Accelerated Fractionation With Concomitant Boost vs. Conventional Radio-chemotherapy for Definitive Treatment of Locally Advanced Squamous Cell Carcinoma of the Head-and-Neck (SCCHN).

BACKGROUND/AIM: Patients with unresectable head-and-neck cancer (SCCHN) unable to tolerate radiochemotherapy may receive unconventionally fractionated radiotherapy. This retrospective study compared both treatments. PATIENTS AND METHODS: Eight patients unsuitable for chemotherapy were assigned to accelerated fractionation with concomitant boost (AF-CB, 69.6 Gy/39 fractions) over 5.5 weeks (group A) and 72 patients to cisplatin-based radiochemotherapy (70 Gy/35 fractions) over 7 weeks (group B). Groups were matched (cancer site, gender, age, performance score, T-/N-stage, histologic grade) and compared for loco-regional control (LRC), metastases-free survival (MFS), overall survival (OS) and toxicities. RESULTS: LRC, MFS, OS and radiation-related toxicities were not significantly different between groups A and B. Improved outcomes were associated with favorable cancer site, better performance score and T3-stage. In group B, toxicity led to reduction/discontinuation of chemotherapy in 38.9% and interruptions of radiotherapy >7 days in 19.3% of patients. CONCLUSION: AF-CB appeared a reasonable alternative for patients who cannot safely receive radio-chemotherapy for unresectable SCCHN.

Accelerated Fractionation Plus Chemotherapy Versus Conventionally Fractionated Radiochemotherapy for Unresectable Head-and-Neck Cancer.

BACKGROUND/AIM: Prognosis of patients with unresectable squamous cell carcinomas of the head and neck requires improvement. This retrospective study compared accelerated radiotherapy plus chemotherapy to conventional radiochemotherapy. PATIENTS AND METHODS: Patients received definitive treatment with accelerated radiotherapy plus chemotherapy (group A, n=10) or conventional cisplatin-based radiochemotherapy (group B, n=85). Groups were matched for several patient and tumor characteristics and compared for locoregional control (LRC), overall survival (OS) and toxicities. Additionally, accelerated radiotherapy plus chemotherapy and chemotherapy regimens in group B were compared for LRC and OS. RESULTS: Treatment type had no significant impact on LRC (p=0.98) and OS (p=0.57). In group A, toxicities occurred more often, including grade ≥3 mucositis (p=0.041), grade ≥2 lymphedema (p=0.007) and grade ≥3 leucopenia (p=0.007). Best 2-year LRC (p=0.39) and OS (p=0.015) was achieved with 20 mg/m2 cisplatin days 1-5 every 4 weeks; accelerated radiochemotherapy resulted in second-worst outcomes. CONCLUSION: Given the limitations of this study, accelerated radiotherapy plus chemotherapy provided no significant benefit but increased toxicity compared to conventional radiochemotherapy.

Comparison of Conventional Fractionation and Accelerated Fractionation With Concomitant Boost for Radiotherapy of Non-metastatic Stage IV Head-and-Neck Cancer.

BACKGROUND/AIM: Some patients with unresectable or incompletely resected head-and-neck cancer (SCCHN) cannot tolerate radiochemotherapy. Alternatives are needed that are more effective than conventional radiotherapy alone. PATIENTS AND METHODS: This retrospective study investigated patients irradiated for non-metastatic stage IV SCCHN who could not receive concurrent chemotherapy. Eight patients received accelerated radiotherapy with concomitant boost (group A) and 31 patients conventionally fractionated radiotherapy (group B). Groups were matched for tumor site, gender, age, performance score and histologic grade. RESULTS: Two-year PFS-rates were 63% in group A vs. 41% in group B, and median PFS-times were 36 vs. 10 months (p=0.48). Two-year OS-rates were 88% vs. 37%, and median OS-times were 44 vs. 14 months (p=0.19). Grade ≥2 radiation dermatitis was significantly (p=0.040) more common in group B; other toxicities were similar. CONCLUSION: Accelerated fractionation with concomitant boost appeared superior to conventional fractionation and can be considered for patients with stage IV SCCHN not suitable for radiochemotherapy. Larger studies are needed to confirm these findings.

