Clinical Oncology xxx (2014) 1e5 Contents lists available at ScienceDirect
Clinical Oncology journal homepage: www.clinicaloncologyonline.net
Short Report
R-CHOP versus R-COMP: Are They Really Equally Effective? €ger x, W. Linkesch {, M. Mian *, I. Wasle *, G. Gamerith *, P. Mondello y, T. Melchardt z, T. Ja M. Fiegl * * Department
of Hematology & Oncology, Medical University of Innsbruck, Innsbruck, Austria Department of Medical Oncology, University of Messina, Messina, Italy z Department of Internal Medicine, University Hospital of Salzburg, Salzburg, Austria x Department of Internal Medicine, Hospital of Feldkirch, Feldkirch, Austria { Department of Internal Medicine, Division of Haematology, Medical University of Graz, Austria y
Received 26 February 2014; received in revised form 28 April 2014; accepted 29 April 2014
Abstract The first-line standard treatment for diffuse large B-cell lymphoma (DLBCL) is the R-CHOP regimen (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone). It is associated with cardiotoxicity, which is why new treatment strategies are needed. Liposomial doxorubicin has been proven to reduce these side-effects, but until now a direct comparison regarding efficacy has not yet been published. We retrospectively assessed 364 consecutive DLBCL patients who underwent either R-CHOP (218; 60%) or R-COMP (doxorubicin replaced by non-pegylated liposomal doxorubicin; 146; 40%) in first line and compared outcome and survival. We provide evidence that both regimens induce a high and comparable number of complete remissions and that both are able to cure patients with DLBCL. Confirmatory data are needed. Ó 2014 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved. Key words: Diffuse large B-cell lymphoma; outcome; R-CHOP; R-COMP
Introduction Diffuse large B-cell lymphoma (DLBCL) is the most common type of non-Hodgkin’s lymphoma (NHL), occurring in about 30% of all new diagnoses [1]. It is a rather aggressive disease and the natural course of this NHL is very dismal. The CHOP chemotherapy regimen (cyclophosphamide, doxorubicin, vincristine, prednisone) proved to be a very efficient treatment [2], especially in combination with the anti CD-20 antibody rituximab [3]. However, this regimen is often poorly tolerated and due to doxorubicin, one of the most important drugs of this regimen, it can cause severe cardiac toxicity [3,4]. Several attempts to reduce the drug doses or to add cardio-protectants did not provide satisfactory results [5]. Therefore, new approaches, such as liposomal doxorubicin, were developed and proved Author for correspondence: M. Mian, Department of Hematology & Oncology, Medical University of Innsbruck, Innsbruck, Austria. Tel: þ43512-504-24003; Fax: þ43-512-504-25615. E-mail address: [email protected] (M. Mian).
to be less cardiotoxic, both in aggressive lymphoma [5,7] and breast cancer [6]. In breast cancer, it was definitely shown that the liposomal preparation of doxorubicin was less cardiotoxic, with efficacy fully maintained [6]. However, it is unknown whether substitution of doxorubicin by liposomal doxorubicin within the classical R-CHOP regimen (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) is equally efficacious. To our knowledge, only the NHL-14 study (NCT00575406) compared R-CHOP with R-COMP (doxorubicin replaced by non-pegylated liposomal doxorubicin; MyocetÒ) prospectively in a phase II trial, and the results were presented at the annual meeting of the American Society of Hematology in 2011 [8]. However, these data have not yet been completely published and the number of enrolled patients was relatively low. Therefore, we retrospectively assessed 364 consecutive DLBCL patients in seven Austrian and one Italian cancer centres (218 [60%] patients underwent rituximab in association with CHOP [3] and 146 [40%] COMP [9]) and compared the efficacy of these two regimens applied in a first-line setting with curative intent.
