Radiotherapy for cancer of the head and neck: altered fractionation regimens

doi:10.1016/S1470-2045(02)00906-3

The Lancet Oncology

Volume 3, Issue 11, November 2002, Pages 693-701

https://doi.org/10.1016/S1470-2045(02)00906-3 Get rights and content

Summary

A greater understanding of radiobiology led to the development of two classes of radiation fractionation schedules for the treatment of head and neck cancers. The aim of accelerated fractionation is to reduce tumour proliferation, which is a major cause of relapse, by shortening the total duration of radiotherapy. By contrast, hyperfractionation exploits the differential sensitivity of tumour cells and normal tissues to radiation, to increase the therapeutic gain. The results of clinical trials of various types of altered fractionation schedules in head and neck carcinomas are examined in this review. Acceleration of radiation by 1 week without dose reduction and hyperfractionation are consistently better than standard fractionation for locoregional control of intermediate to advanced carcinomas without an increase in late toxic effects. However, improvement in survival of patients has not been consistent. Clinical investigations show that improvement in locoregional disease control and consistent gain in survival have been achieved with combinations of radiotherapy and concurrent chemotherapy in patients with mostly stage IV carcinomas. However, these benefits have been at the expense of increased late morbidity. Consequently, concurrent radiochemotherapy is now preferred for non-surgical treatment of patients with locally advanced carcinomas, whereas altered fractionation is generally selected for patients with intermediate-stage tumours or who are medically unfit to receive chemotherapy. Further data is needed before the combination of altered fractionation with chemotherapy can be recommended outside of a study setting.

Section snippets

Pure accelerated fractionation

Table 1 summarises the data of four prospective trials of pure accelerated fractionation versus conventional fractionation.17, 18, 19, 20 The experimental regimens in the first two trials were found to induce unacceptable, mostly acute toxicity, and therefore, have been abandoned. However, the two other trials yielded positive outcomes.

The Vancouver Cancer Center did a trial of ten fractions of 2 Gy per week, in which they shortened the overall treatment time in which to give a total dose of 66

Hybrid accelerated fractionation

Table 2 summarises the results of five randomised trials comparing three types of hybrid accelerated fractionation with the conventional regimen.21, 22, 23, 24, 25 Three trials assessed type A fractionation with varying treatment acceleration and total-dose reduction. The CHART schedule has the most drastic acceleration (4·5 weeks) and the greatest reduction in total radiation dose (18%).²¹ In this trial of 918 patients, most with laryngeal carcinomas, CHART did not improve tumour control and

Hyperfractionation

Table 3 summarises the results of four randomised trials of hyperfractionation versus conventional fractionation in the management of intermediate oropharyngeal²⁶ and locally advanced head and neck carcinoma.25, 27, 28

The conventional regimen of the Princess Margaret Hospital study²⁸ was 51 Gy given in 2·55 Gy per fraction over 4 weeks rather than the more common regimen of 66–70 Gy given in fractions of 2·0 Gy over 6·5–7·0 weeks.25, 26, 27 Consequently, the hyperfractionation in this trial

Accelerated postoperative radiotherapy

Accelerated fractionation similar to the concomitant-boost regimen as postoperative radiotherapy was studied in a joint trial of the MD Anderson Cancer Center, H Lee Moffitt Cancer Center, and Mayo Clinic.²⁹ Patients had advanced head and neck carcinomas with high-risk features based on prognostic data derived from a previous phase III trial;³⁰ those with multiple positive lymph nodes, extranodal disease extension, close or positive resection margins, perineural tumour extension, oral-cavity

Integration of altered-fractionation regimens and chemotherapy

Several randomised studies31, 32, 33, 34 and two meta-analyses35, 36 show a survival benefit with concurrent chemotherapy and radiotherapy. These findings have prompted many investigators to combine altered-fractionation schedules with chemotherapy in an attempt to improve cure rates in advanced head and neck carcinomas.

Table 4 summarises the results of six randomised studies of altered fractionation combined with various concurrent chemotherapy regimens.32, 37, 41 However, the design of most

Conclusion

This review of 18 trials of over 6000 patients leads to several general conclusions, which can contribute to improving the standard of care for patients with head and neck cancer. Although many types of accelerated-fractionation regimens were studied, four findings emerge from the available data.

