Delivery of therapeutic radiation in multiple sessions, or fractions, has been practiced since the discovery of radiation’s potential to cure malignancies. Initially, this was done out of practical necessity: Radiation was delivered at a low dose rate, and the treatment sessions had to be repeated to obtain the desired effect. Technologic improvements eventually allowed for treatments in one session, but clinical observations of improved outcomes with multiple fractions were noted in the 1920s, and the concept of fractionated radiation took hold.
A second clinical observation was also made during this era. When the testes of animals were irradiated in a single fraction, the overlying scrotal tissue broke down as a result of the effects of the higher dose of radiation necessary to achieve sterilization. However, when multiple smaller fractions were delivered, sterilization was accomplished without severe damage to the scrotal skin. Making the analogy that the testes were akin to tumors, whereas the scrotum represented normal tissues, investigators formulated the concept of fractionating radiation to treat malignancies. The practice gained credibility, and spreading a course of radiation over many days is now considered to be the most efficacious method of delivering therapeutic radiation.
While fractionated radiation is recognized as an improved method of delivering radiation, the optimal fractionation schedule remains unknown. Over the decades, clinical practice has led to the development of standard, or conventional, schedules. In the United States, a conventional course of treatment for squamous cell carcinoma entails the use of 1.8 to 2 Gy per fraction, delivered once daily, 5 days a week. In the treatment of advanced head and neck cancers, a total dose of 70 Gy is administered to gross disease. At the dose rates described, a standard course of radiation takes 7 weeks to deliver.
These doses and schedules have evolved from clinical observations. Such observations reflect not only the probability of curing a disease, but also of obtaining these cures with acceptable morbidity. Greater understanding of the radiobiology of both tumor and normal tissues and attempts to increase the therapeutic gain of radiation have led to the development of fractionation schemes that deviate from the conventional.
Two separate concepts of altering the fractionation schedulehyperfractionation and accelerated fractionationhave been studied. The rationale and clinical results of each concept will be described below. Although the rationales differ for each approach, most clinical trials have used schedules that are hybrids of the two concepts.
Theoretically, the greater the total dose, the greater the probability of cure. Yet with conventional fractionation, total doses of radiotherapy for head and neck cancer are limited by normal tissue tolerance. The rationale for hyperfractionation is its potential to increase the total dosetranslating into a higher probability of cure without an increase in late toxicity.
The two types of reactions of normal tissues to radiation are acute (or early) and chronic (or late). The acute type is primarily seen in tissues such as skin or mucosa. These reactions typically manifest as radiation dermatitis and mucositis, develop during a course of fractionated radiation, and resolve over a period of weeks after completion of radiation. Late-responding tissues include fibroblasts, bone, and neural tissues. It can take months, or even years, before the effects of radiation are seen in these tissues.
Normal tissue reactions are dependent on both the dose per fraction and the total dose. Modifying the dose per fraction has more effect on late-responding tissues, and, with lower doses, there is greater repair of these tissues than with the tissues involved in acute reactions. Hyperfractionation attempts to take advantage of these differing normal tissue responses. Compared with a conventional fractionation schedule, hyperfractionation increases the total dose and decreases the dose per fraction. The increase in total dose is to the level at which the same degree of late effects seen with the conventional schedule also occurs with hyperfractionation. Multiple fractions are delivered on each treatment day, and the overall treatment time is therefore unchanged.
Head and neck cancers are believed to have a rapidly proliferating clonogenic population. Their behavior would most likely mimic the acute-responding tissues. Therefore, these tumors would be less likely to be affected by the decrease in dose per fraction. An increase in total dose would enhance the tumor kill, but would also affect normal acute-responding tissues and possibly increase the incidence and/or severity of radiation dermatitis and mucositis.
Other Possible MechanismsWhile the primary rationale for hyperfractionation is to escalate total dose in light of the differences in repair between acute- and late-responding tissues, this approach may also be effective because the malignant clonogens have the opportunity to redistribute more frequently to sensitive portions of the cell cycle. One reason for the incomplete eradication of tumor cells during a fraction of radiation is that some cells are in a portion of the cycle that confers resistance. As these cells are rapidly proliferating, it is probable that between fractions surviving cells will redistribute to a sensitive phase of the cycle, resulting in a greater probability of tumor kill.
