Randomised phase 2 trial of SIR-Spheres plus fluorouracil/leucovorin chemotherapy versus fluorouracil/leucovorin chemotherapy alone in advanced colorectal cancer. Randomised trial of SIR-Spheres plus chemotherapy vs. chemotherapy alone for treating patients with liver metastases from primary large bowel cancer. Randomized comparison of early versus late hyperfractionated thoracic irradiation concurrently with chemotherapy in limited disease small-cell lung cancer: a randomized phase II study of the Hellenic Cooperative Oncology Group (HeCOG). A randomized study with or without intensified maintenance chemotherapy in patients with acute promyelocytic leukemia who have become negative for PML-RARalpha transcript after consolidation therapy: the Japan Adult Leukemia Study Group (JALSG) APL97 study. Phase III study comparing chemotherapy and radiotherapy with preoperative chemotherapy and surgical resection in patients with non-small-cell lung cancer with spread to mediastinal lymph nodes (N2); final report of RTOG 89-01. Radiation Therapy Oncology Group. Survival results from a phase III study of simultaneous versus 1-hour sequential methotrexate-5-fluorouracil chemotherapy in head and neck cancer. Randomized trial of hyperfractionated radiation therapy with or without concurrent chemotherapy for stage III non-small-cell lung cancer. An intergroup phase III comparison of standard radiation therapy and two schedules of concurrent chemoradiotherapy in patients with unresectable squamous cell head and neck cancer. A phase III study of adjuvant chemotherapy in advanced nasopharyngeal carcinoma patients.
Selective internal radiation therapy (SIRT) with SIR-Spheres(R) is a new technique for selectively targeting high doses of radiation to tumours within the liver. The primary objectives of this randomised trial were to compare the response rate, time to progressive disease (PD), and toxicity of a regimen of systemic fluorouracil/leucovorin chemotherapy versus the same chemotherapy plus a single administration of SIR-Spheres in patients with advanced colorectal liver metastases. The trial was designed to presage a larger trial that would have survival as the primary outcome.
                Twenty-one patients with previously untreated advanced colorectal liver metastases, with or without extrahepatic metastases, were randomised into the study.
                Using RECIST criteria, the response rate for 11 patients receiving the combination treatment was significantly greater than for 10 patients receiving chemotherapy alone (First Integrated Response; 10 PR, 1 SD vs. 0 PR, 6 SD, 4 PD, P < 0.001 and Best Confirmed Response; 8 PR, 3 SD vs. 0 PR, 6 SD, 4 PD P < 0.001). The time to PD was greater for patients receiving the combination treatment (18.6 months vs. 3.6 months, P < 0.0005). Median survival was significantly longer for patients receiving the combination treatment (29.4 months vs. 12.8 months, P = 0.02). One patient in the combination arm died from chemotherapy induced neutropenic sepsis after the fourth chemotherapy cycle. There were more Grade 3 and 4 toxicity events in patients receiving the combination treatment. There was no difference in quality-of-life over a 3 month period between the two treatments when rated by patients (P = 0.96) or physicians (P = 0.98).
                This small phase 2 randomised trial demonstrated that the addition of a single administration of SIR-Spheres to a regimen of systemic fluorouracil/leucovorin chemotherapy significantly increased both treatment related response, time to PD, and survival with acceptable toxicity. The combination of SIR-Spheres plus systemic chemotherapy is now the subject of ongoing trials to further define patient benefit.
                (c) 2004 Wiley-Liss, Inc. SIR-Spheres are radioactive yttrium90 microspheres (SIR-Spheres, Sirtex Medical Limited, Australia) used to selectively target high levels of ionising radiation to tumors within the liver. This trial was designed to measure any increased patient benefit by adding a single administration of SIR-Spheres to a regimen of regional hepatic artery chemotherapy (HAC) administered as a 12 day infusion of floxuridine and repeated at monthly intervals, vs. the same chemotherapy alone.
                A phase III randomised clinical trial entering 74 patients was undertaken on patients with bi-lobar non-resectable liver metastases from primary adenocarcinoma of the large bowel. Patient benefit criteria assessed in the trial were tumor response, time to disease progression in the liver, overall survival, quality of life, and treatment related toxicity. Tumor response was measured by serial changes in both cross-sectional tumor areas and total tumor volumes, provided any response lasted not less than three months as well as changes in serum carcino-embryonic antigen (CEA).