A modest acceleration of radiotherapy by 1 week, without total-dose reduction or a break in treatment, by giving six fractions of 2 Gy per week or by a concomitant-boost regimen, consistently yields

Current standard of care and future directions

To improve the standard of care for patients with carcinoma of the head and neck, results of fractionation trials need to be integrated with data on combinations of radiotherapy and chemotherapy. The Meta-analysis of Chemotherapy on Head and Neck Cancer Collaborative Group reported that concurrent radiation, given mainly as conventional fractionation, and chemotherapy had a larger survival benefit than altered-fractionation regimens.³⁶ This benefit, however, has been detected mostly in patients

Search strategy and selection criteria

A literature search was conducted in PubMed for studies from 1985 onwards using the search term “head and neck cancer” plus combinations of “altered fractionation”. “hyperfractionation”, “accelerated fractionation”, “chemotherapy”, and “randomised trial”. Only papers in English were included. Cross-referencing of relevant articles identified further papers. In addition, the proceedings of the annual meetings of the American Society of Therapeutic Radiology and Oncology, the European Society of

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Cited by (92)

Resource-sparing curative-intent hypofractionated-accelerated radiotherapy in head and neck cancer: More relevant than ever before in the COVID era
2020, Oral Oncology
The incidence of head and neck squamous cell carcinoma (HNSCC) is increasing worldwide, with over three quarters of cases now diagnosed in low and middle-income countries (LMICs) with resource-constraints. Loco-regional recurrence remains the predominant pattern of failure mandating adequate local therapy for acceptable loco-regional control and survival. There is high-quality evidence that intensification of treatment by either by adding concurrent chemotherapy or by altering radiotherapy (RT) fractionation improves outcomes in the curative-intent management of loco-regionally advanced HNSCC. Even conservative estimates indicate that >50% of patients in LMIC are unlikely to get access to timely RT, which will only get compounded with the coronavirus disease (COVID)-19 pandemic. The radiation oncology community has been systematically testing altered fractionation schedules in several solid cancers (breast, lung, and head-neck), given the cost-effectiveness, convenience, and compliance to short-course RT regimens. Radiobiological modelling suggests that standard fractionation of 6–7 weeks in HNSCC can be compressed safely into a 4-week schedule to counter accelerated repopulation by increasing the dose per fraction and delivering 5 fractions per week which is currently being tested in the ongoing multicentric trial of hypo- vs normo-fractionated accelerated RT (HYPNO study). Herein, we discuss the radiobiological basis of curative-intent hypofractionated-accelerated RT schedule delivering 55 Gy in 20 fractions over 4 weeks in HNSCC followed by critical appraisal of the published literature on such regimens with concurrent systemic therapy and its inherent resource-sparing potential applicable across large parts of the world particularly in the context of the ongoing COVID-19 pandemic.
Randomized phase-III-trial of concurrent chemoradiation for locally advanced head and neck cancer comparing dose reduced radiotherapy with paclitaxel/cisplatin to standard radiotherapy with fluorouracil/cisplatin: The PacCis-trial
2020, Radiotherapy and Oncology
This multicenter, phase 3 trial investigates whether the incorporation of concurrent paclitaxel and cisplatin together with a reduced total dose of radiotherapy is superior to standard fluorouracil–cisplatin based CRT.
Patients with SCCHN, stage III–IVB, were randomized to receive paclitaxel/cisplatin (PacCis)–CRT (arm A; paclitaxel 20 mg/m² on days 2, 5, 8, 11 and 25, 30, 33, 36; cisplatin 20 mg/m², days 1–4 and 29–32; RT to a total dose of 63.6 Gy) or fluorouracil/cisplatin (CisFU)–CRT (arm B; fluorouracil 600 mg/m²; cisplatin 20 mg/m², days 1–5 and 29–33; RT: 70.6 Gy). Endpoint was 3-year-disease free survival (3y-DFS).
A total of 221 patients were enrolled between 2010 and 2015. With a median follow-up of 3.7 years, 3y-DFS in the CisFU arm and PacCis arm was 58.2% and 48.4%, respectively (HR 0.82, 95% CI 0.56–1.21, p = 0.52). The 3y-OS amounted to 64.6% in the CisFU arm, and to 59.2% in the PacCis arm (HR 0.82, 95% CI 0.54–1.24, p = 0.43). In the subgroup of p16-positive oropharyngeal carcinomas, 3y-DFS and 3y-OS was 84.6% vs 83.9% (p = 0.653), and 92.3% vs. 83.5% (p = 0.76) in arm A and B, respectively. Grade 3–4 hematological toxicities were significantly reduced in arm A (anemia, p = 0.01; leukocytopenia, p = 0.003), whereas grade 3 infections were reduced in arm B (p = 0.01).
