An Overview of Hypofractionation and Introduction to This Issue of Seminars in Radiation Oncology
Article Outline
- The Early Use of Hypofractionation
- Intraoperative Radiotherapy and Investigations of Dose Tolerance From Hypofractionated Radiotherapy
- Degrees of Hypofractionation
- This Issue of Seminars in Radiation Oncology
- References
- Copyright
To the classically trained radiation oncologist, the first thing that comes to mind when considering large dose per fraction radiation treatment is the concern for “late effects.” Late effects, as the name implies, happen later than the effects of most medical therapies, actually months to years after completion of therapy. Aside from the knowledge of radiation-induced neoplasia, the idea of late effects is mostly foreign to our colleagues in surgery and internal medicine given that their therapies mostly cause “early effects” seen soon after administering a drug or in the immediate postoperative period. Thorough knowledge of late effects belongs to the radiation oncologist more than any other specialty, and large dose per fraction treatment, also called hypofractionation, is more likely to cause late effects.
Late effects can be very destructive and result in significant dysfunction to the treated tissue. Exposed tissues slowly become devascularized, denervated, and generally devitalized by a poorly understood process that leads to fibrosis, contraction, stenosis, poor wound healing, and even ulceration. In contrast to the so-called “early effects” of radiation that frequently are associated with damage to exposed epithelial surfaces and mucosa, late effects are more often associated with vascular injury.1 Furthermore, although early effects are mostly acutely inflammatory, late effects are associated with chronic inflammation. Nerves may stop conducting, mucosal surfaces may ulcerate exposing underlying bone or soft tissue, lumens may narrow and obstruct, and lumens may even perforate or form fistulae. To the patient, late effects can be devastating to quality of life or even deadly.
Interestingly, radiation oncologists categorize beneficial tumor control and eradication effects of radiation delivery under the “early effects” category. The basis for this position is that tumor response (cell loss) is observed during or soon after therapy. Psychologically, this is convenient because the bothersome acute inflammatory toxicities observed with high cumulative dose conventional radiotherapy delivery is offset by the benefits of tumor control, all without as much risk for the disastrous normal tissue late effects. Pay no mind that postradiation tumor recurrence and progression, unfortunately, a frequent problem with many common cancers, occurs in the late time frame. Something classically trained radiation oncologists rarely think of is that the dreaded late effects might be very desirable should they occur in the treated tumor (ie, so long as they do not simultaneously occur in uninvolved tissues).
Sure, hypofractionated treatments are more convenient for patients and caregivers. But convenience is not enough to make hypofractionation a mainstay treatment. In some applications, it is used for patients who simply will not live long enough because of their disease process to experience either tumor recurrence or late effects. This is particularly true for palliative treatments. But this notion of guessing a patient's survival and beating the clock will hopefully go by the wayside when systemic treatments finally become more effective.
Is it a given that hypofractionation will result in unacceptable late effects? Many have taken the position that they are synonymous. However, there is evidence that not all hypofractionated treatments are devastating. On the contrary, some experiences have been very positive, even defining standards of care.2 Although the cause and effect of late effects from hypofractionated radiotherapy are in the end biological issues, the more recent safer application of hypofractionation has in fact been enabled by technological innovation in radiation delivery. The integration of technology including better machines, planning systems, and radiation quality have to a great degree defined the implementation of hypofractionation and even the history of radiation oncology.
The Early Use of Hypofractionation
At the onset of using radiation to treat cancer soon after the discovery of x-rays in 1895 and radioactivity in 1896, treatments were mostly hypofractionated. Many of the early practitioners of radiation therapy for cancer were surgeons who were accustomed to single-session interventions. Treatments were technologically crude giving more dose to skin and superficial structures than to a deep-seated target. There were few standards to ensure dose deposition was accurately quantified or delivered. Despite these difficulties, tumors responded, often dramatically. Could radiotherapy be the long-awaited nontoxic cure for cancer? Hopes were dashed with the appearance of late effects.
Nonetheless, investigation into using radiation therapy continued. Radiation delivery techniques were altered, often by trial and error. In 1901, Francis Henry Williams3 from Boston published results of treatments of superficial tumors (basal and squamous skin cancers) using daily or every other day treatments for 5 or more weeks. By 1903, over 2,300 patients were irradiated with these techniques.4 Initial reports regarding the biological effects of radiation all related to observations relating to the skin. In 1904, Hermann Heineke from Hamburg reported that various cells with the body had differential response and repair characteristics as compared with skin.5 This was the early roots of the study of radiobiology.
