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Originally published as JCO Early Release 10.1200/JCO.2004.09.114 on May 10 2004 © 2004 American Society of Clinical Oncology. Severe Pulmonary Toxicity in Patients With Advanced-Stage Hodgkin's Disease Treated With a Modified Bleomycin, Doxorubicin, Cyclophosphamide, Vincristine, Procarbazine, Prednisone, and Gemcitabine (BEACOPP) Regimen Is Probably Related to the Combination of Gemcitabine and Bleomycin: A Report of the German Hodgkin's Lymphoma Study GroupFrom the Department I for Internal Medicine, University Hospital, Cologne; University Hospital Nuremberg, Nuremberg; University Hospital Benjamin Franklin; University Hospital Rudolf Virchow, Berlin, Germany Address reprint requests to Henning Bredenfeld, MD, Department I for Internal Medicine, University Hospital Cologne, Joseph-Stelzmann-Str 9, 50924 Cologne, Germany; e-mail: henning{at}biometrie.uni-koeln.de
PURPOSE: To investigate a new effective, nonleukemogenic polychemotherapy regimen, BAGCOPP (bleomycin, doxorubicin, cyclophosphamide, vincristine, procarbazine, prednisone, gemcitabine) in a phase I/II dose-escalation study in patients with advanced-stage Hodgkin's disease (HD). PATIENTS AND METHODS: Patients in clinical stages IIB with risk factors III and IV were enrolled in this nonrandomized, multicenter trial aimed at defining the maximum-tolerated dose of gemcitabine within a modified escalated BEACOPP regimen. Gemcitabine was given at a starting dose of 800 mg/m2 on days 1 and 4 of each cycle. RESULTS: Twenty-seven patients (eight female, 19 male) were enrolled with a median age of 33 years (range, 19 to 65 years). Due to a higher than expected hematotoxicity, the day-4 application of gemcitabine was omitted after 14 patients were included and 59 cycles were given. A total of eight patients developed lung toxicity, mainly pneumonitis (six of eight), which led to the termination of the study. With a median follow-up of 27 months, 25 patients are in continuing complete remission. CONCLUSION: The substitution of etoposide by gemcitabine in the escalated BEACOPP schema is not feasible and leads to severe pulmonary toxicity. This toxicity is probably related to the concomittant application of gemcitabine and bleomycin.
For nearly two decades, adriamycin, bleomycin, vinblastine, and dacarbazine (ABVD), or mechlorethamine, vincristine, procarbazine, and prednisone (MOPP)/ABVD had been the standard regimens in patients with advanced-stage Hodgkin's disease, resulting in long-term disease-free survival of 60%.1-3 Several trials investigating rearrangements of the drug schedule in different variants could not show additional benefits.4-7 In an attempt to improve the prospect for patients with advanced disease, the German Hodgkin's Lymphoma Study Group (GHSG) developed a regimen consisting of bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (BEACOPP).8 After impressive results observed in the initial run-in study, an alternative BEACOPP variant was subsequently developed. In this granulocyte colony-stimulating factor (G-CSF) -supported, dose-dense regimen (escalated BEACOPP), higher doses of etoposide, adriamycine, and cyclophoshamide were given.9 Subsequently, a large prospectively randomized trial (HD9) in patients with previously untreated advanced Hodgkin's disease (HD) was conducted, in which eight cycles of cyclophosphamide, vincristine, procarbazine, and prednisone (COPP)/ABVD (arm A) were compared with eight cycles of BEACOPP baseline (arm B) and eight cycles of escalated BEACOPP (arm C).10 With 1,195 patients assessable, the final analysis revealed an overall survival (OS) of 83% in arm A, 88% in arm B, and 91% in arm C. Freedom from treatment failure (FFTF) was 69% in arm A, 76% in arm B, and 87% in arm C (P < .0001). Escalated BEACOPP was associated with acute hematological toxicity (WHO grade 3/4) for leukopenia, thrombocytopenia, and anemia in 98%, 70%, and 66% of patients, respectively. There were more secondary leukemias after escalated BEACOPP compared with BEACOPP baseline or COPP/ABVD. However, the total rate of secondary malignancies was not significantly different. Subsequently, eight cycles of escalated BEACOPP were chosen as the new standard for patients with advanced HD in the GHSG follow-up studies HD12 and HD15. An alternative approach for a possibly less leukemogenic BEACOPP variant could include putatively more effective drugs such as the cytarabin analogon gemcitabine.11 The first report on gemcitabine being effective in Hodgkin's lymphoma stems from a GHSG intergroup study involving 23 multiple relapsed or refractory HD patients.12 The response rate in this trial was 39%, which compares more than favorably with other drugs in this setting.13 Studies with gemcitabine in non-Hodgkin's lymphoma (NHL) patients showed promising responses.14 Subsequently, a number of case reports highlighted impressive results in relapsed HD patients.15 The toxicity profile of gemcitabine in these patients was generally mild with little nonhematological toxicity.16 Thromboytopenia was the major toxicity resulting in dose-reduction or delay in many patients. To develop an equieffective and less toxic variant, we substituted etoposide in the escalated BEACOPP regimen with gemcitabine (BAGCOPP). The present phase I/II study evaluated the optimum dose of gemcitabine in this new regimen.