Prognostic Value of Epithelial Cell Adhesion Molecules in T1-2N0M0 Glottic Cancer.

OBJECTIVE: This is an ancillary study of a multi-institutional randomized non-inferiority phase III trial of accelerated fractionation (AF) versus standard fractionation (SF) radiation therapy for T1-2N0M0 glottic cancer (JCOG0701). Biopsy specimens of tumors from the patients enrolled in the JCOG0701 are collected and the association between clinical outcomes and histopathologic features such as expression of epithelial cell adhesion molecule (EpCAM), p53, and p16 were investigated. METHODS: Five slices of undyed slides from biopsy specimens were sent to the National Cancer Center Hospital and all the specimens were assessed for the expression of EpCAM, p53, and p16. The primary objective was to investigate the association between 3-year progression-free survival (PFS) and expression of EpCAM, p53, and p16. RESULTS: A total of 88 out of 370 patients were enrolled in this ancillary study. The 3-year PFS for tumors with strong expression of EpCAM was 70.6% (95% CI 43.1%-86.6%), while that of tumors without strong expression of EpCAM was 77.5% (95% CI 65.9%-85.5%) with no remarkable difference between groups (P = .67). Likewise, there was no significant difference in 3-year PFS between tumors regardless of p53 or p16 status. However, in a subgroup analysis for 17 patients with a strong expression of EpCAM, AF showed better 3-year PFS than SF (100% vs 54.5%, P = .07). CONCLUSIONS: From the current study, it could not be concluded that EpCAM, p16, and p53 were prognostic factors for early-stage glottic cancer after primary radiation therapy. AF might be an appropriate fractionation for tumors with a strong expression of EpCAM. LEVEL OF EVIDENCE: 3 Laryngoscope, 131:1522-1527, 2021.

NPC-0501 trial on the value of changing chemoradiotherapy sequence, replacing 5-fluorouracil with capecitabine, and altering fractionation for patients with advanced nasopharyngeal carcinoma.

BACKGROUND: A current recommendation for the treatment of patients with locoregionally advanced nasopharyngeal carcinoma (NPC) is conventional fractionated radiotherapy (RT) with concurrent cisplatin followed by adjuvant cisplatin and 5-fluorouracil (PF). This randomized NPC-0501 trial evaluated the therapeutic effect of changing to an induction-concurrent sequence or accelerated-fractionation sequence, and/or replacing 5-fluorouracil with capecitabine (X). METHODS: Patients with American Joint Committee on Cancer/International Union Against Cancer stage III to stage IVB NPC initially were randomly allocated to 1 of 6 treatment arms (6-arm full-randomization cohort). The protocol was amended in 2009 to permit centers to opt out of randomization regarding fractionation (3-arm chemotherapy cohort). RESULTS: A total of 803 patients were accrued (1 of whom was nonevaluable) from 2006 to 2012. Based on the overall comparisons, neither changing the chemotherapy sequence nor accelerated fractionation improved treatment outcome. However, secondary analyses demonstrated that when adjusted for RT parameters and other significant factors, the induction-concurrent sequence, especially the induction-PX regimen, achieved significant improvements in progression-free survival (PFS) and overall survival. Efficacy varied among different RT groups: although no impact was observed in the accelerated-fractionation group and the 3-arm chemotherapy cohort, a comparison of the induction-concurrent versus concurrent-adjuvant sequence in the conventional-fractionation group demonstrated a significant benefit in PFS (78% vs 62% at 5 years; P = .015) and a marginal benefit in overall survival (84% vs 72%; P = .042) after adjusting for multiple comparisons. Comparison of the induction-PX versus the adjuvant-PF regimen demonstrated better PFS (78% vs 62%; P = .027) without an increase in overall late toxicity. CONCLUSIONS: For patients irradiated using conventional fractionation, changing the chemotherapy sequence from a concurrent-adjuvant to an induction-concurrent sequence, particularly using induction cisplatin and capecitabine, potentially could improve efficacy without an adverse impact on late toxicity. However, further validation is needed for confirmation of these findings.

