In this study, we assessed the clinical impact of sarcopenia and SMD status in patients with mPCa who received palliative first line gemcitabine-based chemotherapy. To our knowledge, our study on the prognostic value of both sarcopenia and SMD status is the first study to evaluate comprehensively the association between skeletal muscle parameters, SMI and SMD with the largest cohort of patients with metastatic pancreatic cancer.
Our results showed that SMD is positively correlated with SMI. Several previous studies showed that SMI and SMD are positively correlated, in accordance with our research [18, 19]. However, other studies showed no significant correlation between SMI and SMD [20, 21]. It is likely that the cutoff values differed from one study to another and there might be differences among the study populations in terms of cancer type, stage of disease, sex, and age. Our study in particular consisted of those at advanced disease stages (stage 4) and, therefore, with very poor prognoses. In general, decreases in SMD are detected earlier than decreases in SMI. Furthermore, CT-based calculations allow for early detection of decreases in HUs (SMD), even when the muscle area remains unchanged [22]. Because our patients were at an advanced stage with poor prognoses, it is likely that they experienced decreases in both SMD and skeletal muscle area (SMA), which could result in the significant correlation observed between SMI and SMD. This suggests that, when assessing a patient using skeletal muscle parameters as prognostic factors, it may be useful to simultaneously evaluate SMI and SMD, rather than just one of these parameters.
Our results showed that SMD was a better prognostic factor than SMI in terms of statistical significance. Some previous studies also showed that low SMD is a better prognostic factor than SMI [12, 22–25]. Similar to our findings, three previous studies [12, 22, 25] found that a low SMD was significantly associated with poor OS while sarcopenia was not, suggesting that SMD is a more reliable prognostic factor than sarcopenia status. This may also explain findings from a previous study that showed low SMD leads to muscle weakness independently of muscle area, resulting in higher prognostic value [17]. Additionally, intermuscular fat development reflects the level of physical activity [26, 27] and has also been associated with severe inflammation [28], suggesting that these patients are more likely to encounter a higher number of severe adverse events during chemotherapy. It is also possible that SMD could be a more accurate measurement of muscle function and, therefore, precedes the development of sarcopenia development [23]. Furthermore, if reduced muscle density was a manifestation of muscle wasting, SMD can become a useful tool for assessing the patient’s performance status. In fact, performance status is an important prognostic factor among patients receiving chemotherapy [29].
Several previous studies have shown how sarcopenia is a good prognostic factor for patients with cancer, which overlaps with our finding [4, 30]. Further verification is required using a better-defined cutoff on a larger patient number. Also, our results showed that analysis using both SMI and SMD is of better prognostic value than SMI or SMD alone in terms of statistical significance, which has clinical applicability. Our data suggest that comprehensive assessment of skeletal muscle parameters may be more useful prognostic factors.
Based on these results, we also determined whether the prognostic role of the skeletal muscle parameters is associated with the chemotherapy effects. Neither sarcopenia status nor SMD had any association with chemotherapy response; furthermore, changes in these parameters were not related to chemotherapy responses. These results are inconsistent with the results from previous studies. For instance, Chu, M et al. showed that high SMD was strongly associated with radiographic complete responses [18]; however, Daly et al. showed no correlation between skeletal muscle parameters and chemotherapy response [31]. In fact, comparisons with previous studies may not be feasible because variables such as the type of cancer, purpose of chemotherapy, and chemotherapy regimens differed among studies. If no association between chemotherapy response and skeletal muscle parameters is determined, it may be due to the relatively low baseline level of the skeletal muscle parameter, as well as and the rate of change for which no statistical significance could be found. Further studies are needed to clarify this issue.
Our data revealed that severe chemotherapy toxicity was associated with low SMI and low SMD, which was consistent with previous studies [7, 21]. This could be due to the link between body composition and drug pharmacokinetics and has important clinical implications. Patients with sarcopenia or low SMD should be considered for prevention and aggressive management of chemotherapy toxicity.
Although no survival rate differences were observed according to SMD in patients who responded to chemotherapy, non-responder patients with low SMD showed poor survival time after disease progression at 8 weeks. In other words, the worse the chemotherapy response, the better SMD works as a prognostic factor. This should be taken into account when deciding whether to perform second line chemotherapy or best supportive care only after disease progression. As clinicians consider several factors, such as performance status, when deciding whether to provide additional chemotherapy, weakness of skeletal muscle may also be helpful in the decision-making process.
There are limitations to our study owing to its retrospective nature. The first is that the skeletal muscle parameters were evaluated using CT, which represents a single aspect of the muscle functional status. It would be optimal to assess muscle depletion from the perspectives of both function and strength; which should be considered in future studies. The second limitation is that other parameters that reflect nutrition and health status such as food intake, and albumin and C-reactive protein levels were not investigated.
In conclusion, our results showed that SMD and sarcopenia could be considered as prognostic factors in patients with mPCa who received palliative first line gemcitabine-based chemotherapy. Severe toxicity of chemotherapy occurred in the sarcopenia and low SMD groups. Our data suggest that comprehensive assessment of skeletal muscle parameters may be useful prognostic factors.