Paclitaxel/cisplatin–CRT with a reduced RT-dose is not superior to standard fluorouracil/cisplatin–CRT. Subgroup analyses indicate that a reduced radiation dose seems to be sufficient for p16+ oropharyngeal cancer or non-smokers.
Clinical trial information: NCT01126216; EudraCT Number 2005-003484-23.
Cancer of the Head and Neck
2019, Abeloff’s Clinical Oncology
In the United States it is estimated that there will be 51,540 new cases of head and neck cancer in 2018, accounting for 3% of all cancer cases and 1.5% of all cancer deaths. The three major risk factors for head and neck cancer are tobacco, human papillomavirus (HPV) infection, and alcohol. The treatment of head and neck cancer is dictated by the primary site. Most oropharyngeal cancers in the United States are now due to human papillomavirus (HPV) and as such have an improved prognosis. Early-stage oropharynx cancers can effectively be treated with surgery or RT. The standard of care for locally advanced disease is CRT; however, incorporation of transoral robotic surgery (TORS) is under active investigation. Surgery is generally considered the preferred initial treatment modality for oral cavity lesions with adjuvant RT with or without chemotherapy for patients with high-risk features on surgical pathology. In patients with laryngeal cancer, the goal of first-line therapy should be to preserve the function of the larynx, without sacrificing tumor control. Early-stage laryngeal cancer can effectively be treated with either surgery or RT. In early stage disease, the anatomic location and extent of disease will dictate if surgery is feasible. The treatment of choice in most locally advanced larynx cancers is concurrent chemotherapy and radiation. Management of head and neck cancers requires a multidisciplinary approach with effective integration of multiple specialties to achieve the desired goals of cure and functional organ preservation.
Hypofractionated accelerated radiotherapy in T1–3 N0 cancer of the larynx: A prospective cohort study with historical controls
2016, Reports of Practical Oncology and Radiotherapy
The goal of this prospective study was to assess the effectiveness of a hypofractionated accelerated regime in treatment of the larynx cancer.
Multiple radiotherapy delivery regimes are used for treatment of the larynx cancer. Hypofractionated regimes could provide similar results with reduced use of radiotherapy facilities.
223 patients with squamous cell carcinoma of the upper or middle larynx have been treated with 63 Gy delivered in 28 fractions of 2.25 Gy during 38 days, 5 fractions per week. The study endpoints were overall survival, progression-free survival, early and late treatment toxicity. Standard and accelerated radiotherapy groups from the study published by Hliniak et al.²⁰ served as controls.
Five-year actuarial overall survival was 87.5% in the study group, 84.5% in the control group receiving accelerated radiotherapy (33 fractions of 2.0 Gy, 6 fractions per week) and 86.2% in the control group (33 fractions of 2.0 Gy, 5 fractions per week). Five-year progression-free survival was 73.6%, 77.2% and 66.2%, respectively. Overall, treatment toxicity and complication rates did not differ between the study group and the control groups.
The hypofractionated accelerated radiotherapy protocol using 5 fractions per week reduced the use of radiotherapy facilities. There was no significant difference in overall survival and progression-free survival between the study and control groups treated with accelerated or standard radiotherapy.
Does a multidisciplinary team approach in a tertiary referral centre impact on the initial management of head and neck cancer?
2016, Oral Oncology
A multi-disciplinary team (MDT) is essential in the management of cancer. Head and neck cancer (HNC) is a rare, complex and heterogeneous group of malignancies for which different treatment options are available. However, the potential impact of MDT on the management of HNC has been only poorly evaluated to date. This study evaluates the impact of MDT on the management of HNC in a tertiary centre.
We retrospectively analysed records of HNC patients referred to a MDT evaluation at the Istituto Nazionale Tumori of Milan, Italy, from May 2007 to January 2012. All cases were reviewed by a MDT consisting of a head and neck surgeon, a radiation oncologist, and a medical oncologist.
Data from 781 HNC patients were analysed. Approximately 70% of patients were referred to our Institution for a second opinion consultation. Following MDT evaluation, new staging examinations were requested in 49% of patients, and treatment plan was modified in 10%.