Most treatments continued to be hypofractionated, probably because of patient convenience and technical difficulties with treatment delivery. By 1910, radium-contact therapy and brachytherapy were considered more practical for deep-seated tumors. Gosta Forssell from Stockholm was the early pioneer of the “Stockholm Method,” which involved radium-containing tubes placed in proximity to the tumor for intensive radiation for 24 hours. This hypofractionated irradiation was repeated after an interval of 6 weeks and became very popular.6
Even early on, the problems with the state of technology for delivering hypofractionated radiotherapy were appreciated by radiotherapy pioneers including Friedrich Dessauer from Frankfort. In 1905, Dessauer7 reported that improvements could be realized with the application of homogeneous dose to the tissue. Technological limitations made this very difficult, eventually leading Dessauer to formulate the ideas of multibeam or multisource irradiation, especially for total-body irradiation.8
Also in 1905, Claudius Regaud began experiments relating to the irradiation of the testis. Within a seminal tubule, cells existed along a continuum of maturation. First Regaud observed that cell undergoing mitosis were more sensitive to radiation. He also observed that the more mature of differentiated cells were less sensitive to radiation.9 This work led in 1906 to the “Law of Bergonie and Tribondeau” stating the effects of irradiation on the cells are more intense the greater their reproductive activity, the longer their mitotic phases, and the less their morphology and functions are established.10 This law formed a biological basis for fractionation.
By the 1920s, despite the advocacy of such giants as Regaud, Antoine Béclère, and eventually Henri Coutard, multiple fractionated treatments were still less popular than abbreviated hypofractionated treatments. The German approach advocated by Ludwig Seitz and Hermann Wintz favoring intensive short courses of roentgenotherapy for treatment of cervical cancer was widely adopted across the world.11 Competing perspectives, including the recommendation by Leopold Freund from Vienna to perform a greater number of smaller fractions,12 were not well accepted. Coutard believed in both approaches stating that choice of fractionation should depend on the initial volume of the target (small targets warrant hypofractionation, whereas large should be more protracted).13 Furthermore, he believed that the final treatment dose should depend on the ongoing response (eg, cumulative dose for head and neck cancer should depend on the ongoing appearance of mucositis), which was the earliest application of the modern notion of adaptive therapy.14 Two pinnacle presentations at international meetings made between 1928 and 1930 by Coutard describing the results of his experience changed the prevailing philosophy of treatment conduct for the next 100 years.15, 16, 17 The excitement over the better than expected results in treating mostly head and neck cancers was attributed to the long duration of the individual treatments dubbed the protracted-fractionation method.18 From that point forward, radiation oncologists across the world mostly abandoned hypofractionation as a method for curative treatment.
Many years later in the early 1950s, the comeback of hypofractionation started quietly and came from Stockholm, the city where hypofractionation was first championed by Forsell 50 years previously. Again, the advocate of hypofractionation was a surgeon, actually a neurosurgeon, named Lars Leksell. Leksell had developed and improved a system for accurately navigating within the skull called “stereotaxy.” Leksell's arc-quadrant frame allowed him to guide surgical instruments toward a prespecified point in space for the purpose of biopsy, resection, ablation, and so on. Leksell was impressed by the decrease in resulting entry damage within the brain facilitated by these stereotactic navigations as compared with open procedures. He wondered if the system could be used to “steer” a beam of radiation that would theoretically cause even less entry damage than surgical instruments. Working with a radiation physicist, Borge Larsson, they created the first Gamma Knife (Elekta AB, Stockholm, Sweden).19 This was the first machine specifically designed to facilitate hypofractionated radiation delivery, and its inception was quickly followed by other technologies (eg, protons and other charged particles) by SRS pioneers including Kjellberg and Lawrence et al.20, 21, 22, 23, 24
Leksell broke from the perceived wisdom of conventionally fractionated radiotherapy by using large-dose single sessions of radiation delivery in, of all places, the radiointolerant central nervous system. Although a single large-dose radiation treatment was historically intolerable, Leksell's approach defied conventional wisdom by its technology and conduct. Unlike CFRT, which often irradiates much larger volumes of normal tissue to the prescription dose than the tumor itself, Leksell's SRS went to great lengths to avoid delivering high dose to nontargeted tissues. Whatever normal tissue was included, either by being adjacent to the target or by inferior dosimetry, was likely damaged. However, if this damaged tissue was small in volume or noneloquent, the patient did not suffer clinically apparent toxicity, even as a late event. On the other hand, it is undeniable that the large dose per treatments is biologically extremely potent by overwhelming repair mechanisms. The net result was a convenient and reasonably safe and effective treatment as will be discussed in this issue in the article by Nedzi.