0936-6555/$36.00 Ó 2014 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.clon.2014.05.012
Please cite this article in press as: Mian M, et al., R-CHOP versus R-COMP: Are They Really Equally Effective? Clinical Oncology (2014), http:// dx.doi.org/10.1016/j.clon.2014.05.012
2
M. Mian et al. / Clinical Oncology xxx (2014) 1e5
Materials and Methods The chi-squared test was carried out to assess the significance of differences between categorical variables. The response was assessed with computed tomography or positron emission tomographyecomputed tomography, applying the international response criteria for malignant lymphoma [10,11]. Progression-free survival (PFS) and overall survival were plotted as a curve using the KaplaneMeier method. PFS was defined as the time from treatment start until progression or death, whatever occurred first. For patients who necessitated salvage treatment due to insufficient response (n ¼ 11), the date of the PFS event was set at the day of restaging where a response was determined. Overall survival was defined as the time from the start of therapy until death of any cause [11]. The Log-rank test was used to assess the effect on survival of categorical variables. The significance of distribution differences of the number of chemotherapy cycles between the two treatment groups was assessed with the ManneWhitney U-test. A P value 60 years was significantly higher in the latter (54% versus 93%, P < 0.001). In the R-CHOP group, significantly more patients with lymphadenopathy >5 cm were documented. The remaining clinical characteristics assessed at the time of diagnosis were comparable between both treatment groups (Table 1). Overall, the intermediate-/high-risk international prognostic index prevailed, with an occurrence of 71 and 77% in the R-CHOP and R-COMP groups, respectively (P ¼ 0.242). As expected, the percentage of cardiovascular disorders and other comorbidities was higher in R-COMP patients (Table 1), clearly to be attributed to the higher age distribution of the R-COMP group. All patients received at least one cycle of R-CHOP or R-COMP and, overall, 11 patients necessitated immediate salvage therapy due to insufficient response (Table 1). As this analysis was designed as an intention to treat analysis, patients who required a treatment modification (e.g. deletion of vincristine or dose reductions) were included. Overall, a median of six cycles of R-CHOP (range 1e10) or R-COMP (range 1e8) were given. However, the
mean number of cycles applied was six and five cycles in the R-CHOP and R-COMP groups, respectively (P < 0.001). As expected, treatment interruptions occurred more frequently in the R-COMP patients (9% versus 2% in the RCHOP patients; Table 1), certainly to be attributed to the higher age in the R-COMP cohort. Thus, the cumulative MyocetÒ dose ranged between 25 and 459 mg/m2, with a median of 250 mg/m2. Overall, 72 patients underwent additional radiotherapy: 29% in the R-CHOP group and 24% in the other group. This higher percentage of radiotherapy in the former group can be attributed to the higher number of patients with lymphadenopathies >5 cm. RCOMP toxicity is summarised in Table 1. Compared with a previously published cohort of elderly patients [3], the present R-COMP cohort was characterised by comparable grade 3/4 cardiotoxicity (8% in both analyses). However, the percentage of grade 3/4 infections was much higher in our R-COMP cohort (29% versus 12% in the historical RCHOP control) and febrile neutropenia was more frequent (16% versus 2%), whereas gastrointestinal toxicity was less (1% versus 6%). In this group, eight patients died due to treatment-related toxicity: four from cardiovascular events and four from infection (3% each), compared with 1% and 4% in the historical cohort [3]. In order to provide more information regarding the toxicity of MyocetÒ, we are currently evaluating nearly 300 patients affected by lymphoma who received this drug. The percentage of complete remissions was similar in both groups (Table 1) and is comparable with the data reported in the NHL-14 study [8]. Also the relapse rate varied, not statistically significantly, between the two groups. Moreover, after 2.2 years in the R-COMP group and nearly 5 years in the R-CHOP group, no relapses occurred (Figure 1A), suggesting that both treatments are able to cure this rather aggressive disease. The later occurrence of relapse in the R-CHOP group could be explained in part by the availability of positron emission tomographyecomputed tomography in the last few years: therefore, relapses might have been recognised earlier, especially in R-COMP patients. Another factor contributing to the shorter time to relapse in the RCOMP group could be the lower number of administered chemotherapy cycles causing a persistence of minimal residual disease. Without achieving statistical significance, 5 year PFS varied between both groups and was 55% in the R-CHOP group and 43% in the R-COMP group, respectively (P ¼ 0.058). This difference can be explained by the higher number of advanced age patients in the R-COMP cohort, which received significantly fewer chemotherapy cycles (see above). Indeed, PFS curves were overlapping for patients who underwent at least four cycles of immunochemotherapy (Figure 1B). Therefore, a multivariate Cox regression model containing the type of therapy and information on whether the patients underwent more or less than four cycles of chemotherapy was carried out. As expected, PFS was not influenced by R-CHOP or R-COMP (hazard ratio 1.1, confidence interval 0.8e1.5; P ¼ 0.660), but by the number of therapy cycles. As R-COMP is mainly used in clinical routine for the very elderly, we separately analysed PFS differences according to treatment in
Please cite this article in press as: Mian M, et al., R-CHOP versus R-COMP: Are They Really Equally Effective? Clinical Oncology (2014), http:// dx.doi.org/10.1016/j.clon.2014.05.012
Table 1 Clinical characteristics at the time of diagnosis and the response to treatment Parameter
R-CHOP (n ¼ 218) No.
