Non-anthracycline chemotherapy associated with a poor outcome in elderly Egyptian patients with diffuse large B-cell non-Hodgkin lymphoma

Introduction

Non-Hodgkin's lymphoma (NHL) was the 10th most commonly diagnosed cancer and the 9th cause of cancer mortality in the world in 2012. In Egypt, NHL was the 4th most common cancer in males and 5th in females and the 5th cause of cancer mortality. NHL is a diverse group of malignancies with different clinical and biological features. Diffuse large B-cell NHL (DLBCNHL) is the most common NHL type in the world, accounting for 30% of NHL and 80% of its aggressive subtypes. In Egypt, DLBCNHL accounts for 44.5% of lymphoid malignancies in a population-based cancer registryand 50% of NHL subtypes at the Egyptian National Cancer Institute. DLBCNHL treatment mostly relies on multi-agent combination chemotherapy. The addition of the anti-CD20 monoclonal antibody rituximab to the chemotherapy combination dramatically improved overall survival (OS). Anthracyclines, particularly doxorubicin are an integral component of these combination chemotherapy regimens, e.g. cyclophosphamide, doxorubicin, vincristine, prednisone (CHOP); procarbazine, methotrexate, doxorubicin, cyclophosphamide, etoposide- cytarabine, bleomycin, vincristine, methotrexate; methotrexate-bleomycin, doxorubicin, cyclophosphamide, vincristine, dexamethasone; methotrexate, doxorubicin, cyclophosphamide, vincristine, dexamethasone, bleomycin, and many others. Intensive chemotherapy with more agents failed to show additional benefit, and the CHOP regimen was concluded to be the best available for patients with intermediate and high-grade NHL, including DLBCNHL. Reductions in dose intensity clearly determine treatment efficacy. However, patients with older age, comorbidities, particularly cardiovascular, and expected higher morbidity and mortality may hinder the use of an anthracycline. Compared to anthracycline-containing regimens, the 3-year OS is almost halved when a non-anthracycline-containing regimen is used with an absolute survival reduction of 23%.

Thus, the aim of this retrospective study was to investigate the effectiveness of non-anthracycline chemotherapy regimen on elderly DLBCNHL patients by mainly focusing on geriatric organ dysfunction, frailty and comorbidities vs. suboptimal treatment with the cyclophosphamide, vincristine, and prednisone (CVP) vs. the standard CHOP to assess the factors that impact the regimen choice.

Methods

Study population
This retrospective clinical study included 418 patients with a confirmed DLBCNHL diagnosis at Tanta Cancer Center, Gharbiah, Egypt between 2003 and 2006. Diagnosis of DLBCNHL was based on histology and immunohistochemical data on CD19, CD20, and CD 22 expression. Patients were treated with either CHOP chemotherapy regimen (cyclophosphamide 750 mg/m ² intravenous (IV) on day 1, doxorubicin 50 mg/m ² IV on day 1, vincristine 1.4 mg/m ² (maximum 2 mg) IV on day 1 and prednisone 100 mg p.o. for 5 days) or CVP regimen (same as CHOP without doxorubicin) and followed-up until March 2014 via phone conversation. Response to therapy was assessed using the response criteria developed by the lymphoma International Working Group. OS is calculated from the date of diagnosis to the date of death from any cause or last follow-up. Event-free survival (EFS) was calculated from the date of starting treatment to the date of relapse, progression, death or last follows up.  Clinicopathological data were extracted from patients' medical records. This study was approved by the Institutional Review Board of the Egyptian National Cancer Institute.
Statistical analyses
Statistical analyses were performed using IBM SPSS software version 21.0 (SPSS Inc., Chicago, IL, USA). Nominal and categorical variables were compared using the Chi-square or Fisher's exact test. Numerical variables were compared using t-test or Man-Whitney's test. Multivariate logistic regression was used to describe the use of CHOP or CVP, controlling for patient covariates. Unadjusted survival was estimated using the Kaplan-Meier method and groups were compared using the log-rank test. Stepwise Cox regression hazards model was used for calculating adjusted survival for each treatment, controlling for patients covariates. A probability P ≤ 0.05 was considered statistically significant. The primary endpoint was OS. The secondary endpoint included EFS, complete response (CR) rate, and treatment-related toxicities.