Nearly simultaneous with the early investigations of SRS, an independent movement to use hypofractionated radiotherapy was coming into use that involved delivering the radiation to an anesthetized patient in the operating room.25, 26, 27 This approach, centered around the application of irradiation immediately after a surgical exposure and/or resection, was called intraoperative radiotherapy. Generally, the therapy is used as an adjuvant therapy after a near or total surgical resection, but less frequently it was used for gross disease.28 Like SRS, with intraoperative radiotherapy, it is essential to minimize the amount of normal tissues exposed to the intended high tumor dose. With SRS, this was accomplished by innovations in technology. With intraoperative radiotherapy, the same is accomplished by physically moving normal tissues out the path of the radiation field (retraction) or by shielding them with barriers placed at the time of surgery.
Intraoperative Radiotherapy and Investigations of Dose Tolerance From Hypofractionated Radiotherapy
Although never in widespread use because mostly of its logistic challenges, intraoperative radiotherapy has played an important role as a weapon in the arsenal of cancer treatments. The treatment has been particularly useful for selected patients with gastrointestinal tumors in which radial margins are often close as compared with the margins at the anastomosis. In these circumstances, the region at risk is well identified at the time of surgery, even without clips or other indirect guideposts commonly used for postsurgical adjuvant therapy. Various equipment, procedures, and conduct have been used at major centers with impressive published results.29, 30, 31, 32, 33 Similar intraoperative treatments have been used in lung cancer and breast34, 35, 36 and sarcoma37, 38, 39, 40, 41, 42 patients.
Given the half time to repair most tissues of 1 to 2 hours,43, 44 fractions of radiation delivery should be separated by at least 4 to 6 hours to allow around 90% repair. Obviously, patients treated with intraoperative radiotherapy will only have the opportunity to have 1 or at most 2 fractions given the difficulties with prolonged anesthesia and infection risk with an open procedure. Although some dose-limiting structures could be moved away from the radiation exposure, some structures would be badly injured if dissected or skeletonized. Furthermore, areas at risk for small-volume gross or microscopic disease would ideally not be surgically manipulated in fear of tumor cell contamination and seeding of larger areas within the operative cavity. As such, it is required with intraoperative radiotherapy that some critical normal tissues will be exposed to large hypofractionated dose levels. To address this reality, pioneers in intraoperative radiotherapy appropriately followed patients carefully for toxicity with respect to delivered dose. Furthermore, these investigators performed numerous experiments in larger laboratory animals to gather dose-tolerance data for various structures to a single fraction as shown in Table 1.
