A review of hypofractionated palliative radiotherapy
 
Stephen T. Lutz,. Cancer 2007;109:1462

During the 40 years after the discovery of x-rays, the treatment of human cancer with radiation generally was limited to a single dose or to a few large fractions. After researchers in the 1930s discovered that several smaller doses given over a period of weeks were more effective in controlling neoplasms, standard fractionation external-beam radiotherapy (EBRT) evolved into schedules of between 1.8 grays (Gy) and 2.0 Gy delivered 5 days per week for 5 to 8 weeks, depending on tumor histology and clinical circumstances.

Hypofractionation, as the name suggests, refers to the delivery of radiotherapy dose in a smaller number of treatments than would be used to deliver a traditional dosing scheme. The daily fraction size, therefore, is larger than the size given in standard fractionation, commonly measuring between 3 Gy and 8 Gy. Most structures in the human body are divided into either early-responding or late-responding tissues, depending on whether they are more likely to manifest radiation damage around the time of the treatment course or months to years later, and larger fraction size correlates with greater damage to late-responding tissues. Still, patients who are treated for symptom palliation commonly have limited survival, physical discomfort with transportation, and emotional disdain for prolonged treatment courses. Shorter courses exemplify common sense end-of-life care, especially because most patients who are treated for symptom palliation will not survive to face the increased risk of long-term side effects associated with hypofractionated regimens.

Radiotherapy administered with palliative intent commonly makes up 40% to 50% of the workload of any radiation oncology department. These trends in palliative radiotherapy have demonstrated consistency over a lengthy period, with 14% of patients who have newly diagnosed primary tumors and 75% of patients who have recurrences or metastasis receiving only palliative radiation. Although painful bone metastasis is the most common reason for the delivery of palliative radiotherapy, approximately 66% of palliative radiotherapy is delivered for the management of other symptoms.

Radiation therapy provides significant relief of painful bone metastases. Depending on the criteria used, from 50% to 80% of patients will have significant improvement in pain after radiation therapy, and from 10% to 35% will have complete pain relief. The improvement in pain typically occurs beginning at about 2 weeks after treatment, with maximal pain relief seen from 4 to 6 weeks after treatment. There is a better response to radiation therapy when the treatment is given for moderate pain rather than for severe pain.

The standard treatment for palliation of bone metastases has been daily treatment for 2 to 3 weeks with doses of 30 to 35 Gy in 10 to 14 treatments. There have been many randomized, prospective studies evaluating shorter treatment courses compared with the standard treatment course. Over the past 20 years, there have been 9 large trials that compared a single fraction of 8 Gy or 10 Gy with a multiple-fraction, higher dose regimen. In each of those studies (which included a total of >4000 patients), there were no differences reported in pain relief or pain medication requirements between the treatment regimens. There does appear to be a threshold dose to achieve this result. In the 2 studies that evaluated a single dose of 8 Gy versus 4 Gy, the pain response rates were significantly lower for the 4-Gy treatment.

In the studies that compared a single dose of 8 Gy with a longer course of treatment, the rate of retreatment (radiation therapy to the same area at a later date) was significantly higher after the single-dose treatment. The need for retreatment ranged from 11% to 29% after single-fraction therapy, compared with 0% to 24% after multiple-fraction treatment. This need for retreatment is of most concern in patients with good performance status and limited metastatic breast or prostate cancer, in whom the life expectancy may be from 2 to 4 years. However, 1 reason that more patients receive retreatment after a single dose of radiation therapy is because they can. Many radiation oncologists are reluctant to provide a second course of palliative treatment after the patient already has received from 30 to 35 Gy to a painful bone metastasis, particularly if there is spinal cord or other sensitive normal tissues in the treatment volume. This is of much less concern after a single dose of 8 Gy. Thus, for patients with a limited lifespan or poor performance status, the single-fraction treatment should provide palliation as effectively as a longer course, higher dose, less convenient, multiple-fraction regimen.

Along with the treatment of painful bone metastasis, hypofractionationated radiotherapy has been studied most in the setting of nonsmall cell lung cancer, and the results from 13 trials have been reported in the past 2 decades. Chemotherapy was not included in most of those trials, and virtually all of the studies reported on patient groups with significant symptoms who had an overall survival of <1 year. Although the data do not show a single, optimal, short-course fractionation scheme for these patients with locally advanced, inoperable disease, many of the studies suggest equivalent survival and symptom control with either 16 Gy or 17 Gy in 2 fractions compared with more prolonged courses.

Uncontrolled pelvic malignancies may cause significant symptoms, including pain, bleeding, discharge, and hydronephrosis. Because many patients with advanced pelvic malignancies have a limited life expectancy, abbreviated treatment approaches have been attempted and reported in the literature, and the results suggest that adequate palliation may be achieved best with an intermittent, hypofractionated regimen.

