1 Department of Medical Oncology and Hematology, and 3 Division of Pathology, Istituto Clinico Humanitas, Rozzano (Milano); 2 Division of Medical Oncology A, Centro di Riferimento Oncologico, Aviano, Italy
Received 31 January 2002; accepted 11 February 2002
![]() |
Abstract |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Following our previous study of CHOP (cyclophosphamide, doxorubicin, vincristine and prednisone) intensification in non-Hodgkins lymphoma (NHL), in the present report we attempted to further increase dose intensity by shortening the between-course intervals with the support of growth factors.
Patients and methods:
A total of 67 patients were enrolled. With a fixed dose of doxorubicin 75 mg/m2, cyclophosphamide (CTX) was started at a dose of 1750 mg/m2 and increased by 250 mg/m2 in consecutive cohorts of patients provided that no dose-limiting toxicity occurred. After the maximal tolerated dose (MTD) had been identified, this was used to treat more patients in order to confirm the feasibility of the regimen on a large scale, with the number of cycles being varied on the basis of disease extension.
Results:
Twenty-three cases were enrolled in the CTX dose finding phase. Dose-limiting non-hematological toxicity occurred at 2250 mg/m2. As the intermediate level of 2000 mg/m2 had a borderline toxicity profile, a CTX dose of 1750 mg/m2 was defined as the MTD. A total of 53 patients then received the MTD during the course of the study as a whole. At the MTD, toxicity was acceptable. Only 10 of 189 cycles (4%) required hospitalization due to infection or febrile neutropenia. Seventy-four percent of the patients achieved complete remission. Freedom from progression and overall survival at 12 months were 71% and 86% in the whole series, and 58% and 71% for high-risk cases, respectively.
Conclusions:
This intensified CHOP regimen is feasible on an outpatient basis. It can be safely considered a definitive treatment in patients at low and intermediate risk, and as induction before high-dose consolidation in high-risk cases.
Key words: chemotherapy, CHOP, dose finding, dose intensity, non-Hodgkins lymphoma
![]() |
Introduction |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Another way of improving results in aggressive NHL is to optimize the amount of the most active drugs per unit of time by increasing the dose intensity of doxorubicin (DOX) and cyclophosphamide (CTX), because one of the reasons for the failure of second- and third-generation regimens is that the inclusion of a larger number of drugs implies sacrificing the dose intensity of DOX and CTX. Over recent years, and with the support of growth factors, the possibility of increasing dose intensity has been addressed in different ways by a number of groups, with the CHOP regimen usually being chosen, as it still represents the gold standard for NHL [68]. We have recently published the results of a phase III CHOP intensification study in which the maximal tolerated doses (MTD) of CTX and DOX were found to be, respectively, 1750 mg/m2 and 75 mg/m2 in the case of the regimen given every 21 days [9]. In the present report, we attempted to further increase CHOP dose intensity by shortening the between-course interval to 14 days, with the main aim of identifying the MTD and thus the maximal dose intensity of a CHOP regimen given on an outpatient basis.
![]() |
Patients and methods |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
The staging procedures included physical examination, full blood count with differential, and biochemistry profile including lactate dehydrogenase (LDH), standard chest X-ray, gastrointestinal contrast study, clinical evaluation of the Waldeyer ring, chest and abdomen-pelvic computed tomography (CT) scan and unilateral bone marrow biopsy. The disease stage was defined according to both the Ann Arbor staging system and the IPI. The first phase of the study aimed to identify the MTD of I-CHOP given every 2 weeks. Once established, all of the subsequent patients were treated at the MTD with the number of administered courses being varied on the basis of stage and/or IPI score. The aim of this second phase was to test the feasibility of the regimen on a large scale. All of the cycles were given on an outpatient basis, except in the case of patients with bulky disease, who were hospitalized for the first treatment administration in order to monitor tumor lysis.
Treatment program
As in our previous study, the DOX dose was fixed at 75 mg/m2 and vincristine and prednisone were given at conventional CHOP doses. The starting dose of CTX was 1750 mg/m2, representing the MTD not requiring growth factors in our previous study with the regimen given every 21 days. Granulocyte colony-stimulating factor (G-CSF) 300 µg/day was given on days 712 of each cycle. If no dose-limiting toxicity (DLT) occurred during the first three cycles in at least three patients, the CTX dose was increased by 250 mg/m2 in the subsequent cohort. DLT was defined as grade IV neutropenia (absolute neutrophil count <500/mm3) lasting >7 days, or grade III thrombocytopenia (platelet count <50 000/mm3) lasting at least 7 days, or any grade IV non-hematological toxicity other than alopecia.
