Weekly Low-Dose Versus Three-Weekly High-Dose Cisplatin for Concurrent Chemoradiation in Locoregionally Advanced Non-Nasopharyngeal Head and Neck Cancer: A Systematic Review and Meta-Analysis of Aggregate Data.

Three-weekly high-dose cisplatin (100 mg/m2) is considered the standard systemic regimen given concurrently with postoperative or definitive radiotherapy in locally advanced squamous cell carcinoma of the head and neck (LA-SCCHN). However, due to unsatisfactory patient tolerance, various weekly low-dose schedules have been increasingly used in clinical practice. The aim of this meta-analysis was to compare the efficacy, safety, and compliance between these two approaches. We systematically searched literature for prospective trials of patients with LA-SCCHN who received postoperative or definitive conventionally fractionated concurrent chemoradiation. Radiation doses were usually 60-66 gray (Gy) in the postoperative setting and 66-70 Gy in the definitive setting. Standard, three-weekly high-dose cisplatin (100 mg/m2, 3 doses) was compared with the weekly low-dose protocol (≤50 mg/m2, ≥6 doses). The primary endpoint was overall survival. Secondary outcomes comprised response rate, acute and late adverse events, and treatment compliance. Fifty-two studies with 4,209 patients were included in two separate meta-analyses according to the two clinical settings. There was no difference in treatment efficacy as measured by overall survival or response rate between the chemoradiation settings with low-dose weekly and high-dose three-weekly cisplatin regimens. In the definitive treatment setting, the weekly regimen was more compliant and significantly less toxic with respect to severe (grade 3-4) myelosuppression (leukopenia p = .0083; neutropenia p = .0024), severe nausea and/or vomiting (p < .0001), and severe nephrotoxicity (p = .0099). Although in the postoperative setting the two approaches were more equal in compliance and with clearly less differences in the cisplatin-induced toxicities, the weekly approach induced more grade 3-4 dysphagia (p = .0026) and weight loss (p < .0001). In LA-SCCHN, current evidence is insufficient to demonstrate a meaningful survival difference between the two dosing regimens. Prior to its adoption into routine clinical practice, the low-dose weekly approach needs to be prospectively compared with the standard three-weekly high-dose schedule. Given concurrently with conventional radiotherapy in locally advanced head and neck cancer, high-dose three-weekly cisplatin has often been replaced with weekly low-dose infusions to increase compliance and decrease toxicity. The present meta-analysis suggests that both approaches might be equal in efficacy, both in the definitive and postoperative settings, but differ in toxicity. However, some toxicity data can be influenced by unbalanced representation, and the conclusions are not based on adequately sized prospective randomized studies. Therefore, low-dose weekly cisplatin should not be used outside clinical trials but first prospectively studied in adequately sized phase III trials versus the high-dose three-weekly approach.

Szturz P ，Wouters K ，Kiyota N ，Tahara M ，Prabhash K ，Noronha V ，Castro A ，Licitra L ，Adelstein D ，Vermorken JB ... -  《-》

Altered fractionation radiotherapy combined with concurrent low-dose or high-dose cisplatin in head and neck cancer: A systematic review of literature and meta-analysis.

Altered fractionation radiotherapy and concomitant chemoradiotherapy represent commonly used intensification strategies in the management of locally advanced squamous cell carcinoma of the head and neck (LA-SCCHN). This meta-analysis compares compliance, safety, and efficacy between two single-agent cisplatin schedules given concurrently with altered fractionation radiotherapy. We systematically searched for prospective trials of patients with LA-SCCHN who received post-operative or definitive altered fractionation concurrent chemoradiotherapy. High-dose cisplatin once every three to four weeks (100 mg/m2, 2 doses) was compared with a weekly low-dose protocol (≤50 mg/m2, ≥4 doses). The primary outcome was overall survival. The secondary endpoints comprised treatment adherence, acute and late toxicities, and objective response rate. Twelve studies with 1373 patients treated with definitive chemoradiotherapy were included. Compared to the weekly low-dose cisplatin regimen, the three- to four-weekly high-dose cisplatin regimen improved overall survival (p=.0185), was more compliant with respect to receiving all planned cycles of cisplatin (71% versus 95%, p=.0353), and demonstrated less complications in terms of severe (grade 3-4) acute mucositis and/or stomatitis (75% versus 40%, p=.0202) and constipation (8% versus 1%, p=.0066), toxic deaths (4%, versus 1%, p=.0168), 30-day mortality (8% versus 3%, p=.0154), and severe late subcutaneous fibrosis (21% versus 2%, p<.0001). Overall and complete response rates were similar between both chemotherapy schedules. In chemoradiotherapy incorporating altered fractionation, two cycles of high-dose cisplatin with a three to four week interval are superior to weekly low-dose schedules. Further studies should identify those who might derive the greatest benefit from this intensified approach.

