Cachexia in Radiotherapy-Treated Patients With Head and Neck Cancer-Reply

In Reply

Indeed, both the etiopathogenesis and management of skeletal muscle loss in patients with head and neck cancer remain complex. The thoughtful letter of Mazzola and colleagues helps bring into focus the questions raised by our study and the insights thatmay be gleaned fromthese data.We sincerely appreciate the opportunity to expand this discussion. The effect of cachexia on survival in the context of multiple malignant conditions iswell documented.¹ Head and neck cancer is unique among these conditions in that the disease directly involves the aerodigestive tract, leading to dysfunction in deglutition secondary to both local tumor invasion and treatment toxicity. Therefore, although our study identified patients who meet the consensus definition for cachexia, the confounding role of sustained undernutrition could not be excluded. If cachexia is the major contributor to survival affecting skeletal muscle loss, we would expect to see an effect of muscle loss on survival independent of body mass index, as reported by Martin et al.² Yet, our data clearly demonstrated collinearity between these variables along with an apparent protective effect of obesity, suggesting a primary role for undernutrition, rather than cachexia, in mediating skeletal muscle loss. The absence of obese patients with skeletal muscle depletion fromour study limits the validity of this interpretation, as it is unclear whether it represents this overall patient population or is an artifact of retrospective design and study size. Furthermore, without serum cytokine level data we cannot rule out an inflammatory contribution, which prior research suggests may be indicative of cachexia and necessary for muscle wasting.³ Interestingly, pretreatment skeletal muscle depletion predicted survival exclusively among those patients who used a feeding tube during treatment. The fact that the prevalence of feeding tube use did not differ based on body composition suggests that muscle-depleted patients are equally susceptible to radiation therapy–related toxic effects, but that these toxic effects have a greater impact on survival, which is not reversed by the reactive placement of a feeding tube. Diminished swallowing function, as posited by Mazzola et al, may drive this effect and be exacerbated by preexisting muscle depletion. Regrettably, we were unable to assess the role of swallowing function in our study. Together, the above data might suggest that prophylactic, rather than reactive, nutritional and exercise intervention can improve outcomes in patients who present with skeletal muscle depletion.Yet in post hoc analysis ofRTOG90-03, pretreatment nutritional support was associated with inferior outcomes in a similar patient population.⁴ Neither RTOG 90-03 nor our study could exclude cachectic patients from analysis; thus, it remains unclear whether some patients with depleted skeletal muscle masswould benefit fromanearly nutrition intervention approach. Alternatively, efforts to minimize dose to the pharyngeal constrictors⁵ or pharyngeal mucosa may preferentially affect long-term outcome in patients with low skeletal muscle mass. However, the association between body composition and dose-volume-toxicity has not been confirmed. Thus, we agree with Mazzola et al that the issues of cachexia, dysphagia, and hypermetabolic comorbidity must be accounted for in any therapeutic strategy directed toward patients suffering fromskeletal muscle loss.