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A Multidisciplinary Approach to Cancer: A Radiation Oncologist’s View
Radiation therapy forms an integral part of the care of 50% to 60% of cancer patients in the United States. It plays a key role in the multidisciplinary curative treatment of many patients with head and neck, thoracic, genitourinary, gynecologic, and gastrointestinal cancers, lymphoma, sarcoma, brain tumors, and other malignancies. Radiation therapy also provides highly effective palliation of cancer symptoms, including pain, bleeding, and other symptoms of progressive or metastatic cancer.
Although early cancers of the prostate, head and neck, cervix, and other sites are commonly cured with radiation alone, more advanced cancers are usually treated with radiation in combination with surgery, chemotherapy, or other systemic treatments.
In many clinical situations, postoperative radiation therapy after surgical resection improves local control. Frequently the use of radiation before or after surgical resection also permits use of less-radical, organ-preserving operations, without any associated reduction in—and sometimes even with improvement in—local tumor control and survival rates.
For many disease sites, the combination of radiation and chemotherapy has also been demonstrated to improve local disease control, enhance the effectiveness of organ-sparing approaches, and improve the curative potential of local treatments, presumably by sterilizing micrometastatic disease that would otherwise lead to the appearance of distant metastases. Randomized trials have proven that addition of concurrent chemotherapy to radiation improves local control and survival in patients with cervical, head and neck, lung, gastrointestinal, and other types of cancer.
The goal of the radiation oncologist and his or her multidisciplinary team is to sterilize tumor while also minimizing treatment-related side effects and optimizing the patient’s quality of life. The best results depend on a well-integrated team that includes radiation oncologists, medical oncologists, and surgeons, as well as experienced pathologists, diagnostic imagers, nutritionists, radiation physicists, nursing specialists, therapists, and others. Frequent face-to-face communication in tumor boards, multidisciplinary clinics, and sidebars over individual cases is vital to the development of a common language and an understanding of the needs and concerns of each member of the multidisciplinary team.
The relationship and the quality of communication between radiation oncologist and diagnostic imager are particularly crucial. The desire to reduce treatment-related side effects while maintaining or improving local disease control rates has led to increasingly precise, tightly conforming radiation dose delivery methods such as intensity-modulated radiation therapy and proton therapy. The theoretical advantages of these approaches can be realized only through precise understanding of the distribution of disease and regional anatomy as revealed in the patient’s imaging evaluation.
Radiation Biology
Most radiation-induced cell death is caused by damage to nuclear DNA and is referred to as mitotic cell death. The interaction of photons or charged particles with water produces highly reactive free radicals that interact with DNA, causing breaks that can interfere with cell division. Although cells are equipped with very effective mechanisms for repair of the damage caused by free radicals, accumulated injury can lead to irrecoverable DNA breaks that prevent successful mitosis. Oxygen in the environment enhances the lethal effects of radiation by fixing free radical damage. Damaged cells that have lost their ability to reproduce indefinitely may continue to be metabolically active or even undergo several divisions before losing their integrity. For this reason, radiation-induced damage to tumors may not be expressed morphologically for days or even weeks after the radiation exposure.
Another type of radiation-induced cell death is referred to as apoptosis or programmed cell death. Apoptosis can occur before or after mitosis and appears to play an important role in the radiation response of some tumors and in certain normal tissues such as salivary glands and lymphocytes.
In vitro studies of the relationship between radiation dose and cell survival demonstrate that mammalian cells differ widely in their inherent radiosensitivity. These differences contribute to the wide range of doses required to cure tumors of different cell types. Even bulky lymphomas can typically be controlled with doses of 25 to 35 Gy, whereas 2- to 3-cm carcinomas usually require doses of more than 60 Gy. Melanomas and most sarcomas require even higher doses and usually cannot be controlled with tolerable radiation doses if there is more than microscopic residual disease after surgery.
A number of factors influence cellular radiosensitivity and tumor responsiveness. These include the cells’ capacity to repair radiation injury, the effects of cellular repopulation, and the influence of sensitizing agents, including oxygen.
Normal tissues typically have a greater capacity to accumulate and repair radiation damage than cancers; this difference is responsible for the “therapeutic window” that makes it possible to cure cancers without causing unacceptable damage to irradiated normal tissues. However, some normal cells—particularly those that are rapidly proliferating—have relatively little repair capacity, and some tumors, such as prostate cancer, are able to accumulate and repair damage as effectively as most normal tissues. These variations influence the approaches used to treat various tumor types and sites.
Experimental and clinical evidence suggests that most repair is accomplished within 4 to 6 hours. For this reason, schedules that involve more than one daily fraction of radiation are usually designed with a minimum interfraction interval of approximately 6 hours.
