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
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, actinomycin D [Cosmegen],
cisplatin (Platinol), 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.
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