The Radiation Therapy Oncology Group (RTOG) initially administered a prospective, nonrandomized study of patients with advanced gynecologic, gastrointestinal, and prostate carcinomas who received treatment of large pelvic fields to a single, 10-Gy fraction. The dose was repeated at monthly intervals twice more for a potential total dose of 30 Gy in 3 fractions. The overall response rate to treatment was 41%, although the toxicity was unacceptably high with a rate of late grade 3 and 4 gastrointestinal side effects of 49% of patients. In a separate study, the delivery of a single, 10-Gy fraction of radiotherapy was shown to palliate advanced cervical and endometrial primary tumors, with bleeding controlled in 60% of patients and with many of the palliated symptoms remaining under control for the remainder of the patients' lifespan. Once again, however, late bowel toxicity was a concern for those who had a life expectancy of >9 months.

In an effort to minimize late effects, a modified hypofractionated approach was carried out in a Phase II RTOG trial. Patients with advanced gynecologic and genitourinary malignancies received a total dose of 44.4 Gy in 12 fractions. The dose was given as 3.7-Gy fractions twice daily for 2 days with 3-week to 6-week breaks after 14.8 Gy and 29.6 Gy. Sixty percent of the patients completed all 3 courses, whereas 20% completed 2 courses, and 20% received only 1 course. Patients had acceptable acute and long-term side-effect rates, and the results led the investigators to perform a study with the same fractionation scheme but with randomization to either 2-week or 4-week breaks between the treatment courses. Patients who received treatment with shorter break intervals were more likely to suffer acute side effects, yet they also more commonly completed all 3 courses than patients who had the longer breaks. The overall late complication rate did not differ between arms and was approximately 7%, a notable improvement over the late effects of the previously reported 10-Gy-per fraction studies.

A small group of patients with either outlet obstruction symptoms or hematuria caused by locally advanced prostate cancer was randomized to receive either 35 Gy in 15 fractions or 24 Gy in 3 weekly fractions. Eighty-eight percent of those patients had improvement of obstructive symptoms, with the majority successfully passing a voiding trial without a urinary catheter. In addition, all of the patients with hematuria noted resolution of their bleeding. The authors did not describe any differences in either symptom improvement rates or side effects between these fractionation regimens.

A hypofractionated course of EBRT for patients with locally advanced rectal cancer reportedly was successful in limiting the need for palliative surgical colostomy placement to 33%. The regimen delivered 30 Gy in 6 fractions (given twice per week) with continuous infusion 5-fluorouracil to patients with unresectable or locally advanced colorectal cancer who had synchronous metastasis. This regimen provided a good rate of pain control and limited the isolated local progression of the pelvic disease to 18% while causing little significant late toxicity.  Pain relief also reportedly was as high as 70% to 90% in patients who received palliative EBRT for unresectable pelvic recurrences of rectal cancer.

Several studies have evaluated the palliative worth of hypofractionated radiotherapy in the treatment of patients with advanced bladder cancer. One retrospective review of 65 elderly patients (median age, 78years) who received weekly 6-Gy fractions up to total doses of 30 Gy to 36 Gy showed a 92% improvement in hematuria, although with only an approximately 25% decrease in dysuria or urinary frequency. No significant late toxicities were noted, although the median overall survival for the group was only 9 months.Another elderly group of patients with a median age of 81 years received a hypofractionated regimen of radiotherapy consisting of weekly 6-Gy fractions to a total dose of between 30 Gy and 36 Gy. Local control was achieved in 25% of patients, and the median survival for the group was 35 weeks. Those patients who had a longer survival did have a tendency toward increased urinary frequency, although many also had persistent tumors that may have contributed to that difficulty. A hypofractionated regimen given to patients with more limited disease and a longer life expectancy revealed overall and severe late complication rates at 5 years of 33% and 9%, respectively.

A comparison of a hypofractionated course and a more prolonged course of radiotherapy for symptomatic bladder cancer suggested an improvement in symptom control with the abbreviated course. Patients with grade II or III, stage T3 or T4N0M0 tumors that caused pain and/or hematuria received either 45 Gy in 12 fractions over 26 days or 17 Gy in 2 fractions over 3 days. The rates of clearing of hematuria and relief from pain were 59% and 73%, respectively, in the 2-fraction group and 16% and 37%, respectively, in the 12-fraction group. The side-effect profiles of the 2 regimens were similar and mild, whereas the survival of patients in the shorter course group was just under 10 months compared with almost 15 months for patients in the longer course group. A second prospective, randomized trial compared hypofractionated regimens of either 35 Gy in 10 fractions or 21 Gy in 3 fractions for patients with locally advanced, inoperable bladder carcinoma: Seventy-one percent of patients who received 35 Gy and 64% of patients who received 21 Gy had symptomatic relief. Along with similar palliation rates, neither side effects nor overall survival rates differed between the 2 groups.

