Adjuvant chemotherapy prior to postoperative concurrent chemoradiotherapy for locoregionally advanced head and neck cancer

Background and purpose

Induction chemotherapy prior to definitive concurrent chemoradiotherapy (CCRT) is a promising treatment option for unresectable head and neck cancer (HNC). In the postoperative setting, the efficacy of such an approach with adjuvant chemotherapy (AdjCT) followed by postoperative CCRT is unclear.

Materials and methods

Forty-one postoperative patients with stage III-IV (M0) HNC enrolled on 3 consecutive phase II clinical trials were retrospectively analyzed. Twenty-five of the patients were treated on a protocol which included AdjCT with carboplatin and paclitaxel prior to postoperative CCRT (AdjCT group). Sixteen were treated on protocols with similar postoperative CCRT but without AdjCT (control group). CCRT consisted of paclitaxel, 5-fluorouracil, hydroxyurea, and twice-daily radiotherapy.

Results

After a median follow-up of 72 months, there were no locoregional failures (LRF) or distant metastases (DM) in the AdjCT group. In the control group, there were 2 LRF and 2 DM. The 5-year risk of disease recurrence was 0% in the AdjCT group, compared to 28.9% in the control group (p = 0.0074). No patients had disease progression during AdjCT, and all proceeded to postoperative CCRT without delay.

Conclusions

Adjuvant chemotherapy after surgery followed by CCRT may be a treatment strategy associated with favorable disease outcomes in locoregionally advanced HNC. These results pose a hypothesis which warrants further investigation.     

诱导化疗联合同期放化疗与同期放化疗治疗局部晚期鼻咽癌的对比研究

  目的  比较诱导化疗联合同期放化疗与同期放化疗治疗局部晚期鼻咽癌(LA-NPC)的临床结果及探讨预后因素。  方法  分析2005年1月至2006年12月本院收治的433例无转移LA-NPC患者的临床资料, 按是否行诱导化疗分为诱导化疗联合同期放化疗组(A组)209例与同期放化疗组(B组)224例。采用Kaplan-Meier法进行生存分析, 差异比较采用Log-Rank法双侧检验, 预后因素分析采用Cox模型。  结果  A组、B组的3年总生存率(OS)、无局部区域复发生存率(LR-FFS)、无远处转移生存率(D-FFS)、无瘤生存率(FFS)分别为87% vs. 88%、95% vs. 95%、85% vs. 85%、81% vs. 81%;A组、B组的5年OS、LR-FFS、D-FFS、FFS分别为80% vs. 82%(P=0.503), 95% vs. 93%(P=0.673), 82% vs. 82%(P=0.992), 78% vs. 77%(P=0.851)。两组生存差异无统计学意义, 对于Ⅲ期鼻咽癌, A组FFS优于B组(P=0.075)。多因素分析显示老年、临床分期晚、颅神经侵犯、贫血、N分期晚为OS、D-FFS的独立不良预后因素。  结论  与同期放化疗相比, 诱导化疗联合同期放化疗未提高LA-NPC的OS、LR-FFS、D-FFS及FFS, 但具有改善Ⅲ期鼻咽癌FFS的趋势。诱导化疗联合同期放化疗不是鼻咽癌的必选治疗模式。      

A randomized trial of induction chemotherapy plus concurrent chemoradiotherapy versus induction chemotherapy plus radiotherapy for locoregionally advanced nasopharyngeal carcinoma

