Southern Area Radiation, Mater Centre, Brisbane
Efforts to improve the cure rates of advanced squamous cell carcinoma of the head and neck cancer have been made by altering the dose and fractionation schedules for radiation treatment in an attempt to strike a better balance between tumour kill and normal tissue side-effects. Altered fractionation may involve acceleration, hyperfractionation or hypofractionation. Acceleration overcomes the problem of tumour cell repopulation by reducing the overall treatment time with slight reductions in the total dose and dose per fraction. Hyperfractionation aims at reducing the late effects of treatment while improving loco-regional control by reducing the dose per fraction, increasing the total dose and keeping the overall time the same. Hypofractionation applies a high dose per fraction and is useful for palliative radiation where biologically effective doses of radiation can be delivered in a short overall time without unacceptable acute effects of treatment. A recent meta-analysis of altered fractionation schedules has been performed on more than 6500 patients in 15 trials and shows a small but significant absolute survival benefit of 3.4% at five years. This benefit was greatest for the hyperfractionation trials and was of a similar magnitude to the effect of adding chemotherapy synchronously to radiation. By understanding the biological basis for altered fractionation, these schedules can be applied to different scenarios in advanced head and neck cancer and achieve results better than conventional fractionation.
In the past 20 years, many strategies have looked at improving the effectiveness of radiotherapy in advanced squamous cell carcinoma (SCC) of the head and neck. These have included incorporating the use of other treatment modalities such as surgery, chemotherapy and more recently biological modifiers such as the epidermal growth factor receptor antagonists. Small but significant improvements can also be achieved by altering the dose, fractionation and delivery of treatment to target volumes through the use of conformal radiation or intensity modulated radiotherapy (IMRT).
Radiation is delivered in multiple sessions or fractions to allow normal tissues to repair sublethal damage that has been incurred by the radiation. Normal tissues exhibit increased repair capacities compared to tumour cells and fractionation exploits this intrinsic difference. Altered fractionation schedules seek to improve the therapeutic ratio between tumour cell kill and normal tissue damage by exploiting the dissociation between acute and late radiation effects. Increased tumour control and acute toxicity are related to increasing the total dose and decreasing overall treatment time and is relatively unaffected by dose per fraction. Conversely, the late effects of radiation treatment are related to total dose and dose per fraction and are relatively unaffected by overall treatment time. If however, the acute effects become so severe that stem cells are depleted, then consequential late effects can occur.
The biological effective dose (BED) of radiation can be calculated mathematically:1,2
BED= D(1 + d/a/b)
where D= total dose and d= dose per fraction. The a/b ratio varies from tissue to tissue with late responding tissues having an a/b ratio of 1-3 and acute responding tissues and tumours having an a/b ratio of 8-10.
This paper reviews the methods of altering fractionation in the head and neck region and the clinical studies that have investigated its use over the past 20 years. The rationale and effects of altering fractionation are summarised in Table 1.
Conventional radiotherapy is given with external beam radiotherapy once per day in doses of 2 Gy, five days a week. Typical conventional schedules in Australia, the US and Europe are 60-70 Gy in 30–35 fractions given over six to seven weeks. In the UK, schedules tend to be shorter by using a larger dose per fraction, such that 50 Gy is delivered in 20 fractions over four weeks.
Hyperfractionation seeks to increase the total dose, number of fractions and reduce the dose per fraction so that the total treatment can be delivered in the same overall time as a conventional treatment. This is achieved by treating the patient with two or more fractions per day. The reduction in dose per fraction allows the total dose of treatment to be escalated. The linear quadratic equation would predict that this would produce a higher tumour effect and a reduced level of late effects.
One of the earliest prospective randomised trials to test this was the European Organization for Research and Treatment of Cancer (EORTC 22791).3 They randomised 352 patients with T2-3 N0-1 oropharyngeal cancers (excluding tongue base) to receive either a conventional course of 70Gy in 35 fractions over seven weeks or a hyperfractionated treatment of 80.5 Gy given at 1.15 Gy twice per day, so that the total treatment was completed in seven weeks. The five year rates of local control (59% vs 40% [p=0.02]) and survival (40% vs 30% [p=0.08]) were improved in the hyperfractionated arm. Acute effects were more severe and late effects less in the hyperfractionated arm.
