For patients with locally recurrent rectal cancer, multimodality salvage therapy presents the only chance for a cure. Such therapy is offered at just a handful of specialized referral institutions, including The University of Texas MD Anderson Cancer Center.
“We use a multidisciplinary approach to care for patients with locally recurrent rectal cancer and to help define their treatment. This disease is extremely complicated, and typically patients need surgery, chemotherapy, and radiation therapy plus other specialized treatments like reconstructive surgery,” said Prajnan Das, M.D., M.P.H., an associate professor in the Department of Radiation Oncology.
“This institution has a long tradition of offering aggressive multimodality salvage therapy with curative intent to selected patients with locally advanced rectal cancer,” said Y. Nancy You, M.D., an associate professor in the Department of Surgical Oncology. “The stakes are high, and the whole salvage effort is much more difficult than treating the initial tumor.”
Recurrent rectal cancer
Patients with locally recurrent rectal cancer are a heterogeneous group: the extent of their disease, their previous therapies, and the biology of their tumors all vary widely. Similarly, the treatments they received for their initial rectal cancer may have failed for many different reasons.
“These patients might have had a complication after surgery that prevented them from healing well or from getting postoperative treatments like chemotherapy, or they might not have had optimal surgery or chemoradiation,” Dr. You said. “Or maybe their tumors just had very aggressive biology and recurred.”
Given the group’s heterogeneity, MD Anderson physicians carefully evaluate whether each patient with locally recurrent rectal cancer is a candidate for salvage therapy with curative intent. One key factor is whether the patient’s disease can be surgically removed with R0 (microscopically negative) or R1 (microscopically positive) margins. Currently, patients with distant metastasis or disease that cannot be completely removed, i.e., predicted R2 (grossly positive) surgical margins, are not considered candidates for salvage therapy.
When salvage therapy with curative intent is indicated, a team of surgical, medical, and radiation oncologists reviews each patient’s case to create an individualized treatment plan that falls within the framework of a management algorithm for recurrent rectal cancer (see figure at right). In general, patients undergo preoperative chemotherapy or chemoradiation, then repeat pelvic surgery with or without intraoperative radiation and/or soft tissue reconstruction, and often postoperative adjuvant chemotherapy.
“Over time, we have learned that this multidisciplinary approach works really well,” Dr. Das said. “And there have been incremental improvements in the techniques. Surgical techniques have evolved and have become more aggressive. We have become more aggressive in terms of radiation therapy, and systemic therapies have also evolved and improved.”
Improvements in chemotherapy in particular have enhanced the success of salvage therapy. “A decade or two ago, we had only one drug, 5-fluorouracil, available for rectal cancer. But in the past 10–15 years, we’ve had more effective cytotoxic chemotherapy agents like oxaliplatin and irinotecan and biologic agents like bevacizumab and cetuximab, so we have more options in terms of what drugs we can give,” Dr. You said. “The response rates of colorectal cancer in general to those agents have improved. And more patients with locally recurrent rectal cancer are now receiving postoperative chemotherapy, which may help reduce their risk of further disease recurrence.”
Achieving local control
“In the past, once rectal cancer recurred locally, performing re-operative pelvic surgery safely with negative tumor margins was very difficult because of significant inflammation, scarring, and tumor involvement of multiple structures in the tight space of the deep pelvis,” Dr. You said. “But we’ve made some significant advances in the way we approach these patients.”
In patients who will undergo surgery with curative intent for locally recurrent rectal cancer, preoperative three-dimensional conformal or intensity-modulated radiation therapy is given both to reduce the chances of a second local recurrence and to shrink the tumor to make it more amenable to resection. Patients who have not yet had radiation therapy receive conventionally fractionated radiation, typically to a dose of 50.4 Gy delivered in 28 daily fractions of 1.8 Gy each. But treating patients who have already had radiation therapy poses a bit more of a challenge.
“The classic dogma in radiation therapy is that if you treat a part of the body once, you don’t treat it again,” Dr. Das said.