Table 1. Single-Fraction Intraoperative Dose Tolerance in a Canine or Rabbit Model
| Structure | Endpoint | Tolerance Dose (Gy) | Observation Period | Type of Radiation | Reference |
|---|---|---|---|---|---|
| Anastomoses–intestinal | Low-risk dehiscence | 30.0 | 1 year | 11 MeV electrons | 46 |
| Anastomoses–abdominal aorta | Low-risk arteriovenous fistula, low-risk stenosis | 45.0 20.0 | 1year | 11 MeV electrons | 46 |
| Anastomoses–portal vein | Periportal fibrosis but no dehiscence or stenosis | 40.0 | 1year | 290 KV x-rays | 47 |
| Bile ducts | Stenosis with secondary biliary cirrhosis | 20.0 | 1.5years | 11 MeV electrons | 48 |
| Bladder trigone (including ureteral and urethral orifices) | Ureteral obstruction in 20% | 25.0to40.0 | 2years | 12 MeV electrons | 49 |
| Bone–lumbar vertebra | Necrosis in 50% | 28.5 | 5years | 6 MeV electrons | 50 |
| Cartilage | No gross or microscopic change | 50.0 | 15months | X-rays | 51 |
| Duodenum–partial wall | Wall fibrosis/obstruction | 45.0 | 1.5years | 11 MeV electrons | 48 |
| Esophagus–circumferential wall (6 cm) | Ulcertive esophagitis in 100% | 30.0 | 6weeks | 9 MeV electrons | 52, 53 |
| Esophagus–circumferential wall (6 cm) | Mild esophagitis 100%, ulcerative esophagitis in 0% | 20.0 | 2years | 9 MeV electrons | 52, 53 |
| Liver–resection bed | Atrophy but no severe problems | 30.0 | 3years | 6 MeV electrons | 54 |
| Heart–right atrium | Myocardial vascular changes to frank necrosis | 20.0to40.0 | 3months | 12 MeV electrons | 53, 55 |
| Nerve–vagus nerve in neck | Demyelination but no neuropathy | 55 | 6months | Electrons | 56 |
| Nerve–phrenic | Neuropathy in 0% | 40 | 1year | 12 MeV electrons | 55 |
| Trachea | Necrosis in 0% | 40 | 1year | 12 MeV electrons | 53 |
| Vessel–carotid artery | Any effect in 0% | 55 | 6months | Electrons | 56 |
| Vessel–great vessels (eg, aorta)–circumferential | Aneurysm–significant risk | 30.0 | 5years | 57 | |
| Vessel–great vessels (eg, aorta)–circumferential | Partial stenosis in 50% | 38.8 | 5years | 57 | |
| Vessel–hepatic artery | Any effect in 0% | >45.0 | 1.5years | 11 MeV electrons | 48 |
| Vessel–jugular vein | Any effect in 0% | 55 | 6months | Electrons | 56 |
| Vessel–portal vein | Any effect in 0% | >45.0 | 1.5years | 11 MeV electrons | 48 |
The data shown in Table 1 for larger animal irradiation is obviously helpful for choosing prescription dose levels of IORT. It is possible that the observations from IORT will also pertain to using SBRT, particularly if the SBRT is given in 1 fraction. IORT, however, is not entirely similar to SBRT. For example, SBRT would rarely be used in a situation in which a surgical anastomosis lies within the target area. Furthermore, the process of surgical exposure inherent to IORT may affect tolerance. Surgical exposure may devascularize tissues, even skeletonized tissues, making them more prone to subsequent injury. Furthermore, the surgical exposure may contribute to infection or wound-healing problems that affect radiation tolerance. Because SBRT is generally performed noninvasively delivering dose to tissues that are generally undisturbed, SBRT tolerance for the same endpoints found in Table 1 may be different. Finally, SBRT may be fractionated beyond the 1 fraction typical of IORT.
Radiation oncologists have a reasonable appreciation of normal tissue tolerance as determined from patient outcomes from conventionally fractionated radiotherapy.45 This understanding of tolerance was generally not determined from prospective assessments, rather from retrospective chart review directly from outcomes or via mathematical modeling. This is problematic in many respects, but with a century of clinical experience, dose limits can be appreciated. Ideally, though, dose tolerance is determined by prospectively compiling dose and volume information from phase I trials in which the only variable manipulated was the dose. Phase II trial information can be analyzed, but comparisons to outcomes from center to center is potentially problematic because of differences in patient selection, treatment conduct (including dosimetry principles), and follow-up scrutiny. Given the concern of severe late effects, tolerance information related to SRS and SBRT would ideally be gathered from a more formal and rigorous process than the trial-and-error approach used historically for conventionally fractionated radiotherapy. That way, misadventures might not be repeated with each center initiating new programs using hypofractionated radiotherapy.
Admittedly, dose tolerance for SRS and SBRT is far from being fully appreciated. For brain radiosurgery, optic nerve maximum point dose tolerance limits of 8 to 10 Gy are used at most centers. Furthermore, dose is usually limited in eloquent areas like the thalamus or brainstem as compared with other sites. Most importantly, brain SRS complications are avoided by selecting patients with relatively small tumors (eg, <3-4 cm). Otherwise, dose gradients within normal tissues are not so steep, and normal tissue volume effects confound toxicity. Unlike the relatively radio-intolerant brain, tissues in the body may be slightly more forgiving. Parallel organs, for example, may remain overall very functional so long as their inherent reserve is respected by strict avoidance of high or intermediate dose volume using modern technology. Still, serial tissues, like the spinal cord or esophagus, may be badly and irreversibly damaged by ablative dose SBRT especially if irradiated circumferentially.
