Great Debates & Updates in GI Malignancies Meeting
Deborah Schrag: Chemotherapy Alone
It's true that the standard of care for patients with locally advanced rectal cancer is chemo-radiation, said Deborah Schrag MD, MPH, Chief of the Division of Population Sciences in the Department of Medical Oncology and Senior Physician at Dana-Farber Cancer Institute. “Neoadjuvant chemotherapy is an investigational strategy. The efficacy of neoadjuvant chemotherapy without radiation has not yet been established in the context of controlled clinical trials. I'm here to persuade you, though, that a trial to compare neoadjuvant chemoradiation with neoadjuvant chemotherapy with selective radiation is a priority.”
Current Treatment Paradigm
The current treatment paradigm for rectal cancer treatment paradigm includes five and a half weeks of chemotherapy, five to six weeks of recovery, total mesorectal excision (TME) rectal surgery, four to six weeks of recovery, and then adjuvant chemotherapy, she said. “The start of systemic chemotherapy is delayed four to five months from initial presentation.
“Clinical trials show that radiation decreases local recurrence rate, even with good surgery. Preoperative chemo-radiation is preferable to postoperative.”
Why is the use of neoadjuvant radiotherapy questioned? Pelvic radiation causes short- and long-term morbidity, she said. “Each treatment modality has improved since the current treatment paradigm was established. We have better imaging, with widespread availability of MRI to characterize T stage and circumferential radial margin. We have better surgery, with diffusion of modern TME techniques, and better systemic chemotherapy with adjuvant FOLFOX.”
In addition, screening now detects more rectal cancers within stage migration to smaller tumors. “As colorectal cancer screening has improved, we are now seeing smaller rectal cancer tumors,” she said.
Schrag described the experience with neoadjuvant chemotherapy in Stage IV rectal cancer patients and those with contraindications to radiotherapy: “Patients with stage IV rectal cancer have high response rates and conversion to resectability with omitting the pre-op radiotherapy. We also have clinical experience in the treatment of rectal cancer without radiotherapy in special cases, including stage II to III rectal cancer in prostate and gynecologic cancer survivors, women seeking fertility/childbearing preservation, and men and women who are particularly concerned about sexual function.”
Challenges arise from neoadjuvant chemo-radiation in the rectal cancer treatment paradigm, she continued. “Distant disease is the primary site of recurrence and site of death in rectal cancer. There is a risk of under-treatment in node-positive patients who don't complete post-op systemic chemotherapy, and an overtreatment risk in node-negative patients, who may get unnecessary therapy.”
She also mentioned issues with myelosuppression and impaired tolerance to chemotherapy after pelvic radiotherapy, and noted that patients with metastatic rectal cancer get less chemotherapy and have inferior survival compared with patients with metastatic colon cancer.
Ongoing Phase II/III Trial
Schrag noted that the Alliance's ongoing, Phase II/III randomized PROSPECT study is determining if selective use of radiotherapy is a safe alternative to routine use of neoadjuvant radiotherapy for management of locally advanced rectal cancer amenable to sphincter-sparing TME. The study, open for recruitment, plans to randomize 366 patients, with an early stopping rule if there is a failure to complete R0 resections or if there is an unacceptably high rate of local recurrences.
The Phase III component of the trial will include 644 additional patients if stopping criteria are not met. As of the time of her talk, about 310 patients had been accrued, and she noted that radiation in the intervention arm is to be used selectively.
In conclusion, Schrag said: “Neoadjuvant chemotherapy strategies are an investigational approach for patients with resectable rectal cancer amenable to sphincter-sparing TME. Patients with threatened margins are inappropriate candidates for selective use of radiotherapy. Induction FOLFOX merits consideration for patients who can't have radiotherapy due to prior therapy, who have stage IV disease amenable to R0 resection, or who have suspected metastatic disease.”
She encouraged oncologists to enroll clinical stage II/III rectal cancer patients in the PROSPECT trial “to help address this ‘great debate.’”
Michael Haddock: Chemo-radiation
“Chemo-radiation is preferred over chemotherapy alone or short-course radiation as preoperative therapy for adenocarcinoma of the rectum,” said Michael G. Haddock MD, Professor of Oncology at Mayo Clinic College of Medicine. “There is no evidence that chemo-radiation can be replaced by chemotherapy alone.”
