Obesity linked to longer survival in metastatic castration-resistant prostate cancer
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Men with metastatic castration-resistant prostate cancer and obesity had a higher survival probability than their counterparts with overweight and normal weight, according to study results.
In addition to identifying BMI as a significant predictor of OS among men with this type of advanced prostate cancer, the study presented during the virtual European Association of Urology Congress showed no relationship between the protective effect of BMI and higher dosage of chemotherapy.
“The obesity paradox has been studied in other malignancies and in prostate cancer, as well. In this context, the findings are conflicting,” Alberto Martini, MD, of the department of urology at San Raffaele University in Italy, told Healio.
Previous studies on genitourinary malignancies showed patients with high BMI had a survival advantage. This phenomenon, dubbed the “obesity paradox,” has been attributed to an inverse correlation between oncogenes and BMI. However, studies of the relationship between BMI and survival outcomes in prostate cancer have yielded conflicting findings.
“Very few studies have examined the association between BMI and survival outcomes in men with [metastatic castration-resistant prostate cancer (mCRPC)],” Giuseppe Ottone Cirulli, MD, urology resident at IRCCS San Raffaele Hospital, said in an interview with Healio. “Our study demonstrates that obesity is a protective factor for both overall mortality and death [of prostate cancer] in the setting of mCRPC.”
“In our work," Martini added, "we analyzed a very homogeneous population of patients enrolled in important phase 3 trials testing the role of docetaxel in metastatic castration-resistant prostate cancer. The strength of our findings lies in the patient population that has been analyzed.”
The analysis included 1,577 men (median age, 69 years; interquartile range [IQR], 63-74; median BMI, 28 kg/m2; IQR, 25-31) with mCRPC from three randomized phase 3 trials: ASCENT2, MAINSAL and VENICE. Cancer-specific mortality and overall cancer mortality data were available for two of the three trials, which encompassed 1,104 patients.
Researchers investigated the association of BMI and survival outcomes both as a continuous and categorical variable, with BMI of more than 30 km/m2 classified as obese.
They predicted OS with a Cox semi-proportional hazard model and used competing risks regression to predict cancer-specific mortality, adjusting analyses for age, PSA, ECOG performance status, number of metastasis and prior treatment. They also excluded any possible effect of higher chemotherapy doses given to larger men by checking for eventual interactions between BMI and chemotherapy dose, both as continuous-continuous and as categorical-continuous interactions.
More than 41% of the men (n = 655 of 1,577) died by the end of the studies. Median follow-up for survivors was 12 months.
Results showed BMI was a protective factor for death due to any cause, both as a continuous variable (HR = 0.96; 95% CI, 0.94-0.99) and as a categorical variable (obesity HR = 0.71; 95% CI, 0.53-0.96).
Additionally, data confirmed the impact of BMI on cancer-specific mortality as a continuous variable (subdistribution HR = 0.94; 95% CI, 0.91-0.98) and as a categorical variable (obesity subdistribution HR = 0.65; 95% CI, 0.45-0.93).
Martini and colleagues reported no significant interaction between BMI categories and dosage of docetaxel during any level of analyses.
At 3 years, about 30% of men with obesity remained alive compared with 20% of men with overweight and normal weight.
Researchers called for additional research to help illuminate the biological reasons for the BMI-survival relationship in mCRPC.
Observational studies such as this may indirectly lead to improved survival for patients, Martini told Healio.
“Understanding the role of BMI and survival has led researchers to the discovery of some oncogenes that are downregulated in the case of obesity,” Martini said. “Let’s take the example of renal cell carcinoma: here, as well, patients who have advanced disease and obesity have a survival advantage. It has been demonstrated [by Albiges and colleagues] that obese patients have an oncogene, FASN, that is implicated in the anabolic pathway of fatty acids and is downregulated in obese patients, because they have ‘enough’ fatty storage and the anabolic pathway is partly inhibited. That being said, understanding the biology has led researchers to develop medications that trigger the inhibition of the aforementioned oncogene.”
Peter Albers, MD, professor in the department of urology at Heinrich-Heine University Düsseldorf and chair of the EAU Scientific Congress Office, concurred on the need for further research to identify the biological mechanism behind the outcomes.
“There are many possible explanations for the association of body weight with positive outcome in metastatic cancers,” Albers, who was not involved with the study, said in the press release. “It might be that patients with higher BMI are able to tolerate the toxicity of the treatments and their side effects better; in prostate cancer, it might be to the protective impact of hormones found in tissue fat; and it is known that healthy men with a slightly higher BMI have a higher overall life expectancy compared to very slim ones.
“However, at the moment,” he added, “these are just hypotheses.”
Perspective
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Vinayak G. Wagaskar, MBBS, MCh
This interesting study of 1,577 men with mCRPC involved in three different clinical trials highlighted that men with obesity (BMI 30 kg/m2) had better cancer-specific survival and OS than men with overweight and normal weight. We compliment authors for this interesting concept and methodology of the study.
The study has basic limitations that we believe to be important:
- Within its large pool of patients, the study lacks prostate cancer-specific mortality data for about one-third of its patients. OS is a nonspecific indicator for men with mCRPC.
- BMI of men in these studies was noted after men developed mCRPC and may have been affected by secondary factors such as hormones, steroid medications or associated comorbidities. Previous literature has shown that elevated BMI is associated with higher incidence of prostate cancer and poor long-term outcomes.
- For most people, BMI provides a “reasonable measure” of body fat but is not accurate for people who weigh more because of muscle. Our concern related to the study is that BMI was measured after men developed treatment-resistant prostate cancer and not immediately after diagnosis of prostate cancer, which would have been more appropriate.
- The study brings out an interesting concept of “obesity paradox.” We need more studies with appropriate BMI measures (measured at the time of prostate cancer diagnosis) and focusing on prostate cancer-related survival. OS mentioned in the study does not specify prostate cancer-specific events.
We believe further studies addressing above limitations would help in better clarifying this concept.
References:
- Freedland SJ, et al. Rev Urol. 2004;6:73-81.
- Freedland SJ, et al. Urology. 2008;doi:10.1016/j.urology.2008.05.044.
- Martini A, et al. Prostate Cancer Prostatic Dis. 2021;doi:10.1038/s41391-021-00418-0.
- Vidal AC, et al. Prostate Cancer Prostatic Dis. 2017;doi:10.1038/pcan.2016.47.
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