SBRT is a relatively new treatment option with little long-term follow-up. As such, physicians designing prospective clinical trials using SBRT have been forced to formulate a starting point of normal tissue dose constraints. One such formulation of SBRT dose constraints from investigators at the University of Texas Southwestern is shown in Table 2. These constraints are not validated by long-term follow-up. Rather, they are derived in some cases by toxicity observation, in some cases from conversions from broader experience using mathematical models, and in other cases by educated guessing. In all likelihood, these constraints will be modified many times over upcoming years such that they would serve more as a starting point. The Radiation Therapy Oncology Group is collecting patient dosimetry information in 3 dimensions for all patients enrolled to SBRT trials with the hope of eventually making formal comparisons to toxicity outcome data. Ideally, in the end, educated guessing about normal tissue constraints for hypofractionated radiotherapy will be replaced by solid clinically outcome data. Some patients will undoubtedly be hurt by ignorance of tolerance limits related to hypofractionated treatments. By thorough ongoing assessment practices and early reporting of toxicity, however, as few patients as possible will be exposed to such misadventures.
Table 2. Mostly Unvalidated Normal Tissue Dose Constraints for SBRT
| Serial Tissue | Volume (mL) | Volume Max (Gy) | Max Point Dose (Gy) | Endpoint (≥Grade 3) |
|---|---|---|---|---|
| SINGLE-FRACTION TREATMENT | ||||
| Optic pathway | <0.2 | 8 | 10 | Neuritis |
| Cochlea | 12 | Hearingloss | ||
| Brainstem | <1 | 10 | 15 | Cranialneuropathy |
| Spinal cord | <0.25 | 10 | 14 | Myelitis |
| <1.2 | 7 | |||
| Cauda equina | <5 | 14 | 16 | Neuritis |
| Sacral plexus | <3 | 14.4 | 16 | Neuropathy |
| Esophagus⁎ | <5 | 14.5 | 19 | Stenosis/fistula |
| Ipsilateral brachial plexus | <3 | 14.4 | 16 | Neuropathy |
| Heart/pericardium | <15 | 16 | 22 | Pericarditis |
| Great vessels | <10 | 31 | 37 | Aneurysm |
| Trachea and ipsilateral bronchus⁎ | <4 | 8.8 | 22 | Stenosis/fistula |
| Skin | <10 | 14.4 | 16 | Ulceration |
| Stomach | <10 | 13 | 16 | Ulceration/fistula |
| Duodenum⁎ | <5 | 8.8 | 16 | Ulceration |
| Jejunum/ileum⁎ | <5 | 9.8 | 19 | Enteritis/obstruction |
| Colon⁎ | <20 | 11 | 22 | Colitis/fistula |
| Rectum⁎ | <20 | 11 | 22 | Proctitis/fistula |
| Bladder wall | <15 | 8.7 | 22 | Cystitis/fistula |
| Penile bulb | <3 | 14 | 34 | Impotence |
| Femoral heads (right and left) | <10 | 14 | Necrosis | |
| Renal hilum/vascular trunk | <2/3volume | 10.6 | Malignanthypertension | |
| Parallel Tissue | Critical Volume (mL) | Critical Volume Dose Max (Gy) | Endpoint (≥Grade 3) |
|---|---|---|---|
| Lung (right and left) | 1,500 | 7 | Basiclungfunction |
| Lung (right and left) | 1,000 | 7.4 | Pneumonitis |
| Liver | 700 | 9.1 | Basicliverfunction |
| Renal cortex (right and left) | 200 | 8.4 | Basicrenalfunction |
| Serial Tissue | Volume (mL) | Volume Max (Gy) | Max Point Dose (Gy) | Endpoint (≥Grade 3) |
|---|---|---|---|---|