Hyperfractionated radiotherapy has also been compared to accelerated split course, concomitant boost and conventional radiotherapy in the four arm Radiation Therapy Oncology Group (RTOG) 9003 trial.4 Patients treated with hyperfractionated and concomitant boost had better loco-regional control than those treated with standard fractionation. There was no difference in survival that could be demonstrated. Acute side-effects were worse in the altered fractionation arms compared to conventional radiotherapy, but there were no increased late effects.
These two trials and those of the Pinto5,6 have been combined in a meta-analysis of hyperfractionated trials.7 There was a survival benefit of 8% at five years which is similar in magnitude to synchronous chemo-radiotherapy. The hazard ratio of death for hyperfractionated treatment was 0.78 [0.69-0.89].
The rationale for accelerating radiation schedules is predicated on tumour cells undergoing accelerated repopulation during the treatment course after a lag time.8 By shortening the overall treatment time, less of the total dose of radiation will be wasted in compensating for accelerated tumour cell repopulation during the treatment course. Approximately 40-60 cGy per day is required to correct for accelerated repopulation. Accelerating the treatment course will also result in an increase in normal tissue toxicity, especially mucositis. Reductions in overall treatment time are difficult for head and neck cancer patients to tolerate unless reductions in total dose are made. Strong acceleration may only partially compensate for decreasing the total dose of radiation. Accelerated protocols can be divided into those without a dose reduction and those with an overall dose reduction. Examples of each of these will be given.
The potential hazard of not reducing total dose or fraction size in accelerated radiotherapy is illustrated in the British Columbia Cancer Agency study.9 In this trial, both arms received a dose of 66 Gy in 2 Gy fractions, but the accelerated group received two fractions per day. Acute effects were more severe in the accelerated arm and grade 4 late effects were also much higher. This led to the trial being abandoned after accruing only 82 of a target total of 226 patients.
In a trial run by the French Head and Neck Oncology Group, 268 patients with advanced head and neck were randomised to 70 Gy in seven weeks using 2 Gy daily fractions, or 63-64 Gy in three weeks using twice daily 2 Gy fractions.10 Acute toxicity was worse in the accelerated arm. However, there was an improvement in loco-regional control and a marginal improvement in overall survival and disease free survival.
Mucosal reactions may be problematic even in accelerated regimens delivered over five weeks. A study from Poland11 randomised 109 patients to continuous accelerated irradiation (CAIR) with daily treatment seven days a week, including Saturday and Sunday, or to conventional fractionation 5 fractions per week. The dose per fraction was initially 2 Gy, but was reduced to 1.8 Gy due to a high number of consequential late effects. The total dose in CAIR was 66-72 Gy depending on stage. Confluent mucositis was significantly more severe and lasted longer in the CAIR arm, but the relative risk of tumour relapse or death was six-fold lower.
The EORTC (split course) accelerated protocol12 introduced a deliberate break in treatment to allow 72 Gy to be delivered in 45 fractions over a total of five weeks. This regimen produced a 13% improvement in loco-regional control over the conventional arm (70 Gy in 35 fractions over seven weeks), but both acute and late morbidities were increased substantially. It was speculated that the observed increase in late effects may have been due to insufficient intervals (four hours) between fractions. However, it is also possible that the increase in acute toxicity resulted in consequential late radiation injury.
The importance of even small amounts of acceleration was emphasised by the results from the Danish Head and Neck Cancer Study Group (DAHANCA) 6 and 7 trial.13 A one week reduction in overall treatment time by giving six fractions per week instead of five fractions per week achieved a 10% improvement in loco-regional control with no impact on late morbidity. It did result in increased confluent mucositis (66% versus 46%), but the skin toxicity was the same.
