This study showed that sarcopenia at the time of recurrence was an independent, unfavorable prognostic factor in patients with recurrent pancreatic cancer. In addition, the combination of sarcopenia at the time of recurrence and time to recurrence after pancreatectomy more accurately predicted post-recurrent prognoses in patients who underwent surgery for pancreatic cancer than did sarcopenia alone.
Skeletal muscle loss negatively affects the outcomes of various diseases such as chronic diseases and many cancers [11, 26, 27] [12–15].
In pancreatic cancer, preoperative skeletal muscle loss is closely correlated with overall survival [18–20]. However, the prognostic significance of skeletal muscle loss, i.e., sarcopenia, at the time of recurrence has remained unclear. In the present study, skeletal muscle loss at the time of recurrence was a significant prognostic factor in patients with recurrent pancreatic cancer.
The mechanism for the association between skeletal muscle loss and prognosis in cancer patients remains unclear. Skeletal muscle is the largest organ in the human body, accounting for more than 40% of the adult human body weight . Skeletal muscle is also a secretory organ, and accumulating data have shown that muscle cells produce and secrete several hundreds of cytokines and other peptides, termed myokines, which influence various systemic responses .
Among numerous myokines, myostatin, a member of the transforming growth factor-β (TGF-β) superfamily, is a key regulator of skeletal muscle mass. Myostatin with inactivation increases skeletal muscle volume. On the other hand, activated myostatin decreases skeletal muscle volume . TGF-β is a multifunctional regulatory factor and responds to tumor cells by regulating tumor development by suppressing epithelial cell tumorigenesis early in the carcinogenic process via the TGF-β-SMAD pathway. In advanced stages however, TGF-β switches to promote tumor progression. Increased TGF-β expression by tumor cells promotes tumor progression by enhancing migration, invasion and survival of tumor cells by stimulating extracellular matrix deposition and tissue fibrosis, perturbing immune and inflammatory functions, and stimulating angiogenesis [30, 31]. Therefore, high TGF-β expression can promote muscle wasting and tumor progression in late-stage cancer patients. In pancreatic cancer, TGF-β plays a paradoxical role by both suppressing and promoting tumors. Previous studies showed that patients with unresectable pancreatic cancer had increased soluble TGF-β; thus, TGF-β was identified as a prognostic factor [32, 33].
Proinflammatory cytokines, such as interleukin (IL)–1, IL–6, and tumor necrosis factor alpha (TNFα), cause skeletal muscle proteolysis by suppressing muscle genes and activating ubiquitin-proteasome-mediated proteolysis and are closely associated with both sarcopenia and cancer-related cachexia .
A strong relationship exists between skeletal muscles and the immune system. Skeletal muscle contains more leukocytes, such as CD8+ T cells, regulatory T cells, and neutrophils, which play important roles in antitumor immunity and are the same as those in the total blood of human adults . Hence, skeletal muscle wasting induces decreased leukocyte numbers and impairs tumor immunity in cancer patients with sarcopenia, which in turn results in tumor progression. Therefore, these relationships may explain the correlation between sarcopenia at the time recurrence and poor prognoses in the current study.
Post-recurrence overall survival in an early recurrence group after curative surgery for pancreatic cancer was reported to be significantly worse than that of the late recurrence group . In that study, larger tumor sizes, high preoperative serum carbohydrate antigen 19–9 levels, poor differentiation on histological grading, presence of microscopic lymphovascular invasion, and highly positive lymph node ratios were reported as risk factors for early recurrence. Another study found more distant metastasis in patients whose pancreatic cancer recurred within 12 months . These findings suggest that patients with early recurrence already had more aggressive tumor biology that led to shorter recurrence-free survival after the initial surgery and a more rapid progression to death. In our study, both sarcopenia and early recurrence were independent prognostic factors in patients whose pancreatic cancer recurred. Sarcopenia is regulated by factors related to patients’ physical and functional conditions, whereas time to recurrence is regulated by tumor behavioral factors. We hypothesized that the combination of these two factors regulated by differ factors might better predict the prognosis in patients with recurrent pancreatic cancer than can sarcopenia alone. The combination of sarcopenia and time to recurrence predicted the prognosis in patients with recurrent pancreatic cancer more accurately than did sarcopenia alone.
This study had several limitations. First, it was retrospective with a small sample size and was conducted in a single institution, which could generate bias. No standard methods exist to precisely evaluate sarcopenia because skeletal muscle mass and strength are influenced considerably by ethnicity, body size, age, lifestyle, and cultural background. Although the criteria for sarcopenia using PMI measurement as reported by Hamaguchi et al. were used to evaluate sarcopenia in this study, these criteria were determined from data from healthy Asian young-adult donors for living donor liver transplantation. Therefore, the optimal PMI cut-off value that defines sarcopenia in patients with recurrent pancreatic cancer remains unclear. A large-scale prospective study is needed to verify our results. Additionally, further studies should be conducted to define sarcopenia corresponding to patients’ various conditions to more accurately evaluate sarcopenia-related events.
In conclusion, sarcopenia is a useful prognostic factor in patients with recurrent pancreatic cancer. The combination of sarcopenia and time to recurrence might more accurately predict post-recurrence survival than can sarcopenia alone. Not only systemic chemotherapy but also regular exercise and nutritional therapy after curative surgery might be needed to improve the prognosis in the patients with recurrent pancreatic cancer.