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
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
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
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
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 (5-FU). The
chemotherapy arm demonstrated improved results similar to those seen in the
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
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