Eligibility and Staging Patients eligible for the BAGCOPP pilot study had histologically proven, untreated, advanced-stage HD and were aged between 18 and 65 years. Advanced stage was defined according to the Ann Arbor classification as clinical stage IIB with risk factors large mediastinal mass or extranodal involvement, as well as patients in stage III or IV. Large mediastinal mass was defined as tumor measuring one-third or more of the maximum intrathoracic diameter as determined on a posterior-anterior chest radiograph. A malignant disease in the past as well as severe impairment of heart, lung, kidney, or liver function were exclusion criterias. Minimal hematologic requirements were WBC more than 3,000/µL and platelet count more than 100,000/µL. Written informed consent was obtained from all patients. Routine staging included medical history; physical examination; abdominal ultrasound; chest radiography; computed tomography of the chest, abdomen, and pelvis; bone marrow biopsy; CBC; and serum chemistry. In addition, echocardiography, thyroidal function, and lung function tests were performed routinely before treatment. Histologic diagnosis was initially made by local pathologists and then sent to a central pathology review panel involving six leading German lymphoma experts, for a reclassification of all biopsy samples received. Patients with a diagnosis other than HD were excluded from this study.
Trial Design and Chemotherapy
Biometry The present trial was aimed at defining the optimal dose of gemcitabine within the BEACOPP escalated regimen. Gemcitabine doses planned were 800 mg/m2, 1,000 mg/m2, 1,250 mg/m2, and 1,500 mg/m2. The intended dose-finding strategy was based on the Continual Reassessment Method in which the currently available data on toxicity for patients already treated is continually reassessed during the study.17 At each reassessment, data were modeled in order to estimate the maximum tolerable dose (MTD). The next patient is then treated at this estimated dose level. Thus, the given doses should converge rapidly toward the MTD, which is beneficial both for the patients involved and for the estimation of MTD. FFTF was defined as the time from beginning of the therapy to the first of the following events: progression during treatment, failure to attain complete remission (CR), relapse, or death from any cause. The evaluation of OS was also based on the time calculated from beginning of therapy until death from any cause or date of last information, respectively.
Radiotherapy
Recruitment
Response Assessment
Patient Characteristics Table 2 presents the characteristics of the 27 assessable patients. In total, 19 male and eight female patients were recruited, with a median age of 33 years (range, 19 to 65 years). Five patients had stage IIB; three patients, stage III A; and 19 patients, stage IIIB or IV. Nodular sclerosis11 and mixed cellularity13 were the predominant histological subtypes. According to the International Prognostic Factors Project for advanced Hodgkin's lymphoma,18 five patients (19%) had a prognostic score of 0 to 1, 16 patients (59%) had a score of 2 to 3, and six patients (22%) had a score between 4 and 7.
Application of Therapy Of 27 patients, 24 received the planned number of eight cycles of BAGCOPP. Two patients received seven cycles, and one patient received six cycles. The initial schedule with gemcitabine on days 1 and 4 had to be modified during the course of the trial. From a total of 212 cycles, 54 cycles were given as initially planned. Due to a higher than expected hematotoxicity, gemcitabine application on day 4 was subsequently omitted. Thus, 97 cycles were given with gemcitabine on day 1 only (800 mg/m2). Due to unexpected pulmonary toxicity in a total of eight patients, the BAGCOPP trial was stopped in July 2001. All patients who were still on treatment at the time of discontinuation of the trial completed treatment with escalated BEACOPP in subsequent cycles (n = 61 cycles). Patients with documented pulmonary toxicity received no further bleomycin in the following cycles. Sixteen (59%) of 27 patients were treated with consolidative radiotherapy to sites of initial bulky or residual disease.
Toxicity
Pulmonary Toxicity In May 2001, the study coordinating center received the first report on pulmonary complications within the trial cohort. A 28-year-old female patient in CR presented with Pneumocystis carinii pneumonia (PCP) 4 weeks after finishing eight BAGCOPP cycles without problems. The patient showed a mild dyspnea, rapidly worsening within days. There was no benefit from standard antibiotics, and the patient died after 2 weeks of intensive-care treatment due to a massive cardiogenic infarction of the arteria media. The autopsy showed signs of pulmonary fibrosis in both lungs, which was possibly the underlying cause for this fatal outcome. As a consequence, regular carbon monoxide diffusion capacity (DLCO) tests and PCP prophylaxis became mandatory for all patients in this study. In case of presumed pneumonitis or any other lung toxicity, adequate imaging by high-resolution CT and invasive diagnostic procedures, including bronchial lavage and/or biopsy, had to be performed. A total of eight patients developed pulmonary symptoms. Pneumonitis was seen in six cases and was histologically confirmed in three cases; two were detected with high-resolution CT (Fig 1); and one, with gallium-scan. Another two patients showed a significantly reduced DLCO, which gradually improved after omitting gemcitabine. Cases of pneumonitis were observed after a minimum of three cycles applied. The minimum doses of gemcitabine and bleomycin associated with histologically confirmed pneumonitis were 5,200 mg (gemcitabine), and 64 mg (bleomycin), as presented in Table 4. The remaining nonhematological toxicity was moderate (Table 5). All patients but the one who died recovered from pulmonary toxicity and completed treatment subsequently without bleomycin or gemcitabine.