                The partial and complete response rate (PR + CR) was significantly greater for patients receiving SIR-Spheres when measured by tumor areas (44%) vs. 17.6%, P = 0.01) tumor volumes (50% vs. 24%, P = 0.03) and CEA (72% vs. 47%, P = 0.004). The median time to disease progression in the liver was significantly longer for patients receiving SIR-Spheres in comparison to patients receiving HAC alone when measured by either tumor areas (9.7 vs. 15.9 months, P = 0.001), tumor volumes (7.6 vs. 12.0 months, P = 0.04) or CEA (5.7 vs. 6.7 months, P = 0.06). The one, two, three and five-year survival for patients receiving SIR-Spheres was 72%, 39%, 17% and 3.5%, compared to 68%, 29%, 6.5% and 0% for HAC alone. Cox regression analysis suggests an improvement in survival for patients treated with SIR-Spheres who survive more than 15 months (P = 0.06). There was no increase in grade 3-4 treatment related toxicity and no loss of quality of life for patients receiving SIR-Spheres in comparison to patients receiving HAC alone.
                The combination of a single injection of SIR-Spheres plus HAC is substantially more effective in increasing tumor responses and progression free survival than the same regimen of HAC alone. Concurrent platinum etoposide chemotherapy given in combination with hyperfractionated thoracic radiation therapy (HTRT) in limited disease (LD) small cell lung cancer (SCLC) is associated with a high response rate and significant prolongation of survival. Given these results, the Hellenic Cooperative Oncology Group (HeCOG) performed a multicenter randomized phase II study in patients with LD SCLC to evaluate the timing of HTRT (early vs. late) when given concurrently with chemotherapy.
                To be eligible for the study, patients were required to have histologically or cytologically proven LD SCLC, confined to one hemithorax and/or ipsilateral mediastinal or supraclavicular lymphnodes and absence of pleural effusion or controlateral supraclavicular lymphnode involvement. Moreover, patients had to have a good performance status and adequate haematological, liver and renal function. Patients with LD SCLC were randomized to receive HTRT either concurrently with the first (Group A) or with the fourth (Group B) cycle of chemotherapy. Chemotherapy consisted of carboplatin administered at an AUC of six given as an i.v. 1-hour-infusion immediately followed by etoposide at a dose of 100 mg/m2 i.v. as a two-hour infusion for three consecutive days every three weeks up to a total of six cycles. Prophylactic cranial irradiation was also given to patients achieving a complete response.
                42 and 39 patients, were eligible for efficacy evaluation in group A and B respectively. The overall response rate was 76% in group A and 92.5% in group B (P = 0.07) with a complete response rate of 40.5% and 56.5%, respectively. After a median follow-up of 35 months, time to progression was 9.5 months in group A and 10.5 in group B (NS) while overall median survival was 17.5 and 17 months respectively (NS). The 2-year survival was 36% in group A and 29% in group B (NS) and the 3-year survival 22% and 13%, respectively (NS). The distant relapse rate was 38% in group A and 61% in group B (P = 0.046). Severe grade 3 4 anemia was recorded in 19% of group A and 12.5% of group B (NS), while severe leucopenia was recorded in 35.5% and 20.5% (P = 0.09) and neutropenic fever in 5% and 2.5% (NS), respectively. Severe thrombocytopenia did not differ significantly between the two treatment groups being 21.5% and 23%, respectively. Severe grade 2-3 esophageal toxicity was 19% in group A and 23% in group B (NS), while grade 3 lung toxicity was 5% and 7.5% (NS), respectively. No toxicity-related deaths were recorded.
                Concurrent administration of HTRT with carboplatin etoposide is associated with a high response and survival rate. Although a trend for higher response rate was recorded in the group of patients who received late HTRT, the overall median, 2-year and 3-year survival rates did not differ significantly between the two treatment groups. The toxicity of this promising therapeutic approach was acceptable. Comparative phase III studies with an adequate number of patients are recommended in order to answer this question. To examine the efficacy of intensified maintenance chemotherapy, we conducted a prospective multicenter trial in adult patients with newly diagnosed acute promyelocytic leukemia treated with all-trans retinoic acid and chemotherapy. Of the 302 registered, 283 patients were assessable and 267 (94%) achieved complete remission. Predicted 6-year overall survival in all assessable patients and disease-free survival in patients who achieved complete remission were 83.9% and 68.5%, respectively. A total of 175 patients negative for PML-RARalpha at the end of consolidation were randomly assigned to receive either intensified maintenance chemotherapy (n = 89) or observation (n = 86). Predicted 6-year disease-free survival was 79.8% for the observation group and 63.1% for the chemotherapy group, showing no statistically significant difference between the 2 groups (P = .20). Predicted 6-year survival of patients assigned to the observation was 98.8%, which was significantly higher than 86.2% in those allocated to the intensified maintenance (P = .014). These results indicate that the intensified maintenance chemotherapy did not improve disease-free survival, but rather conferred a significantly poorer chance of survival in acute promyelocytic leukemia patients who have become negative for the PML-RARalpha fusion transcript after 3 courses of intensive consolidation therapy. To compare the outcome of treatment of mediastinoscopy-verified N2 non-small-cell lung cancer treated with induction chemotherapy followed by either surgery or radiotherapy (RT), with both options followed by consolidation chemotherapy.