| THREE-FRACTION TREATMENT | ||||
| Optic pathway | <0.2 | 15(5Gy/fx) | 19.5(6.5Gy/fx) | Neuritis |
| Cochlea | 20(6.67Gy/fx) | Hearingloss | ||
| Brainstem | <1 | 18(6Gy/fx) | 23(7.67Gy/fx) | Cranialneuropathy |
| Spinal cord | <0.25 | 18(6Gy/fx) | 22(7.33Gy/fx) | Myelitis |
| <1.2 | 11.1(3.7Gy/fx) | |||
| Cauda equina | <5 | 21.9(7.3Gy/fx) | 24(8Gy/fx) | Neuritis |
| Sacral plexus | <3 | 22.5(7.5Gy/fx) | 24(8Gy/fx) | Neuropathy |
| Esophagus⁎ | <5 | 21(7Gy/fx) | 27(9Gy/fx) | Stenosis/fistula |
| Ipsilateral brachial plexus | <3 | 22.5(7.5Gy/fx) | 24(8Gy/fx) | Neuropathy |
| Heart/pericardium | <15 | 24(8Gy/fx) | 30(10Gy/fx) | Pericarditis |
| Great vessels | <10 | 39(13Gy/fx) | 45(15Gy/fx) | Aneurysm |
| Trachea and ipsilateral bronchus⁎ | <4 | 15(5Gy/fx) | 30(10Gy/fx) | Stenosis/fistula |
| Skin | <10 | 22.5(7.5Gy/fx) | 24(8Gy/fx) | Ulceration |
| Stomach | <10 | 21(7Gy/fx) | 24(8Gy/fx) | Ulceration/fistula |
| Duodenum⁎ | <5 | 15(5Gy/fx) | 24(8Gy/fx) | Ulceration |
| Jejunum/ileum⁎ | <5 | 16.2(5.4Gy/fx) | 27(9Gy/fx) | Enteritis/obstruction |
| Colon⁎ | <20 | 20.4(6.8Gy/fx) | 30(10Gy/fx) | Colitis/fistula |
| Rectum⁎ | <20 | 20.4(6.8Gy/fx) | 30(10Gy/fx) | Proctitis/fistula |
| Bladder wall | <15 | 15(5Gy/fx) | 30(10Gy/fx) | Cystitis/fistula |
| Penile bulb | <3 | 21.9(7.3Gy/fx) | 42(14Gy/fx) | Impotence |
| Femoral heads (right and left) | <10 | 21.9(7.3Gy/fx) | Necrosis | |
| Renal hilum/vascular trunk | <2/3volume | 18.6(6.2Gy/fx) | Malignanthypertension | |
| Parallel Tissue | Critical Volume (mL) | Critical Volume Dose Max (Gy) | Endpoint (≥Grade 3) |
|---|---|---|---|
| Lung (right and left) | 1,500 | 10.5(3.5Gy/fx) | Basiclungfunction |
| Lung (right and left) | 1,000 | 11.4(3.8Gy/fx) | Pneumonitis |
| Liver | 700 | 17.1(5.7Gy/fx) | Basicliverfunction |
| Renal cortex (right and left) | 200 | 14.4(4.8Gy/fx) | Basicrenalfunction |
| Serial Tissue | Volume (mL) | Volume Max (Gy) | Max Point Dose (Gy) | Endpoint (≥Grade 3) |
|---|---|---|---|---|
| FIVE-FRACTION TREATMENT | ||||
| Optic pathway | <0.2 | 20(4Gy/fx) | 25(5Gy/fx) | Neuritis |
| Cochlea | 27.5(5.5Gy/fx) | Hearingloss | ||
| Brainstem | <1 | 26(5.2Gy/fx) | 31(6.2Gy/fx) | Cranialneuropathy |
| Spinal cord | <0.25 | 22.5(4.5Gy/fx) | 30(6Gy/fx) | Myelitis |
| <1.2 | 13.5(2.7Gy/fx) | |||
| Cauda equina | <5 | 30(6Gy/fx) | 34(6.4Gy/fx) | Neuritis |
| Sacral plexus | <3 | 30(6Gy/fx) | 32(6.4Gy/fx) | Neuropathy |
| Esophagus⁎ | <5 | 27.5(5.5Gy/fx) | 35(7Gy/fx) | Stenosis/fistula |
| Ipsilateral brachial plexus | <3 | 30(6Gy/fx) | 32(6.4Gy/fx) | Neuropathy |
| Heart/pericardium | <15 | 32(6.4Gy/fx) | 38(7.6Gy/fx) | Pericarditis |
| Great vessels | <10 | 47(9.4Gy/fx) | 53(10.6Gy/fx) | Aneurysm |
| Trachea and ipsilateral bronchus⁎ | <4 | 18(3.6Gy/fx) | 38(7.6Gy/fx) | Stenosis/fistula |
| Skin | <10 | 30(6Gy/fx) | 32(6.4Gy/fx) | Ulceration |
| Stomach | <10 | 28(5.6Gy/fx) | 32(6.4Gy/fx) | Ulceration/fistula |
| Duodenum⁎ | <5 | 18(3.6Gy/fx) | 32(6.4Gy/fx) | Ulceration |
| Jejunum/ileum⁎ | <5 | 19.5(3.9Gy/fx) | 35(7Gy/fx) | enteritis/obstruction |
| Colon⁎ | <20 | 25(5Gy/fx) | 38(7.6Gy/fx) | colitis/fistula |
