Some Cases of Severe Normal Tissue Toxicity Can Be Anticipated With Ablated Fractionated Radiation With Appropriate Long-term Follow-up

doi:10.1016/j.semradonc.2008.04.003

Seminars in Radiation Oncology

Volume 18, Issue 4, October 2008, Pages 229-233

https://doi.org/10.1016/j.semradonc.2008.04.003 Get rights and content

As new technologies have allowed physicians to both better image and characterize malignant disease as well as deliver radiation dose with high precision and accuracy, there has been a resurgence in interest in hypofractionated or even single-fraction radiation therapy schemas. Late-reacting tissues have a low α/β ratio (compared with early reacting tissues) and are therefore more sensitive to increments in fraction size. When we hypofractionate, we may lose some of the biological advantages associated with fractionation while we may simultaneously increase our risk of damaging late-responding normal tissues. The ideal 4 R's for tumor cells are exactly opposite those 4 R's ideally desired for normal tissues, and this represents the major dilemma to the practicing radiation oncologist. The long-term safety profile for modern hypofractionated radiation schemes will depend on the area and volume treated, the total dose delivered, and the level of baseline function observed before initiating radiation therapy. These issues are raised in the context of hypofractionation for central nervous system malignancies, lung cancers, pelvic malignancies, head and neck cancers, and breast cancers. If we are careful when choosing the site (and most importantly the volume), it is likely that hypofractionation may benefit our patients. However, history has taught us to be very careful when using hypofractionation to large volumes or when incorporating critical structures. With appropriate long-term follow-up, some cases of severe normal tissue toxicity can be anticipated. Hypofractionation should continue to be studied in randomized clinical trials, with a particular focus on careful follow-up.

Section snippets

The Central Nervous System

Leksell⁹ pioneered the use of large, ablative fractions of radiation to the central nervous system (CNS) guided by accurate 3-dimensional imaging over 50 years ago. Stereotactic radiosurgery has become more and more common as familiarity with its concepts and technologies has increased. This method seeks to create necrosis in small volumes, which makes sense in the center of a tumor but is obviously not a desirable endpoint for normal brain tissue.

Because stereotactic radiation has begun

The Lung

Medically inoperable lung cancer patients with peripheral tumors are a logical choice for consideration of novel treatment strategies. The 5-year overall survivals for these patients treated with radiation alone range from 10% to 30%,¹⁴ and these results compare poorly with surgical series of patients with similar clinical stages. Local control remains a major problem with such patients, and there is a potential advantage to decreasing overall treatment time to limit accelerated tumor-cell

Pelvic Malignancies

In rectal cancer, the benefit of radiotherapy, given either preoperatively or postoperatively, has been repeatedly shown with randomized trials.20, 21, 22 A well-known Dutch trial showed an improvement in local control in the radiotherapy arm²³ after randomizing 1,861 patients to 5 Gy × 5 days followed by total mesorectal excision within 1 week or surgery alone. Patients were assessed for chronic toxicity using a questionnaire, and 597 patients responded. With a median follow-up of 5.1 years,

Head and Neck Cancer

Hypofractionated treatment regimens have been studied in head and neck cancer. In an important (and frequently overlooked) study, Byhardt et al²⁸ analyzed the hypofractionation experience with oral cavity and oropharynx tumors at the Medical College of Wisconsin from 1965 to 1975. Keeping the total time and total doses constant, they compared 3 fractions per week (usually 300 cGy per fraction) to conventional fractionation and found not only more morbidity but also poorer local control rates

Breast Cancer

New technologies have emerged that have popularized interest in accelerated hypofractionation for breast cancer when applied to a section of the breast. Accelerated partial-breast irradiation (APBI) in practice has become common in the United States, despite a paucity of long-term data to support its superiority or even equality to standard whole breast radiotherapy. APBI can be delivered with a variety of techniques and with limited follow-up (a large majority of publications with less than 5

Conclusions

Hypofractionation is certainly not going to disappear from our armamentarium nor should it be discarded. There is a place and a time to consider this form of radiation therapy. We use palliative hypofractionation to benefit our patients with limited life expectancies. If we are careful when choosing the site (and most importantly volume), it is likely that hypofractionation can do our patients some good. However, history has taught us to be very careful when using hypofractionation to large