                A randomized Phase III trial for Stage IIIA (T1-T3N2M0) non-small cell lung cancer was conducted by the Radiation Therapy Oncology Group (RTOG) and Eastern Cooperative Oncology Group between April 1990 and April 1994. After documentation of N2 disease by mediastinoscopy or anterior mediastinotomy, patients received induction chemotherapy with cisplatin, vinblastine, and mitomycin-C. Mitomycin-C was later dropped from the induction regimen. Patients were then randomized to surgery or RT (64 Gy in 7 weeks) followed by cisplatin and vinblastine.
                RTOG 89-01 accrued 75 patients, of whom 73 were eligible and analyzable. Twelve patients received induction chemotherapy but were not randomized to RT or surgery thereafter. Forty-five patients were randomized to postinduction RT or surgery. Of the analyzable patients, 90% had a Karnofsky performance score of 90-100, 18% had weight loss >5%, 37% had squamous cell histologic features, and 54% had bulky N2 disease. The distribution of bulky N2 disease was uniform among the treatment arms. The incidence of Grade 4 toxicity was 56% in patients receiving mitomycin-C and 29% in those who did not. Only 1 patient in each group had acute nonhematologic toxicity greater than Grade 3 (nausea and vomiting). No acute Grade 4 radiation toxicity developed. The incidences of long-term toxicity were equivalent across the arms. Three treatment-related deaths occurred: 2 patients in the surgical arms (one late pulmonary toxicity and one pulmonary embolus), and 1 patient in the radiation arm (radiation pneumonitis). Induction chemotherapy was completed in 78% of the patients. Complete resection was performed in 73% of 26 patients undergoing thoracotomy. Consolidation chemotherapy was completed in 75% of the patients. No statistically significant difference was found among the treatment arms. The overall progression-free survival rate was 53% at 1 year and 17% at 3 years. The median progression-free survival was 14 months. No difference in the 1-year survival rate (70% vs. 66%) or median survival time (19.4 vs. 17.4 months) between the surgery and RT arms. The median survival in the patients receiving induction chemotherapy only was 8.9 months. Mitomycin-C had no impact on survival (p = 0.75). No statistically significant difference was noted in the time to local failure between the surgical and RT arms.
                The patient accrual to this trial made its results inconclusive, but several observations are notable. In this trial, histologic confirmation of N2 disease in the surgical and nonsurgical arms eliminated the usual biases from clinical staging. In this setting, local control and survival were essentially equal between the surgical and RT arms. The 3- and 5-year survival rates of nonsurgical therapy were comparable to published surgical trials of N2 disease. There were 79 patients with squamous cell head and neck cancer randomized to receive simultaneous or 1 hour sequential methotrexate-5 fluorouracil (MTX--5-FU) chemotherapy: 47 patients were previously untreated and 32 patients had recurrent disease. The treatment groups were comparable for important prognostic features. The median survival for the 47 newly presenting patients was 22 months and for recurrent disease patients was 14 months. No difference could be detected in the survival of patients who received simultaneous versus sequential chemotherapy. When only chemotherapy responders were compared, no difference in survival was detected for those who received sequential versus simultaneous therapy. Subsequently, 19 chemotherapy responders received radical radiation therapy, and 15 were rendered disease-free whereas only 4 of 17 chemotherapy nonresponders were rendered disease-free by subsequent radiation (P = .002). The survival of the 19 chemotherapy responders was 34 months compared with 16 months for the 17 chemotherapy nonresponders treated with radiation. We conclude that there is no therapeutic advantage for 1 hour sequential MTX-5 FU chemotherapy compared with simultaneous use of these drugs in squamous cell head and neck cancer. Chemotherapy responders are more likely to respond to radiation therapy. To investigate the efficacy of combined hyperfractionated radiation therapy (HFX RT) and concurrent chemotherapy (CHT) in stage IIIA or IIIB non-small-cell lung cancer (NSCLC) compared with that of HFX RT alone.
