1 Division of Hematology and Oncology, National Cancer Center Hospital East, Kashiwa; 2 JCOG Data Center, Cancer Information and Epidemiology Division, National Cancer Center Research Institute, Tokyo; 3 Department of Hematology and Chemotherapy, Aichi Cancer Center, Nagoya; 4 Department of Medical Oncology, Niigata Cancer Center Hospital, Niigata; 5 Department of Hematology, Sapporo National Hospital, Sapporo; 6 Department of Hematology, National Kyusyu Cancer Center, Fukuoka; 7 Department of Internal Medicine, Daisan Hospital, The Jikei University School of Medicine, Tokyo; 8 Division of Hematology and Immunology, Department of Internal Medicine, Ohtsu Red Cross Hospital, Ohtsu; 9 Department of Hematology, Sasebo City General Hospital, Sasebo, 10 Department of Internal Medicine, Iwaki Kyoritsu General Hospital, Iwaki; 11 Third Department of Internal Medicine, Kyoto Prefectural University School of Medicine, Kyoto; 12 Institute for Clinical Research, Kumamoto National Hospital, Kumamoto; 13 Department of Internal Medicine, Tokai University, Isehara; 14 Nagoya National Hospital, Nagoya; 15 Hematology Division, National Cancer Center Hospital, Tokyo, Japan
Received 10 December 2001; revised 20 March 2002; accepted 22 May 2002
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Abstract |
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CHOP (cyclophosphamide, doxorubicin, vincristine and prednisone) is accepted as the best available standard treatment for first-line chemotherapy in aggressive non-Hodgkins lymphoma (NHL). However, the therapeutic efficacy of CHOP remains unsatisfactory, particularly in high-intermediate risk and high risk patients, and a new strategy is warranted in this patient population. The aim of the present study was to explore a suitable therapeutic-intensified regimen for the treatment of aggressive NHL.
Patients and methods:
Between May 1995 and July 1998, a total of 70 patients with high-intermediate risk or high risk aggressive NHL, according to the International Prognostic Index, were enrolled and randomly assigned to receive either eight cycles of standard CHOP (cyclophosphamide 750 mg/m2, doxorubicin 50 mg/m2, vincristine 1.4 mg/m2 and prednisolone 100 mg for 5 days) every 2 weeks, or six cycles of dose-escalated CHOP (cyclophosphamide 1,500 mg/m2, doxorubicin 70 mg/m2, vincristine 1.4 mg/m2 and prednisolone 100 mg for 5 days) every 3 weeks. Lenograstim (glycosylated rHuG-CSF), at a dose of 2 µg/kg/day s.c., was administered daily from day 3 until day 13 with biweekly CHOP and until day 20 with the dose-escalated CHOP. The primary endpoint was complete response rate.
Results:
The complete response rate was 60% [21 of 35; 95% confidence interval (CI) 42% to 76%] with biweekly CHOP and 51% (18 of 35; 95% CI 34% to 69%) with dose-escalated CHOP. The major toxicity was grade 4 neutropenia and was more frequent in the dose-escalated CHOP arm (86%) than in the biweekly CHOP arm (50%). Grade 4 thrombocytopenia was also more frequent in the dose-escalated CHOP arm (20%) than the biweekly CHOP arm (3%). Non-hematological toxicities were acceptable in both arms. One treatment-related death (due to cardiac arrhythmia) was observed in a dose-escalated CHOP patient. Progression-free survival at 3 years was 43% (95% CI 27% to 59%) in the biweekly CHOP arm and 31% (95% CI 16% to 47%) in the dose-escalated CHOP arm. Although seven patients were deemed ineligible by central review of the pathological diagnosis, the results for both eligible and all enrolled patients were similar.
Conclusions:
Similar complete response rates and progression-free survival rates, but lower toxicity, indicated that biweekly CHOP was superior to dose-escalated CHOP in the treatment of aggressive NHL. Based on these results, the Lymphoma Study Group of the Japan Clinical Oncology Group is conducting a randomized phase III study comparing biweekly CHOP with standard CHOP in newly diagnosed patients with advanced-stage aggressive NHL.
Key words: biweekly CHOP, dose-escalated CHOP, dose intensity, G-CSF, non-Hodgkins lymphoma
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Introduction |
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With regard to dose intensity, high-dose chemotherapy with autologous stem cell support has been established as an optimal therapy to improve the event-free and overall survival (OS) rates for patients with chemosensitive relapsed aggressive NHL [9]. Moreover, myeloablative chemotherapy followed by autologous stem cell support in the front-line setting might be useful for patients with high-intermediate and high risk according to the International Prognostic Index (IPI) for NHL [1012]. Therefore, a dose intensification strategy in the treatment of NHL is worthy of further investigation.
