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Original Article Efficacy of Metronomic Chemotherapy with Oral Cyclophosphamide and Methotrexate in Patients with Non-Hodgkin

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Original Article Efficacy of Metronomic Chemotherapy with Oral Cyclophosphamide and Methotrexate in Patients with Non-Hodgkin Int J Clin Exp Med 2016;9(2):3893-3900 www.ijcem.com /ISSN:1940-5901/IJCEM0015875 Original Article Efficacy of metronomic chemotherapy with oral cyclophosphamide and methotrexate in patients with non-Hodgkin lymphoma: a retrospective analysis at a single institution Joo Young Jung, Geundoo Jang, Hunho Song, Hyeong Su Kim, Dae Ro Choi, Jung Hye Kwon, Ho Young Kim, Boram Han, Jung Han Kim, Hyo Jung Kim, Dae Young Zang Department of Internal Medicine, Hallym University Sacred Heart Hospital, Hallym University Medical Center, Anyang-si, Korea Received September 8, 2015; Accepted January 12, 2016; Epub February 15, 2016; Published February 29, 2016 Abstract: Metronomic chemotherapy is an emerging strategy offering a potentially less toxic yet effective treatment modality. We evaluated the efficacy and safety of low-dose metronomic (LDM) chemotherapy in relapsed or refracto- ry non-Hodgkin lymphoma (NHL) by retrospectively reviewing the data of 16 NHL patients who were treated with oral cyclophosphamide plus methotrexate (CM) as LDM chemotherapy. The patients received oral cyclophosphamide (50 mg per day) and oral methotrexate (2.5 mg twice weekly) until disease progression or unacceptable toxicity was noted. Fifteen NHL patients were evaluable in the study. The overall best response rate was 53.3% (2 complete responses and 5 partial responses), with 6.7% of patients achieving stable disease. The median treatment duration was 4.8 months (range, 1.45-25.3 months); the median overall and progression-free survival times were 12.1 and 6.6 months, respectively; and the median response duration was 8.7 months. Only 4 patients were managed with further salvage chemotherapy. The CM regimen was generally well tolerated, and there was no treatment-related mortality. We concluded that metronomic therapy with an oral CM regimen administered for continuous, prolonged periods represents a well-tolerated treatment for recurrent NHL, especially in elderly patients. Keywords: Metronomic, cyclophosphamide, methotrexate, non-Hodgkin lymphoma Introduction ous therapy or frail patients who are unable to tolerate conventional chemotherapy. Metronomic chemotherapy is a novel cancer treatment strategy defined as the frequent, The principalgoalsoflow-dose metronomic (LD- repetitive administration of chemotherapeutic M) chemotherapy are the inhibition of angio- drugs at low doses (between one-tenth and genesis [2-7], immunomodulation [8, 9], induc- one-third of the maximum tolerated dose tion of tumour dormancy [10-12], and a “drug- [MTD]), with no prolonged drug-free breaks [1]. driven dependency/deprivation” effect [13, 14]. Conventional chemotherapy usually involves The most commonly investigated cancers with the administration of the MTD in order to respect to LDM chemotherapy are breast can- destroy as many cancer cells as possible. cer [5, 15-17], followed by prostate cancer However, this can result in considerable toxici- [18], ovarian cancer [19], and colorectal cancer ties that may necessitate termination of treat- [20]. Among haematological malignancies, non- ment, and requires treatment-free intervals to Hodgkin lymphoma (NHL) [21, 22] and multiple allow normal cells to recover. In contrast, met- myeloma [23, 24] are candidates for LDM ronomic chemotherapy is associated with lower chemotherapy. treatment-related toxicity than conventional chemotherapy, and can therefore be an attrac- Cyclophosphamide, a nitrogen mustard alkylat- tive strategy in clinical practice, especially for ing agent, is the cornerstone of many combina- patients who have residual toxicity from previ- tion regimens for the treatment of lymphoma, Metronomic CM chemotherapy in non-Hodgkin lymphoma Table 1. Clinical characteristicsof the patients included in this study (n=16) could be a po- Characteristics Number (%) tentially less to- Age, years, median (range) 80 (44-88) xic yet effective treatment strat- Sex egy. We asse- Male/Female 7 (43.8)/9 (56.3) ssed the effica- Type of non-Hodgkin lymphoma cy and toxicity of Diffuse large B cell 7 (43.8) metronomic che- Mantle cell 2 (12.5) motherapy with Angioimmunoblastic T-cell 2 (12.5) oral cyclophosp- Marginal zone B cell lymphoma 2 (12.5) hamide and me- Mucosal-associated lymphoid tissue lymphoma 1 (6.3) thotrexate (CM) Small lymphocytic lymphoma 1 (6.3) in relapsed/refr- Primary cutaneous diffuse large B cell lymphoma 1 (6.3) actoryor frail pa- ECOG performance status at treatment tients with NHL. 1/2/3 5 (31.3)/6 (37.5)/5 (31.3) Material and International prognostic index at treatment methods Low 5 (31.3) Low-intermediate 6 (37.6) The medical re- High-intermediate 2 (12.5) cords of 16 NHL High 3 (18.8) patientswho re- Treatment setting ceived CM-bas- 1st-line/2nd-line/3rd-line/4th-line 2 (12.5)/10 (62.5)/2 (12.5)/2 (12.5) ed chemothera- Abbreviations: ECOG, Eastern Cooperative Oncology