The aim of this randomized study was to compare the efficacy of induction chemotherapy plus concurrent chemoradiotherapy (IC+CCRT) versus induction chemotherapy plus radiotherapy (IC+RT) for patients with locoregionally advanced nasopharyngeal carcinoma. From August 2002 to April 2005, 408 patients were randomly divided into two groups: an IC+CCRT group and an IC+RT group. Patients in both groups received the same induction chemotherapy: two cycles of floxuridine (FuDR)+carboplatin (FuDR, 750mg/m(2), d1-5; carboplatin, area under the curve [AUC]=6). The patients received radiotherapy 1week after they finished the induction chemotherapy. The patients in the IC+CCRT group also received carboplatin (AUC=6) on days 7, 28, and 49 of radiotherapy. Eight patients did not meet the inclusion criteria, and the remaining 400 cases were analyzed. Grade III or IV toxicity was found in 28.4% of the patients in the IC+CCRT group and 13.1% of those in the IC+RT group (P<.001). Five-year overall survival rates were 70.3% and 71.7% (P=0.734) in the IC+CCRT and IC+RT groups, respectively. No significant differences in failure-free survival, locoregional control, and distant control were found between the two groups. Compared with the IC+RT program, the IC+CCRT program used in the present study did not improve the overall survival and failure-free survival in patients with locoregionally advanced nasopharyngeal carcinoma. Using carboplatin in the concurrent chemoradiotherapy was not suitable for nasopharyngeal carcinoma.     

Long-term outcome of phase II trial evaluating chemotherapy,chemoradiotherapy, and surgery for locoregionally advanced esophageal cancer

PURPOSE: To evaluate the long-term outcome of chemotherapy, chemoradiotherapy, and surgery for patients with locoregionally advanced esophageal cancer. METHODS AND MATERIALS: Thirty-eight patients with locoregionally advanced esophageal cancer were entered into a Phase II study between November 1996 and October 1998 at the University of Texas M. D. Anderson Cancer Center. Patients initially received two cycles of chemotherapy with paclitaxel (200 mg/m(2)), 5-fluorouracil (750 mg/m(2)/d for 5 days), and cisplatin (15 mg/m(2)/d for 5 days), followed by chemoradiotherapy, consisting of radiation (45 Gy during 5 weeks) with 5-fluorouracil (300 mg/m(2)/d during radiation) and cisplatin (15 mg/m(2)/d for 5 days). Surgical resection was performed 4-6 weeks after the completion of the chemoradiotherapy. RESULTS: Most patients had adenocarcinoma (n = 32; 84%). Pretreatment endoscopic ultrasonography revealed T3 tumors in 33 patients (87%) and N1 disease in 25 patients (66%). Thirty-seven patients (97%) completed the planned chemotherapy and chemoradiotherapy, and 35 patients (92%) underwent surgery, with a 30-day mortality rate of 6% (2 of 35 patients). A pathologic complete response or microscopic residual carcinoma (<10% viable) was found in 25 (71%) of 35 patients and was associated with a disease-free survival rate of 72% at 3 years and 51% at 5 years. On the basis of an intention-to-treat analysis and a median potential follow-up of 58 months, the 3- and 5-year overall survival rate for all 38 patients was 63% and 39%, respectively. CONCLUSION: The long-term results of this study suggest that the strategy of induction chemotherapy followed by chemoradiotherapy and surgery is safe and warrants further evaluation in the treatment of patients with locoregionally advanced esophageal cancer.     

Neoadjuvant chemotherapy followed by concurrent chemoradiotherapy versus concurrent chemoradiotherapy alone in locoregionally advanced nasopharyngeal carcinoma: A phase III multicentre randomised controlled trial