Szturz P ，Wouters K ，Kiyota N ，Tahara M ，Prabhash K ，Noronha V ，Adelstein D ，Vermorken JB ... -  《-》

The evidence on effectiveness of weekly vs triweekly cisplatin concurrent with radiotherapy in locally advanced head and neck squamous cell carcinoma (HNSCC): a systematic review and meta-analysis.

Jacinto JK ，Co J ，Mejia MB ，Regala EE ... -  《-》

Single-Arm Phase 2 Trial of Elective Nodal Dose Reduction for Patients With Locoregionally Advanced Squamous Cell Carcinoma of the Head and Neck.

To evaluate a novel chemoradiation therapy (CRT) regimen for patients with squamous cell carcinoma of the head and neck (SCCHN) incorporating a lower intensity modulated radiation therapy dose to electively treated neck lymph nodes than is currently standard. Eligible patients had locally advanced SCCHN of the oral cavity, oropharynx, larynx, or hypopharynx. The 7-week CRT course consisted of weekly cisplatin at 35 mg/m2 concurrently with sequential-boost intensity modulated radiation therapy: 36 Gy to high- and low-risk planning target volumes followed by a sequential boost to the high-risk planning target volume to 70 Gy. The primary endpoint was elective nodal failure. Secondary endpoints were survival, toxicity, feeding tube duration, and quality of life evaluated by the FACT-HN and QOL-RTI surveys. Between 2011 and 2014, 54 patients were enrolled, 31 (57%) of whom had human papillomavirus (HPV)-positive disease. Of the patients, 35 (65%) had stage IVa disease. The median follow-up period for survivors was 36 months (range, 12-66 months). Elective nodal failure did not develop in any patient. The actuarial 3-year survival rate for the entire cohort was 91% (95% confidence interval [CI] 0.79-0.96); for the HPV-negative group, 85% (95% CI 0.61-0.95); and for the HPV-positive group, 96% (95% CI 0.77-0.99). Common grade 3 toxicities were dysphagia (79%), mucositis and/or stomatitis (41%), nausea (20%), xerostomia (13%), vomiting (11%), and neutropenia (10%). The median feeding tube duration was 142 days. Patient FACT-HN scores were higher at 3, 6, and 12 months versus at the end of treatment (P < .0001). Total FACT-HN scores returned to pretreatment baseline by 6 months. Overall QOL-RTI scores were lower from pretreatment to the end of treatment through 12 months (P = .0001). This CRT regimen for patients with advanced SCCHN demonstrated the potential feasibility of reducing the elective dose to the neck, a topic that requires additional study in future clinical trials.

Maguire PD ，Neal CR ，Hardy SM ，Schreiber AM ... -  《-》

Phase 2 study of docetaxel, cisplatin, and concurrent radiation for technically resectable stage III-IV squamous cell carcinoma of the head and neck.

We investigated the efficacy and safety of weekly low-dose docetaxel and cisplatin therapy concurrent with conventionally fractionated radiation in patients with technically resectable stage III-IV squamous cell carcinoma of the head and neck. Between March 2004 and October 2011, we enrolled 117 patients, of whom 116 were analyzable (43 had oropharyngeal cancer, 54 had hypopharyngeal cancer, and 19 had laryngeal cancer), and 85 (73%) had stage IV disease. Radiation consisted of 66 Gy in 33 fractions. Docetaxel, 10 mg/m(2), followed by cisplatin, 20 mg/m(2), administered on the same day were given once a week for 6 cycles. The primary endpoint was overall complete response (CR) rate after chemoradiation therapy. Human papillomavirus (HPV) DNA in oropharyngeal cancer was examined by PCR. Of 116 patients, 82 (71%) completed treatment per protocol; 102 (88%) received the full radiation therapy dose; and 90 (78%) and 12 (10%) patients received 6 and 5 chemotherapy cycles, respectively. Overall CR rate was 71%. After median follow-up of 50.9 months (range: 15.6-113.9 months for surviving patients), 2-year and 4-year overall survival rates were 82% and 68%, respectively. Cumulative 2-year and 4-year local failure rates were 27% and 28%, respectively, whereas distant metastasis rates were 15% and 22%, respectively. HPV status in oropharyngeal cancer was not associated with treatment efficacy. Acute toxicity included grade 3 and 4 in-field mucositis in 73% and 5% of patients, respectively, whereas myelosuppression and renal injury were minimal. No patients died of toxicity. Feeding tube dependence in 8% and tracheostomy in 1% of patients were evident at 2 years postchemoradiation therapy in patients who survived without local treatment failure. Local control and survival with this regimen were satisfactory. Although acute toxicity, such as mucositis, was common, late toxicity, such as laryngoesophageal dysfunction, was minimal. Therapy using weekly low-dose docetaxel and cisplatin concurrent with radiation warrants further evaluation.

Inohara H ，Takenaka Y ，Yoshii T ，Nakahara S ，Yamamoto Y ，Tomiyama Y ，Seo Y ，Isohashi F ，Suzuki O ，Yoshioka Y ，Sumida I ，Ogawa K ... -  《-》