Despite improvements in the ability to shape and target radiation beams to deliver higher doses to tumor tissue and lower doses to the surrounding normal tissues, the failure of radiation therapy to control tumor growth locally is still a major clinical problem.[1-3] Some causes of local tumor recurrence include: (1) the exclusion of part of the gross tumor mass from the radiation field (referred to as a geographic miss); (2) regrowth from tumor cells at the edge of the radiation field that have received less than the full therapeutic dose (a marginal miss); and (3) colonization of irradiated tissues by tumor cells migrating in from regional or distant sites (repopulation). However, it is likely that the major cause of local tumor recurrence is the failure of radiation to eradicate all of the tumor cells within the treatment fields.
Radiation resistance of tumor cells is a relative phenomenon. In principle, all cancers could be controlled locally if a sufficiently high dose of radiation could be delivered to a treatment volume that encompassed all of the tumor cells. In practice, tumors often recur because it is not possible to deliver a sufficiently high dose of radiation to sterilize all of the tumor cells in the treatment field without an unacceptably high risk of severe damage to normal tissues.
In evaluating treatment protocols, it is important to understand the concept of the therapeutic ratio, ie, the ratio of the dose required to eradicate all of the tumor cells to that which results in unacceptable toxicity to normal tissues.[2,3] On the one hand, a treatment protocol that achieves increased local tumor control by providing a higher effective radiation dose may not be an improvement over conventional therapy if there is a corresponding increase in the risk for severe toxicity. On the other hand, a treatment protocol that delivers the same local tumor control as the conventional therapy but with a lower risk of long-term severe toxicity may offer a therapeutic advantage, even though the tumor cure rate is unchanged.
As an example, clinicians treating patients with prostate cancer have observed that by using modern techniques to better shape the radiation dose distribution to the target volumeeg, three-dimensional conformal radiotherapy based on computed tomography of the prostate and surrounding normal tissues it is possible to administer the same dose of radiation to the tumor volume with reduced toxicity to the bowel and bladder, or to deliver higher doses of radiation with little or no increase in toxicity.[4-6] Moreover, newly emerging data suggest that by further increasing the dose delivered to the tumor volume, it is possible, for the first time, to significantly increase the rate of local tumor control without an unacceptable increase in treatment-related morbidity.[7,8]
In addition, it is possible to further conform the radiation dose distribution to prostate and other cancers to exclude normal tissue by the use of intensity-modulated radiation therapy. Long-term follow-up studies will be required to determine whether the delivery of higher doses by three-dimensional conformal radiotherapy and intensity-modulated radiation therapy will lead to a significant improvement in the survival of patients with prostate cancer.
Unfortunately, there is a practical limit on the degree to which technologic improvements in the delivery of therapeutic radiation (eg, three-dimensional conformal radiotherapy, intensity-modulated radiation therapy, accelerated fractionation, hyperfractionation, optimized combinations of radiation with radiosensitizing cytotoxic chemotherapy drugs) will improve the therapeutic ratio. In the late 1990s, we probably came very close to the point at which it is no longer possible to achieve significant improvement in the therapeutic index solely through advances in the technology of radiation delivery. Only through an understanding of the mechanisms that govern the sensitivity of malignant cells and normal tissues to radiation will it be possible to devise new biologically based methods to improve the therapeutic ratio, and, therefore, the probability of obtaining permanent tumor control without incurring unacceptable injury to normal tissues.
In the first part of this two-part review, we will discuss the clinical and tissue kinetic factors that govern the sensitivity of normal tissues to ionizing radiation (x-rays or gamma rays). Practical knowledge of the radiation tolerance of tissues and organs is based on many years of clinical observations, as well as on experimental studies. In part 2, which will appear in next months issue, we will explore some of the recent insights into the cellular and molecular pathways that determine the sensitivity of normal and tumor cells to ionizing radiation.
The toxic side effects of radiotherapy are divided into two general categories: (1) acute effects, ie, side effects that occur during treatment and resolve within 1 to 2 months after its completion; and (2) late effects, ie, complications that are first observed at least 6 to 9 months after the completion of therapy (Table 1).[10-20]
Some clinicians use a third category of intermediate effects to describe certain types of normal tissue damage that are first manifested about 2 to 6 months after the end of treatment and may last for several months thereafter. The category of intermediate effects includes radiation pneumonitis occurring after lung irradiation and Lhermittes syndrome, a mild transient form of myelitis following irradiation of the spinal cord. This syndrome is self-limited and is not related to the development of the severe and permanent radiation myelopathy, which can occur when spinal cord tolerance is exceeded. Radiation pneumonitis may be mild and resolve spontaneously or may be severe and progress to pulmonary fibrosis.