Evaluation of purely accelerated six fractions per week radiotherapy in postoperative oral cavity squamous cell carcinoma.

OBJECTIVES: Randomized controlled trials have shown improved loco-regional control (LRC) and disease-free survival (DFS) by modest acceleration using six fractions per-week radiotherapy (RT) as compared to conventional fractionation in patients of head and neck squamous cell carcinoma. We aimed to evaluate the role of pure modestly accelerated fractionated radiotherapy (PM-ART) using six fractions per-week in patients of postoperative oral cavity squamous cell carcinoma (OCSCC). MATERIALS AND METHODS: Between May 2015 and July 2016, 40 OCSCC patients with ≥ 1 indication of RT were treated with adjuvant PM-ART, 60 Gray in 30 fractions over 5 weeks by three-dimensional conformal technique on a linear accelerator with a sixth 2 Gray fraction on Saturday using same fields. Primary endpoint was to assess acute toxicity, which was reviewed weekly during RT using Radiation Therapy Oncology Group criteria. RESULTS: Maximal grade 3 oral mucositis, pharynx/esophageal toxicity, and skin toxicity were seen in 77.5%, 25%, and 17.5%, respectively. Two patients had grade 4 mucositis. 47.5% were on tube feeding during RT. All the patients were taken off Ryle's tube within 4 weeks of RT completion. The median RT completion duration was 36 days. Three patients had treatment interruptions. With a median follow-up of 21.2 months, the 2-year LRC, DFS, and overall survival rates were 87.5%, 83.5%, and 85%, respectively. There were two distant failures. CONCLUSION: PM-ART is feasible and tolerable. The high acute mucositis rates did not result in increased consequential late toxicity.

Accelerated vs. conventionally fractionated adjuvant radiotherapy in high-risk head and neck cancer: a meta-analysis.

BACKGROUND: Adjuvant radiotherapy in advanced head and neck squamous cell cancer (HNSCC) reduces the risk of local-regional failure and most likely increases the survival rate. Patients at high risk for tumor recurrence may benefit from more aggressive altered fractionation schedules in order to reduce the overall time from surgery to completion of radiotherapy. Here, we reviewed the results of six randomized trials addressing the above hypothesis. METHODS: In the six trials of interest, a total of 988 patients with locally advanced HNSCC were randomly assigned to receive either accelerated or conventionally fractionated adjuvant radiotherapy. Hazard ratios (HR) were extracted from available publications for local-regional control, distant metastasis as well as overall-, cancer specific- and disease-free survival. Meta-analysis of the effect sizes was performed using fixed and random effect models. Acute and late side effects were categorized and summarized for comparison. RESULTS: Accelerated radiotherapy did not improve the loco-regional control (n = 988, HR = 0.740, CI = 0.48-1.13, p = 0.162), progression-free survival (HR = 0.89, CI = 0.76-1.04, p = 0.132) or overall survival (HR = 0.88, CI = 0.75-1.04, p = 0.148) significantly. Acute confluent mucositis occurred with significant higher frequency with accelerated radiotherapy. Late side effects did not differ significantly in either group. CONCLUSION: Accelerated radiotherapy does not result in a significant improvement of loco-regional control or overall survival in high-risk patients. Acute but not late radiation toxicity were more frequent with the accelerated RT technique. In clinical practice accelerated postoperative radiation therapy might be a suitable option only for a subset of patients.

Accelerated Radiation Therapy Using Weekend Boost with Concurrent Cisplatin in Head and Neck Squamous Cell Cancers: An Indian Institutional Experience.

