Summary
A study presented at the 2020 ASCO Annual Meeting confirmed that palliative chemotherapy for metastatic colorectal cancer (mCRC) has a higher toxicity in women, but its efficacy is not better (Abstract 4029). The finding has implications for the future of precision medicine and continues the discussion around sex as a modulator of cancer biology and treatment outcomes.
“The point why this is important is because if we always think [men and women] are the same and treat them the same, we lose an opportunity to individualize treatments and make progress. But if we analyze differences in disease biology and treatment outcomes and ask: What can we learn from them? Are there any differences in pharmacogenetics, pharmacokinetics, or tumor biology? Are we administering the optimal doses for both men and women? Is there anything we can optimize? I think we can really learn something from this,” said Anna Dorothea Wagner, MD from the Department of Oncology at the University Hospital and University of Lausanne in Switzerland, and first author on the study.
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Original Article
Uncovering Sex Differences in Colorectal Cancer Treatment
Oncology Times
By Sarah LaCorte
A study presented at the 2020 ASCO Annual Meeting confirmed that palliative chemotherapy for metastatic colorectal cancer (mCRC) has a higher toxicity in women, but its efficacy is not better (Abstract 4029). The finding has implications for the future of precision medicine and continues the discussion around sex as a modulator of cancer biology and treatment outcomes.
“The point why this is important is because if we always think [men and women] are the same and treat them the same, we lose an opportunity to individualize treatments and make progress. But if we analyze differences in disease biology and treatment outcomes and ask: What can we learn from them? Are there any differences in pharmacogenetics, pharmacokinetics, or tumor biology? Are we administering the optimal doses for both men and women? Is there anything we can optimize? I think we can really learn something from this,” said Anna Dorothea Wagner, MD from the Department of Oncology at the University Hospital and University of Lausanne in Switzerland, and first author on the study.
The background of the study centered on previous data demonstrating a higher toxicity of adjuvant chemotherapy in women (ASCO 2018, Abstract 3603; JAMA Oncol 2018; doi:10.1001/jamaoncol.2018.1080). It is well known that the clearance of 5-fluorouracil (5-FU) is about 20 percent higher in men. As a result, women have higher plasma levels, which could explain the higher toxicity.
“There's very good data showing that the clearance of 5-FU is higher in men. So, women have higher plasma levels, which may explain the higher toxicity, but if the tumor sensitivity for the treatment would be the same, they should have a higher efficacy.
“This is why we conducted the study presented at this year’s ASCO to find out if the higher toxicity which was known before does translate into a higher efficacy, and this is not the case,” Wagner said. “Thus, in addition to differences in pharmacokinetics, there are probably as well differences in drug sensitivity.”
Study Details
In the study, Wagner and team analyzed patient and tumor characteristics, toxicities (which included nausea, vomiting, diarrhea, and neutropenia), and efficacy (overall survival [OS], progression-free survival [PFS]) according to sex. They studied treatment groups consisting of chemotherapy alone, chemotherapy + bevacizumab, and chemotherapy + EGFR antibodies, with subgroup analyses in the chemotherapy alone group for single agent, doublets and triplets, as well as irinotecan- and oxaliplatin-based regimens. OS and PFS were assessed using Kaplan-Meier and Cox models adjusted for primary tumor location and performance status (PS).
The researchers analyzed data from 18,399 patients (11,352 men and 7,047 women) across 28 first-line trials. The women in the study were generally younger than men (61 vs. 63 years); more often had a PS of 1 (49% vs. 45%), BRAF mutations (10% vs. 7%), and right-sided tumors (42% vs. 35%); and less often had rectal tumors (26% vs. 32%). The authors reported significant differences in toxicity; however, rates of diarrhea were similar.
“This is an important observation. And it suggests potential differences in drug sensitivity between men and women. It is possible that for women we need smaller doses and for men we need higher doses, but we need clinical trials to find this out,” said Wagner.
“The second thing which is important, is that the tumor characteristics are not the same in both groups. Colorectal cancers are not distributed randomly between men and women, but according to a characteristic pattern, with more right-sided cancers in women and more rectal cancers in men. As well, BRAF mutations are more frequent in women. Unfortunately, we don't have data on other biomarkers, such as microsatellite instability, but I'm sure that if you look for other biomarkers, you will find many more differences.”
Wagner and co-authors concluded the abstract with the observation that men and women with mCRC differ significantly regarding patient and tumor characteristics. They noted that “the significant higher toxicity in women does not translate in a higher treatment efficacy. Apart from known sex differences in pharmacokinetics of 5-FU, differences in pharmacodynamics must be postulated.” Further trials are necessary to define the optimal doses for both men and women with colorectal cancer.
“The first and most important point is that really all outcomes in clinical trials—efficacy and toxicity—need to be analyzed separately in men and in women. At present, this is not the case,” Wagner noted. “Usually in oncology, authors analyze the treatment efficacy separately, but not the treatment toxicity. They do a subgroup analysis for men and women. If the result is the same, then it's fine. If the result is not the same, this is ignored. I think this is something which needs to be changed.”
“If both the toxicity and the efficacy are the same, and there are no arguments for differences, then we can continue and think about other topics. But if there are tumor types and/or treatment effects where significant differences are observed, then I think we have to ask: Why is this the case and is there anything we can do either to improve the efficacy or to reduce the toxicity?”
The challenge in analyses of individual trials is that, due to multiple testing, one may have false-positive results. Therefore, analyses of individual-patient data in large databases, like the ACCENT database are necessary to understand how the patients’ sex modulates treatment outcomes.
Wagner said these observations of a higher percentage of right-sided tumors in women were unsurprising because this is in line with epidemiologic data also showing that women have more right-sided cancers and men have more rectal cancer. She said what was not known is if there would be any difference in overall and progression-free survival.
“Not only in the colon and rectum, there is a characteristic distribution of tumors between men and women. This is the same in the upper GI tract. For example, men more often have tumors in the distal esophagus and at the gastroesophageal junction, while women more often have tumors in the middle esophagus, gastric corpus, and distal stomach. So, there is a characteristic distribution for which I have no explanation for you at the moment, but is something that needs further research,” Wagner noted.
Sarah LaCorte is an associate editor.