The treatment was given every 14 days unless the neutrophil count was <1500/mm3 and/or the platelet count <100 000/mm3 on the day the therapy was planned. Toxicity was recorded according to WHO criteria. The patients were asked to undergo at least three full blood counts with differential during the home period, starting from day 8 of each cycle. If two patients experienced DLT, the previous dose was defined as the MTD. Once the MTD had been established (see below), this dose was given to all of the subsequent patients.
The treatment program was based on three to four I-CHOP cycles in patients with limited disease (Ann Arbor stage IIIA), followed by involved-field radiotherapy at 2530 Gy. The patients in an advanced stage (Ann Arbor IIB/bulky, III, IV) were given five to six cycles followed by radiotherapy (2530 Gy) on bulky site(s) of disease at diagnosis. Starting in 1999, patients with high-risk characteristics according to IPI underwent consolidation with high-dose chemotherapy and peripheral blood progenitor cell support after four courses of I-CHOP as induction.
Dose intensity evaluation
In accordance with the method described by Hryniuk and colleagues [10, 11], dose intensity was calculated as the number of milligrams of drug delivered per square meter per week during the whole treatment program (e.g. from day 1 of the first cycle to day 15 of the last cycle). At each dose level, the actual (received) dose intensity (ADI) of single-agent DOX and CTX was compared with the projected dose intensity (PDI). The average relative received dose intensity of the whole regimen was calculated at each dose level by averaging the ADI to the PDI for each drug in the standard CHOP regimen, thus enabling a comparison of the dose intensity of I-CHOP and standard CHOP. The PDI and ADI of single-agent DOX and CTX, as well as the average PDI and ADI of the whole regimen (standardized to conventional dose CHOP) were calculated at each CTX dose level.
Evaluation of response and survival parameters
In the absence of tumor progression, the disease was completely restaged after the third course and upon the completion of the chemotherapeutic program. Although this was a dose-finding study, treatment outcome was also evaluated. Complete remission (CR) was defined as the disappearance of all physical and radiological signs of disease for at least 4 weeks, and partial remission (PR) as a reduction of at least 50% in the sum of the products of the largest tumor diameters recorded before treatment. Increases of 25% or more in the sum of the products of pre-treatment tumor diameters or the development of any new abnormalities were considered as induction failure. After completing the treatment program, the patients in complete remission were monitored every 34 months for the first 2 years and every 612 months thereafter unless symptoms or signs of disease progression appeared. Freedom from progression (FFP) and overall survival (OS) were calculated from the date of the first treatment administration to the date of the first evidence of progression or the date of death, according to the KaplanMeier method [12].
![]() |
Results |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
|
As expected, the majority of the patients experienced grade IV neutropenia related to 5677% of the administered courses (Table 2). Grade IIIIV thrombocytopenia occurred in 8% of courses at 2000 mg/m2, in 11% at 2250 mg/m2 and in no case at the starting dose-level of CTX (1750 mg/m2). No patient required platelet transfusion, whereas red blood cells were transfused to two of nine, three of 10 and three of four patients at each dose level, respectively. In terms of non-hematological toxicity, grade III stomatitis and fever of unknown origin occurred during 3%, 8% and 21%, and 3%, 8% and 26% of the evaluable cycles at each dose level, respectively.
|
Feasibility of CHOP at MTD
As a further 44 patients were treated at MTD (1750 mg/m2 of CTX), the following description relates to a total of 53 patients. A total of 141 courses are evaluable for toxicity (Table 3). Nine patients (16 of 141 cycles, 11%) required red blood cell transfusions because of hemoglobin levels of <7.5 g/dl, and three (2% of cycles) required platelet support because of a platelet count of <20 000 with fever. Thirty-six percent of the administered cycles were complicated by mild/moderate and 8% by severe mucositis. Grade III infection or fever of unknown origin occurred during 25% of the courses and grade III during 2%. Thirteen patients were admitted to the hospital at some time during the treatment program, making a total of 20 hospitalizations for the 189 administered courses (11%). Six of these admissions were due to the need for blood products, one was due to deep venous thrombosis, one to vincristine-related gastrointestinal toxicity, two to cystitis, one to suvraventricular paroxystic arrhythmia and the remaining nine to febrile neutropenia. No life-threatening toxicity or treatment-related death occurred during treatment.
|
|
As regards evaluation of response, one patient was lost at follow-up and six were not evaluable for response because of no evidence of disease after diagnostic surgery in one case and because of still ongoing treatment in the remaining five. Four patients with high-risk characteristics or unfavorable histology received after I-CHOP second-line ara-C-based consolidation therapy as part of a high-dose program with stem-cell rescue, and were not considered for the survival analysis.
Thus, the following description concerns 62 patients for the survival analysis and 61 for the response analysis, respectively.