Valid
%
No.
Valid
%
Male:female B symptoms Age categories (years) UNL International prognostic index 2 Lymphadenopathy >5 cm and/or maximum spleen diameter 20 cm Pre-existing comorbidities Cardiovascular disease Diabetes mellitus COPD and/or asthma Gastrointestinal disorders Other neoplasias Creatinine >2 mg/dl Neurological disorders Rheumatological diseases Psychiatric disorders Sum of comorbidities None 1e2 3e4 >4 Outcome Salvage chemotherapy Response Complete remission Partial remission Stable disease Progressive disease Interruption Death Unknown Relapses Toxicity Cardiac toxicity grade 3/4 Leukopenia grade 3/4 Neutropenia grade 3/4 Anaemia grade 3/4 Thrombocytopenia grade 3/4 Infections grade 3/4 Paresthesia grade 3 Febrile neutropenia grade 3/4 Granulocyte-colony stimulating factor administration Gastrointestinal toxicity grade 3/4
118:100 77
218 187
54:46 41
75:71 58
146 146
51:49 40
93 50 61 12
216
43 23 28 6
13 30 62 41
146
9 20 43 28
Clinical Oncology journal homepage: www.clinicaloncologyonline.net
Short Report
R-CHOP versus R-COMP: Are They Really Equally Effective? €ger x, W. Linkesch {, M. Mian *, I. Wasle *, G. Gamerith *, P. Mondello y, T. Melchardt z, T. Ja M. Fiegl * * Department
of Hematology & Oncology, Medical University of Innsbruck, Innsbruck, Austria Department of Medical Oncology, University of Messina, Messina, Italy z Department of Internal Medicine, University Hospital of Salzburg, Salzburg, Austria x Department of Internal Medicine, Hospital of Feldkirch, Feldkirch, Austria { Department of Internal Medicine, Division of Haematology, Medical University of Graz, Austria y
Received 26 February 2014; received in revised form 28 April 2014; accepted 29 April 2014
Abstract The first-line standard treatment for diffuse large B-cell lymphoma (DLBCL) is the R-CHOP regimen (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone). It is associated with cardiotoxicity, which is why new treatment strategies are needed. Liposomial doxorubicin has been proven to reduce these side-effects, but until now a direct comparison regarding efficacy has not yet been published. We retrospectively assessed 364 consecutive DLBCL patients who underwent either R-CHOP (218; 60%) or R-COMP (doxorubicin replaced by non-pegylated liposomal doxorubicin; 146; 40%) in first line and compared outcome and survival. We provide evidence that both regimens induce a high and comparable number of complete remissions and that both are able to cure patients with DLBCL. Confirmatory data are needed. Ó 2014 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved. Key words: Diffuse large B-cell lymphoma; outcome; R-CHOP; R-COMP
Introduction Diffuse large B-cell lymphoma (DLBCL) is the most common type of non-Hodgkin’s lymphoma (NHL), occurring in about 30% of all new diagnoses [1]. It is a rather aggressive disease and the natural course of this NHL is very dismal. The CHOP chemotherapy regimen (cyclophosphamide, doxorubicin, vincristine, prednisone) proved to be a very efficient treatment [2], especially in combination with the anti CD-20 antibody rituximab [3]. However, this regimen is often poorly tolerated and due to doxorubicin, one of the most important drugs of this regimen, it can cause severe cardiac toxicity [3,4]. Several attempts to reduce the drug doses or to add cardio-protectants did not provide satisfactory results [5]. Therefore, new approaches, such as liposomal doxorubicin, were developed and proved Author for correspondence: M. Mian, Department of Hematology & Oncology, Medical University of Innsbruck, Innsbruck, Austria. Tel: þ43512-504-24003; Fax: þ43-512-504-25615. E-mail address: [email protected] (M. Mian).
