The aim of radiation oncology is the achievement of uncomplicated locoregional
control of malignancy by the use of radiation therapy (RT). Accomplishing this
goal requires precise knowledge of tumoricidal and tolerance doses of the various
normal tissues at risk within the RT field.
Types of RT injury
Radiation injuries can be divided into functional impairment and oncogenesis.
There are also different phases of RT injury.
Early effects are usually seen during treatment or within the first few weeks
after its completion. These reactions are common, can be significant and symptomatic,
but eventually seem to heal completely. Nevertheless, despite what
may appear to be total recovery, significant residual damage is often present.
Intermediate effects typically occur several weeks to months after the
completion of RT.
Late effects are usually rare and are encountered many months to years after
RT. Functional impairments may take a long time to become apparent; an example
is memory problems in children who have received cranial irradiation.
Oncogenesis is usually a late effect of RT.
Tolerance doses of radiation
Numerous studies have attempted to specify RT tolerance doses for the various
tissues and structures of the body. The minimal tolerance dose (TD 5/5) and
maximal tolerance dose (TD 50/5) refer to a severe complication rate of 5% and
50%, respectively, within 5 years of RT completion (Table 1). These tolerance
doses have been valuable but were drastically revised recently because of the
advent of combined-modality therapy (see section on "Combined chemotherapy
and irradiation") and altered RT fractionation regimens.
Chemoradiosensitivity of normal tissues Cell-cycle kinetics, mitotic behavior,
and differentiation determine the chemoradiosensitivity of normal tissues.
The dividing cell is more vulnerable to RT than the quiescent cell, especially
one that is functionally mature.
Dose-limiting organs and tissues have been divided into three classes according
to their RT tolerance doses and importance to survival:
Class I organs are those in which irreparable damage leads to death or
Class II organs are those in which damage is associated with moderate
Class III organs are those in which damage produces minimal
Combined chemotherapy and irradiation
In combined-modality therapy, several temporal strategies with different rationales
are utilized: concurrent RT and chemotherapy, local RT followed by
chemotherapy, chemotherapy followed by local RT, and alternating chemotherapy
and RT cycles.
When used in combination, RT and chemotherapy can act independently, with
each mode acting in isolation in different parts of the body. The combined use
of the two modalities can also result in increased or decreased therapeutic activity,
as well as various possible adverse interactions:
- Damaging effects of RT on the target organ can be increased by chemotherapy.
Some chemotherapeutic agents are RT enhancers or
reactivators, which, when used concurrently with RT, can produce reactions
in various tissues at much lower RT doses than expected.
Damaging effects of chemotherapy on the target organ can be increased
Independent injuries can be caused by the individual treatment modality
in the same organ, which can combine to increase the resulting
dysfunction. Subclinical residual injury from one treatment modality
may be uncovered by the subsequent use of a seemingly safe dose of
An injury can be produced that is not commonly seen with either modality
The inherent difficulty in understanding these consequences is further complicated
by the number of chemotherapeutic agents generally combined in
treatment protocols and the variety of conventional or altered RT delivery
Quantification of treatment toxicity
In addition to therapeutic efficacy, quantification of RT toxicity is crucial for
evaluating new regimens and selecting therapy for individual patients. The
optimal therapeutic ratio requires not only complete tumor clearance but also
minimal residual injury to surrounding vital normal tissues.
Morbidity scoring schemes developed by the Radiation Therapy Oncology
Group (RTOG), European Organization for Research and Treatment
of Cancer (EORTC), and the National Cancer Institute (NCI) are used
most commonly. The late effects of normal tissues (LENT) scoring system
was adopted by the RTOG and EORTC in 1995. It graded toxicity according
to four parameters, denoted by the acronym "SOMA," which
stands for subjective (symptoms reported), objective (signs on examination),
management (instituted), and analytic (tissue function assessed by
objective diagnostic tools).
In 1997, the NCI with other American (eg, RTOG) and international cooperative
groups, the pharmaceutical industry, and the World Health Organization
(WHO) revised and expanded the Common Toxicity Criteria (CTC) by integrating
systemic agent, radiation, and surgical criteria into a comprehensive
and standardized system. The CTC v. 2.0 replaced the previous NCI, CTC,
and the RTOG Acute Radiation Morbidity Scoring Criteria.
The third version of the CTC has been renamed Common Terminology Criteria
for Adverse Events v. 3.0 (CTCAE v. 3.0). The purpose of renaming it was
to move away from the term toxicity, which implies causation and does not fit
the jargon commonly used across all modalities. It is anticipated that after October
2003, all NCI-sponsored trials will use CTCAE v. 3.0, which represents
the first comprehensive multimodality grading system to include both acute
and late effects. The new system is designed for application to all modalities.
TOXIC EFFECTS AND THEIR MANAGEMENT
The incidence and severity of normal tissue toxicity from RT depend on a wide
variety of factors, including total dose, fraction size, interval between fractions,
quality and type of RT, dose rate, intrinsic radiosensitivity, and specific tissue
irradiated. The most common toxic effects seen in different organ systems are
outlined here and in Table 2, along with recommended treatments. Where appropriate,
the specific effects of chemoradiation therapy are discussed separately.
Benson AB III, Ajani JA, Catalano RB, et al: Recommended guidelines for the treatment
of cancer treatment-induced diarrhea. J Clin Oncol 22:2918–2926, 2004.
Brizel DM, Wasserman TH, Henke M, et al: Phase III randomized trial of amifostine
as a radioprotector in head and neck cancer. J Clin Oncol 18:3339–3345, 2000.
Epstein JB, Schubert MM: Oropharyngeal mucositis in cancer therapy. Oncology
Komaki R, Lee JS, Milas L, et al: Effects of amifostine on acute toxicity from concurrent
chemotherapy and radiotherapy for inoperable non-small cell lung cancer: Report of a
randomized comparative trial. Int J Radiat Oncol Biol Phys 58:1369–1377, 2004.
Okunief P, Augustine E, Hicks JE, et al: Pentoxifylline in the treatment of radiation
induced fibrosis. J Clin Oncol 22:2207–2213, 2004.
Pasquier D, Hoelscher T, Schmutz J, et al: Hyperbaric oxygen therapy in the treatment
of radiation induced lesions in normal tissues: A literature review. Radiother Oncol
Rubin P, Constine LS, Fajardo LF, et al: Late effects of normal tissues (LENT) scoring
system. Int J Radiat Oncol Biol Phys 31:1041–1042, 1995.
Schuchter LM, Hensley ML, Meropol NJ, et al: 2002 Update of recommendations for
the use of chemotherapy and radiotherapy protectants: Clinical Practice Guidelines of
the American Society of Clinical Oncology. J Clin Oncol 20:2895–2903, 2002.
Trotti A, Byhardt R, Stetz J, et al: Common toxicity criteria: Version 2.0: An improved
reference for grading the acute effects of cancer treatment: Impact on radiotherapy. Int
J Radiat Oncol Biol Phys 47:13–47, 2000.
Trotti A, Colevas AD, Setser A, et al: CTCAE v3.0: Development of a comprehensive
grading system for the adverse effects of cancer treatment. Semin Radiat Oncol 13:176–
Yarbro JW, Mastrangelo MJ, Curran WJ: The Fourth International Cytoprotection
Investigators Congress. Semin Oncol 31(suppl 18), 2004.