The effect of cellular proliferation during a course of radiation therapy depends on the doubling time of the neoplastic cells and the duration of treatment. Although the tolerable weekly dose of radiation is limited by normal tissue effects, many studies demonstrate that unnecessary protraction compromises tumor control rates. Also, evidence suggests that radiation therapy, as well as other cytotoxic treatments and even surgery, can accelerate the rate of repopulation. This enhances the detrimental effects of delayed postoperative radiation and may explain why neoadjuvant chemotherapy has often proven less effective than expected.
Because oxygen is needed to fix the free radicals that mediate radiation-induced DNA damage, the dose of sparsely ionizing radiation required to effect a given level of cell killing is about three times greater under anoxic conditions than under fully oxygenated conditions. Although regions of hypoxia are present in many solid tumors, the clinical importance of hypoxia is diminished by reoxygenation that occurs as initially hypoxic cells become better oxygenated during a course of fractionated radiation therapy.
Normal Tissue Effects Of Radiation
The extent, nature, and likelihood of radiation-related normal tissue effects depend on the structure of the irradiated tissue, the dose and the volume of tissue irradiated, and other clinical factors.
Normal tissues can be categorized as “serial” or “parallel” according to the organization of their functional subunits. Serial structures, such as the spinal cord, small bowel, and ureter, may fail when even a small portion of the organ is irradiated to a high dose. In contrast, parallel structures, such as liver, kidney, and lung, can sustain very high doses to partial volumes but are less tolerant of moderate whole-organ doses.
Tissues and cells that have a rapid turnover rate (e.g., bone marrow stem cells, skin, oral mucosa, hair follicles, and gastrointestinal epithelium) tend to exhibit side effects during or soon after a course of fractionated radiation therapy; these are referred to as acutely responding tissues. The renewal rate of acutely responding tissues typically limits the rate at which radiation therapy can be safely delivered to 900 to 1000 cGy/week. However, most acute side effects resolve within weeks of the completion of a course of radiation therapy.
Tissues that are more slowly proliferating are referred to as late-responding tissues and tend to manifest side effects weeks or months after radiation therapy. These effects may reflect direct damage to parenchymal cells or damage to vascular stroma, and the dose–response relationship varies according to the tissue irradiated and other factors. Table 4.1 presents some of the conclusions of a 1991 task force charged with summarizing relevant data concerning the effect of ionizing radiation on normal tissues. A more detailed update was subsequently published in 2010. Although these summaries provide some guidance as to the risks of radiation-related side effects, analyses of treatments using modern conformal image-based planning methods will continue to refine our understanding of the relationships between the dose and volume of radiated tissues and the risk of adverse effects.
Table 4.1
Approximate Dose/Volume/Outcome Data for Several Organs After Conventionally Fractionated Radiation Therapy
| ORGAN | DOSE (Gy) or DOSE/VOLUME PARAMETERS | RATE (%) | ENDPOINT |
|---|---|---|---|
| Brain | D max < 60 | <3 |
|
| D max = 72 | 5 | ||
| D max = 90 | 10 | ||
| Brainstem | D 1-10 cc ≤ 59 Gy | <5 | Permanent cranial neuropathy or necrosis |
| Optic nerve/chiasm | D max < 55 | <3 | Optic neuropathy |
| D max = 55–60 | 3–7 | ||
| Spinal cord a | D max = 50 | 0.2 | Myelopathy |
| D max = 60 | 6 | ||
| D max = 69 | 50 | ||
| Parotid b | Mean dose < 25 | <20 | Long-term salivary function < 25% of preradiation level |
| Lung b | V20 ≤ 30% | <20 | Symptomatic pneumonitis |
| Mean dose = 7 | 5 | ||
| Mean dose = 13 | 10 | ||
| Mean dose = 24 | 30 | ||
| Esophagus | Mean dose < 34 | 5–20 | Grade ≥ 3 acute esophagitis |
| Heart | V25 < 10% | <1 c | Long-term cardiac mortality |
| Liver d | Mean dose < 30–32 | <5 | Classic RILD; does not apply to patients with preexisting liver disease or hepatocellular cancer |
| Mean dose < 42 | <50 | ||
| Kidney b | Mean dose < 15–18 | <5 | Clinically relevant renal dysfunction |
| Mean dose < 28 | <50 | ||
| Stomach | D max < 45 | <7 | Ulceration |
| Small bowel | V45 < 195 cc e | Grade ≥ 3 acute toxicity | |
| Rectum | V50 < 50% | <10 | Grade ≥ 3 late toxicity; based on current RTOG recommendations for prostate cancer treatment |
| V65 < 25% | <15 | ||
| V75 < 15% | <15 | ||
| Bladder | D max < 65 | <6 | Grade ≥ 3, RTOG scoring |
BED , Biologic effective dose; RILD , radiation-induced liver disease; RTOG , radiation therapy oncology group.
a Partial length; including full cord cross-section.
c Believed to be an overly safe risk estimate based on model predictions.
d Excludes patients with preexisting liver disease or hepatocellular carcinoma because tolerance doses are lower in these patients.
e Based on segmentation of the entire potential bowel space within the peritoneal cavity.