To overcome this challenge, radiation oncologists use hyperfractionated accelerated radiation therapy to deliver doses of 30–39 Gy in twice-daily fractions of 1.5 Gy each; the lower dose per fraction helps reduce the risk of side effects from the treatment.
“The key to re-irradiation is knowing when and in which patients this can be safely done. We have to pay attention to the surrounding normal tissues, and we have to pay attention to designing a radiation plan that is tolerable,” Dr. Das said. “The treatment has to be individualized to the patient.”
Intraoperative radiation—radiation delivered to the tumor bed in the open surgical field—also enhances the likelihood that salvage surgery will succeed. “Many of these patients with recurrences have tumors that are very close to the acceptable excision planes, which means that there is a potential that microscopic disease gets left behind,” Dr. Das said. The aim of intraoperative radiation therapy is to eliminate this residual disease.Intraoperative radiation is used selectively. Once the tumor has been removed, if the surgical margin is found to be close, concentrated radiation in the form of high-dose-rate brachytherapy is used to destroy any tumor cells that may remain.Typically, this brachytherapy is delivered via a thin, flexible applicator. First, the applicator is secured to the surface of the tumor bed. Next, a pellet of a radioactive iridium isotope is passed through channels in the applicator and held at different points for a predetermined time; tissues immediately below the applicator receive a high dose of radiation, whereas those farther away receive little or no radiation. Once the radiation has been delivered, the applicator is removed, and the surgery is completed.
Since all of this is done in the middle of surgery, we can move normal tissue away from the area where we’re giving radiation, and we can put in lead shields to protect sensitive structures,” Dr. Das said. “Specifically for recurrent rectal cancer, we’ve found that intraoperative radiation therapy is quite beneficial.”
In addition to innovations in radiation therapy, improvements in surgical techniques themselves have advanced the treatment of locally recurrent rectal cancer. Dr. You said that the most important surgical change over the past decade has been the emphasis on total mesorectal excision and, in some patients, even more extensive, multivisceral resection (i.e., the en bloc removal of adjacent involved organs or structures) or surgery in the extra-mesorectal tissue in the lateral pelvis to achieve a cure.
“When we operate on a patient with rectal cancer or recurrent rectal cancer, we want to be sure to take out not only the rectum with the tumor in it but also the entire fatty tissue envelope around the rectum because the tumor may have metastasized to lymph nodes in that fatty envelope,” Dr. You said. “By performing a total mesorectal excision, we’re much more sure that all the tumor is removed, along with the potential lymph node spread. Following the same principles, when faced with recurrent rectal cancer that has spread beyond the rectum and the mesorectum, we aim to remove all structures involved by disease.”
Additionally, Dr. You said, preoperative planning in general has improved. “We are much more ready to involve other surgeons before the patient goes to surgery,” she said, noting that in addition to colorectal surgeons, other surgeons—including urologists, gynecologists, vascular surgeons, orthopedic surgeons, and neurosurgeons—may be called to review a patient’s case. “It’s much better to assemble a multispecialty surgical team before surgery, get the surgeons’ expert input, and have them on standby than to have to intraoperatively call in somebody who’s unfamiliar with the case.”
Improving patient selection
The key to successful salvage therapy for locally recurrent rectal cancer—especially salvage surgery—is appropriate patient selection. However, identifying the patients who are most likely to benefit from such therapy continues to vex even experienced oncologists. To help determine whom to select for salvage therapy, Drs. You and Das, along with other MD Anderson researchers, recently reviewed the institution’s experience with treating patients with locally recurrent rectal cancer over the past 2 decades. Perhaps not surprisingly, they found that the ability to achieve an R0 resection and the avoidance of a second recurrence were independent predictors of the long-term success of salvage therapy.