There are two ways to increase the therapeutic intensity of CHOP, namely dose escalation and interval shortening. The doses intensities of doxorubicin and cyclophosphamide can be escalated with granulocyte colony-stimulating factor (G-CSF) support [1315]. Another strategy for therapeutic-intensification of CHOP is also possible with G-CSF, by shortening the interval of standard CHOP [1618].
However, it is not known which type of therapeutic-intensified CHOP is suitable for comparison with the therapeutic efficacy of standard CHOP in a phase III study. To address this issue, the Lymphoma Study Group of the Japan Clinical Oncology Group (JCOG-LSG) conducted a randomized phase II study, in order to choose a more suitable regimen for a further phase III trial between dose-escalated CHOP and biweekly CHOP in patients with high-intermediate and high risk aggressive NHL.
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Patients and methods |
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Other eligibility criteria included a white blood cell count 3000/µl, neutrophil count
1200/µl, platelet count
75 000/µl, total bilirubin level
2 mg/dl, aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels
5 times the upper limit of the normal range, serum creatinine level
2 mg/dl, PaO2 level
60 mmHg, normal ECG and normal cardiac left ventricular ejection fraction (
50%). If AST and ALT were within normal limits, patients who were positive for anti-hepatitis C virus (HCV) and/or positive for hepatitis B virus surface antigen (HBs) were deemed eligible for the study. After the study activation, the protocol was amended and patients with HCV antibody or HBs antigen became ineligible. Pre-treatment staging procedures included a physical examination, complete blood count with differential and platelet counts, biochemical analyses, bone marrow aspiration and/or biopsy, chest X-ray, computed tomography (CT) scan of the chest and abdomen, fiberscopic examination of the upper gastrointestinal tract and gallium scintigraphy. Toxicities were evaluated according to the JCOG toxicity criteria [20], which was an expanded version of the National Cancer Institute-Common Toxicity Criteria (NCI-CTC) version 1 [21]. Written or oral informed consent was obtained from all patients or their families before randomization, in accordance with the policies of JCOG in 1995. The study protocol was approved by the Clinical Trials Review Committee of JCOG and the institutional review board (IRB) of each participating institution that had already established an IRB in 1995, before study activation.
Treatment
The patients were randomly assigned to receive either biweekly CHOP or dose-escalated CHOP by the minimization method of balancing the groups according to the institution, high-intermediate or high risk by IPI. Randomization was performed at the JCOG Data Center (JCOG-DC) by telephone or fax. Biweekly CHOP consisted of eight cycles of standard CHOP every other week [cyclophosphamide 750 mg/m2 i.v. day 1, doxorubicin 50 mg/m2 i.v. day 1, vincristine 1.4 mg/m2 (maximum 2 mg) i.v. day 1 and prednisolone 100 mg p.o. for 5 days]. Dose-escalated CHOP consisting of cyclophosphamide 1.5 g/m2 i.v. day 1, doxorubicin 70 mg/m2 i.v. day 1, vincristine 1.4 mg/m2 (maximum 2 mg) i.v. day 1 and prednisolone 100 mg p.o. for 5 days was repeated every 3 weeks for six cycles. Drug dosages in the dose-escalated CHOP group were based on the dose-escalation study of CHOP with prophylactic use of G-CSF conducted at the National Cancer Center Hospital East of Japan [15]. Lenograstim (glycosylated rHuG-CSF), at a dose of 2 µg/kg/day s.c., was administered daily from day 3 until day 13 with biweekly CHOP, and until day 20 with the dose-escalated CHOP. Sixty-three patients participated in a companion study for evaluation of mobilization kinetics of circulating CD34+ cells by lenograstim, which was supported by Chugai Pharmaceutical Co., Tokyo, Japan [22]. Unless progression or relapse of lymphoma occurred, the treatment was repeated every 2 or 3 weeks provided that the patient fulfilled the following criteria: white blood cell count 2000/µl, neutrophil count
1200/µl, platelet count
75 000/µl, total bilirubin level <3 mg/dl, AST and ALT levels
5 times the upper limit of the normal range, serum creatinine level <2 mg/dl, and any non-hematological toxicity, except nausea/vomiting and alopecia, of grade 1 or less. If there was grade 4 leukopenia lasting for 3 days or more, or grade 3 or 4 thrombocytopenia, dose reduction of both cyclophosphamide and doxorubicin to 75% was made for the subsequent cycles. If there was liver injury with a total bilirubin level of >1.2 mg/dl, the dose of doxorubicin was reduced to 50%, and if there was grade 2 or higher cardiotoxicity, doxorubicin was omitted. If there was grade 2 or higher hemorrhagic cystitis, the dose of cyclophosphamide was reduced to 75% for the subsequent cycles. If there was grade 2 neurotoxicity, the dose of vincristine was reduced to 50%; vincristine was omitted in the case of grade 3 or higher neurotoxicity.