BackgroundThe role of neoadjuvant chemotherapy (NACT) for locoregionally advanced nasopharyngeal carcinoma (NPC) is unclear. We aimed to evaluate the feasibility and efficacy of NACT followed by concurrent chemoradiotherapy (CCRT) versus CCRT alone in locoregionally advanced NPC.MethodsPatients with stage III–IVB (excluding T3N0-1) NPC were randomly assigned to receive NACT followed by CCRT (investigational arm) or CCRT alone (control arm). Both arms were treated with 80 mg/m² cisplatin every 3 weeks concurrently with radiotherapy. The investigational arm received cisplatin (80 mg/m² d1) and fluorouracil (800 mg/m² civ d1–5) every 3 weeks for two cycles before CCRT. The primary end-point was disease-free survival (DFS) and distant metastasis-free survival (DMFS). Secondary end-point was overall survival (OS). Survival curves for the time-to-event endpoints were analyzed by the Kaplan–Meier method and compared using the log-rank test. The P value was calculated using the 5-year endpoints.ResultsFour hundred seventy six patients were randomly assigned to the investigational (n = 238) and control arms (n = 238). The investigational arm achieved higher 3-year DFS rate (82.0%, 95% CI = 0.77–0.87) than the control arm (74.1%, 95% CI = 0.68–0.80, P = 0.028). The 3-year DMFS rate was 86.0% for the investigational arm versus 82.0% for the control arm, with marginal statistical significance (P = 0.056). However, there were no statistically significant differences in OS or locoregional relapse-free survival (LRRFS) rates between two arms (OS: 88.2% versus 88.5%, P = 0.815; LRRFS: 94.3% versus 90.8%, P = 0.430). The most common grade 3–4 toxicity during NACT was neutropenia (16.0%). During CCRT, the investigational arm experienced statistically significantly more grade 3–4 toxicities (P < 0.001).ConclusionNACT improved tumour control compared with CCRT alone in locoregionally advanced NPC, particularly at distant sites. However, there was no early gain in OS. Longer follow-up is needed to determine the eventual therapeutic efficacy.     

Concomitant chemoradiotherapy as primary therapy for locoregionally advanced head and neck cancer.

PURPOSE: To achieve locoregional control of head and neck cancer, survival, and organ preservation using intensive concomitant chemoradiotherapy. PATIENTS AND METHODS: This study was a phase II trial of chemoradiotherapy with cisplatin 100 mg/m(2) every 28 days, infusional fluorouracil 800 mg/m(2)/d for 5 days, hydroxyurea 1 g orally every 12 hours for 11 doses, and radiotherapy twice daily at 1.5 Gy/fraction on days 1 through 5 (total dose, 15 Gy). Five days of treatment were followed by 9 days of rest, during which time patients received granulocyte colony-stimulating factor. Five cycles (three with cisplatin) were administered over 10 weeks (total radiotherapy dose, locoregional). Surgery after concomitant chemoradiotherapy is feasible. Compliance with adjuvant chemoprevention is poor. Identification of less toxic regimens and improved distant disease control emerge as important future research goals.     

Concomitant boost radiotherapy with concurrent weekly cisplatin in advanced head and neck cancers: a phase II trial.

BACKGROUND AND PURPOSE: To determine the safety and efficacy of concomitant boost radiotherapy (CBRT) with concurrent cisplatin chemotherapy (CT) in advanced head and neck cancers. PATIENTS AND METHODS: Between February 2000 and June 2001, 95 previously untreated patients of advanced head and neck cancers were treated with CBRT and concurrent cisplatin CT. CBRT consisted of: phase I--44 Gy/22fx/4.5 weeks, phase IIa--16 Gy/8fx/1.5 weeks and phase IIb--10 Gy/8fx (delivered as a second daily fraction after a gap of 6h along with phase IIa). CT (cisplatin 35 mg/m(2)) was administered weekly usually preceding CBRT by an hour. RESULTS: The median follow-up was 39 months (range 8-50 months). CBRT compliance (70 Gy in 40-44 days) was seen in 66% (63/95). Six cycles of CT was delivered in 73% (69/95). Acute grade III/IV mucosal toxicity was seen in 79% and resulted, on average, in a total weight loss of 7.9 kg from a mean pretreatment weight of 51 kg. Nasogastric tube placements were required in 26% (25/95) for an average duration of 19.3 days. Grade III leucopenia was seen in 2%. Mortality during and within 30 days of treatment was seen in 14% (13/95). Crude incidence of late subcutaneous fibrosis (grade III) was 21% (12/57) and a case of mandibular necrosis and thyroid cartilage necrosis each were seen. Initial loco regional disease clearance was seen in 59% (56/95) and the Kaplan-Meier estimates of 3-year loco-regional control rate and overall survival were 25% (median 7 months, 95% C.I. 3-11) and 27% (median 12 months, 95% C.I. 8-16), respectively. CONCLUSIONS: On present evidence, in the settings of a developing country, CBRT with concurrent cisplatin cannot be recommended as primary therapy in advanced head and neck cancers without formal comparison with other treatment modalities.     