Preoperative therapy is indicated for patients with T3-4 disease who are node positive at any location, or for patients with T3-4 disease who have no nodes and have disease in the mid-low rectum. “If the goal is a cure, this requires elimination of locoregional disease,” Haddock said.
In the intermediate-risk group, most patients who have surgery alone do not have local recurrence. In high-risk patients, local failure is quite low. A combination of radiation therapy and chemotherapy has the lowest occurrence, and survival is better than with chemotherapy, he said.
Haddock noted that the Gastrointestinal Tumor Study Group trial in 1985 established chemo-radiation therapy as the standard of care, showing that radiation therapy plus chemotherapy improved the rates of both overall survival and local recurrence. A German Rectal Cancer Study in 2004 found that preoperative chemo-radiation improved local control and reduced toxicity, but did not affect overall survival.
“Late toxicity was significantly lower in the pre-op group—this is the preferred method,” he said. “There is not much evidence to give chemotherapy alone. There are a host of negative Phase III trials.”
Chemo-radiation also has a favorable impact on bowel function. Bowel symptoms improve with radiation therapy, with no significant impact on quality of life.
There is some evidence to support the use of short-course radiation therapy, Haddock said. Short-course radiation comes up short, though, in comparison with longer chemo-radiation. “Longer chemo-radiation has a survival advantage, and positive margins are better.” Adjuvant randomized trials in rectal cancer show higher five-year survival rates with chemo-radiation than with short-course radiation.
In conclusion, Haddock said: “Chemo-radiation leads to a survival benefit in the post-op setting. Pre-op chemo-radiation is better than post-op. The evidence supporting the benefits of chemotherapy alone is weak. Bowel toxicity after chemo-radiation is not bothersome for most patients. Evidence of a survival benefit is lacking with short-course radiation.”
Christopher Crane: Short-course Radiation
A third speaker for the debate, Christopher H. Crane, MD, Professor, Program Director, and Chief of the Gastrointestinal Section and Director of the Residency and Fellowship Program of the Department of Radiation Oncology at the University of Texas MD Anderson Cancer Center, argued that short-course radiation therapy best: “safe, effective, cost-effective, and efficient,” he said.
He pointed to the Swedish Rectal Cancer Trial, which found that node-positive patients who had preoperative radiation therapy and surgery had a 43 percent overall survival rate after 13 years of follow-up compared with 23 percent for patients who received surgery alone.
In addition, the Dutch TME Trial showed that preoperative radiation plus TME reduced local and overall recurrence. Radiation therapy did induce more late side effects, including incontinence and what was described as loss of anal mucus and anal blood.
Crane said that comparisons of short- versus long-course radiation show only small differences in local failure, with similar grade 3 rates of late toxicity and overall survival, and no evidence of higher post-operative complications. “The interval between radiation and surgery seems to be no problem, except if you delay more than 10 days,” he said.
The acute effect of radiation peaks within 10 days, and surgery should be conducted within 10 days or beyond 17 days.
The reason for there being no short-course radiation in the U.S. comes down to economics, he said: “There is a strong trend to deliver stereotactic body radiation therapy [SBRT] in one-week regimens in lung, liver, or pancreatic cancers because these popular regimens are reimbursed. A radiation regimen of 5 × 5 Gy to the whole pelvis is not ‘SBRT.’ The charges for long-course therapy are five times higher.”
The 5 × 5 Gy Iong-course radiation regimen is increasingly in demand, he said. Efficiency will need to increase and bundled care plans instituted.
In summary: “Short-course radiotherapy is effective. Multiple randomized trials demonstrate a role for short-course radiotherapy. It is safe, with late side effects not clearly a concern; cost effective; and convenient.”
Before the debate, most of the audience (86%) voted that they believed that chemo-radiation was the best choice for preoperative therapy for rectal cancer, while seven percent said they thought that chemotherapy alone was appropriate and seven percent chose short-course radiation.
Afterward, even more participants (94%) voted for chemo-radiation, and none voted for short-course radiation, making chemo-radiation the clear therapeutic winner.