To SMILE or Not: Supportive Care Matters
Authors: Alexandre Chan, Tiffany Tang, Terence Ng, Vivianne Shih, Kevin Tay, Miriam Tao, Richard Quek, Soon Thye Lim
Journal: Journal of Clinical Oncology (2012)

Yamaguchi et al 1 evaluated the effectiveness of the corticosteroid (dexamethasone), methotrexate, ifosfamide, L-asparaginase, and etoposide (SMILE) regimen in a phase II trial.The authors concluded that the regimen is effective in patients with newly diagnosed stage 4 relapsed or refractory extranodal natural killer/T-cell lymphoma, nasal type (ENKL).Given that the prognosis of ENKL remains poor, we need to identify an effective regimen.SMILE appears to be active for ENKL; however, it is apparent that the regimen is extremely toxic, with grade 4 neutropenia occurring in 92% of patients.In essence, supportive care must play an essential role if a clinician decides to treat a patient with ENKL with SMILE.As Yamaguchi et al 1 discussed extensively, myelosuppression has led to two deaths (of 38 patients) in this study.An excessive number of patients (60%) have also experienced grade 3 and above infections.Hence, clinicians must not neglect the importance of providing sufficient and appropriate antimicrobial prophylaxis (including antibacterial and antifungal prophylaxis) to patients receiving SMILE. 2 It is unknown whether patients have received antimicrobial prophylaxis in this study.Interestingly, the authors recommended the routine administration of sulfamethoxazoletrimethoprim (TMP/SMX) to prevent Pneumocystis jirovecii infection.It is highly discouraged to coadminister TMP/SMX and methotrexate. 3Through the mechanism of protein-binding displacement, concomitant administration of the two agents can potentiate the risk for methotrexate toxicities, such as myelotoxicity and pancytopenia.TMP/SMX may be omitted during the administration of methotrexate and reintroduced after the clearance of methotrexate.Other options, such as aerosolized pentamidine, may be instituted in place of TMP/SMX as prophylaxis.Another important issue relates to the management of hypersensitivity reactions (HSR) with L-asparaginase.The incidence ranges from 10% to 15% among patients receiving L-asparaginase.Strategies to manage L-asparaginase-induced HSR are available, including the use of premedications and test doses, or to switch to a different formulation of L-asparaginase. 4Erwinia asparaginase and Escherichia coli asparaginase are different immunologic entities, and the Erwinia formulation is less likely to trigger the occurrence of HSR. 4,5 In contrast to common practice, the authors proposed reducing the dose of L-asparaginase by 50% if patients experience grade 1 or 2 HSR and discontinuing L-asparaginase if patients develop grade 3 or 4 HSR.Notably, a total of five patients in the study who developed HSR would require such interventions.Knowing the cytotoxic activity of L-asparaginase against ENKL, [6][7][8] it would be imperative to preserve the dose-intensities of Lasparaginase, if at all possible.Recently, we administered SMILE to 10 patients who were diagnosed with ENKL at our center.The median overall survival of these patients was 9 months (95% CI, 7.48 to 10.52).Among six patients who were newly diagnosed with ENKL, the overall response rate was 66% after 2 cycles of SMILE.Despite the decent response, the median overall survival was merely 8 months (95% CI, 1.99 to 14.0) among those 6 patients.Similar to the results presented by Yamaguchi et al, 1 all 10 of our patients had experienced grade 4 neutropenia in their course of treatment, and one patient died as a result of septic shock.Thus, although data presented by the authors suggest SMILE is an effective regimen, additional confirmatory studies are needed, especially in view of its toxicity profile.It should be noted that two (25%) of eight patients achieved complete remission despite having their L-asparaginase discontinued in the study.In addition, the majority of the patients in the study have undergone hematopoietic stem-cell transplantation after chemotherapy.Hematopoietic stem-cell transplantation may have played an important role to the improvement of overall survival in these patients.We believe that the optimal treatment of ENKL remains to be determined.The molecular pathogenesis of ENKL remains poorly understood.There is an urgent need to identify oncogenic pathways of this condition to develop effective targeted therapeutic agents. 9,10On the basis of the results from our own preclinical studies, we have recently developed a new regimen, B-GIFOX (consisting of bortezomib, gemcitabine, ifosfamide, and oxaliplatin) for treatment of ENKL. 11Currently, we are conducting a phase I study to validate the efficacy and safety of this regimen.In summary, SMILE is highly toxic, and patients receiving this regimen must be well selected for this treatment.Clinicians must not neglect the importance of maximizing all supportive care strategies to minimize the occurrence of treatment-induced toxicities.Additional advances are needed in the management of this fatal disease.