Uracil/tegafur plus cisplatin with concurrent radiotherapy for locally advanced non-small-cell lung cancer: a multi-institutional phase II trial.

PURPOSE: To evaluate the efficacy and toxicity of a novel combination treatment using concurrent radiotherapy with cisplatin plus UFT, which is comprised of uracil and tegafur, in locally advanced non-small cell lung cancer (NSCLC) patients. EXPERIMENTAL DESIGN: In this Phase II trial, patients with unresectable stage III NSCLC were treated with the oral administration of UFT (400 mg/m(2)/d tegafur) on days 1-14 and days 29-42 whereas 80 mg/m(2) cisplatin was administered i.v. on days 8 and 36. Radiotherapy, with a total dose of 60 Gy, was delivered in 30 fractions from day 1. RESULTS: Seventy patients were enrolled and eligible, as follows: 57 males/13 females; mean age 61 ranging from 36 to 74; performance status 0/1:45/25; stage IIIA/IIIB, 14/56. A complete response was observed in two patients and a partial response in 54 patients, and the overall response rate was 81% (95% confidence interval; 70-89%). The median survival, the 1- and 2-year survival rates were 16.5 months, 67% and 33%, respectively. Grade 3/4 leukopenia occurred in 14%/1% of the patients. Grades 3 non-hematological toxicities were only reported in three patients with nausea, two with esophagitis and one with pneumonitis whereas no grade 4 non-hematological toxicity was observed. CONCLUSIONS: UFT plus cisplatin with concurrent radiotherapy is considered to be a feasible and effective treatment for locally advanced NSCLC patients. Additional study of this concurrent chemoradiotherapy is warranted.     

A prospective phase II trial of S-1 and cisplatin-based chemoradiotherapy for locoregionally advanced esophageal cancer

Purpose

S-1 is a novel oral fluoropyrimidine anticancer agent designed to enhance clinical efficacy, reduce gastrointestinal toxicity, and enhance radiotherapy effectiveness. A phase II trial was conducted to evaluate the efficacy and safety of preoperative chemoradiation with S-1 and cisplatin in locoregionally advanced esophageal cancer.

Methods

Eligible patients had stage IIA-IVA esophageal cancer. Patients received two cycles of S-1 (days 1–14 and days 22–35) and cisplatin (days 1 and 22) with concurrent radiotherapy (50.4 Gy total; 1.8 Gy/fraction). Esophagectomy was performed between weeks 12 and 18 as determined by the specialist multidisciplinary team.

Results

Sixty patients were enrolled in this study between March 2008 and August 2011, and 59 were eligible. The clinical stage was ≥T3 in 28 patients (47 %) and N1 in 43 patients (72 %), with squamous cell carcinoma histology in 58 patients (97 %). Fifty-four patients (90 %) completed the planned chemoradiation. After chemoradiation, the clinical tumor response rate was 64.4 %. The primary toxicities included neutropenia (24 %) and esophagitis (8.5 %). Three treatment-related deaths were noted. Twenty-five patients (42 %) underwent esophagectomy following chemoradiation, and 15 achieved complete pathologic regression. The estimated overall survival and progression-free survival rates after 2 years were 65 and 48 %, respectively.

Conclusions

Concurrent chemoradiation with S-1 and cisplatin exhibited encouraging results with complete pathologic regression. The survival data were promising compared with the historical data of 5FU/cisplatin and should be confirmed in a randomized phase III trial. Toxicities were significant but clinically manageable.     