Radiation resistance also increases with tumor hypoxia. At lower doses per fraction, tumor sensitivity to radiation is less dependent on the presence of oxygen. Thus, hyperfractionation may circumvent the protection that hypoxia provides to tumor cells.
Clinical Results of Hyperfractionation
Retrospective TrialsIn the United States, the largest reported experiences using hyperfractionation as therapy for head and neck cancers have been retrospective. At the University of Florida, hyperfractionation regimens using 1.2 Gy twice a day to total doses of 74.4 to 81.6 Gy have been used to treat over 350 patients with carcinomas of the oropharynx, hypopharynx, and larynx.[1,2] An improvement in local control was seen in cases of intermediate-stage tumors of the larynx and hypopharynx treated with hyperfractionation, compared with historical controls treated with conventional radiation.
At The University of Texas M. D. Anderson Cancer Center, we reported our experience treating more than 200 patients with carcinomas of the supraglottic larynx and hypopharynx with hyperfractionation. Subsite analysis suggested an improvement in local control, particularly for patients with T2 hypopharyngeal carcinoma.[4,5] Clinicians were cautioned against overinterpreting the role of hyperfractionation in these retrospective results, however, because coinciding technologic advances in treatment and diagnostic imaging may have contributed to the improvements.
Prior to a randomized trial of various altered fractionation studies (discussed below), the Radiation Therapy Oncology Group (RTOG) conducted a study comparing a conventional radiation schedule ranging from 66 to 73.8 Gy with hyperfractionation to 60 Gy at 1.2 Gy twice daily. Despite a lower dose in the hyperfractionation arm, locoregional control at 2 years was equivalent in both arms. This study, as well as the retrospective experiences described above, showed that hyperfractionation results in greater acute reactions than conventional therapy. These studies also demonstrated the critical importance of the interfraction interval: Both acute and late reactions were fewest when the interfraction interval was at least 6 hours.
Randomized TrialsSeveral international randomized trials of hyperfractionation have also been reported. Pinto and associates at the National Cancer Institute of Brazil randomized 112 patients with stage III/IV squamous cell carcinoma of the oropharynx to either 66 Gy in 33 fractions or 70.4 Gy in 64 fractions twice daily. There were significant improvements in both local control and survival in the patients treated with hyperfractionation.
In Spain, Sanchiz and colleagues performed a randomized trial comparing the same hyperfractionation regimen used in Brazil with 60 Gy in 30 fractions. They enrolled 859 patients with stage T3/T4 head and neck cancer. The authors described an improvement in median duration of response and overall survival for patients treated with hyperfractionation. Disease control rates were not reported, although for the stages of disease treated, the expected control rates with only 60 Gy in 30 fractions would be poor. This was one of the first randomized trials evaluating the role of concurrent chemotherapy as well, with a third arm receiving 60 Gy combined with fluorouracil(Drug information on fluorouracil) (5-FU). The chemotherapy arm demonstrated improved results similar to those seen in the hyperfractionation arm.
The European Organization for Research and Treatment of Cancer (EORTC) randomly assigned 356 patients to conventional radiation, 70 Gy in 35 fractions, or to hyperfractionation, 80.5 Gy in 70 fractions at 1.15 Gy twice daily. The study (EORTC 22791) was restricted to patients with T2/T3, N0/N1 squamous cell carcinomas of the oropharynx (excluding base-of-tongue tumors). The patient population was selected to eliminate patients with a low probability of surviving 2 years. Patients treated with hyperfractionation had a 5-year local control rate of 59%, compared with 40% for patients treated with conventional treatment (P = .02). Analysis by stage suggested these differences were due to improvements in control in patients with T3 disease. An improvement in 5-year overall survival was also reported for patients treated with hyperfractionation (P = .08). Table 1 summarizes the randomized hyperfractionation trials.[6-11]