Overall, 45 of 61 patients (74%) achieved CR, 13 (21%) PR and three (4%) did not respond. After a median follow-up of 12 months (range 241 months), a total of 15 patients had experienced disease progression or relapse. Thirteen of them were candidates for high-dose therapy with stem-cell rescue: six could not undergo the treatment program due to rapid disease progression, and among the remaining six, four achieved durable CR, two experienced further relapse and one is still ongoing. One patient did not undergo high-dose salvage therapy because of a diagnosis of T-cell cutaneous lymphoma and one for a poor performance status, respectively.
Of the 62 patients considered for survival, 12 have died: eight of progressive lymphoma, one due to septic shock while receiving salvage therapy for a rapid disease progression, one of an unspecified cerebral mass and one of HBV-hepatitis reactivation. One patient treated in the dose-finding phase died of an acute cardiac complication (probably myocardial infarction) 3 months after the completion of therapy. In an intention-to-treat analysis, 12-month FFP and OS for the whole series are 71% and 86%, respectively. On the basis of the IPI categories, FFP was 74% and 58% (P = 0.103), and OS was 92% and 71% (P = 0.005) for patients with 02 or >3 adverse factors, respectively (Figures 1 and 2).
|
|
![]() |
Discussion |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Another attempt to improve CHOP consisted of giving high-dose chemotherapy with peripheral progenitor cell support as part of a front-line program. Three randomized comparisons have so far been published using three different approaches. The Milan group has published the results of an early intensification program (methotrexate, doxorubicin, cyclophosphamide, vincristine and bleomycin) comparing MACOP-B, and high-dose sequential chemotherapy with progenitor cell support at onset [16]; the GELA (Groupe dEtude des Lymphomes de lAdulte) group randomized high-dose versus standard-dose consolidation in a late intensification program in patients with documented CR after induction [4]; and the Italian Cooperative Group randomized high-dose consolidation or observation in all patients completing the induction program (whatever the response) [3]. The last two trials retrospectively detected an advantage in terms of FFP in patients at high risk according to the IPI, and the larger scale French trial (236 versus 70 patients) also found an advantage in terms of OS.
Other studies have considered intensifying the dose of CHOP using different administrations in heterogeneously selected patients [8]. The high-dose CHOP regimen used at Dana Farber [8] to treat 30 patients with advanced aggressive lymphoma included CTX 4000 mg/m2 and DOX 70 mg/m2, with all of the patients being admitted to hospital for treatment administration. Stoppa et al. [7] demonstrated the feasibility of multiple courses of an intensified CHOP regimen (CTX 3000 mg/m2 and DOX 75 mg/m2 every 21 days, each followed by stem-cell apheresis), which was consolidated by a more intensive regimen supported by repeated blood progenitor cell reinfusions. Our own group [9] has published the results of a step-by-step dose-finding trial, which indicated that the MTDs of CTX and DOX were, respectively, 2750 mg/m2 and 75 mg/m2, with an ADI of 1.76, when the I-CHOP course was given every 21 days.
Up to now, only one trial from the GELA group [17] has prospectively evaluated the role of dose intensity in large-cell lymphoma with favorable characteristics. In this subset, the author could not find any difference in terms of both FFP and OS between patients receiving standard therapy [eight 3-week courses of M-BACOD (low-dose methotrexate, bleomycin, doxorubicin, cyclophosphamide, vincristine, dexamethasone)] or intensified therapy [three 2-week courses of ACVBP (doxorubicin, cyclophosphamide, vindesine, bleomycin, prednisone), followed by intermediate-high dose consolidation including methotrexate, etoposide, ifosfamide, asparaginase and cytarabine]. However, our program consists of a very short-term treatment where cases at low-risk receive three 2-week courses of chemotherapy followed by radiotherapy, for an overall duration of the whole treatment program of <3 months.
In this study, we explored the feasibility of further intensifying the CHOP regimen by shortening the between-course interval. The starting CTX dose of 1750 mg/m2 was chosen because our previous study had indicated that it was the highest dose not requiring growth factors. After testing two higher doses, the dose of 1750 mg/m2 was taken as the MTD because one of the aims of the study was to find an outpatient treatment that can be delivered on a large scale and even outside major referral centers. Furthermore, analysis of the dose-intensity parameters of the two single agents and the regimen as a whole showed that the highest ADI was reached at the CTX starting level of 1750 mg/m2 because, at higher doses, delays and dose reductions were more frequent and the ADI progressively declined.
The treatment was feasible at this MTD because only a minority of the patients had to be hospitalized for reasons of toxicity. The main reason for hospitalization was to receive blood product support; only 4% of the cases were due to febrile neutropenia. The therapeutic results compare well with those of the other studies mentioned above [1, 2, 6, 7]. The CR level was 74%, with the patients at an intermediate-high risk according to the IPI having a FFP and OS at 12 months of 58% and 71%, respectively (Figures 1 and 2). In the above-mentioned reports [6, 7, 17], FFP ranges from 56% to 65% for patients with high-risk disease. As already outlined, the regimens utilized in these trials require hospitalization for cycle administration, or repeated outpatient admission for stem-cell collection and reinfusion. With the exception of the first course for cases at high risk of tumor-lysis syndrome, our I-CHOP was always delivered on an outpatient basis, which translates into lower costs in terms of both time and money.