to be less cardiotoxic, both in aggressive lymphoma [5,7] and breast cancer [6]. In breast cancer, it was definitely shown that the liposomal preparation of doxorubicin was less cardiotoxic, with efficacy fully maintained [6]. However, it is unknown whether substitution of doxorubicin by liposomal doxorubicin within the classical R-CHOP regimen (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) is equally efficacious. To our knowledge, only the NHL-14 study (NCT00575406) compared R-CHOP with R-COMP (doxorubicin replaced by non-pegylated liposomal doxorubicin; MyocetÒ) prospectively in a phase II trial, and the results were presented at the annual meeting of the American Society of Hematology in 2011 [8]. However, these data have not yet been completely published and the number of enrolled patients was relatively low. Therefore, we retrospectively assessed 364 consecutive DLBCL patients in seven Austrian and one Italian cancer centres (218 [60%] patients underwent rituximab in association with CHOP [3] and 146 [40%] COMP [9]) and compared the efficacy of these two regimens applied in a first-line setting with curative intent.
0936-6555/$36.00 Ó 2014 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.clon.2014.05.012
Please cite this article in press as: Mian M, et al., R-CHOP versus R-COMP: Are They Really Equally Effective? Clinical Oncology (2014), http:// dx.doi.org/10.1016/j.clon.2014.05.012
2
M. Mian et al. / Clinical Oncology xxx (2014) 1e5
Materials and Methods The chi-squared test was carried out to assess the significance of differences between categorical variables. The response was assessed with computed tomography or positron emission tomographyecomputed tomography, applying the international response criteria for malignant lymphoma [10,11]. Progression-free survival (PFS) and overall survival were plotted as a curve using the KaplaneMeier method. PFS was defined as the time from treatment start until progression or death, whatever occurred first. For patients who necessitated salvage treatment due to insufficient response (n ¼ 11), the date of the PFS event was set at the day of restaging where a response was determined. Overall survival was defined as the time from the start of therapy until death of any cause [11]. The Log-rank test was used to assess the effect on survival of categorical variables. The significance of distribution differences of the number of chemotherapy cycles between the two treatment groups was assessed with the ManneWhitney U-test. A P value 60 years was significantly higher in the latter (54% versus 93%, P < 0.001). In the R-CHOP group, significantly more patients with lymphadenopathy >5 cm were documented. The remaining clinical characteristics assessed at the time of diagnosis were comparable between both treatment groups (Table 1). Overall, the intermediate-/high-risk international prognostic index prevailed, with an occurrence of 71 and 77% in the R-CHOP and R-COMP groups, respectively (P ¼ 0.242). As expected, the percentage of cardiovascular disorders and other comorbidities was higher in R-COMP patients (Table 1), clearly to be attributed to the higher age distribution of the R-COMP group. All patients received at least one cycle of R-CHOP or R-COMP and, overall, 11 patients necessitated immediate salvage therapy due to insufficient response (Table 1). As this analysis was designed as an intention to treat analysis, patients who required a treatment modification (e.g. deletion of vincristine or dose reductions) were included. Overall, a median of six cycles of R-CHOP (range 1e10) or R-COMP (range 1e8) were given. However, the