局部晚期鼻咽癌诱导加同期化放疗与诱导化放疗的对照研究

背景与目的：诱导化放疗与同时期化放疗被认为是治疗局部晚期鼻咽癌最有效的两种策略。本随机研究目的在于比较诱导化疗加同时期化放疗与诱导化放疗治疗局部区域晚期鼻咽癌的疗效。方法：从2002年8月到2005年4月,408例患者随机分为诱导化放疗（induction chemoradiotherapy, IC/RT）和诱导加同时期化放疗（induction-concurrent chemoradiotherapy, IC/CCRT）两组。两组患者接受同样的诱导化疗方案：两程氟尿嘧啶脱氧核苷（floxuridine,FuDR）（750mg/m^2,d1-5）＋卡铂（carboplatin,CBP）（AUC=6）,化疗结束后1周行放疗。诱导加同时期化放疗组的患者在在放疗的第7、28、49d接受卡铂AUC=6的化疗。8例不符合人组标准的患者被排除。剩余的400例患者被纳入进行了分析。结果：诱导加同时期化放疗组和诱导化放疗组Ⅲ、Ⅳ度毒性率分别为28．4％和13．1％（P〈0．001）。中位随访3．9年。诱导加同时期化放疗组和诱导化放疗组的3年总生存分别为75．9％和83．4％（P=0．12）。两组的无病生存、局部区域控制和远处转移控制率无统计学差异。结论：本研究采用的诱导加同时期化放疗方案未能较诱导化放疗进一步提高局部区域晚期鼻咽癌患者的总生存率。     

A multi-institutional phase II trial of consolidation S-1 after concurrent chemoradiotherapy with cisplatin and vinorelbine for locally advanced non-small cell lung cancer

AimTo evaluate the efficacy and feasibility of the consolidation therapy of the oral fluoropyrimidine agent S-1 after concurrent chemoradiotherapy for unresectable stage III non-small cell lung cancer (NSCLC).MethodsEligible patients had unresectable stage III NSCLC with performance status of 0 or 1. Chemoradiotherapy at a total dose of 60 Gy consisted of cisplatin (80 mg/m²) on days 1 and 29, vinorelbine (20 mg/m²) on days 1, 8, 29 and 36. Sequential consolidation S-1 therapy was commenced at a dose of 80–120 mg twice daily on day 57 with two cycles of 4 weeks administration and 2 weeks withdrawal.ResultsOf the 66 patients, 65 were evaluated. Chemoradiotherapy was completed in 57 (87.7%) patients, and S-1 consolidation therapy was administered in 45 (69.2%) and completed in 31 (47.6%). Grade 3 pneumonitis developed in three patients with one dying of it. The response rate was 61.5% (95% confidence interval [CI], 48.6–73.3%). The median progression-free survival was 10.2 (95% CI, 8.6–13.7) months and median survival time 21.8 (95% CI, 15.6–27.6) months. The 1- and 3-year survival rates were 73.9% and 34.0%, respectively.ConclusionsChemoradiotherapy with cisplatin and vinorelbine followed by S-1 consolidation demonstrated a reasonable overall survival in patients with stage III NSCLC. However, less than half of the patients completed this regimen, and the additional effect of S-1 was marginal compared with historical control.We concluded that chemoradiotherapy alone is still the recommended standard treatment for patients.     

Functional organ preservation in patients with locoregionally advanced head and neck squamous cell carcinoma treated by platinum-based multidrug induction chemotherapy and concurrent chemoradiotherapy

BackgroundThe objective of this study was to evaluate the feasibility, safety, and efficacy in terms of functional organ preservation of multidrug induction chemotherapy and concurrent chemoradiotherapy (IC–CCRT) protocol in patients with locoregionally advanced head and neck squamous cell carcinoma (LA-HNSCC).Patients and methodsPatients with previously untreated, inoperable, histologically proven nonmetastatic stage III or IV HNSCC were eligible. Following one cycle of IC, two cycles of cisplatinum and 5-fluorouracil CCRT with conventional fractionated radiotherapy up to a dose of 66–70 Gy were administrated.ResultsBetween January 2000 and July 2007, a total of 139 patients were candidates to receive IC–CCRT for LA-HNSCC. Overall, 83% of the patients completed the treatment. Three-year overall survival estimate was 68% [95% confidence interval (CI) 57% to 79%]. Three-year progression-free survival (PFS) estimate was 62% (95% CI 50% to 74%). Three-year functional PFS was 57% (95% CI 44% to 69%). There were no cases of treatment-related deaths. The most frequent severe acute toxicity was pharyngeal mucositis.ConclusionsCisplatinum-based multidrug IC–CCRT can result in functional organ preservation and curative treatment in most patients with LA-HNSCC. The toxicity profile and patients’ compliance to treatment confirmed the safety and tolerability of this approach.     

