Although in recent decades a downward trend in primary surgical resection of Stage IV colorectal tumors has corresponded with an increase in survival due to more effective combination chemotherapy and biologics, many patients are still undergoing radical primary tumor procedures that may be unnecessary. That is the conclusion of a new study by researchers at the University of Texas MD Anderson Cancer Center published in the March issue of JAMA Surgery (2015;150:245-251).
The decline in primary tumor resection rates has not been uniform, but there is mounting evidence that most patients fare just as well with combination therapy, said the lead author, George J. Chang, MD, Associate Professor of Surgical Oncology.
He and his colleagues conducted a retrospective analysis of patient data in the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) colorectal cancer registry, focusing on primary tumor resection and mortality rates for 64,157 patients with metastatic colorectal cancer diagnosed between 1988 and 2010. The annual rate of primary tumor resection (PTR) fell from 74.5 to 57.4 percent in 2010, with a 2.39 percent drop between 2001 and 2010 when many newer agents were introduced.
In an interview, Chang noted that although the study was not designed to establish a causal association between the trend and mortality, the investigators also found that the median relative survival more than doubled over the study period independent of the PTR rate—from 8.6 percent in 1988 to 17.8 percent in 2009, an annual change of 2.18 percent between 1988 and 2001 and 5.43 percent between 1996 and 2009.
“With effective modern chemotherapeutic and biologic agents, primary tumor resection for these patients may not be routinely necessary,” he said. “The vast majority of patients require only chemotherapy, yet despite the availability of more effective chemotherapeutic options, a considerable number of patients continue to undergo PTR. In fact, our findings suggest that there may be a potential for overuse.”
Overall, a total of 43,273 patients (67.4%) underwent primary tumor resection, with those receiving surgery more likely to be younger, female, of white race or ethnicity, married, living in southern states, having higher tumor grades, and having tumors in the colon. Patients with metastatic colorectal cancer, however, underwent fewer PTR procedures, as did those with rectal tumors.
Only 51.5 percent of patients with tumors in the rectosigmoid or rectum underwent PTR compared with 76.8 percent with colon tumors, Chang continued, adding that several factors might explain this, including higher infection rates after rectal surgery, the complexity of such surgery, patients' fear of a permanent colostomy, and better local control with multimodality therapy.
For about two-thirds of patients who did undergo PTR, surgery failed to cure their disease despite increased risk of morbidity and mortality, he said, adding that current colorectal cancer guidelines may not fully reflect findings about the benefits of more recent agents: “We need to better understand treatment decisions and their outcomes. Many doctors and patients believe PTC provides better survival. In small groups of patients this might be true, but not as a rule.”
The decline in primary tumor resection could be the result of more effective systemic therapy or of greater reluctance among surgeons to operate on patients with asymptomatic stage IV colorectal cancer, he noted.
The study did not directly compare survival among PTR and non-PTR patients because of the potential for bias in the SEER database, he noted. Also, because the database does not provide information regarding chemotherapy, the researchers were unable to confirm that the reduction resulted from more effective chemotherapeutic agents. Moreover, SEER does not provide information regarding the intent of PTR, so patients could have undergone palliative resection or PTR and resection of metastasis with curative intent, he explained.
He and his colleagues were left with questions about why primary tumor resection rates have not kept up with the benefits of modern chemotherapy drugs. “Although fewer people are getting primary tumors resected, a large proportion of patients with metastatic disease at diagnosis are still having them removed. Our observation that primary tumor resection was more likely performed in younger patients who have colon rather than rectal cancers suggests that there may still be an overutilization of PTR and that careful consideration of the indication for such surgery should be made.”
PTR in metastatic cancer is typically for patients who develop obstruction and/or bleeding, but this is a small group of colorectal cancer patients, he said. Yet many physicians and patients remain concerned that intact primary tumors may metastasize with chemotherapy alone.
“We hope our findings will help patients and physicians make informed decisions about the need for PTR, and encourage more study of the potential benefit or harm of PTR in the absence of symptoms. Beyond the current primary indication for PTR, there may be a group of patients for whom it may be beneficial because it may allow them to continue to receive chemotherapy. However, in the general population of metastatic colorectal cancer patients, PTR may result in delays or inability to receive systemic therapies that have been shown to provide benefit.”
Chang said the issue remains controversial, and he noted preliminary findings presented by his team and another group of researchers in January at the Gastrointestinal Cancers Symposium: In an an observational study in 6,735 patients with stage IV colon cancer, he and his colleagues (first author was Zeinab Alawadi) found that PTR offered no survival benefit over systemic chemotherapy alone at one year, and that “subject to selection and survivor treatment bias, standard regression analysis may overestimate the benefit of PTR” (Abstract 674).
However, another group of researchers, whose poster at the symposium was right next to the MD Anderson study, found just the opposite (Abstract 675). Canadian researchers looking at colorectal cancer patients who underwent primary tumor resection and received chemotherapy between 1992 and 2005 found that the median overall survival time for those who underwent surgery and received chemotherapy was 27 months compared with 14 months if patients did not have surgery.
The first author of that study, Shahid Ahmed, MD, Clinical Professor of Medicine and Site Leader of the Gastrointestinal Cancer Group at Saskatoon Cancer Center at the University of Saskatchewan, told OT that he believes the reason for the disparity in findings between the two teams has to do with the depth of information that he and his colleagues were able to review: “Dr. Chang's data is based on administrative data and there was limited information about patients' individual medical records, whereas we had access to individual patient information and adjusted for all important covariates including chemotherapy and biologics.”
Ahmed and his colleagues followed up with a validation study for 2006 to 2010 and reported that median overall survival times for patients who underwent PTR and received chemotherapy was 27 months versus 14 months for the patients who received only chemotherapy. Again, analysis showed that PTR independently correlated with superior survival with a hazard ratio of 0.44 after being adjusted for chemotherapy, age, comorbid illness, performance status, metastasectomy, and other prognostic variables.
Two Phase III trials are now enrolling patients with stage IV colorectal cancer to confirm the findings, he said.
Variable Practice Patterns
Asked for his perspective, Al B. Benson, MD, Professor of Hematology/Oncology at Northwestern University Robert H. Lurie Comprehensive Cancer Center, said he hopes the study and ongoing research by Chang and colleagues will help shed light on colorectal cancer practice patterns.
“There has been a lot of discussion on the topic since 2010 and a great deal of effort on finding patients who would benefit from chemotherapy versus surgery, but I think the findings in the JAMA Surgery study reflect, for the most part, what is now included in treatment guidelines issued by the National Comprehensive Cancer Network,” he said.
“This has been the trend in clinical practice because of the increased use of combination chemotherapy. Today, many patients can have excellent control without surgery. Some patients continue to need surgery, especially those with obstruction and bleeding, but we generally have good response to chemotherapy over time.”
And while some surgeons continue to rely on excision of colorectal tumors, the number has decreased dramatically in recent years, he agreed. “But this reflects the variability in cancer care across the country. There are differences in who is evaluating a patient. If a general surgeon is doing the evaluation rather than a surgical oncologist, they might be more likely to operate, especially in smaller practices where they may not see that many cases each year and/or are not aware of the guidelines.
“There are a lot of efforts underway to make people more aware that surgery may be avoided, and we encourage patients to read the guidelines.”