Group; PS, performance scale. pyfor more than 1 month at Ha- llym University Table 2. Treatment responseof metronomic- Sacred Hospital between January 2003 and chemotherapy with cyclophosphamide and June 2015 at any point during the course of methotrexate in patients with NHL their disease were reviewed retrospectively. Patients (%) This study was approved by the local ethics Intention-to- Per-protocol committee. Response treat (n=16) (n=15) The metronomic chemotherapy regimen con- Complete response 3 (18.8) 3 (20.0) sisted of oral cyclophosphamide, 50 mg daily; Partial response 5 (31.3) 5 (33.3) and oral methotrexate, 2.5 mg twice weekly. Th- Stable disease 1 (6.3) 1 (6.7) e regimen was continued until disease progre- Progressive disease 6 (37.5) 6 (40.0) ssion or unacceptable toxicity was noted. The Non evaluable 1 (6.3) Not applicable primary objective was to assess the response Abbreviation: NHL, non-Hodgkin lymphoma. rate to the regimen. The secondary objectives were to determine the progression-free survival (PFS), overall survival (OS), and treatment toxic- multiple myeloma, and some solid tumours. It ity. Response criteria were defined according to is usually administered intravenously at a dose the Revised Response Criteria for Malignant of 600-750 mg/m2 every 3 weeks when used Lymphoma [26]. The PFS was defined as the conventionally. Furthermore, oral cyclophos- time from the beginning of the first chemother- phamide-based LDM chemotherapy is the most apy cycle to the appearance of any treatment widely investigated metronomic regimen, eith- failure-related symptoms (including disease er as a single-agent or as combined therapy for haematological malignancies as well as solid progression), or discontinuation of treatment cancers [15, 17-19, 22, 23, 25]. for any reason (i.e., toxicity, patient preference, initiation of a new treatment without document- Frail, elderly patientswith recurrent or heavily ed progression, or death). OS was defined as treated NHL usually cannot tolerate standard the duration from the beginning of first-line che- conventional MTD-based chemotherapy. In motherapy to the date of death from any cause. these patients, metronomic chemotherapy The OS and PFS were estimated based on the 3894 Int J Clin Exp Med 2016;9(2):3893-3900 Metronomic CM chemotherapy in non-Hodgkin lymphoma Figure 1. Kaplan-Meier curves. Kaplan-Meier curves of (A) progression-free survival (PFS) and (B) overall survival (OS)of patients who received metronomic chemotherapy with cyclophosphamide and methotrexate for more than 1 month. CI: confidence interval. Kaplan-Meier method with corresponding two- The full dose of cyclophosphamide was main- sided 95% confidence intervals (CIs) for surviv- tained in all patients (50 mg/day), and the al proportions. Tolerability was evaluated mean weekly dose and mean dose intensity of according to the Common Toxicity Criteria for methotrexate were 4.1 ± 1.25 mg (range, 2.5-5 Adverse Events v.3.0. We performed data anal- mg) and 81.3% (range, 50-100%), respectively. yses with the Statistical Software Package for The median treatment duration was 4.8 months the Social Sciences (SPSS version 18.0 for (95% confidence interval [CI], 1.29-8.24 Windows; SPSS, Chicago, IL). months; range, 1.45-25.30 months). Therapy was eventually discontinued in all patients Results owing to disease progression (n=7), infection (n=2), poor performance status (n=1), or a deci- Patient characteristics sion taken by the patient (n=3) or their doctor Seven of the 16 patients were men. The medi- (n=3). The median PFS and OS were 6.6 months an age of all patients was 80 years (range, (95% CI, 0-18.74 months) and 12.1 months 44-88 years). Diffuse large B-cell lymphoma (95% CI, 0-48.6 months), respectively (Figure (n=7) was the most common histologic sub- 1). The median response duration was 8.7 type, followed by mantle cell lymphoma (n=2), months (range, 0-23.73 months). Only 4 angioimmunoblastic T-cell lymphoma (n=2), patients required further salvage chemoth- marginal zone B cell lymphoma (n=3), small erapy. lymphocytic lymphoma (n=1), and primary cuta- Safety neous diffuse large B-cell lymphoma (n=1). The baseline clinical characteristics of the patients The most common haematological toxicity was are summarized in Table 1. All but 2 patients neutropenia, including 4 events worse than had previously received chemotherapy, consist- grade 3. Other grade 3/4 haematological ing of a single regimen in 10 patients (62.5%) adverse events were anaemia (n=3) and throm- and more than 2 regimens in 4 patients (25%). bocytopenia (n=2). With respects to non-hae- Efficacy matological toxicities, anorexia was the most common (n=7); 2 patients had grade 3 anorex- Fifteen of the 16 patients were evaluable for ia. Among the other grade 3 non-haematologi- response. Three patients achieved a complete cal events, 2 patients had viral infections, and response and 5 showed a partial response 1 patient each had nausea, cellulitis, respira- (Table 2). Another patient had stable disease. tory infection, urinary tract infection, musculo- The overall best response rate and disease skeletal pain, and oliguria (Table 3).
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