Prospective pilot study of consolidation chemotherapy with docetaxel and cisplatin after concurrent chemoradiotherapy for advanced head and neck cancer

PURPOSE: With the improvement concurrent chemoradiotherapy (CCRT) in the management of patients with locoregionally advanced head and neck squamous cell carcinoma (HNSCC), distant failures have become a more relevant problem in terms of survival. The primary objective of this Phase II study is to assess the feasibility of docetaxel and cisplatin consolidation after primary CCRT for patients with HNSCC. METHODS AND MATERIALS: Patients with locoregionally advanced HNSCC received chemotherapy with three cycles of cisplatin, 100 mg/m(2), on Days 1, 22, and 43. Concurrent radiotherapy to the primary tumor and neck was given in a daily dose of 2 Gy to a total dose of 70-70.2 Gy over 7 weeks. After completion of CCRT, patients without evidence of disease progression received an additional four cycles of consolidation chemotherapy with docetaxel, 75 mg/m(2), and cisplatin, 75 mg/m(2), every 3 weeks. RESULTS: Of 33 patients, 27 (81%) completed CCRT. After CCRT, three complete and 19 partial responses were recorded, giving an overall response rate of 67%. Of 19 patients who went to the consolidation phase, only 4 (21%) received all four cycles of docetaxel and cisplatin. Causes of failure of consolidation chemotherapy were toxicity in 11 patients, including three treatment-related deaths, and progression in 4 patients. Three patients died of sepsis during the consolidation phase. Median survival was 11 months for all patients and 8 months for those treated with consolidation chemotherapy. CONCLUSION: The poor compliance and high incidence of severe toxicities prompted no further evaluation of this consolidation chemotherapy after CCRT.     

Accelerated hyperfractionated radiotherapy and concurrent protracted venous infusion chemotherapy in locally advanced head and neck cancer

Concurrent radiotherapy and chemotherapy result in a significant benefit with respect to induction chemotherapy followed by radiotherapy or radiotherapy alone, although with a significant increase of toxicity. To discover a more tolerated and effective chemoradiation regimen, the feasibility and efficacy of a hyperfractionated accelerated irradiation with concurrent protracted venous infusion chemotherapy was investigated. Sixty-five patients with advanced head and neck cancer underwent a definitive (53 patients) or a postoperative adjuvant (12 patients) chemoradiation treatment. Chemotherapy consisted of an intravenous protracted infusion of 5 and 200 mg/m /d cisplatin and 5-fluorouracil, respectively. Radiotherapy consisted of a split-course accelerated hyperfractionation of two 150-cGy (split twice a day) or three 100-cGy fractions per day (split three times a day) at more than 6-hour intervals, for 2 weeks followed, after a 1-week interruption, by 2-to-3-week treatment, with the same fractionation schedule, to a total dose of 60 Gy to 69 Gy. Confluent mucositis was tolerable and was the cause of treatment delay of more than 10 days in only 20% of patients. Grade 3 or greater systemic toxicity occurred only in 9 of 65 (14%) patients and was never the cause of drug dose reduction. Complete responses were observed in 69% of patients with gross diseases. At a median follow-up of 43.5 months, 45% of patients were alive and free of disease and 38% died of cancer. The 5-year actuarial local regional failure was 35%. The 5-year actuarial disease-specific survival was 50%. Preservation of larynx function was achieved in 47% of living patients and in 74% of all patients, with advanced tumors of the laryngopharynx. The long-term results of this study suggest that this chemoradiation regimen has the potential of achieving a significant improvement over standard therapy while avoiding significant toxicity.