PURPOSE: The purpose of the study was to evaluate the feasibility and efficacy of an accelerated radiotherapy schedule using weekend boost in terms of tumor response, compliance, and acute toxicities for head and neck squamous cell carcinoma, and to report long-term clinical outcomes. MATERIALS AND METHODS: Twenty-six patients with stages III-IV head and neck squamous cell carcinoma receiving radical chemoradiotherapy were accrued prospectively into the study. External beam radiation therapy to a total dose of 66-70 Gy in 33-35 fractions, 1.8-2.0 Gy per fraction along with concurrent weekly cisplatin was planned. Radiation regimen included delivery of six fractions per week, with boost field delivered as the sixth fraction on the weekend. The compliance, tumor response, and toxicities were recorded. Survival curves were estimated using the Kaplan-Meier method. RESULTS: Twenty-one of 26 patients (81%) completed treatment as planned and five patients died during the course of treatment. Sixteen patients (62%) completed treatment in less than 44 days and, at the end of 3 months' follow-up, 18 patients (69%) showed complete response and two patients (8%) showed partial response. The 2- and 5-year actuarial disease-free survival were 90% and 65%, respectively, and 2- and 5-year actuarial overall survival were 60% and 38%, respectively. CONCLUSION: Accelerated fractionation using weekend boost, along with concurrent weekly concurrent cisplatin, is an effective and promising approach with favorable impact on initial tumor response, comparable results, and acceptable toxicities.

Differences in health related quality of life in the randomised ARTSCAN study; accelerated vs. conventional radiotherapy for head and neck cancer. A five year follow up.

BACKGROUND AND PURPOSE: Health related quality of life (HRQoL) was assessed in the randomised, prospective ARTSCAN study comparing conventional radiotherapy (CF) with accelerated radiotherapy (AF) for head and neck cancer. MATERIAL AND METHODS: 750 patients with squamous cell carcinoma (of any grade and stage) in the oral cavity, oro-, or hypopharynx or larynx (except T1-2, N0 glottic carcinoma) without distant metastases were randomised to either conventional fractionation (2 Gy/day, 5 days/week in 49 days, total dose 68 Gy) or accelerated fractionation (1.1+2.0 Gy/day, 5 days/week in 35 days, total dose 68 Gy). HRQoL was assessed with EORTC QLQ-C30, QLQ-H&N35 and HADS at baseline, at end of radiotherapy (eRT) and at 3 and 6 months and 1, 2 and 5 years after start of treatment. RESULTS: The AF group reported HRQoL was significantly lower at eRT and at 3 months for most symptoms, scales and functions. Few significant differences were noted between the groups at 6 months and 5 years. Scores related to functional oral intake never reached baseline. CONCLUSION: In comparison to CF, AF has a stronger adverse effect on HRQoL in the acute phase.

Mature results from a Swedish comparison study of conventional versus accelerated radiotherapy in head and neck squamous cell carcinoma - The ARTSCAN trial.

BACKGROUND AND PURPOSE: This report contains the mature five-year data from the Swedish ARTSCAN trial including information on the influence of p16 positivity (p16+) for oropharyngeal cancers. MATERIAL AND METHODS: Patients with previously untreated squamous cell carcinoma without distant metastases of the oral cavity, oropharynx, larynx (except T1-2, N0 glottic cancers) and hypopharynx were included. Patients were randomised between accelerated fractionation (AF) (1.1Gy+2Gy per day, 5days/week for 4.5weeks, total dose 68Gy) and conventional fractionation (CF) (2Gy per day, 5days/week for 7weeks, total dose 68Gy). Human papillomavirus (HPV)-associated p16-expression was assessed retrospectively in tumour tissues from patients with oropharyngeal carcinoma. RESULTS: There was no significant difference in loco-regional control (LRC) between AF and CF (log-rank test p=0.75). LRC at 5years was 65.5% for AF and 64.9% for CF. Overall survival (OS) was similar in both arms (p=0.99). The estimated cancer specific survival (CSS) at 5years was 62.2% (AF) and 63.3% (CF) (p=0.99). 206 specimens were analysed for p16 with 153 specimens (74%) identified as p16+. P16 status did not discriminate for response to AF vs. CF with regard to LRC, OS or CSS. Patients with p16+ tumours had a statistically significant better overall prognosis compared with p16- tumours. CONCLUSION: This update confirms the results of the 2-year report. We failed to identify a positive effect resulting from AF with regards to LRC, OS and CSS. The addition of information on the HPV-associated p16 overexpression did not explain this lack of effect.

