Are patients with metastatic colorectal cancer (mCRC) in the United States getting less than the most up-to-date treatment for their disease?
A new study of chemotherapy usage patterns in these patients, published in the February issue of the Journal of the National Cancer Institute, suggests that the answer is yes.
Of the 4877 mCRC patients examined, 53% received second-line therapies and 28% received third-line therapies, suggesting that only a minority were exposed to all active agents in the course of their treatment.
The patients were treated at academic, private practice, and nonacademic hospital-based centers across the United States from 2004 to 2011.
Perhaps even more concerning, the researchers say, is the finding that even in academic centers, only 50% of patients were tested for KRAS mutations to see if they would be candidates for EGFR antibodies.
In fact, only 26% of the patients ever received an anti-EGFR monoclonal antibody — either cetuximab (22%) or panitumumab (6%) — at some point during their treatment course.
"What we see here may not be what we would have expected," lead author Thomas A. Abrams, MD, from the Dana-Farber Cancer Institute, Harvard Medical School, Boston, told Medscape Medical News.
"The main surprises are how little anti EGFR antibodies are used and how few patients were getting second-line or third-line therapy," Dr. Abrams said.
The study presents a portrait of real-world practice, he suggested.
"You would think that more people would get third-line therapy, but things may be different in the community and there are different challenges. Patients may have to go long distances to get therapy, and they might be in poorer shape than the patients we see in academic centers. I think that our results reflect real-world challenges that we don't see in the ivory tower."
Dr. Abrams and his group analyzed data obtained from the IntelliDose nationwide chemotherapy order entry system, which is run by IntrinsiQ.
"Instead of writing the chemotherapy orders using pen and paper and figuring the doses on a calculator, doctors enter the patient data, chemotherapies, and doses on the computer. This information is electronically transmitted to the pharmacy, which makes up the chemo, ready to be dispensed. IntrinsiQ collects and downloads all of those data, and they partnered with us to examine it," he explained.
During the study period, the most common first-line regimen was the combination of fluoropyrimidine and oxaliplatin, used in 71% of mCRC patients in 2007.
On average, first-line bevacizumab was used in 51% of patients; its use peaked at 55% in 2006.
Of those who received first-line bevacizumab, 34% continued to receive it as second-line therapy. The rate of bevacizumab continuation increased sharply in 2005, peaked at 39% in 2006, and declined to 25% in 2011.
Bevacizumab was more likely to be continued in females than males (odds ratio [OR], 1.21; 95% confidence interval [CI], 1.02 - 1.44), and in those receiving treatment at academic centers than at private practices (OR, 1.40; 95% CI, 1.08 - 1.82).
Other predictors of bevacizumab continuation were first-line combination chemotherapy, compared with fluoropyrimidine monotherapy (OR, 2.31; 95% CI, 1.68 - 3.17); duration of first-line treatment lasting at least 180 days, compared with less than 60 days (OR, 3.01; 95% CI, 2.14 - 4.24); and receiving care from an oncologist who treats more than 20 colorectal cancer patients per year, compared with less than 10 per year (OR, 1.33; 95% CI, 1.07 - 1.66).
"This study actually has data on the experience of physicians, and it is true that the more experience an oncologist has treating colon cancer, the more likely he or she is to prescribe combination therapy with biologics and go on to second- and third-line chemotherapy. Experience counts," Dr. Abrams said.
The researchers compared actual prescribing with treatment guidelines from the National Comprehensive Cancer Network.
Valuable Insights, Despite Study Limitations
There are some study limitations, note Joleen M. Hubbard, MD, and Axel Grothey, MD, from the Mayo Clinic in Rochester, Minnesota, in an accompanying editorial.
Using data from a commercial chemotherapy vendor has shortcomings, they explain.
For instance, there were no data on patient outcomes. Also, the definition of line of therapy required extrapolation and modeling of treatment sequences, based on chemotherapy prescriptions and time-interval assumptions. Further, no data are available on the reasons therapies changed.
Despite these limitations, the analysis "provides valuable insights into the treatment preferences of oncologists in the United States," they write.
The editorialists acknowledge that making appropriate treatment decisions has become more challenging over the years because of the availability of multiple active agents, combination regimens, and prognostic and predictive biomarkers for mCRC.
"The overwhelming amount of information from clinical trials could make oncologists preferably rely on one familiar, default therapeutic approach and resort to FOLFOX plus bevacizumab as standard first-line therapy. Although this treatment is likely appropriate for the majority of patients, a more individualized approach would be preferable to take more patient- and tumor-related factors into account," they note.
The editorialists note that the study demonstrates the importance of having treatment algorithms for patients with mCRC, but that only a few prospective clinical trials have investigated such treatment strategies.
Moreover, they pessimistically add, with the challenges the federally funded clinical trials system is facing in the United States, "it is not likely that this situation will change."
A solution might be to establish a national tumor registry that documents treatment algorithms that are eventually linked to outcomes.
"This registry could provide valuable information not obtainable from clinical trials and also serve as a tool to monitor guideline adherence to improve the care of patients with mCRC and other tumor entities," they conclude.
Results Not Surprising
"I find the results of this study interesting, but not surprising," said Raymond N. DuBois, MD, PhD, executive director of the Biodesign Institute at Arizona State University in Tempe.
The variability found in the study could exist for numerous reasons, he told Medscape Medical News.
These include inappropriate attention by practitioners to clinical guidelines and updates; local pharmaceutical reps giving providers biased information; variations in high-volume and low-volume oncology practices because of specialization; new drugs for the treatment of patients with mCRC; and an attempt by some practitioners to personalize care for mCRC patients based on molecular profiles, microsatellite instability status, and other characteristics of the disease, Dr. DuBois noted.
He added that colorectal cancer is interesting because a couple of decades ago, there was really only 1 drug to treat the disease — 5-fluorouracil.
"Over the past 10 to 15 years, a number of new options have been approved by the FDA, some of which have had less than dramatic effects on overall survival. However, these targeted therapies did extend survival by a couple of months, which was statistically significant," Dr. DuBois explained. "It seems that clinical oncologists who treat patients with mCRC have not settled on what they agree are the most effective treatment regimens."
This study was funded by Bristol-Myers Squibb. Dr. Abrams reports receiving research funding for this study from Bristol-Myers Squibb. Dr. Hubbard, Dr. Grothey, and Dr. DuBois have disclosed no relevant financial relationships.
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