mean number of cycles applied was six and five cycles in the R-CHOP and R-COMP groups, respectively (P < 0.001). As expected, treatment interruptions occurred more frequently in the R-COMP patients (9% versus 2% in the RCHOP patients; Table 1), certainly to be attributed to the higher age in the R-COMP cohort. Thus, the cumulative MyocetÒ dose ranged between 25 and 459 mg/m2, with a median of 250 mg/m2. Overall, 72 patients underwent additional radiotherapy: 29% in the R-CHOP group and 24% in the other group. This higher percentage of radiotherapy in the former group can be attributed to the higher number of patients with lymphadenopathies >5 cm. RCOMP toxicity is summarised in Table 1. Compared with a previously published cohort of elderly patients [3], the present R-COMP cohort was characterised by comparable grade 3/4 cardiotoxicity (8% in both analyses). However, the percentage of grade 3/4 infections was much higher in our R-COMP cohort (29% versus 12% in the historical RCHOP control) and febrile neutropenia was more frequent (16% versus 2%), whereas gastrointestinal toxicity was less (1% versus 6%). In this group, eight patients died due to treatment-related toxicity: four from cardiovascular events and four from infection (3% each), compared with 1% and 4% in the historical cohort [3]. In order to provide more information regarding the toxicity of MyocetÒ, we are currently evaluating nearly 300 patients affected by lymphoma who received this drug. The percentage of complete remissions was similar in both groups (Table 1) and is comparable with the data reported in the NHL-14 study [8]. Also the relapse rate varied, not statistically significantly, between the two groups. Moreover, after 2.2 years in the R-COMP group and nearly 5 years in the R-CHOP group, no relapses occurred (Figure 1A), suggesting that both treatments are able to cure this rather aggressive disease. The later occurrence of relapse in the R-CHOP group could be explained in part by the availability of positron emission tomographyecomputed tomography in the last few years: therefore, relapses might have been recognised earlier, especially in R-COMP patients. Another factor contributing to the shorter time to relapse in the RCOMP group could be the lower number of administered chemotherapy cycles causing a persistence of minimal residual disease. Without achieving statistical significance, 5 year PFS varied between both groups and was 55% in the R-CHOP group and 43% in the R-COMP group, respectively (P ¼ 0.058). This difference can be explained by the higher number of advanced age patients in the R-COMP cohort, which received significantly fewer chemotherapy cycles (see above). Indeed, PFS curves were overlapping for patients who underwent at least four cycles of immunochemotherapy (Figure 1B). Therefore, a multivariate Cox regression model containing the type of therapy and information on whether the patients underwent more or less than four cycles of chemotherapy was carried out. As expected, PFS was not influenced by R-CHOP or R-COMP (hazard ratio 1.1, confidence interval 0.8e1.5; P ¼ 0.660), but by the number of therapy cycles. As R-COMP is mainly used in clinical routine for the very elderly, we separately analysed PFS differences according to treatment in
Please cite this article in press as: Mian M, et al., R-CHOP versus R-COMP: Are They Really Equally Effective? Clinical Oncology (2014), http:// dx.doi.org/10.1016/j.clon.2014.05.012
Table 1 Clinical characteristics at the time of diagnosis and the response to treatment Parameter
R-CHOP (n ¼ 218) No.
Valid
%
No.
Valid
%
Male:female B symptoms Age categories (years) UNL International prognostic index 2 Lymphadenopathy >5 cm and/or maximum spleen diameter 20 cm Pre-existing comorbidities Cardiovascular disease Diabetes mellitus COPD and/or asthma Gastrointestinal disorders Other neoplasias Creatinine >2 mg/dl Neurological disorders Rheumatological diseases Psychiatric disorders Sum of comorbidities None 1e2 3e4 >4 Outcome Salvage chemotherapy Response Complete remission Partial remission Stable disease Progressive disease Interruption Death Unknown Relapses Toxicity Cardiac toxicity grade 3/4 Leukopenia grade 3/4 Neutropenia grade 3/4 Anaemia grade 3/4 Thrombocytopenia grade 3/4 Infections grade 3/4 Paresthesia grade 3 Febrile neutropenia grade 3/4 Granulocyte-colony stimulating factor administration Gastrointestinal toxicity grade 3/4
118:100 77
218 187
54:46 41
75:71 58
146 146
51:49 40
93 50 61 12
216
43 23 28 6
13 30 62 41
146
9 20 43 28
