.00) for trials using concurrent chemotherapy. CONCLUSIONS: Evidence on chemotherapy in women with advanced cervical cancer is not encouraging for major survival benefits. However, small benefits have been observed in some trials, especially with short-length cycles of cisplatin-based regimens and concurrent chemotherapy and radiotherapy.     

Randomized scheduling feasibility study of S-1 for adjuvant chemotherapy in advanced head and neck cancer

The purpose of this study was to determine the feasible adjuvant therapy administration schedule of S-1 for locoregionally advanced squamous cell carcinoma of the head and neck (SCCHN). Patients receiving definitive treatments were randomly assigned to either arm A (51 cases) receiving oral S-1 of 2-week administration followed by 1-week rest for 6 months, or arm B receiving S-1 of 4-week administration followed by 2-week rest for 6 months. Planned treatment was given in 40% of patients in arm A and 29% in arm B. The cumulative rates of the relative total administration dose of S-1 at 100% were 54.9% (95% CI: 40.1-69.7%) in arm A and 34.3% (95% CI: 21.1-47.4%) in arm B, respectively (P=0.054). Adverse events were recorded in 41 patients (82.0%) in arm A and 48 patients (94.1%) in arm B (P=0.060). The incidences of diarrhoea (10 vs 28%; P<0.05) and skin toxicities (18 vs 37%; P<0.05) were significantly higher in arm B. One-year disease-free survival was similar in both arms: arm A 81.2% (95% CI: 70.0-92.4%); arm B 77.0% (95% CI: 65.0-89.0%). The schedule of 2-week administration followed by 1-week rest seems to be more feasible for oral 6-month administration of S-1 in adjuvant chemotherapy of locoregionally advanced SCCHN.     

Single-agent versus combination chemotherapy in advanced non-small-cell lung cancer: the cancer and leukemia group B (study 9730).

PURPOSE: We compared the efficacy of combination chemotherapy versus single-agent therapy in patients with advanced non-small-cell lung cancer. PATIENTS AND METHODS: A total of 561 eligible patients were randomly assigned to receive paclitaxel alone or in combination with carboplatin. RESULTS: The response rate was 17% in the paclitaxel arm and 30% in the carboplatin-paclitaxel arm (P < .0001). Median failure-free survival was 2.5 months in the paclitaxel arm and 4.6 months in the carboplatin-paclitaxel arm (P = .0002). Median survival times were 6.7 months (95% CI, 5.8 to 7.8) and 8.8 months (95% CI, 8.0 to 9.9), and 1-year survival rates were 32% (95% CI, 27% to 38%), and 37% (95% CI, 32% to 43%), respectively. The overall survival distributions were not statistically different: hazard ratio = 0.91 (95% CI, 0.77 to 1.17; P = .25). Hematological toxicity and nausea were more frequent in the combination arm, but febrile neutropenia and toxic deaths were equally low in both arms. There was no significant survival difference in elderly patients. Performance status 2 patients treated with combination chemotherapy had a better survival rate than those treated with single-agent therapy (P = .019). CONCLUSION: Combination chemotherapy improves response rate and failure-free survival compared with single-agent therapy, but there was no statistically significant difference in the primary end point of overall survival. The results in elderly patients were similar to younger patients. Performance status 2 patients had a superior outcome when treated with combination chemotherapy.     

Adjuvant postoperative radiotherapy, chemotherapy, and immunotherapy in stage III breast cancer. II. 5-year results and influence of levamisole

One hundred twenty pathologically confirmed operable Stage III breast cancer patients were randomized to receive either postoperative radiotherapy or chemotherapy, or a combination of these, with or without levamisole immunotherapy. Radiotherapy was given to regional lymph nodes and chest wall. Chemotherapy consisted of six cycles of vincristine, doxorubicin, and cyclophosphamide. Radiotherapy provided local and chemotherapy systemic control over the tumor, but the best patient-saving results were achieved with a combination of radiotherapy and chemotherapy. This clinical trial was commenced in 1976, and the first 60 of 120 patients also received oral levamisole, 150 mg/day, on 2 consecutive days weekly as immunotherapy. All patients were followed for at least 5 years. At this stage levamisole seems to increase disease-free and overall survival in all three treatment arms (radiotherapy, chemotherapy, combined treatment). Significance is reached in disease-free survival (P = 0.035) and overall survival, adjusted for all other treatment modalities (P = 0.019).     

Continuous hyperfractionated accelerated radiation therapy week-end less in combination with neoadjuvant chemotherapy for the treatment of stage III non-small-cell lung cancer

PURPOSE: Current treatment for unresectable stage III lung cancer includes standard radiotherapy with chemotherapy. Continuous hyperfractionated radiotherapy has been shown to be more effective than standard radiotherapy but may be associated with increased toxicity. In this study, we evaluated the feasibility and outcomes of patients treated with a hyperfractionated accelerated regimen in combination with neoadjuvant chemotherapy. METHODS AND MATERIALS: We prospectively studied 61 consecutive patients with unresectable stage III non-small-cell lung cancer. All patients received three dimensional conformal radiotherapy using three daily fractions of 1.5 Gy to a total dose of 54-60 Gy omitting elective mediastinal irradiation. Approximately two-thirds of the patients also received platinum-based neoadjuvant chemotherapy. The primary outcome was locoregional disease-free survival. Secondary analyses were performed to assess tolerability, response rates, and overall and disease-free survival among study participants. RESULTS: Overall, 56% of patients had a complete response. Locoregional recurrence was observed in 55% of patients with only a 3% rate of dissemination to non-irradiated mediastinal lymph nodes. Median locoregional disease-free survival, disease-free survival, and overall survival were 16 months (95% CI: 12-20), 15 months (95% CI: 12-18), and 19 months (95% CI: 15-30), respectively. Additionally, no episodes of severe toxicity were reported among study participants. Poor performance status and radiation response were independent predictors of survival. CONCLUSIONS: This study suggests that conformal three-dimensional hyperfractionated accelerated radiotherapy omitting elective node irradiation can be used in combination with neoadjuvant chemotherapy to treat patients with stage III lung cancer. Future studies should compare this approach with the standard treatments for patients with stage III lung cancer.     