As the achievement of CR is of major concern in aggressive NHL, the dose-intensification strategy, as well as the association of chemotherapy with targeted immunotherapy [18], seems to address this attempt even in the high-curable early-stage cases, and are suitable of further investigation.
In conclusion, our results demonstrate the feasibility of a highly dose-dense CHOP regimen in aggressive NHL, which also allows a further decrease in the duration of the treatment program. At this dose, I-CHOP can be safely given as definitive treatment in patients with low-intermediate risk characteristics, and as an induction regimen in patients at high risk who are suitable for high-dose consolidation.
![]() |
Footnotes |
---|
![]() |
References |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
2. Gordon LI, Harrington D, Andersen J et al. Comparison of a second generation regimen (m-BACOD) with a standard regimen (CHOP) for advanced diffuse non-Hodgkins lymphoma. N Engl J Med 1992; 327: 13421349.[Abstract]
3. Santini G, Salvagno L, Leoni P et al. VACOP-B versus VACOP-B plus autologous bone marrow transplantation for advanced diffuse non-Hodgkins lymphoma: results of a prospective randomized trial by the non-Hodgkins Lymphoma Cooperative Study Group. J Clin Oncol 1998; 16: 27962802.[Abstract]
4. Haioun C, Lepage E, Gisselbrecht C et al. Benefit of autologous bone marrow transplantation over sequential chemotherapy in poor-risk aggressive non-Hodgkins lymphoma: updated results of the prospective study LNH87-2. Groupe dEtude des Lymphomes de lAdultes. J Clin Oncol 1997; 15: 11311137.[Abstract]
5. The International Non-Hodgkins Lymphoma Project. A predictive model for aggressive non-Hodgkins lymphoma. N Engl J Med 1993; 329: 987994.
6. Shipp MA, Neuberg D, Janicek M et al. High-dose CHOP as initial therapy for patients with poor-prognosis aggressive non-Hodgkins lymphoma: a dose-finding pilot study. J Clin Oncol 1995; 13: 29162923.[Abstract]
7. Stoppa AM, Bouabdallah R, Chabannon C et al. Intensive sequential chemotherapy with repeated blood stem-cell support for untreated poor-prognosis non-Hodgkins lymphoma. J Clin Oncol 1997; 15: 17221729.[Abstract]
8. Santoro A, Balzarotti M, Castagna L. Intensified CHOP in non-Hodgkins lymphoma: what we know and what we need to know. Ann Oncol 1999; 10: 875876.[ISI][Medline]
9. Santoro A, Balzarotti M, Tondini C et al. Dose-escalation of CHOP in non-Hodgkins lymphoma. Ann Oncol 1999; 10: 519525.[Abstract]
10. Hryniuk W. The importance of dose intensity in outcome of chemotherapy. In Hellman S, DeVita V, Rosenberg S (eds): Important Advances in Oncology. Philadelphia, PA: Lippincott 1988; 121124.
11. Meyer RM, Hryniuk WM, Goodyear MD. The role of dose intensity in determining outcome in intermediate-grade non-Hodgkins lymphoma. J Clin Oncol 1991; 9: 339347.[Abstract]
12. Kaplan ER, Meier P. Non-parametric estimation from incomplete observations. J Am Stat Assoc 1958; 53: 157181.
13. Harris NL, Jaffe ES, Stein H et al. A revised EuropeanAmerican classification of lymphoid neoplasms: a proposal from the International Lymphoma Study Group. Blood 1994; 84: 13611392.
14. Harris NL, Jaffe ES, Diebold J et al. The World Health Organization classification of neoplastic disease of the hematopoietic and lymphoid tissues. Ann Oncol 1999; 12: 14191432.
15. Goldie JH, Coldman JA. A mathematical model for relating the drug sensitivity of tumors to their spontaneous mutation rate. Cancer Treat Rep 1979; 63: 17271733.[ISI][Medline]
16. Gianni AM, Bregni M, Siena S et al. High dose chemotherapy and autologous bone marrow transplantation compared with MACOP-B in aggressive B-cell lymphoma. N Engl J Med 1997; 336: 12901297.
17. Tilly H, Mounier N, Lederlin P et al. Randomized comparison of ACVBP and M-BACOD in the treatment of patients with low-risk aggressive lymphoma: the LNH 87-1 study. J Clin Oncol 2000; 18: 13091315.
18. Vose JM, Link BK, Grossbard ML et al. Phase II study of rituximab in combination with CHOP chemotherapy in patients with previously untreated, aggressive non-Hodgkins lymphoma. J Clin Oncol 2001; 19: 389397.