The researchers also found that the 5-year overall survival rate of patients treated between 2005 and 2012 (50%) was significantly higher than that of patients treated between 1997 and 2004 (43%) or between 1988 and 1996 (32%). Several factors have contributed to the increased survival rate. In addition to advances in surgical techniques, radiation therapy approaches, and systemic therapies, the study period saw remarkable improvements in imaging studies: positron emission tomography/computed tomography is now used to ensure that patients do not have distant disease before they undergo surgery with curative intent, and high-resolution magnetic resonance imaging of the pelvis affords surgeons a clearer picture of the tumor’s involvement with nearby structures and a better idea of whether the tumor can be resected with negative margins.
Despite the myriad advances underlying the increase in the survival rates of patients with locally recurrent rectal cancer, challenges in treating the disease remain. When salvage therapy fails, it often fails because of distant metastasis. Having a method that more accurately identifies the patients in whom salvage therapy will fail—and that predicts those in whom it will fail distantly—would be good, Dr. You said, but being able to address distant disease itself would be better. A subset of patients who present with local recurrence may have some tumor cells in their blood that surgery cannot remove and radiation cannot kill; these cells may persist and become distant metastases. Dr. You and her colleagues are developing a protocol to identify circulating tumor cells and treat them before embarking on aggressive surgery in hopes of reducing the distant failure rate.
“One of the questions we’re raising is whether, rather than giving just pelvic radiation before surgery, we should actually be giving all patients systemic chemotherapy up front and try to reduce the volume of these microscopic circulating cells that can metastasize after surgery,” Dr. You said.
Advances like these, she said, will help further improve outcomes in patients with recurrent rectal cancer. In the meantime, it is essential that such patients are considered for salvage therapy.
“A subset of patients whose disease recurs after primary rectal cancer treatment can be cured by salvage therapy. And these patients deserve a multidisciplinary evaluation,” Dr. You said. “We want to be able to help the patients who can be helped.”
For more information, contact Dr. Prajnan Das at 713-563-2379, Dr. Marta Davila at 713-792-1151, or Dr. Y. Nancy You at 713-794-4206.
The Beyond TME Collaborative. Consensus statement on the multidisciplinary management of patients with recurrent and primary rectal cancer beyond total mesorectal excision planes. Br J Surg. 2013;100:1009–1014.
Das P, Delclos ME, Skibber JM. Hyperfractionated accelerated radiotherapy for rectal cancer in patients with prior pelvic irradiation. Int J Radiat Oncol Biol Phys. 2010;77:60–65.
Hyngstrom JR, Tzeng CW, Beddar S, et al. Intraoperative radiation therapy for locally advanced primary and recurrent colorectal cancer: ten-year institutional experience. J Surg Oncol. 2014;109:652–658.
You YN, Habiba H, Chang GJ, et al. Prognostic value of quality of life and pain in patients with locally recurrent rectal cancer. Ann Surg Oncol. 2011;18:989–996.
You YN, Skibber JM, Hue C-Y, et al. Improved long-term salvage potential of locally recurrent rectal cancer with evolving multimodal therapy. Br J Surg. 2016. doi: 10.1002/bjs.10079.[Epub ahead of print]
OncoLog, April 2016, Volume 61, Issue 4
Surveillance for Success
After finishing their treatments, most cancer patients undergo close surveillance for recurrent and secondary cancers. Patients who have completed treatment for rectal cancer are no exception, and catching recurrences early increases these patients’ chances of being able to undergo salvage therapy with curative intent.
“Prompt diagnosis is extremely important,” said Marta Davila, M.D., a professor in the Department of Gastroenterology, Hepatology, and Nutrition. “And once we have the diagnosis, we can begin aggressive treatment with curative intent.”
At MD Anderson, Dr. Davila said, patients who have completed treatment for rectal cancer are followed up with scheduled colonoscopies and imaging studies. “Usually, these patients will have their first colonoscopy within 1 year of the initial resection and repeated evaluations over the next 5 years,” she said. After 5 years, follow-up examinations are less frequent for symptomatic patients.
“We have a very systematic follow-up, and we have a multidisciplinary approach. These two elements set us apart,” Dr. Davila said.