Patient characteristics can also strongly influence the risks of treatment-related side effects. Tissues that have been compromised by injury or illness may be more susceptible to radiation injury than healthy tissues. A history of smoking or other substance abuse, infection, poor nutrition, and other factors can increase the likelihood of serious treatment-related side effects. Surgery, chemotherapy, and other treatments may also enhance the acute and late effects of radiation. An understanding of the complex relationships between these factors and normal tissue effects is critical in radiation therapy treatment planning.
The duration of a course of radiation therapy has little impact on the incidence of late complications, but the dose per fraction has a major impact. In general, radiation schedules that involve fractional doses of 2 Gy or less permit maximal recovery of sublethal damage to normal tissues. For this reason, and because acute side effects usually limit the weekly dose of radiation to no more than approximately 10 Gy, radiation therapy is most commonly delivered with a schedule of 1.8 to 2 Gy per fraction, five times per week. Because most tumors repair cellular damage less effectively than late-responding normal tissues, the differential effect on tumor versus normal tissues is increased when a dose of radiation is fractionated. This is referred to as the fractionation effect.
Under certain circumstances, alternate fractionation schedules may be used to reduce the overall duration of treatment. Hypofractionation, the use of daily fractional doses of more than 2 Gy per fraction, is routinely used for palliative radiation therapy to optimize convenience, cost, and the rapidity of symptom relief. Common schedules used for palliation include 30 Gy in 10 fractions, 20 Gy in five fractions, and in some cases 8 to 10 Gy in a single dose of radiation. The development of highly conforming radiation technique has also led investigators to explore the value of hypofractionated radiation therapy for curative radiation therapy in certain situations. This approach is most effective if adjacent critical structures receive a significantly lower dose and dose per fraction than the target. Stereotactic body radiation therapy is a form of ultrahypofractionated radiation therapy in which very large daily doses of radiation are delivered with great precision under image guidance. In contrast, hyperfractionation is the delivery of small doses of radiation two or more times daily (usually with a minimum interfraction interval of 5–6 hours). This approach is most useful when repopulation is considered to be an important factor in tumor curability, but proximate late-reacting normal tissues prohibit the use of hypofractionation.
Therapeutic Gain
The goal of radiation therapy is to sterilize tumor with the fewest possible side effects. The difference between the rate of tumor control and the rate of normal tissue complications is referred to as the therapeutic gain or therapeutic ratio ( Fig. 4.1 ). The probabilities of tumor control and late normal tissue effects can generally be described by two sigmoid dose–response relationships. Below a threshold dose, the probability of tumor control is very low; it then rises steeply to a dose above which little additional benefit can be achieved by further increases in dose. The shape and slope of the curve are related to the type and size of the tumor and other factors, including the use of concurrent systemic treatments. The likelihood of complication-free tumor control is determined by the separation between the tumor control and the late effects dose–response curves. The most successful treatment strategies are those that maximize the separation between these curves. Strategies that combine surgery or chemotherapy with radiation in a way that shifts the tumor control dose–response curve to the left without a commensurate shift in the complication curve probability increase the likelihood of a good result. Conversely, multidisciplinary treatments that increase the risk of complications without significant improvement in the probability of tumor control should be avoided.
The position of the tumor control probability curve is also related to the volume of disease. For carcinomas, microscopic nodal disease can usually be controlled with a dose of 40 to 45 Gy. However, for most carcinomas, the likelihood of controlling a 1- to 2-cm tumor is negligible with doses less than 55 Gy, but may be as high as 90% to 95% after doses greater than 60 Gy. The steepness of this dose–response relationship highlights the importance of diagnostic accuracy. An entire course of treatment can be rendered ineffective if a single grossly involved node fails to receive the necessary added dose.
Surgery And Radiation Therapy
In some cases, the close proximity of critical structures prohibits delivery of a dose of radiation sufficient to eradicate gross disease. In other cases, surgical resection leaves microscopic disease that could lead to future recurrence. In cases such as these, judicious combinations of surgical resection and radiation therapy may significantly improve local control and survival and preserve organ function. Postoperative radiation therapy is often used to prevent local recurrence after gross total resection. In some cases preoperative radiation therapy is used to “downstage” tumor, improve local control, or enable the surgeon to use organ-sparing operations. This approach has been particularly effective in the treatment of rectal cancers. However, unnecessary multimodality treatment can increase complications, and poorly chosen surgical procedures can, in some cases, compromise the ability to deliver curative radiation therapy.
The information gained from surgery can also help guide planning of radiation therapy. Operative findings frequently provide critical information about local and regional disease extent that can guide the radiation oncologist in target volume definition. However, optimal combined-modality treatment requires careful communication between surgeon and radiation oncologist, preferably before any treatment has been initiated.
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