Accelerated radiotherapy for T1 to T2 glottic cancer.

BACKGROUND: Accelerated fractionation radiotherapy (RT) was administered in an attempt to improve the local control rates in patients with T1/T2 N0 glottic cancer. METHODS: Medical charts of 148 consecutive patients who had undergone RT using 2.4 Gray (Gy) once-daily fractionation between July 1999 and April 2007 were reviewed. RESULTS: Of 104 patients with T1 disease treated by RT, 82 received 60 Gy/25 fractions, and the remaining 22 with large tumor volumes and/or slow response to RT received 64.8 Gy/27 fractions. All 44 patients with T2 disease received 64.8 Gy/27 fractions. The 5-year local control and overall survival (OS) rates were 93% and 96%, respectively, in patients with T1 disease, and 77% and 91%, respectively, in patients with T2 disease. No severe acute toxicities were observed, although 2 patients (1%) developed severe late toxicity. CONCLUSION: Accelerated RT for early glottic cancer is feasible, with encouraging local control rates.

Preliminary results of trial NPC-0501 evaluating the therapeutic gain by changing from concurrent-adjuvant to induction-concurrent chemoradiotherapy, changing from fluorouracil to capecitabine, and changing from conventional to accelerated radiotherapy fractionation in patients with locoregionally advanced nasopharyngeal carcinoma.

BACKGROUND: A current recommendation for locoregionally advanced nasopharyngeal carcinoma (NPC) is conventional fractionated radiotherapy with concurrent cisplatin plus adjuvant cisplatin and fluorouracil (PF). In this randomized trial, the authors evaluated the potential therapeutic benefit from changing to an induction-concurrent chemotherapy sequence, replacing fluorouracil with oral capecitabine, and/or using accelerated rather than conventional radiotherapy fractionation. METHODS: Patients with stage III through IVB, nonkeratinizing NPC were randomly allocated to 1 of 6 treatment arms. The protocol was amended in 2009 to permit confining randomization to the conventional fractionation arms. The primary endpoint was progression-free survival. Secondary endpoints included overall survival and safety. RESULTS: In total, 803 patients were accrued, and 706 patients were randomly allocated to all 6 treatment arms. Comparisons of induction PF versus adjuvant PF did not indicate a significant improvement. Unadjusted comparisons of induction cisplatin and capecitabine (PX) versus adjuvant PF indicated a favorable trend in progression-free survival for the conventional fractionation arm (P = .045); analyses that were adjusted for other significant factors and fractionation reflected a significant reduction in the hazards of disease progression (hazard ratio [HR], 0.54; 95% confidence interval [CI], 0.36-0.80) and death (HR, 0.42; 95% CI, 0.25-0.70). Unadjusted comparisons of induction sequences versus adjuvant sequences did not reach statistical significance, but adjusted comparisons indicated favorable improvements by induction sequence. Comparisons of induction PX versus induction PF revealed fewer toxicities (neutropenia and electrolyte disturbance), unadjusted comparisons of efficacy were statistically insignificant, but adjusted analyses indicated that induction PX had a lower hazard of death (HR, 0.57; 95% CI, 0.34-0.97). Changing the fractionation from conventional to accelerated did not achieve any benefit but incurred higher toxicities (acute mucositis and dehydration). CONCLUSIONS: Preliminary results indicate that the benefit of changing to an induction-concurrent sequence remains uncertain; replacing fluorouracil with oral capecitabine warrants further validation in view of its convenience, favorable toxicity profile, and favorable trends in efficacy; and accelerated fractionation is not recommended for patients with locoregionally advanced NPC who receive chemoradiotherapy.