Acute radiation effects are caused by transient suppression of cell proliferation in tissues with a high rate of cell turnover, such as bone marrow, epidermis, and the mucosa of the aerodigestive tract.[reviewed in references 17 and 18]. The time at which these effects (ie, myelosuppression, epidermitis, and mucositis) are first observed is determined by the time required for maturation of basal precursor cells into functional nonproliferating end cells and by the lifetime of these end cells.
For example, radiotherapy commonly causes desquamation of the skin by inhibiting the proliferation of the basal keratinocytes. However, even if the radiation dose is high enough to abolish proliferation of these cells, desquamation is not observed until the existing basal cells mature into squamous cells and are sloughed off.
The acute effects of radiation are ameliorated by normal homeostatic mechanisms. These include: (1) repair of sublethal radiation damage between treatments during a course of fractionated radiotherapy; (2) recruitment of stem cells from the resting (G0) state into the actively cycling state; (3) a decrease in the cell cycle time for proliferating cells; and (4) repopulation of the irradiated site via the migration of cells from the surrounding normal tissue.
For example, oral mucositis may occur after several weeks of radiotherapy for head and neck tumors. If the patient is given a treatment break (approximately 1 week) to allow the mucosa to heal, it is often possible to complete radiotherapy without further interruption. Recruitment of resting mucosal epithelial cells into proliferation and more rapid proliferation of cycling cells, coupled, if necessary, with a small reduction in the dose fraction size (eg, from 200 cGy to 180 cGy), is sufficient to compensate for the proliferation delay and cell loss caused by daily radiation treatments.
In addition to the tissue kinetic factors described above, acute effects of radiation therapy are also determined by the radiation energy (orthovoltage vs megavoltage), dose fraction size, and fractionation schedule, but not by the total dose of radiation.
In most cases, the dose-limiting toxicity of radiation therapy is due to late radiation effects, and the severity of these late effects does not necessarily correlate well with the degree of acute damage.[18,20] This lesson was learned by clinicians who found that they could deliver very high doses of external-beam megavoltage radiation (> 8,000 cGy) to breast or head and neck tumors with little, if any, acute skin or mucosal reaction, simply by administering small dose fractions over a protracted time interval. Despite the virtual absence of acute side effects, however, severe late reactions (eg, severe skin atrophy, telangiectasias, tissue fibrosis, and necrosis) occurred.
The late complications of radiotherapy and the susceptible patient populations can be divided into several different categories, as follows (see Table 1):
delayed damage to organs or tissues within the radiation field (all patients);
impaired development (pediatric patients);
carcinogenesis (all patients, but especially those younger than 15); and
teratogenesis (women irradiated during pregnancy).
Fortunately, the effects of therapeutic radiation on the embryo and fetus occur relatively rarely since it is uncommon for pregnant women to receive therapeutic radiation. Teratogenesis will not be considered here. A discussion of this subject can be found elsewhere.
Delayed organ or tissue damage is the most common dose-limiting toxicity of therapeutic radiation. The severity of late damage depends on or is modified by a variety of clinical factors: (1) radiation quality and quantity (eg, type and energy of radiation, dose fraction size, total dose, volume treated, dose rate, and mode of delivery); (2) the inherent radiosensitivity of the irradiated organ or tissue; (3) the volume of tissue irradiated; (4) the administration of secondary therapies that may exacerbate or add to radiation toxicity (eg, chemotherapy, surgery); (5) the age and general medical condition of the patient; (6) any coexisting medical problems that may exacerbate radiation damage to a specific site (eg, inflammatory bowel disease in patients receiving pelvic irradiation); and (7) individual genetic factors that may affect intrinsic cellular radiosensitivity (see below).
For patients treated who received megavoltage external-beam radiotherapy, the dose fraction size is a particularly important determinant of late tissue effects. Late-reacting tissues, such as the central nervous system (brain and spinal cord), can tolerate higher total doses when radiation is delivered in conventional fraction sizes (180 to 200 cGy) than in larger fractions (250 to 300 cGy).
For example, in the radiation treatment of pituitary adenomas and craniopharyngiomas, a high proportion of patients treated to doses of £ 5,000 cGy in dose fractions of 250 to 300 cGy suffered visual loss consistent with radiation-induced optic neuropathy. In contrast, no patients receiving dose fractions < 250 cGy developed this complication, even at total doses as high as 6,000 cGy.
