For a patient with ENKTL nasal type (nose/sinus involvement) who has hepatic toxicity with pegasparaginase but a CR after 2 cycles of chemotherapy with a plan for "sandwich" radiotherapy - what, if any, chemotherapy would you resume after completion of radiation?

This is an interesting situation as there is not much data. The cure rate is high for early-stage disease after chemoradiation, even with VIPD and no asparaginase regimens (see de Pádua Covas Lage et al., PMID 36446856). Nature reviews which show in Table 2 survival curves similar for asparaginase regimens and VIPD. You could consider 2 cycles of VIPD after radiation. Checkpoint inhibitors have high response rates in relapsed/refractory but no experience yet in the front line.

ENKTCL are often intrinsically resistant to anthracycline-based therapies due to high level expression of the multidrug resistant P-glycoprotein resulting in efflux of certain drugs from cancer cells, which underpins the importance of asparaginase in the management of this disease.

However, there is data supporting efficacy of non-asparaginase-containing platinum-based regimens in combination with radiation in the management of early stage disease (i.e., RT plus cisplatin followed by VIDP [etoposide, ifosfamide, cisplatin, and dexamethasone] or RT plus 2/3 DeVIC [dexamethasone, etoposide, ifosfamide, and carboplatin]).

Therefore, if the patient has one or more risk factors that would indicate a likely benefit of the addition of chemotherapy to XRT for stage I or II diseases, such as age >60 years, ECOG >1, stage II disease, elevated LDH, and primary disease extending into neighboring structures and/or organs (Yang et al., PMID 26109206), then I would favor a combined modality approach as above (RT plus CDDP followed by VIDP [Kim et al., PMID 19884539] if less fit vs 2/3 DevIC plus RT for more fit patients [Yamaguchi et al., PMID 19805668]) if the patient is unable to tolerate asparaginase.