A MDT approach in a tertiary referral hospital leads to staging refinement of disease or changes in treatment plan in about 60% of patients.
Systematic Review and Meta-analysis of Conventionally Fractionated Concurrent Chemoradiotherapy versus Altered Fractionation Radiotherapy Alone in the Definitive Management of Locoregionally Advanced Head and Neck Squamous Cell Carcinoma
2016, Clinical Oncology
Citation Excerpt :
Recent emphasis on preservation of organ form and function [5,6] with a potential favourable impact on quality of life has prompted more widespread use of definitive non-surgical approaches, particularly for cancers of the laryngo-pharynx. Traditionally, the most common non-surgical approach has been radical radiotherapy using conventional fractionation defined as radiotherapy given at a dose of 1.8–2 Gy per fraction, one fraction per day, five fractions per week to the prescribed total dose (generally 66–70 Gy in HNSCC) over 6.5–7 weeks [7,8]. It is now firmly established that the intensification of such treatment either by the addition of chemotherapy or by the alteration of the conventional fractionation schedule improves outcomes in the radiotherapeutic management of locoregionally advanced HNSCC [9].
Treatment intensification either by using concurrent chemoradiotherapy (CCRT) or altered fractionation radiotherapy (AFRT) improves outcomes of locoregionally advanced head and neck squamous cell carcinoma (HNSCC). The superiority of one approach over the other, however, remains to be firmly established. The aim of the present study was to compare outcomes of CCRT versus AFRT in the definitive non-surgical management of locoregionally advanced HNSCC for evidence-based decision making.
An electronic search of Medline via PubMed was conducted with no language, year, or publication status restrictions. The Cochrane Central Register of Controlled Trials (CENTRAL) and Database of Abstracts of Reviews of Effectiveness (DARE) were also searched electronically. Only randomised controlled trials assigning HNSCC patients randomly to conventionally fractionated CCRT or AFRT alone were included. Data were extracted independently by two reviewers and pooled using the Cochrane methodology for meta-analysis and expressed as a hazard ratio with 95% confidence intervals. Overall survival was the primary outcome of interest, whereas disease-free survival, locoregional control and toxicity were secondary end points.
Five randomised controlled trials (involving 1117 patients and 627 deaths) directly comparing conventionally fractionated CCRT with AFRT alone were included. The risk of bias in included studies was low for efficacy outcomes, but high for toxicity outcomes. The overall pooled hazard ratio of death was 0.73 (95% confidence interval = 0.62–0.86), which significantly favoured conventionally fractionated CCRT over AFRT alone (P < 0.0001). Similarly, disease-free survival (hazard ratio = 0.79, 95% confidence interval = 0.68–0.92; P = 0.002) and locoregional control (hazard ratio = 0.71, 95% confidence interval = 0.59–0.84; P < 0.0001) were significantly improved with CCRT. There were no significant differences in the incidence of severe acute toxicity (dermatitis and mucositis) between the two approaches of treatment intensification. Late xerostomia was significantly increased with CCRT. Significant haematological toxicity and nephrotoxicity were seen exclusively with chemotherapy.
There is moderate quality evidence that conventionally fractionated CCRT improves survival outcomes compared with AFRT alone in the definitive radiotherapeutic management of locoregionally advanced HNSCC. No form of acceleration can potentially compensate fully for the lack of concurrent chemotherapy.

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ReviewRadiotherapy for cancer of the head and neck: altered fractionation regimens

Summary

Section snippets

Pure accelerated fractionation

Hybrid accelerated fractionation

Hyperfractionation

Accelerated postoperative radiotherapy

Integration of altered-fractionation regimens and chemotherapy

Conclusion

Current standard of care and future directions

Search strategy and selection criteria

Int J Radiat Oncol Biol Physics

Radiother Oncol

Int J Radiat Oncol Biol Physics

Int J Radiat Oncol Biol Physics

Int J Radiat Oncol Biol Physics

Radiother Oncol

Int J Radiat Oncol Biol Physics

Radiother Oncol

Int J Radiat Oncol Biol Physics

Int J Radiat Oncol Biol Physics

Radiother Oncol

Radiother Oncol

Radiother Oncol

Radiother Oncol

Int J Radiat Oncol Biol Physics

Radiother Oncol

Int J Radiat Oncol Biol Physics

Int J Radiat Oncol Biol Physics

Int J Radiat Oncol Biol Physics

Lancet

Review
Radiotherapy for cancer of the head and neck: altered fractionation regimens