Responses
Complete response (CR) was defined as the disappearance of all measurable lesions and symptoms of disease for at least 4 weeks. Partial response (PR) was defined as a reduction of 50% or greater in the sum of the products of the perpendicular diameters of all measurable lesions and the lack of appearance of new lesions for at least 4 weeks. CR unconfirmed (CRu) was defined as maintenance of the PR without chemotherapy for >3 months after completion of the study. Progressive disease was defined as an increase of 25% in the size of any existing lesion or development of any new lesions. Relapse was defined as an increase of 25% in the size of any existing lesion or development of any new lesions in CR and CRu patients. All other circumstances were considered to indicate stable disease.
Statistical methods
All patients randomized were analysed on an intention-to-treat basis. It was anticipated that the CR rate achieved would be at least 65% in both groups. To achieve a 90% probability of selecting the better arm when the CR rate is 15% higher on one arm than the other, at least 30 patients would be required in each arm [23]. It was therefore planned to randomize a total of 70 patients.
Overall survival was calculated from the date of randomization until the date of death from any cause or the date of the last follow-up. Progression-free survival (PFS) was calculated from the date of randomization until the date of progression, death from any cause or the date confirmed to be progression free. Overall survival and PFS curves were calculated using the KaplanMeier method.
All patient information forms were collected and managed at JCOG-DC. In-house interim monitoring was performed at JCOG-DC for quality control, and the monitoring reports were submitted to and reviewed by the Data and Safety Monitoring Committee of JCOG semi-annually.
Central review of the pathological diagnosis
Following enrolment of the patients, biopsy specimens were collected and forwarded to the central pathology group for review. Four hematopathologists reviewed the pathology specimens and classified each according to Working Formulation [19]. A modified WHO system [24] was also used to classify the cases. Immunohistochemical studies were performed on paraffin sections by the avidinbiotinperoxidase complex technique using a panel of monoclonal antibodies. Antibodies employed in the central review of the pathological diagnosis were CD20 (L26; Dako A/S, Glostrup, Denmark) and CD3 (UCHT-1; Dako A/S). When further immunohistochemical staining was necessary to establish a specific diagnosis, the following antibodies were also used: CD15 (LeuM-1; Becton Dickinson, Research Triangle Park, NC, USA) and CD30 (BerH2; Dako A/S) for Hodgkins disease; anti-cyclin D1 (Medical & Biological Labs, Nagoya, Japan) for mantle cell lymphoma; CD10 (SS2/36, Dako A/S) and bcl-2 (124; Dako A/S) for follicular lymphoma; CD56 (H28.123; Immunotech SA, Marseilles, France) for natural killer (NK)/T-cell lymphoma; anti-TdT (polyclonal; Supertech, Bethesda, MD, USA) for lymphoblastic lymphoma; and anti-ALK protein (ALK1; Dako A/S) and CD30 for anaplastic large cell lymphoma. EpsteinBarr virus (EBV) was detected by in situ hybridization in NK cell lymphoma and Hodgkins disease. An EBER PNA probe (Dako A/S) was used for this purpose. Central pathological review was performed by four hematopathologists with knowledge of the patients outcome when it was difficult to reach a consensus on the diagnosis. Sixty-five cases out of all 70 randomized cases were reviewed independently by each of the four pathologists in order to reach a diagnosis. A consensus diagnosis was established when a three-quarters majority was reached. If the agreement was less than three-quarters, the cases were shown on a video monitor and discussed by the four pathologists who reached a three-quarters majority by reconciliation with knowledge of the patients outcome when it was difficult to reach a consensus on the diagnosis.
Following the consensus diagnosis, response, PFS and OS were evaluated in both the group of eligible patients as well as in all those randomized.
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Results |
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Hematological toxicities are shown in Table 3. Grade 4 neutropenia was the major toxicity and occurred more frequently in the dose-escalated arm than in the biweekly arm. Similarly, grade 3 or 4 thrombocytopenia was observed more frequently in the dose-escalated arm than in the biweekly arm. In the dose-escalated arm, two patients went off-treatment because of prolonged hematological toxicity after cycles 2 and 3, respectively.