                Between January 1988 and December 1989, 169 patients were divided randomly into the following groups: group I, HFX RT with 1.2 Gy twice daily to a total dose of 64.8 Gy (n = 61); group II, same HFX RT with CHT consisting of 100 mg of carboplatin (CBDCA) on days 1 and 2 and 100 mg of etoposide (VP-16) on days 1 to 3 of each week during the RT course (n = 52); and group III, same HFX RT with CHT consisting of 200 mg of CBDCA on days 1 and 2 and 100 mg of VP-16 on days 1 to 5 of the first, third, and fifth weeks of the RT course (n = 56).
                The median survival time (MST) was 8 months for group I, 18 months for group II, and 13 months for group III. The 3-year survival rates were 6.6%, 23%, and 16%, respectively. There was a significant difference in the survival rate between groups I and II (P = .0027, log-rank test), but not between groups I and III (P = .17) or between groups II and III (P = .14). The relapse-free survival rate in group II was also higher than that in group I (P = .0024), which was largely due to improved local control in group II patients. Patients in groups II and III showed a higher incidence of acute and/or late high-grade toxicity compared with group I patients, but no patient died of treatment-related toxicity.
                The combination of HFX RT and continuous CBDCA/VP-16 CHT was tolerable and substantially increased the survival rate. The Head and Neck Intergroup conducted a phase III randomized trial to test the benefit of adding chemotherapy to radiation in patients with unresectable squamous cell head and neck cancer.
                Eligible patients were randomly assigned between arm A (the control), single daily fractionated radiation (70 Gy at 2 Gy/d); arm B, identical radiation therapy with concurrent bolus cisplatin, given on days 1, 22, and 43; and arm C, a split course of single daily fractionated radiation and three cycles of concurrent infusional fluorouracil and bolus cisplatin chemotherapy, 30 Gy given with the first cycle and 30 to 40 Gy given with the third cycle. Surgical resection was encouraged if possible after the second chemotherapy cycle on arm C and, if necessary, as salvage therapy on all three treatment arms. Survival data were compared between each experimental arm and the control arm using a one-sided log-rank test.
                Between 1992 and 1999, 295 patients were entered on this trial. This did not meet the accrual goal of 362 patients and resulted in premature study closure. Grade 3 or worse toxicity occurred in 52% of patients enrolled in arm A, compared with 89% enrolled in arm B (P <.0001) and 77% enrolled in arm C (P <.001). With a median follow-up of 41 months, the 3-year projected overall survival for patients enrolled in arm A is 23%, compared with 37% for arm B (P =.014) and 27% for arm C (P = not significant).
                The addition of concurrent high-dose, single-agent cisplatin to conventional single daily fractionated radiation significantly improves survival, although it also increases toxicity. The loss of efficacy resulting from split-course radiation was not offset by either multiagent chemotherapy or the possibility of midcourse surgery. To evaluate the role of adjuvant chemotherapy in locally advanced nasopharyngeal carcinoma (NPC) patients, we conducted a randomized Phase III trial comparing radiotherapy (RT) followed by adjuvant chemotherapy to RT alone in patients with advanced NPC.
                Between November 1994 and March 1999, 157 patients with Stage IV, M(0) (UICC/AJCC, 1992) advanced NPC disease were randomized to receive standard radiotherapy, as follows: 35-40 fractions, 1.8-2.0 Gy/fraction/day, 5 days/week, to a total dose 70-72 Gy with or without 9 weekly cycles of 24-h infusional chemotherapy (20 mg/m(2) cisplatin, 2,200 mg/m(2) 5-fluorouracil, and 120 mg/m(2) leucovorin) after RT. Of 157 patients enrolled, 154 (77 radiotherapy, 77 combined therapy) were evaluable for survival and toxicity analysis.
                With a median follow-up of 49.5 months, the 5-year overall survival and relapse-free survival rates were 60.5% vs. 54.5% (p = 0.5) and 49.5% vs. 54.4% (p = 0.38) for the radiotherapy-alone group and the combined radiotherapy and adjuvant chemotherapy group, respectively. The Cox regression showed that the hazard rates ratio of combined treatment to RT alone was 0.673 (p value = 0.232); the 95% confidence interval was 0.352 and 1.288, respectively. Patients who received combined treatment had a lower systemic relapse rate than radiotherapy-alone patients, according to relapse pattern analysis. The incidence of leukopenia (>or= Grade 3) occurred in 17 out of 819 (2.1%) cycles of weekly chemotherapy. No patient developed moderate to severe mucositis (>or= Grade 3).
                We conclude that adjuvant chemotherapy after RT for patients with advanced NPC has no benefit for overall survival or relapse-free survival.
There is a need for well designed, adequately powered phase III trials assessing the effect of SIRT when used with modern combination chemotherapy regimens. Further studies are also needed for patients with refractory disease with a particular focus on the impact on quality of life.