The Continuous Hyperfractionated Accelerated Radiotherapy Trial (CHART)14 showed that acceleration can produce equivalent results to conventional radiation even when significant reductions in overall dose occur. In this study, 54 Gy in 36 fractions over 12 days was compared with a conventional arm of 66 Gy in 33 fractions over six-and-a-half weeks. There was no improvement in loco-regional control compared to the conventional arm, with the exception of advanced laryngeal tumours. Acute morbidity was increased in CHART but the reduction in total dose and dose per fraction was associated with a reduction in later morbidities including osteochondritis, skin telangiectasia, mucosal ulceration and laryngeal oedema.
Concomitant boost achieves modest acceleration and no dose reduction by treating twice a day in the last week of treatment when tumour cells should be undergoing rapid repopulation. This limits the intense radiation to the areas of gross disease so that areas of microscopic involvement only receive standard fractionation. The RTOG 90-03 study 14 showed that concomitant boost (72 Gy in 42 fractions over six weeks) and hyperfractionation (81.6 Gy in 68 fractions over seven weeks) had better loco-regional control than conventional fractionation, but there was no difference in overall survival. The acute effects were increased, but there were no increases in the late effects.
The Trans Tasman Radiation Oncology Group (TROG) 91:01 study compared a modest acceleration protocol of 59.4 Gy in 33 fractions over 24 days with a conventional schedule of 70 Gy in 35 fractions over 49 days.15 Differences in loco-regional control, disease free survival and overall survival could not be demonstrated. There were more acute mucosal reactions in the accelerated arm, but late effects were reduced with the exception of late mucosal reactions.
A meta-analysis of accelerated protocols has been performed.7 There were eight randomised trials without dose reduction and five with a total dose reduction. The hazard ratio for death for the first group was 0.97 [0.89-1.05] and for the second group was 0.92 [0.86-0.97]. The absolute survival improvement at five years was 2% and 1.7% respectively and the improvements in loco-regional control at five years were 7.3% and 2.3%.
Hypofractionated radiotherapy utilises a small number of fractions with a larger dose per fraction. The overall time is usually shorter than an accelerated protocol. These regimes produce worse late effects than conventional fractionation when used in the curative setting.16 The acute reactions are acceptable if treatment volumes are kept small and tolerability can be improved by introducing treatment breaks into the protocol.
This type of schedule is most suited to the patient with poor performance status in whom the aim of treatment is to palliate symptoms and cause as little as possible in the ways of side-effects. These patients have a poor prognosis with a median survival of four to eight months.17
There are a number of phase I and II studies that have looked at hypofractionated palliative radiotherapy for advanced SCC of the head and neck. The QUAD SHOT18 was developed with the aim of delivering short intense doses of radiation that were below the threshold for mucositis. The protocol consists of 14 Gy in four fractions over two days and can be repeated in responders up to a total dose of 42 Gy in 12 fractions. In patients with very advanced disease and poor performance status, objective responses were produced in 53% of cases and 44% had improvements in their quality of life. Other palliative schedules include that of Paris19, who used 3.7 Gy twice a day for two days and repeated this monthly for three months. Although 40% did not complete the full course, responses were achieved in 77% of cases. We are evaluating a hypofractionated schedule which involves treating patients twice per week in 6 Gy fractions to a total dose of 30-36 Gy. This is well tolerated in terms of acute reactions and is equivalent to 40 Gy in 2 Gy fractions in terms of tumour and mucosal effects (Porceddu S, personal communication). Comparing these protocols with each other is difficult because of the heterogeneity of advanced SCC of the head and neck and the problems associated with measuring quality of life rather than just survival.
There is level one evidence indicating that altered fractionation achieves better results than conventional radiotherapy in advanced SCC of the head and neck, although the margin of improvement is modest. The greatest benefits have been achieved in hyperfractionation and acceleration without dose reductions. The margin of benefit is similar to that achieved with synchronous chemotherapy and radiotherapy which has now become the gold standard for advanced SCC of the head and neck. Accelerated and hyperfractionated radiotherapy will both increase acute side-effects of treatment, especially mucositis. The late effects are usually reduced, but there may be an increase in late effects through consequential acute effects. If the acceleration is too intense, significant dose reductions or treatment splits have to be applied to mitigate the acute side-effects and this will only be partially compensated by reducing the tumour cell repopulation. As hyperfractionation involves an increased number of radiation treatments, this may have limited application in Australia and Europe where there is a huge demand on limited radiotherapy resources.