One prospective, randomized trial evaluated conventionally fractionated versus hypofractionated palliative EBRT schedules for patients with locally recurrent or advanced head and neck cancers. That study compared 60 Gy with 70 Gy in 6 to 7 weeks versus 40 Gy to 48 Gy in 64 patients with stages III and IV surgically unresectable squamous cell carcinoma of the head and neck. No differences were noted in tumor control, acute side effects, or long term sequelae.

In a Phase II study, the value of hypofractionated radiotherapy was examined in patients with previously untreated head and neck cancer. The regimen (entitled the Quad Shot) consisted of 14 Gy in 4 fractions given twice per day for 2 consecutive days. The regimen was repeated at 4-week intervals for an additional 2 courses if there was no tumor progression. The median survival in this poor prognostic group was 5.7 months, and quality of life improvements were documented in 44% of patients. In a separate study, >500 patients with poor-prognosis, stage IV head and neck cancer were treated with palliative radiotherapy to 20 Gy in 5 fractions in 1 week. Patients who had regression 50% in their tumor size went on to receive additional radiotherapy on a more standard fractionation scheme up to a total of 70 Gy. Thirty percent of patients received the full 70-Gy dose and had a median survival of 13 months, whereas the less responsive group that was limited to 20 Gy had a median survival of approximately 6 months. Palliative relief in the patients who received only 5 fractions measured between 47% and 59% for symptoms that including pain, dysphagia, hoarseness, cough, and otalgia.

Radiation can palliate the pain associated with hypersplenism. In 1 review, total radiation doses >5 Gy were identified as more effective at palliation, with 60% of patients reporting relief in splenomegaly and 91% reporting relief in splenomegaly in splenic pain. It was observed that the palliative response persisted for only approximately 6 months, so the authors recommend a radiotherapeutic approach in patients who had a <1 year life expectancy. A separate study reviewed the results from patients with splenomegaly who received 2 times 0.5-Gy treatments in Week 1, 2 times 0.75-Gy treatments in Week 2, and 2 times 1 Gy treatments in Week 3. Symptomatic improvement was noted in nearly 90% of the patients, although the life expectancy for 41% of the patients was less than 1 month after treatment. Retreatment seemed to be effective for those who survived for >6 months and who suffered recurrent splenomegaly. Again, the authors recommend surgical resection rather than radiotherapy for patients who had sufficient performance status and longer life expectancy.

Hypofractionated radiotherapy provides efficient palliation of end-of-life symptoms. Many patients who receive treatment near the end of life require an intense effort to achieve transportation out of the home; thus, the optimal intervention for this group is 1 visit that includes consultation, dose planning, and delivery of a single-fraction treatment; a series of tasks that may be completed within 2 hours at most radiotherapy centers. If additional fractions are necessary, then those treatments should require only approximately 15 minutes each. Palliative relief after radiation therapy commonly has its onset in from 1 week to 10 days, it achieves its full benefit within 1 month, and it lasts for most of a patient's remaining lifetime.

The toxicity profile of radiotherapy has an advantage over systemic therapy in that the deleterious effects, other than fatigue, are limited anatomically to the site of treatment, whereas chemotherapy agents often cause functional deficits in several organ systems. In addition, the acute side effects of radiotherapy most commonly are limited to a short time frame of days or weeks after therapy, whereas systemic agents can cause repetitive toxicity that is additive with each cycle and that may have a negative influence on quality of life over a patient's remaining lifespan. Recent evidence suggests that chemotherapy recipients incur large, incremental expenditures for medical management of chemotherapy-related adverse effects of >$17,000 per patient year.

Palliative medicine and radiation oncology have begun to merge along lines of common interest, as evidenced by the fact that 12 board-certified radiation oncologists also hold dual certification from the American Board of Hospice and Palliative Medicine. The role of radiation oncologists in palliative care should grow, because the American Board of Radiology has agreed to act as 1 of the 11 cosponsoring specialties for the newly recognized Hospice and Palliative Medicine specialty designated by the American Board of Medical Specialties. The National Board of Medical Examiners will administer the certification testing, and the Accreditation Council for Graduate Medical Education will direct fellowship training.  The American Society for Therapeutic Radiation Oncology and the National Hospice and Palliative Care Organization also have begun collaboration in research, education, and patient advocacy. The expected increase in the need for palliative radiotherapy, coupled with the likelihood of decreasing medical resources, demands additional interest in hypofractionated regimens for the group of patients shared by these caregivers.