Despite the potential unpredictable disadvantages of any retrospective analysis, in the dose and schedule utilized here, present results showed that besides being beneficial in prevention of weight loss, unplanned treatment delays, severity and incidence of acute and late RIE, co-administration of Gln during C-CRT has no detectable negative impact on tumor control and survival outcomes in patients with stage IIIB NSCLC.
One strategy to reduce radiation-induced normal tissue toxicity is the use of protective pharmacologic agents shortly before and/or during the course of RT/C-CRT. Recent preclinical studies revealed that Gln, the primary fuel of enterocytes and lymphocytes, not only plays a crucial role in maintaining gut integrity and cellular immunity
[3, 21–24] but also protects against acute and late radiation-induced injury by inhibiting bacterial translocation and stimulating production of the antioxidant GSH
[25–29]. Clinically, oral Gln reduces the incidence and severity of RT- and/or chemotherapy-induced mucosal injury at various tumor sites, including the esophagus in NSCLC
[9, 10, 30–32]. Similarly, our current findings showed that Gln prophylaxis was associated with significantly reduced rates of grade 3 ARIE incidence (7.2% vs.16.8%; p=0.02), and delayed onset of maximum grade ARIE (24.5 vs. 16.4 days; p=0.001) with no add on toxicity.
Considering its selective protective function in normal non-cancerous tissues, ease of use, and mild and easily manageable toxicity profile, Gln appears to be an ideal radioprotector. However, there are concerns that Gln may protect tumor cells, or even promote tumor growth, when used in conjunction with anticancer treatment
[13–15]. To our knowledge, no previous clinical study has specifically addressed the influence of Gln on tumor control and survival outcomes when administered during C-CRT in NSCLC patients, and the results of studies on other tumor sites are conflicting
[17, 33–36]. Therefore, this is the first report of the effects of Gln on survival outcomes, and indirectly, tumor growth kinetics of LA-NSCLC in the era of RT/C-CRT.
Although the fact that human tumors exhibit a 5- to 10-fold faster rate of Gln consumption than normal healthy tissues
[37–39] might suggest that supplemental Gln would promote growth of tumor calls
[13–15], Gln did not stimulate tumor growth or negatively affect the outcome of any type of anti-tumor treatment in this study and previously published reports
[8, 21, 22, 40, 41]. In experimental studies, Gln supplementation has repeatedly been shown to replete Gln stores in muscle with no promotion of tumor growth which was proved by absence of any notable increment in tumor DNA content
[8, 21, 22, 40]. Furthermore, Fahr and colleagues
 demonstrated that Gln gavage and pair-fed food combination was associated with a 30% increment in natural killer (NK) cell activity and a 40% reduction in tumor growth. Use of Gln in conjunction with chemotherapy and/or RT has been investigated in only a limited number of clinical trials. In a large randomized, double-blind, placebo-controlled study
, oral Gln supplementation was associated with significantly reduced mouth pain and, more importantly, improved survival rates at 28 days in 193 patients undergoing autologous or allogeneic bone marrow transplant. In a similar patient group, Schloerb and Skikne
 reported significantly improved long-term survival with parenteral Gln supplementation. In the setting of RT or C-CRT, the few published studies concentrated on the radioprotective actions of Gln without considering its potential impact on tumor growth and survival outcomes
[9, 10, 32, 42, 43]. Consistent with recently reported C-CRT studies without Gln
[44–49], the similar PFS, LRPFS, and OS for Gln+ and Gln- cohorts observed in the current study demonstrated no association between tumor growth stimulation and high-dose Gln administered during C-CRT of LA-NSCLC patients.
If Gln is not provided exogenously tumor cells can successfully manipulate host metabolism to cover their needs, therefore artificial depletion of Gln cannot stop, or even retard, tumor growth. In fact, Gln-deprivation increases tumor cell survival through the induction of pro-angiogenic, pro-metastatic, pro-inflammatory, and tumor motility factors such as VEGF, IL-8, and NF-KB
. Moreover, lack of supplementary Gln can lead to serious Gln depletion, which is closely associated with impaired physiological functions such as disturbances in mucosal integrity, immune competence, maintenance of normal tissue GSH levels, and inhibition of bacterial translocation, resulting in serious medical complications. Therefore, exogenous Gln utilized here appears to improve the general metabolic condition and host defense mechanisms, and decrease the C-CRT-induced toxicity and related detrimental effects on quality of life measures and clinical outcomes.
One important consequence of dose-limiting acute toxicities of RT, and particularly C-CRT, in LA-NSCLC patients is the need for unplanned treatment breaks, which mandates reductions in doses of chemotherapy/RT and/or prolongs the overall treatment time with the potential to induce accelerated tumor repopulation
. Overall, any prolongation in treatment course is strongly associated with significantly reduced efficacy of C-CRT and therefore reduced rates of locoregional control and survival
. Our study showed that Gln significantly reduced the incidence and delayed the onset of grade ≥3 ARIE, reduced the need for unplanned treatment breaks, and reduced hospitalization. Although our study failed to show a significant survival advantage, further studies with larger study cohorts and sufficient statistical power to detect a moderate survival advantage are warranted.
The present study has several limitations. First, as for any retrospective study, unpredictable biases may have influenced our results. Second, heterogeneity due to inclusion of both adeno- and squamous cell cancer histologies, together with the limited cohort size, probably decreased the statistical power to identify a subgroup that may have benefited from Gln supplementation in terms of tumor control and survival outcomes. Third, although not significant statistically, the survival rates of the Gln+ cohort were higher than those of the Gln- cohort at all time points, suggesting that patients who received Gln supplementation tended to do better than those who did not. This may be partly associated with the small sample size and relatively short follow-up period and should be further addressed in larger studies with a longer follow-up period. Finally, although our institutional policy mandates arrangement of nutritional status of patients prior to treatment, nutritional differences are strongly associated with general feeding behaviors and socioeconomic status and cannot easily be controlled between the groups which may also affected our results.