Hyperfractionation and accelerated fractionation should be considered in advanced SCC of the head and neck where the patient is not fit for synchronous chemo-radiotherapy. By understanding the biological basis for altered fractionation, these schedules can be applied to different scenarios in advanced head and neck cancer and achieve results better than conventional fractionation.
3. Horiot JC. et al. Hyperfractionated versus conventional fractionation in oropharyngeal carcinoma: the final analysis of the EORTC co-operative group of radiotherapy. Radiother Oncol. 1992;25:231-241.
4. Fu KK, et al. A Radiation Therapy Oncology Group (RTOG) phase III randomized study to compare hyperfractionation and two variants of accelerated fractionation to standard fractionation radiotherapy for head and neck squamous cell carcinomas: first report of RTOG 9003. Int J Radiat Oncol Biol Phys. 2000;48(1):7-16.
5. Pinto L, et al. Prospective randomised trial comparing hyperfractionated versus conventional radiotherapy in Stage III and IV oropharyngeal carcinoma. Int J Radiat Oncol Biol Phys. 1991;21:557-562.
7. Bourhis J, et al. Randomised trials of hyperfractionated and /or accelerated compared to conventional radiotherapy in HNSCC: a meta-analysis of updated individual patient data. Submitted for publication, 2006. (In press)
10. Bardet E, et al. Preliminary data of the GORTEC 2000-02 phase III trial comparing intravenous and subcutaneous administration of amifostine for head and neck tumors treated by external radiotherapy. Semin Oncol. 2002;29(6 Suppl 19):57-60.
12. Horiot JC, et al. Accelerated fractionation (AF) compared to conventional fractionation (CF) improves loco-regional control in the radiotherapy of advanced head and neck cancers: results of the EORTC 22851 randomized trial. Radiother Oncol. 1997;44:111-121.
13. Overgaard J, et al. Five compared with six fractions per week of conventional radiotherapy of squamous-cell carcinoma of head and neck: DAHANCA 6 and 7 randomised controlled trial. Lancet. 2003;362(9388):933-40.
15. Poulsen MG, et al. A randomised trial of accelerated and conventional radiotherapy for stage III and IV for squamous cell carcinoma of the head and neck: A Trans Tasman radiation Oncology Group Study (TROG 91:01). Radiother Oncol. 2001;60:113-122.
20. Olmi P, et al. Loco-regionally advanced carcinoma of the oropharynx: conventional versus accelerated hyperfractionated radiotherapy versus conventional radiotherapy and chemotherapy- a multicentre randomised trial. Int J Radiat Biol Phys. 2003;55:78-92.
21. Skladowski K, et al. Randomised trial on 7-days continuous accelerated irradiation (CAIR) of head and neck cancer- report on 3 year tumour control and normal tissue toxicity. Radiother Oncol. 2000;55:101-110.
22. Hliniak A, et al. A multicentre randomised controlled trial of conventional versus modestly accelerated radiotherapy in the laryngeal cancer: influence of a 1 week shortening of overall treatment time. Radiother Oncol. 2002;62:1-10.
23. Marcial VA, et al. Hyperfractionated photo radiation in the treatment of advanced sqamous cell carcinoma of the oral cavity, pharynx, larynx, sinus, using radiation therapy as the only planned modality (preliminary report) by the RTOG. Int J Radiat Biol Phys. 1987;13:41-47.
26. Poulsen MG, et al. A randomised trial of accelerated and conventional radiotherapy for stage III and IV squamous carcinoma of the head and neck: a Trans-Tasman Radiation Oncology Group Study. Radiother Oncol. 2001;60(2):13-22.