| Rectum⁎ | <20 | 25(5Gy/fx) | 38(7.6Gy/fx) | proctitis/fistula |
| Bladder wall | <15 | 18.3(3.65Gy/fx) | 38(7.6Gy/fx) | cystitis/fistula |
| Penile bulb | <3 | 30(6Gy/fx) | 50(10Gy/fx) | Impotence |
| Femoral heads (right and left) | <10 | 30(6Gy/fx) | Necrosis | |
| Renal hilum/vascular trunk | <2/3volume | 23(4.6Gy/fx) | Malignanthypertension | |
| Parallel Tissue | Critical Volume (mL) | Critical Volume Dose Max (Gy) | Endpoint (≥Grade 3) |
|---|---|---|---|
| Lung (right and left) | 1,500 | 12.5(2.5Gy/fx) | Basiclungfunction |
| Lung (right and left) | 1000 | 13.5(2.7Gy/fx) | Pneumonitis |
| Liver | 700 | 21(4.2Gy/fx) | Basicliverfunction |
| Renal cortex (right and left) | 200 | 17.5(3.5Gy/fx) | Basicrenalfunction |
⁎Avoid circumferential irradiation. |
Degrees of Hypofractionation
The main objective of therapeutic radiation is to disrupt clonogenicity. Clonogenicity is the ability of cells to form colonies by cellular division. Cellular division is a very complicated process regulated by a multitude of genes. Because damage to any one of these genes can disrupt the process, the entire process can be stymied by a relatively modest dose of radiation. In contrast, cellular function, like the secretion of a hormone, is usually only coded for by 1 gene or a few genes. Therefore, radiation must damage every one of those genes in every cell to completely prevent the function. As such, it takes a very high dose of radiation to disrupt cellular function. As an illustration, growth control of a pituitary adenoma is achieved at a relatively modest dose, but to stop the secretion of a hormone from a hormone-secreting pituitary adenoma takes a much higher dose. Another example can be borrowed from the use of radioactive iodine to treat thyroid cancer. The therapy is so well targeted that massive doses reach both the thyroid cancer and residual functioning thyroid gland. These doses both disrupt clonogenicity and cellular function. Such a treatment has been termed ablative.
Not all hypofractionated radiotherapy is ablative. In general, ablation occurs at dose levels that correspond to the exponential (linear region on a logarithmic scale) portion of the cell-survival curve, which would generally involve daily dose levels of >8 Gy. Below this dose range, cells have more capacity to repair. The logarithm of cell survival as a function of dose in the lower-dose region exhibits a curviness called the shoulder. More conventional and nonablative hypofractionated radiotherapy is delivered on the shoulder. The range of 2.25 to 8 Gy per fraction, still considered hypofractionated, has mostly been used for palliation of metastatic disease. More recently, though, investigators treating common diseases like breast and prostate cancer have used nonablative hypofractionation in patients with curable tumors. This was partly championed for the cost savings associated with fewer overall fractions, but in some cases such hypofractionation has a biological rationale for improving the therapeutic ratio. A summary of the degrees of hypofractionated radiotherapy and their effects is shown in Table 3.