Results

Patients' characteristics
CHOP and CVP were administered to 351 (84%) and 67 (16%) patients, respectively. Compared with those receiving CVP, patients receiving CHOP were significantly younger, having less comorbidity, better performance status (PS), fewer B-symptoms, and lower International Prognostic Index-risk (IPI-risk) categories [Table 1]. Logistic regression analysis assessed the impact of different baseline characteristics on the likelihood to receive CHOP or CVP. Only age and comorbidities were independent determinants of the regimen received [Table 2]. Older patients had 10.5 odds of not receiving CHOP compared to the younger patients (95% confidence interval (CI): 4.6-23.6; P < 0.001). Patients with comorbidities had 37.2 odds of not receiving CHOP compared to those with no comorbidities (95% CI: 12.6-109.6; P < 0.001).

Treatment responses and toxicities

Patients with CHOP treatment received more chemotherapy cycles than those treated with CVP (median 6 and 3 cycles, respectively; P < 0.001; [Table 4]). CR rate was higher in CHOP-treated patients than in CVP-treated patients (69.9% vs. 29.9%; P < 0.001). More patients received radiotherapy after CHOP treatment achieved CR than CVP-treated patients (22.2% vs. 3%; P = 0.001; [Table 3]). Compared to CVP, CHOP was associated with significantly higher toxicities (48.4% vs. 23.9%; P < 0.001), particularly fatigue, alopecia, and gastrointestinal tract toxicities. However, early deaths following one or two chemotherapy courses were significantly higher in patients with CVP treatment than with CHOP treatment (43.3% vs. 8.6%; P < 0.001).

Discussion

Since its development in the late 1960's, doxorubicin has been firmly established as the most effective single agent in the treatment of malignant lymphoma. The CHOP regime was invented in the late 1970's and after its efficacy in NHL was established, it became the standard of care as it produced high CR rate and durable effects.Its known adverse effects mainly affect the cardiovascular system. Reduction of inter-treatment intervals (CHOP-14) and the addition of rituximab (R-CHOP) were shown to improve treatment outcomes.   CHOP-14 does not appear to be superior to CHOP-21 when given with rituximab, but associates with increased toxicities, including an increased risk of Pneumocystis Jiroveci Pneumonia. Use of R-CHOP-21 is recommended rather than R-CHOP-14. This is primarily due to decreased need for growth factor support, and a lack of data showing the superiority of one regimen over another in the rituximab era. More intensive chemotherapy or additional agents have failed to show additional benefit.  However, elimination of anthracycline from the treatment regimen reduced the CR rate, duration of response and disease stabilization, and OS.

In the current study, 16% of DLBCNHL patients (67/418) did not receive anthracycline, whereas other studies showed a higher percentage (20-67%) as they only included patients aged 66 years or older. However, Link et al reported a lower percentage in an older population. Different studies in the different period of time and inclusion criteria may explain this variance. The rate of anthracycline use in the treatment of DLBCNHL did not vary with time, that is, between the pre-rituximab era and the post-rituximab era.  Furthermore, similar to other studies,  our current study showed that older age and comorbidities were strong indictors of treatment regimen selection without doxorubicin in addition to cardiovascular diseases and diabetes mellitus but the lower relevance of kidney and liver disease.  Pre-therapy heart disease, diabetes, hypertension, and older age were reported to be independent predictors of cardiotoxicity and subsequent death from the same cause. Our results also concur with those of van de Schans et al and Peters et alregarding the impact of poor PS and estimated short survival on the likelihood of treatment regimens without anthracycline. We showed that early death, that is, following 1-2 chemotherapy courses was encountered more in the non-anthracycline group (43.3% vs. 8.6%). Expected higher toxicities are another important reason. While this is difficult to assess quantitatively before therapy is given, it was confirmed by the higher rates of toxicities in the CHOP compared to the CVP group (48.4% vs. 23.9%).

The lower response rate with the CVP regimen without anthracycline than anthracycline-containing CHOP regimen confirms the established fact that anthracycline is the most active single agent in the treatment of lymphoma. In the current study, doxorubicin contributed almost 40% of the CRs exceeding the combination of cyclophosphamide, vincristine, and prednisolone (from 29.9% to 69.9%) in DLBCNHL treated solely by chemotherapy. Achieving CR is crucial for long-term survival and cure.  Our current study clearly shows that patients are failing to achieve CR only had a median OS of 4.4 months compared to 76.8 months in those who achieved CR with almost 11-fold higher relative risk of death. CHOP-produced CR rates is comparable to those reported by Khaled et al., Burton et al.,  Hallack Neto et al. [Table 7]. However, a large Egyptian study by Abdelhamid et alreported a 10% higher CR rate. This latter study only included younger patients with a maximum age of 60, better PS, and lower aaIPI scores. In contrast, our current study included older patients with a maximum age of 82, poorer PS, and higher aaIPI scores. Patients that are older and have poor PS frequently received reduced doses or interrupted and delayed therapy. This reduced dose intensity is a key determinant of CR and survival.

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