Similarly, the spinal cord can tolerate radiation doses of 4,500 to 5,000 cGy in 180- to 200-cGy fractions without permanent damage. However, when delivered in higher dose fractions, the same or even a smaller total dose of radiation may cause irreversible myelopathy, with symptoms similar to those caused by spinal cord transection.[23,24] In addition to dose fraction size, the probability of permanent spinal cord damage increases with the total dose, length of the irradiated spinal cord segment, and existence of prior damage caused by the tumor itself, previous surgical procedures, or chemotherapy.
Tissues other than the central nervous system are also sensitive to large-dose fractions of external beam radiation. For example, radiation doses ³ 4,500 to 5,000 cGy to a generous volume of small bowel may lead to enteritis, ulceration, fistulas, or fibrosis.[25-27] Although these are serious complications, they may often be managed by conservative medical treatment or, if necessary, by corrective surgery. A moderate volume of rectosigmoid can usually tolerate about 6,000 cGy.
Segments of small and large bowel are necessarily included within the radiation portals in the treatment of pelvic tumors (eg, cancers of the cervix, uterus, and rectosigmoid). In addition to fraction size and total dose, the volume of irradiated bowel tissue is a major determinant of the probability and severity of late effects. Thus, other factors being equal, pelvic irradiation is less likely to cause severe late effects when the uterus is present than in women who have undergone hysterectomy. The absence of the uterus allows additional loops of bowel to drop into the pelvic radiation field, and, in addition, postsurgical adhesions may cause trapping of loops of small bowel within the radiation field. Patients with regional enteritis or ulcerative colitis are more sensitive to radiation to the small and large bowel, respectively.
Impaired DevelopmentAge at the time of treatment has a significant influence on both the severity and type of late effects. Elderly patients generally do not tolerate large-field radiotherapy as well as younger patients, with the following exceptions. Children are prone to develop additional problems from radiation, including growth retardation and second benign and malignant tumors in the radiation treatment field; also, the effects of central nervous system radiation are more severe in very young children than in older children or adults. A full discussion of these serious effects of radiation in young children can be found elsewhere.[28,29]
Radiation during infancy or childhood can impair the growth of bone, muscle, and soft tissue in the radiation portal. The severity of the growth impairment depends on the amount of remaining growth potential (ie, age at the time of irradiation), total dose, and volume treated. Thus, a dose of 2,000 cGy to the spine will reduce the remaining growth potential by about 50%, while a dose of ³ 4,000 cGy will abolish further growth.
Irradiation of the diaphysis of long bones has a much smaller effect than irradiation of the growth plates, and inclusion of both growth plates will cause a greater reduction in growth than inclusion of a single growth plate. Asymmetric irradiation of the spine (ie, splitting the vertebral bodies) can lead to scoliosis. Thus, it is generally preferable to include the entire width of the vertebral body in the treatment field.
Radiosensitization by Chemotherapeutic DrugsIn addition to their own characteristic spectrum of side effects, some chemotherapeutic drugs (eg, doxorubicin(Drug information on doxorubicin), actinomycin D [Cosmegen], cisplatin (Platinol), fluorouracil(Drug information on fluorouracil)) may sensitize normal tissues to radiation damage. Such radiosensitization may occur even when the chemotherapy is delivered before or after a course of fractionated radiotherapy. One particularly striking example of a side effect due to nonsimultaneous chemoradiotherapy is the observation of normal tissue toxicity within a previously irradiation field during a subsequent course of chemotherapy (radiation recall). An example of radiation recall is the development of a brisk epidermitis corresponding to the previously irradiated field in a child receiving multiagent chemotherapy for Wilms tumor.
Simultaneous radiotherapy and chemotherapy can increase the likelihood and severity of the acute and late effects of radiation. In this case, the increased toxicity must be weighed against the likely benefit (ie, increased tumor control rate) derived from concurrent radiochemotherapy. It may be necessary or advisable to decrease the radiation dose in patients receiving combined-modality therapy, particularly children who are receiving an intensive multiagent chemotherapy regimen.
Very Late Complications
Although the onset of most late complications (eg, myelopathy, brain necrosis, enteritis, proctosigmoiditis) usually occurs within the first few years after irradiation, longitudinal follow-up of cancer survivors irradiated as children or young adults reveals classes of very late complications that occur more than 5 years after treatment and may increase in incidence over 5, 10, and even 15 years after treatment. For example, survivors of Hodgkins disease who have received mantle (neck and chest) irradiation exhibit an increasing risk of solid tumors (eg, breast cancer among women treated during childhood) and accelerated coronary and carotid atherosclerosis. Long-term follow-up studies indicate that these patients are at increased risk of death due to cardiac and cerebrovascular disease.