Ideal dose intensity of R-CHOP in diffuse large B-cell lymphoma

ABSTRACTIntroduction The standard of care for diffuse large B-cell lymphoma (DLBCL) is rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP). However, its ideal dose intensity varies among cases.Areas covered This review provides the latest insights on the dose intensity of R-CHOP for DLBCL patients. Specifically, we discussed the optimal dose intensity for elderly patients, the optimal number of treatment cycles for limited or advanced-stage diseases, and the role of dose-intensified therapies or adding targeted inhibitors.Expert opinion Performing a comprehensive or simplified geriatric assessment can distinguish elderly DLBCL patients who will likely benefit from curative R-CHOP. Very elderly or medically unfit patients may need dose reduction in R-CHOP; the Age, Comorbidities, and Albumin index may aid decision-making. Four cycles of R-CHOP followed by two rituximab cycles comprise a new standard for low-risk, limited-stage DLBCL patients. Compared to eight cycles, six cycles of R-CHOP have similar efficacy and fewer toxicities for advanced-stage DLBCL. Dose-intensified therapy is not recommended in most DLBCL cases but may be considered for patients with double (or triple)-hit lymphoma. Applying targeted inhibitors and not merely escalating R-CHOP dose intensity through molecular subtyping will improve the treatment outcome for DLBCL.PLAIN LANGUAGE SUMMARYDiffuse large B-cell lymphoma (DLBCL) is one of the most common blood cancers. Patients with DLBCL are usually treated with a standard (immuno-) chemotherapy called R-CHOP, which stands for rituximab, cyclophosphamide, hydroxydaunorubicin (doxorubicin), Oncovin, and prednisone. Of these, cyclophosphamide and doxorubicin are particularly toxic but effective. Therefore, the dosages of these drugs are adjusted according to the patient's body size. However, the ideal amounts of these drugs (dose intensity) can vary from case to case. For instance, the regular dose intensity of R-CHOP is too toxic for some people, such as very older patients. Furthermore, ideal total amounts of these drugs, that is, ideal cycle numbers of R-CHOP, are also different between patients with limited disease and advanced disease. Therefore, oncology/hematology researchers have been seeking the optimal dose intensity of R-CHOP in each patient with DLBCL for years. The goal of this review is to provide the latest insights on the ideal dose intensity of R-CHOP in DLBCL treatment. In this article, we discuss: how R-CHOP was established as the standard of care for DLBCL, how to identify candidates for standard R-CHOP among older patients, how to adjust the dose intensity of R-CHOP for patients who are not candidates for standard R-CHOP, optimal cycle number of R-CHOP for limited-disease DLBCL, optimal cycle number of R-CHOP for advanced DLBCL, how to treat patients with a large mass, and the role of more intensive therapies other than R-CHOP in DLBCL treatment. Finally, we demonstrate how experts determined the dose intensity of R-CHOP for some example cases with DLBCL.KEYWORDS: Chemotherapydiffuse large B-cell lymphomadose intensityelderlyR-CHOP AbbreviationR-CHOPRituximab,cyclophosphamide,doxorubicin,vincristine,prednisoloneDLBCLdiffuse large B-cell lymphomaGAgeriatric assessmentACAAge, Comorbidities, and AlbuminRDIrelative dose intensityG-CSF granulocyte-colony stimulating factoraaIPIage-adjusted International Prognostic IndexECOG PS Eastern Cooperative Oncology Group performance statusLDHlactate dehydrogenaseRTradiation therapyCRcomplete responsePRpartial responseSDstable diseasePDprogressive diseaseArticle highlights Half of patients with diffuse large B-cell lymphoma (DLBCL) are older adults. For these patients, comprehensive or simplified geriatric assessments are useful to identify fit patients who can tolerate standard rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP).There is no standard of care for DLBCL in very elderly or medically unfit patients who are unlikely to tolerate standard R-CHOP. R-miniCHOP is widely applied in patients aged ≥80 years. The Age, Comorbidities, and Albumin index may help decide the extent to which the dose of cytotoxic components of R-CHOP should be reduced in these settings.If patients with DLBCL have no risk factor according to the age-adjusted International Prognostic Index (i.e. serum lactate dehydrogenase within normal upper limit, Eastern Cooperative Oncology Group performance status ≤1, or Ann Arbor stage I or II) and no bulky disease ≥7.5 cm in diameter, they can be effectively treated with four cycles of R-CHOP followed by two additional doses of rituximab.Six cycles of R-CHOP is the standard of care for DLBCL patients with bulky or stage III/IV disease. The benefit of two additional R-CHOP cycles has not been shown. Similarly, the interim positron emission tomography-guided treatment strategy has not exhibited definite clinical benefits. Involved-field radiotherapy to a primary bulky site after completing R-CHOP may be considered after taking treatment response and anticipated toxicities into account.To date, most trials failed to show the superiority of dose-intensified therapies over standard R-CHOP for DLBCL patients with advanced International Prognostic Index scores. Modifying treatment per the cell-of-origin of DLBCL may be beneficial, but such a concept requires further investigation.Double- or triple-hit lymphomas should be carefully distinguished from conventional DLBCL. If feasible, patients with these features may be better treated with intensive regimens such as dose adjusted-etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab.AcknowledgmentsThe authors would like to thank collaborating members of the Society of Lymphoma Treatment Japan and the West Japan Hematology Oncology Group for valuable contributions to this work.Declaration of interestK Miura has received honoraria from AstraZeneca, Janssen, Nippon Shinyaku, Chugai, Kyowa Kirin, Novartis, Takeda, Ono, and Bristol Myers Squibb. H Takahashi and M Nakagawa has received honoraria from Bristol-Myers Squibb. N Iriyama received honoraria from Bristol Myers Squibb, Novartis, Otsuka, Takeda, Ono Pharma, and Pfizer. Y Hatta has received honoraria from Chugai, Eisai, Kyowa Kirin, Novartis, Takeda, Ono, Bristol Myers Squibb, Otsuka, Takeda, Pfizer, and SymBio. H Nakamura has received research grants from MSD, Asahi Kasei Pharma, Astellas, AbbVie, Japan Blood Products organization, Eisai, Otsuka Pharmaceutical, Ono Pharma, Kyowa Kirin, Sanofi, Shionogi, Daiichi Sankyo, Taiho, Takeda, Mitsubishi Tanabe, Chugai, Teijin Pharma, Eli Lilly, Nippon Kayaku, Nihon Pharmaceutical, Boehringer Ingelheim, and Pfizer.Reviewer disclosuresPeer reviewers on this manuscript have no relevant financial or other relationships to disclose.Additional informationFundingThe authors reported there is no funding associated with the work featured in this article.