Prospective randomized trial to compare the outcome and tolerability of delivering the same total dose of radiation in 61/2 weeks versus 51/2 weeks time in head and neck cancers.

BACKGROUND: Concurrent chemoradiation is currently considered to be the standard of care in the treatment of head and neck cancer. In developing countries like ours, a good number of patients cannot tolerate chemoradiation because of the poor general condition and financial constraints. Those patients are treated with radiation alone. The optimum radiotherapy (RT) schedule for best local control and acceptable toxicity is not yet clear. We aimed to find out whether shortening of treatment time using six instead of five RT fractions per week improves the locoregional control in squamous cell carcinoma of head and neck. MATERIALS AND METHODS: We conducted a prospective randomized study for a period of 2 years from September 2007 to August 2009 in 109 untreated patients of squamous cell carcinoma of head and neck with histologically confirmed diagnosis and no evidence of distant metastasis. Study group (55 patients) received accelerated RT with 6 fractions per week (66 Gy/33#/51/2 weeks). Control group (54 patients) received conventional RT with 5 fractions per week (66 Gy/33#/61/2 weeks). Tumor control, survival, acute and late toxicities were assessed. RESULTS: At a median follow-up of 43 months, 29 patients (52.7%) in the 6 fractions group and 24 patients (44.4%) in the 5 fractions group were disease-free (P = 0.852). The benefit of shortening was higher for advanced disease control though it was not statistically significant. Grade 3 and 4 skin toxicity was significantly higher in the accelerated RT (70.9%) arm as compared to conventional (35.1%) arm (P = 0.04). Grade 3 mucositis was significantly higher in the accelerated RT arm (32.7% vs. 16.6%; P = 0.041). Those acute toxicities were managed conservatively. There was no difference in late toxicities between the two arms. CONCLUSION: Use of 6 fractions per week instead of 5 fractions per week is feasible, tolerable, and results in a better outcome in the patients of head and neck cancers.

Different fractionation schedules of radiotherapy in locally advanced head and neck malignancy: A prospective randomized study to compare the results of treatment and toxicities of different protocols.

CONTEXT: Altered fractionated radiotherapy may have better result than conventional radiotherapy and concomitant chemoradiotherapy to treat locally advanced head and neck cancers. AIMS: Evaluation of the response and toxicities in different fractionated radiotherapy schedules in locally advanced head and neck cancer. MATERIALS AND METHODS: Sixty four histologically proved patients of locally advanced head and neck cancer were included in the study according to protocol and were randomized into three arms. Arm A (n = 21) received 66 Gy in 33 fractions (5 fractions/week from Monday to Friday) single fraction daily in 6½ weeks along with concomitant chemotherapy (injection Cisplatin 30 mg/m(2) intravenous once weekly) for 6 weeks. Arm B (n = 21) received 66 Gy in 33 fractions (6 fractions per week) single fraction daily in 5½ weeks, and arm C (n = 22) received late hyperfractionation after 3 weeks; 30 Gy in 15 fractions in 3 weeks followed by 1.4 Gy twice daily (time gap between 2 fractions were 6 hours) for 15 days with a total of 72 Gy in 6 weeks. Response to treatment, compliance, and toxicities were compared in all the three arms. STATISTICAL ANALYSIS USED: Frequency table and chi square tests done. RESULTS: Baseline data were comparable in all the three arms. Complete response in arm A, arm B, and arm C were 15%, 26.315%, and 23.81%, respectively (P = 0.339). Grade 1 Neutropenia in arm A was 15%, arm B was 26.32%, and arm C was nil (P = 0.0486). CONCLUSION: Altered fractionation and concurrent chemoradiation showed similar response with comparable acute toxicities except nutropenia, which was significantly higher in arm B.