Functional polymorphisms of the microsomal epoxide hydrolase gene: a reappraisal on a early-onset lung cancer patients series

As concomitant chemoradiotherapy for stage III NSCLC is associated with survival advantage in comparison to a sequential approach, we conducted a phase III randomised study aiming to determine the best sequence and safety of chemotherapy (CT) and chemoradiotherapy (CT-RT), using a regimen with cisplatin (CDDP), gemcitabine (GEM) and vinorelbine (VNR). Unresectable stage III NSCLC patients received CDDP (60 mg/m(2)), GEM (1g/m(2), days 1 and 8) and VNR (25mg/m(2), days 1 and 8) with reduced dosage of GEM and VNR during radiotherapy (66Gy). Two cycles of CT with radiotherapy followed by two further cycles of CT alone were administered in arm A or the reverse sequence in arm B. The study was prematurely closed for poor accrual due to administrative problems. Forty-nine eligible patients were randomised. Response rates and median survival times were, respectively 57% (95% CI: 36-78%) and 17 months (95% CI: 9.3-24.6 months) in arm A and 79% (95% CI: 64-94%) and 23.9 months (95% CI: 13.3-34.5 months) in arm B (p>0.05). Chemotherapy dose-intensity was significantly reduced in arm A. Grade 3-4 oesophagitis occurred in 5 patients. One case of grade 5 radiation pneumonitis was observed. In conclusion, chemoradiotherapy with CDDP, GEM and VNR appears feasible as initial treatment or after induction chemotherapy. Consolidation chemoradiotherapy seems less toxic with a better observed response rates and survival although no valid conclusion can be drawn from the comparison of both arms.     

High-dose therapy and autologous stem-cell transplantation versus conventional therapy for patients with advanced Hodgkin's lymphoma responding to front-line therapy.

PURPOSE: To determine whether high-dose therapy (HDT) with autologous stem-cell transplantation (ASCT) should be included in the initial consolidative treatment of patients with advanced, unfavorable Hodgkin's lymphoma (HL). PATIENTS AND METHODS: One hundred sixty-three patients achieving complete remission (CR) or partial remission (PR) with four initial courses of doxorubicin, bleomycin, vinblastine, and dacarbazine, or other doxorubicin-containing regimens, were randomly assigned to receive HDT plus ASCT (83 patients) versus four courses of conventional chemotherapy (80 patients). Unfavorable HL was defined as the presence of at least two of the following poor prognostic factors: high lactate dehydrogenase level, large mediastinal mass (greater than at least 33% of the thoracic diameter), more than one extranodal site, low hematocrit level, and inguinal involvement. RESULTS: At the end of the treatment program, 92% of patients in arm A and 89% in arm B achieved a CR (P =.6). After a median follow-up of 48 months, the 5-year failure-free survival rates were 75% (95% confidence interval [CI], 65 to 85) in arm A and 82% (95% CI, 73 to 90) in arm B (P =.4). The 5-year overall survival rates were 88% (95% CI, 80 to 96) in arm A and 88% (95% CI, 79 to 96) in arm B (P =.99). The 5-year relapse-free survival rates were 88% in arm A (95% CI, 80 to 96) and 94% in arm B (95% CI, 88 to 100), and the difference was not significant (P =.3). CONCLUSION: Patients with advanced unfavorable HL achieving CR or PR after four courses of doxorubicin-containing regimens have a favorable outcome with conventional chemotherapy. No benefit from an early intensification with HDT and ASCT was shown.     

Standard thoracic radiotherapy with or without concurrent daily low-dose carboplatin in elderly patients with locally advanced non-small cell lung cancer: a phase III trial of the Japan Clinical Oncology Group (JCOG9812)

BACKGROUND: The purpose of this study was to evaluate whether radiotherapy with carboplatin would result in longer survival than radiotherapy alone in elderly patients with unresectable stage III non-small cell lung cancer (NSCLC). METHODS: Eligible patients were 71 years of age or older with unresectable stage III NSCLC. Patients were randomly assigned to the radiotherapy alone (RT) arm, irradiation with 60 Gy; or the chemoradiotherapy (CRT) arm, the same radiotherapy and additional concurrent use of carboplatin 30 mg/m(2) per fraction up to the first 20 fractions. RESULTS: This study was terminated early when 46 patients were registered from November 1999 to February 2001. Four patients (one in the RT arm, three in the CRT arm) were considered to have died due to treatment-related causes. The JCOG Radiotherapy Committee assessed these treatment-related deaths (TRDs) and the compliance with radiotherapy in this trial. They found that 60% of the cases corresponded to protocol deviation and 7% were protocol violation in dose constraint to the normal lung, two of whom died due to radiation pneumonitis. As to the effectiveness for the 46 patients enrolled, the median survival time was 428 days [95% confidence interval (CI) = 212-680 days] in the RT arm versus 554 days (95% CI = 331 to not estimable) in the CRT arm. CONCLUSIONS: Due to the early termination of this study, the effectiveness of concurrent use of carboplatin remains unclear. We re-planned and started a study with an active quality control program which was developed by the JCOG Radiotherapy Committee.