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Protocol violation was observed in three patients in the biweekly arm and in seven patients in the dose-escalated arm. Chemotherapy was repeated in one patient in the biweekly arm, although the criteria for the next cycle of chemotherapy were not fulfilled. Doxorubicin was not reduced in one patient in the biweekly arm with slight hyperbilirubinemia. CHOP was repeated in one patient who received extended chemotherapy for >4 weeks, biweekly. Doses of drugs were not reduced in four patients in the dose-escalated arm with grade 3 or 4 thrombocytopenia. Among these patients, slight hyperbilirubinemia was also observed in two patients and vincristine was not reduced in one patient regardless of grade 2 neurotoxicity. On the contrary, drug doses were excessively reduced in two patients in the dose-escalated arm. One patient in the dose-escalated arm received 150 mg prednisolone for 5 days. Thus, all patients received >90% of the planned dose, except for two in the dose-escalated arm and one in the biweekly arm.
Responses in all randomized and eligible patients are shown in Table 4. The CR rate, including CRu among all randomized patients in the biweekly CHOP group (60%), was higher than in the dose-escalated CHOP group (51%), and similar results were observed in eligible patients. Progression-free survival and OS rates of all randomized patients are shown in Figures 2 and 3. Progression-free survival and OS rates of eligible patients were similar to those of all randomized patients. Progression-free survival at 3 years was 43% [95% confidence interval (CI) 27% to 59%] and 41% (95% CI 24% to 58%) respectively, in all randomized and eligible patients on biweekly CHOP, and 31% (95% CI 16% to 47%) and 36% (95% CI 19% to 52%), respectively, in the dose-escalated CHOP group. Overall survival at 4 years was 42% (95% CI 25% to 59%) and 39% (95% CI 22% to 57%), respectively, in all randomized and eligible patients on biweekly CHOP, and 42% (95% CI 26% to 59%) and 44% (95% CI 27% to 62%), respectively, in the dose-escalated CHOP.
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Discussion |
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Comparing the therapeutic efficacy of different regimens is difficult, since the anticancer drugs are administered at different doses and in various combinations. Although several retrospective studies have suggested that response and survival might be related to the relative dose intensity of chemotherapy [8, 2527], the significance of dose intensity in the treatment of aggressive NHL remains controversial. A prospective randomized trial by Meyer et al. [28] failed to demonstrate the superiority of dose intensification on the outcome of patients with NHL. In that study, however, the received dose intensity of doxorubicin in the escalated BACOP arm (bleomycin, doxorubicin, cyclophosphamide, vincristine and prednisolone) was 30% greater than in the standard BACOP arm, and the dose of cyclophosphamide was not escalated. In the present study, the projected therapeutic intensities of doxorubicin and cyclophosphamide were 1.5 times and 1.52 times greater, respectively, than those in standard CHOP. Considering the therapeutic-intensity of CHOP, it was of interest that PFS and OS in weekly CHOP given at one-third of the standard dose was probably not superior to standard CHOP in elderly patients with aggressive NHL [29]. In summary, as compared with the study of Meyer et al. [28], the present study employed a greater degree of dose intensification and the patient population was not confined to the elderly. Given these differences, it is difficult to make meaningful comparisons between the two studies regarding the efficacy of therapeutic-intensification regimens.
The role of high-dose chemotherapy with autologous stem cell support in the initial treatment of NHL is still uncertain. Some reports suggest the superiority of high-dose chemotherapy over conventional-dose chemotherapy in patients with high-intermediate and high risk NHL in the front line setting [10, 11, 30, 31]; however, other reports have failed to confirm these findings [3236]. Although high-dose chemotherapy with autologous stem cell support might be beneficial for high risk young patients who responded to induction chemotherapy, not all patients with high risk NHL would be able to receive high-dose chemotherapy because of older age, lack of chemosensitivity, inadequate organ function or concomitant conditions. Accordingly, it is still important to search for a new effective conventional-dose strategy.
In patients with chemosensitive relapsed lymphoma, high-dose chemotherapy with autologous stem cell support has been established as an optimal therapy [9]. In terms of stem cell harvest, biweekly CHOP was suggested to be a better option in the case of repeated and/or late harvest of circulating CD34+ cells [22].
