Is short-course radiation for rectal cancer finally ready for prime time? This was the topic of a lively debate at the Society of Surgical Oncology’s 2021 International Conference on Surgical Cancer Care.
Pro: Short-Course Is Ready For Prime Time
Cornelius Van de Velde, MD, PhD, a professor of surgery at Leiden University Medical Center, in the Netherlands, argued for the pro side. “I coordinated four phase 3 studies utilizing short-course radiation therapy for rectal cancer, and I conclude on these and many other studies that it is ready for prime time. Short-course radiation therapy has proven to be very effective.”
He said the first proof that short-course radiation works for rectal cancer comes from five years of follow-up from the Swedish Rectal Cancer Trial of patients younger than 80 years of age who had resectable rectal cancer (N Engl J Med 1997;336[14]:980-987). This trial compared surgery alone (n=557) with surgery and preoperative short-course radiation therapy with 25 Gy delivered in five fractions in one week (n=553). At five years, the researchers identified a gain of 10% in overall survival (58% vs. 48%; P=0.004) with short-course radiation therapy. Short-course radiotherapy also reduced the local recurrence rate from 27% to 11% (P<0.001) and increased cancer-specific survival from 65% to 74% (P=0.002).
The Polish I study compared long-course chemoradiotherapy (n=157) with short-course radiotherapy (n=135) in patients with T3 or T4 resectable primary tumors and no evidence of sphincter involvement on digital rectal examination (Br J Surg 2006;93[10]:1215-1221). The lower tumor margin had to be accessible by digital rectal examination. Patients receiving long-course chemoradiotherapy received 50.4 Gy in 28 fractions of 1.8 Gy, plus bolus 5-fluorouracil and leucovorin with surgery after four to six weeks. Patients receiving short-course radiotherapy received 25 Gy in five fractions of 5 Gy and surgery within seven days. At four years, there was no significant difference in overall survival, disease-free survival or local recurrence between groups.
“The results indicated that radiation toxicity was significantly more after long-course radiation therapy, but all the other results were the same,” Dr. Van de Velde said. Although severe late toxicities did not differ significantly, early radiation toxicity was greater with long-course radiation (18% vs. 3%; P<0.001).
The Tasman Radiation Oncology Group trial 01.04 compared long-course chemoradiotherapy (50.4 Gy, 1.8 Gy per fraction in 5.5 weeks plus fluorouracil 225 mg/m2 per day; surgery in four to six weeks; four courses of adjuvant chemotherapy; n=163) with short-course radiotherapy (5×5 Gy in one week, early surgery, six courses of adjuvant chemotherapy; n=163) (J Clin Oncol 2012;30[31]:3827-3833). Patients had stage 3N0 to 2M0 rectal adenocarcinoma with 12 cm from the anal verge. The study indicated no significant differences between the two groups in terms of control of the tumor or toxicity.
The Stockholm III trial compared short-course radiotherapy with long-course radiotherapy and immediate versus delayed surgery. In the study, 840 patients with stage I to III rectal cancer were randomized to receive 5×5 Gy followed by direct surgery (less than one week), 5×5 Gy followed by delayed surgery (four to eight weeks), or 25×2 Gy followed by delayed surgery (four to eight weeks) (Lancet Oncol 2017;18[3]:336-346). The study concluded there were no significant differences among the three regimens in local or distant recurrence, recurrence-free survival, overall survival or surgical complications. There was a trend toward fewer postoperative complications with short-course and delayed surgery.
“With the possibility of delayed surgery as a valid option in the treatment, a window of opportunity opens bringing forward chemotherapy after radiation therapy before surgery, treating micrometastases in these advanced rectal cancer patients,” Dr. Van de Velde said.
The RAPIDO trial included 920 patients with locally advanced rectal cancer randomized to standard chemoradiation therapy and then surgery after a delay of eight to 10 weeks, followed optionally by chemotherapy after six to eight weeks, or to the experimental arm of 5×5 Gy radiation therapy followed by CAPOX (capecitabine plus oxaliplatin) or FOLFOX (folinic acid, fluorouracil and oxaliplatin) for 18 weeks, and then surgery after two to four weeks (Lancet Oncol 2021;22[1]:29-42). The experimental arm was superior in terms of three-year, disease-related treatment failure (24% vs. 30%; P=0.019), three-year distant metastases (20% vs. 27%; P=0.005), and pathologic complete response (28% vs. 14%; P<0.001). There was no difference in postoperative complications or number of stomas.
Dr. Van de Velde said short-course radiation therapy has better patient compliance than long-course radiation therapy, and this was evident in the RAPIDO trial (100% vs. 93%) (Radiother Oncol 2020;147:75-83).