Table 3. Once-Daily Fractionation Options
| Type of Radiotherapy | Typical Dose per Fraction (Gy) | Characteristics |
|---|---|---|
| Conventionally fractionated radiotherapy | 1.5to2.0 | High cumulative doses, less apt to cause “late effects” |
| Hypofractionated radiotherapy | >2.0to8.0 | Most commonly used for palliative treatment for patients near end of life, increasingly used for curative treatment in breast and prostate cancer therapy |
| Ablative radiotherapy | >8.0 | Stops both cellular division and cellular function, overwhelms tumor repair, more likely to cause “late” effects |
This Issue of Seminars in Radiation Oncology
Only 10 to 15 years ago, a review of the topic of hypofractionation would be limited to IORT, SRS, and the more moderate hypofractionated regimens associated with breast and prostate cancer. With the increasing use of SBRT to treat a number of cancers, the topic has dramatically broadened with dose per fraction of over 30 Gy. Implementing hypofractionation within any daily dose beyond conventional for curable patients constitutes an extremely contentious topic. Clinical practice may be ahead of prudent assessment of effects, particularly for SBRT.
In this issue covering the topic of hypofractionation for nonpalliative therapy, we will not pretend there is consensus. We will take on some of the more controversial issues head on by including provocative articles using a point/counterpoint format. All authors were asked to present the historical experience, rational and opportunity, observed benefits, honest assessment of toxicities, and applications for the future.
The first point/counterpoint discussion concerns the implementation of technology and whether technology can facilitate ablative hypofractionation. Dolinsky and Glatstein take the position that technology cannot always overcome biology. Their article shows great insight into clinical results and realities that must be faced. In the article by Kavanagh, he contends that the negative historical experience with ablative hypofractionation can be overcome by normal tissue avoidance using modern technologies not previously available. Kavanagh uses “modern” arguments in a “modern” prose to make his interesting observations.
The second point/counterpoint discussion relates to the common use of mathematical models used to describe both biological and clinical aspects of radiation response. Kirkpatrick et al take the position that the commonly used linear-quadratic model fails to accurately predict effects of large dose per fraction therapy. They point out clinical results that suggest mechanisms beyond chromosomal damage of the tumor may be involved in affecting outcomes after radiosurgery. Taking the counterpoint, Brenner argues that the linear-quadratic model is both rigorous and founded in a mechanistic understanding of radiation effect. He argues that the clinical data currently shows no inconsistencies when modeling with linear-quadratic formalism. Both articles make very interesting observations that will stimulate hypotheses and likely lead to future clinical trials.
Although much focus has been placed with technology in relation to hypofractionation, Story et al point out that there has been relatively little biological investigation into mechanisms of injury and possibilities for modulating this injury. These authors point out the known distinctions between conventional radiation and hypofractionation and importantly provide considerations that might help generate testable hypotheses for future translational and clinical testing.
Considerable clinical testing of hypofractionation has been performed in the treatment of prostate cancer. Ritter is one of the foremost leaders in this area of investigation. In his article on hypofractionation of prostate cancer, Ritter paints a thoughtful and realistic picture of the status of hypofractionation, both the biological basis and published clinical experience.
Like with prostate cancer, mature clinical data are available for consideration in the hypofractionated treatment of breast cancer. Whelan et al's article provides a thoughtful historical perspective, biological basis, and thorough review of clinical outcomes for treating breast cancer. With obvious concerns about late effects in a disease with considerable emphasis on avoiding cosmetic problems, hypofractionation in breast cancer constitutes one of the more difficult challenges in balancing competing effects.
Finally, Nedzi reports clinical results from ablative fractionation treatments within the body and brain. In this article, Nedzi emphasizes the balance between control and toxicity with special attention to experiences that have reasonable follow-up assessment.
Collectively, this issue of Seminars in Radiation Oncology presents a cross-section of views and experiences regarding the clinical implementation of hypofractionation. Much of this subject is surrounded by ongoing controversy. Much is at stake in that the avoidance of dreaded late effects obviously cannot be confirmed without long and careful follow-up. The use of hypofractionation in the curative management of cancer has been tested before with not so ideal results. Of course, times have changed. Technology has improved. The biology of radiation response is better understood. Whether these improvements are enough remains to be seen. Hopefully, though, this issue of Seminars in Radiation Oncology will serve to stimulate the formulation of testable hypotheses that will lead to improvements in therapy and patient outcomes. Understandably, long-term follow-up from prospective trials will be needed to dispel controversy about the feasibility of hypofractionation.
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PII: S1053-4296(08)00030-1
doi:10.1016/j.semradonc.2008.04.001
© 2008 Elsevier Inc. All rights reserved.