The CR and PFS rates of dose-intensified CHOP in the present study were comparable to those of standard CHOP, and second- or third-generation regimens in large, randomized, phase III trials [26]. However, the issue of whether biweekly CHOP is more beneficial than standard CHOP will be resolved by the phase III trial currently being conducted by the JCOG-LSG. Recently, Coiffier et al. [37, 38] reported that CHOP plus rituximab, a chimeric IgG monoclonal antibody against the CD20 B-cell antigen, might be more beneficial than CHOP alone for elderly patients with previously untreated diffuse large B-cell lymphoma, including those with low-risk IPI. Moreover, it was reported that the effect of chimeric IgG against the CD20 B-cell antigen was enhanced in vitro by addition of G-CSF or granulocytemacrophage colony-stimulating factor [39]. Therefore, it might be worthwhile investigating the clinical efficacy of a dose-intensified CHOP regimen in combination with rituximab and the prophylactic use of G-CSF.
Finally, it is noteworthy that interstitial pneumonitis occurred in three patients and was suspected to have been related to G-CSF administration. Similar observations have been reported by Niitsu et al. [40], who observed that most of the patients who developed interstitial pneumonitis had NHL and were those treated with G-CSF following anticancer chemotherapy. Accordingly, careful monitoring for the development of interstitial pneumonitis during G-CSF administration is needed.
In conclusion, biweekly CHOP was no less effective and resulted in less toxicity than dose-escalated CHOP, and is therefore a more suitable regimen for comparison with standard CHOP therapy. Based on these findings, JCOG-LSG is now conducting a prospective randomized phase III study comparing the clinical benefits of biweekly CHOP with those of standard CHOP in previously untreated patients with aggressive NHL.
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Acknowledgements |
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Study participants: Kensei Tobinai (study chairman), Kuniaki Itoh, Tomoko Ohtsu, Yasutsuna Sasaki, Tadahiko Igarashi, Hirofumi Fujii (National Cancer Center Hospital East, Kashiwa); Michinori Ogura, Yasuo Morishima, Yoshitoyo Kagami (Aichi Cancer Center, Nagoya); Takeaki Takenaka, Yukio Kobayashi, Kensei Tobinai (National Cancer Center Hospital, Tokyo); Kouki Yoshida, Masanobu Nakata, Keiko Aikawa (Sapporo National Hospital, Sapporo); Yoshio Kiyama, Masaharu Kasai (Sapporo Hokuyu Hospital, Sapporo); Toshiaki Sai (Iwaki Kyoritsu General Hospital, Iwaki); Shin Matsuda (Ohta Nishinouchi Hospital, Kouriyama); Takaaki Chou (Niigata Cancer Center Hospital, Niigata); Yoshiharu Maeda, Tsuneo Sasaki (Tokyo Metropolitan Komagome Hospital, Tokyo); Fumi Mizorogi (The Jikei University School of Medicine, Tokyo); Akira Masumoto, Tomomitsu Hotta (Tokai University, Isehara); Fumiaki Sano, Haruhisa Nagoshi (St Marianna University, Kawasaki); Yasufumi Masaki, Susumu Sugai (Kanazawa Medical University, Kanazawa); Hiroshi Tsutani, Takanori Ueda (Fukui Medical School, Fukui); Kazunori Ohnishi (Hamamatsu University, Hamamatsu); Keitaro Tsushita (Nagoya National Hospital, Nagoya); Hirokazu Nagai, Tomohiro Kinoshita (Nagoya University, Nagoya); Masanobu Kasai (Japanese Red Cross Nagoya First Hospital, Nagoya); Atsushi Wakita, Ryuzo Ueda (Medical School, Nagoya City University, Nagoya); Tatsuharu Ohno (Ohtsu Red Cross Hospital, Ohtsu); Masafumi Taniwaki (Kyoto Prefectural University School of Medicine, Kyoto); Yuji Yufu, Naokuni Uike (National Kyusyu Cancer Center, Fukuoka); Masahiro Yamamoto (National Kyusyu Medical Center Hospital, Fukuoka); Takuya Fukushima, Shuichi Ikeda (Sasebo City General Hospital, Sasebo); Isao Sanada, Fumio Kawano (Kumamoto National Hospital, Kumamoto); Masao Tomonaga (Nagasaki University, Nagasaki). Pathology panel: Koichi Ohshima (Fukuoka University, Fukuoka); Shigeo Nakamura (Aichi Cancer Center, Nagoya); Tadashi Yoshino (Okayama University, Okayama); Yoshihiro Matsuno (National Cancer Center, Tokyo).
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Footnotes |
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Members of the Lymphoma Study Group of the JCOG are listed in the Acknowledgements.
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References |
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