Another benefit of short-course radiation therapy is that it has a survival benefit in elderly patients with locally advanced rectal cancer, shown by results in 101 patients in the PRODIGE-42 study, presented at the American Society of Clinical Oncology’s Gastrointestinal Cancers Symposium (abstract 4) last January. In this trial, arm A involved preoperative long-course chemoradiation (50 Gy, 2 Gy per fraction; five fractions plus capecitabine) and delayed surgery, while arm B involved preoperative short-course radiotherapy (25 Gy; 5 Gy per fraction, five fractions) and delayed surgery. The inclusion criteria were patients 75 years or older with T3/T4 rectal cancer tumors. The six-month mortality rate was higher with long-course radiation (10% vs. 3.92%), and the researchers concluded that short-course radiotherapy should be recommended as the new standard of care.
Dr. Van de Velde noted that short-course radiation therapy requires fewer visits to health care facilities, which is very important in the era of COVID-19.
“We also see in the Dutch M1 trial in metastatic rectal cancer patients and in the RAPIDO trial of locally advanced rectal cancer patients that there is a considerable pathologic complete response rate [with short-course radiation] which can be used to initiate a watch-and-wait strategy in selected patients,” Dr. Van de Velde said.
“Short-course radiation therapy is here to stay,” he said. “There are many reasons, especially now, to recommend short-course radiation therapy.”
Con: Short-Course Is Not Ready for Prime Time
Philip Paty, MD, an attending surgeon in the Colorectal Surgery Service at Memorial Sloan Kettering Center, in New York City, offered a contrary opinion. “Is short-course radiation ready for prime time in rectal cancer? Absolutely not. The true story of short-course radiation is a sorrowful tale of burned bottoms, poor healing and smelly stomas. As we say in America, you get what you pay for.”
To bolster his argument, Dr. Paty pointed to four randomized trials comparing short- and long-course neoadjuvant radiotherapy: the Polish I trial, Tasman Radiation Oncology Group trial 01.04, Polish II trial and Stockholm III trial (Br J Surg 2006;93[10]:1215-1221; J Clin Oncol 2012;30[31]:3827-3833; Ann Oncol 2016;27[5]:834-842; and Lancet Oncol 2017;18[3]:336-346). Dr. Paty pointed out that the three Northern European trials enrolled patients with resectable cancers and made adjuvant chemotherapy optional. The Polish II trial tested long-course oxaliplatin-based preoperative chemoradiation versus 5×5 Gy and consolidation chemotherapy for cT4 or fixed cT3 rectal cancer.
“There was no impact of radiation method across the board telling us that stage and surgery were the determinants of local recurrence. Survival end points were also no different,” Dr. Paty said. “However, we can find one measure of radiotherapy efficacy that is different between the radiation methods: the rates of pathologic complete response, which were higher following long-course radiation. We learn that long-course radiation therapy is more effective in sterilizing primary tumors than is short-course radiotherapy. Of note, quality-of-life data may not be an accurate representation because data were reported only in underpowered subsets that excluded patients with adverse outcomes (tumor recurrence, ongoing treatment), thereby excluding many of the patients most likely to have problems.”
Dr. Paty also said one clear outcome difference is found between short- and long-course radiotherapy: rates of permanent stoma. “The three trials with resectable cancers show the same trend of increased permanent stoma rates for short-course radiation.” In the Polish I trial, the rates of permanent stoma were twice as high with short-course radiation, due to more patients requiring colostomy because of impaired healing (leak, stenosis, infection and fistula) or poor anorectal function. Dr. Paty pointed out that this outcome difference is supported by pooled data from the three randomized trials studying resectable rectal cancer, which show permanent colostomy rates are higher with short-course radiation (46% vs. 36%).
Finally, Dr. Paty shared a paper from England that evaluated bowel function in a population-based study of rectal cancer patients without stomas (Int J Rad Onc Bio Phys 2018;103:1132-1142). “Preoperative long-course radiation was bad for continence and for urgency. Short-course radiation was even worse, with 30% fewer patients achieving complete continence. Again, we learn that the large fraction sizes and hypofractionation of short-course radiotherapy damages sphincter muscles and anastomoses,” Dr. Paty said.
Dr. Paty concluded that the four randomized trials directly comparing short- and long-course neoadjuvant radiotherapy show there is higher long-term morbidity and higher permanent stoma rates with short-course radiation. “So, if you get a rectal cancer, what do you want to buy?” he said. “You can go to Professor Van de Velde, save a few euros, and live with a stoma or a diaper for the rest of your life, or you can spend a few dollars and go back to dignity and having fun.”
Dr. Paty said eradicating rectal cancer without surgery is the best solution to the problems being discussed and that watch-and-wait with nonoperative management is where clinical trials should be pushing forward.
“The oncologic results, quality of life and cost savings of the watch-and-wait patients are the best of any group you can find among locally advanced rectal cancer patients,” Dr. Paty said. “There is no data for watch-and-wait using short-course radiation, but given the data discussed in this talk, it is likely that fewer patients will achieve clinical CR [complete response], and functional outcomes will likely be worse. … Finally, I want to say that long-course radiation is inherently better because it employs standard fractionation, which widens the therapeutic window between tumor cells and normal stem cells. Long-course radiation is also a more flexible platform allowing anatomic targeting, use of radiosensitizers and adaptive therapy.”
This article is from the June 2021 print issue.
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