Treatment Outcome Following an intent-to-treat analysis, 25 from 27 patients achieved a CR after the end of therapy, resulting in 93% primary response rate. One patient died after completing eight cycles of BAGCOPP while in complete remission; one patient was lost to follow-up after six cycles with a CR at that time point. At a median follow-up of 27 months, 25 patients are in continued CR.
This pilot study was designed to evaluate the feasibility of a new multidrug chemotherapy regimen, BAGCOPP, in which gemcitabine replaced etoposide in the escalated BEACOPP schedule. After 27 patients with advanced stage HD were enrolled, the study was stopped due to unexpected pulmonary toxicity. The major findings to emerge from this study are: (1) substituting etoposide by gemcitabine in the escalated BEACOPP regimen results in unacceptable pulmonary toxicity; (2) the most likely explanation for the unexpected pulmonary toxicity is the combined use of bleomycin and gemcitabine within the BAGCOPP protocol; and (3) the response rate was 93% (25 of 27). With a median follow-up of 27 months, 25 patients are in continued CR. In a variety of clinical trials, gemcitabine was shown to be safe, both when given as a single agent or as part of a multidrug regimen. The gemcitabine dose used in most of these trials was 800 mg/m2, with a maximum of 1,600 mg/m2. Most data on safety and efficacy were based on a regimen administered on days 1, 8, and 15, given at 4-week intervals. However, the majority of toxicity data available stem from studies with palliative intention in pretreated patients. The present schedule, BAGCOPP, incorporated gemcitabine on a days 1 to 4 schedule in the escalated BEACOPP regimen, replacing etoposide. This was thought to be very similar to the BEACOPP concept, in which the myelotoxic drugs are given within the first 3 days of each cycle. In a meta-analysis involving 979 patients with various solid tumors, gemcitabine was demonstrated to have a low toxicity profile. Hematotoxicity WHO grades 3 and 4 were seen in less than 10% of patients.16 Studies with gemcitabine in lymphoma patients refractory to primary treatment showed higher levels of severe hematological toxicity, with leukopenia and trombocytopenia in up to 33% and 60%, respectively.13,14 In the present study, WHO grade 3/4 leukopenia and anemia were substantial, occurring in 58% and 14%, respectively, of patients treated with gemcitabine twice per cycle (days 1 and 4). This was lower when compared with those data reported for escalated BEACOPP (76% and 25%). Thrombocytopenia with BAGCOPP was detected in 34% of cycles, which was very similar to escalated BEACOPP (35%). While dose-reduction relating to hematotoxicity was frequent in patients receiving the initial BAGCOPP regimen with gemcitabine given on days 1 and 4, this was substantially less frequent after omitting the day-4 application. The modified schedule with a single application of gemcitabine seemed to be feasible with respect to dose-limiting hematotoxicity. Drug-induced respiratory disorders are common side effects in cancer therapy and were increasingly reported in association with high-dose chemotherapy programs. The clinical presentation includes an acute infiltrate mimicking pneumonia, the adult respiratory distress syndrome, cardiac and noncardiac pulmonary edema, obstructive airflow disease, and pleural diseases.19 There are many antitumor drugs with potential pulmonary toxicity. The drug most often associated with this adverse effect is bleomycin, which induces pulmonary toxicity in approximately 10% of patients, with fatal outcome in 1%. The effect is dose-related and more common in elderly patients. The alkylating agent cyclophosphamide has been reported to cause severe lung injury when given as single agent in 1% of cases.19-21 Since the introduction of gemcitabine as a novel agent with very good efficacy even in patients with multiple relapsed lymphoma, the number of case-reports indicating gemcitabine-induced lung toxicity has increased.22-27 Most authors reported mild pulmonary toxicity associated with gemcitabine which was self-limiting in most cases or successfully treated with steroids.28,29 However, there were some cases with life-threatening lung injury. A retrospective review using commercial databases estimated the incidence of serious pulmonary toxicity associated with gemcitabine to be lower than 1%.30 However, data from prospective trials are not available. The patient developing a PCP after the end of treatment in the present study showed no unusual features during the course of the therapy. In accordance with the protocol, the gemcitabine dose had been reduced twice due to leukopenia. In addition, the day-4 gemcitabine application was omitted after the fifth cycle, resulting in a total dosage of 15,400 mg gemcitabine and 120 mg bleomycin, respectively. Leukemia and lymphoma patients are at particular high risk for PCP infection.31 Reports on PCP after gemcitabine-based treatment are, however, rare and respond sufficiently to adequate treatment with cotrimoxazol and methylprednisolone.32 The more relevant finding in the postmortem examination was a severe fibrosis of both lungs, probably as a result of undiagnosed pneumonites. In total, six cases were reported during this study. Unfortunately, there was no typical pattern of symptoms or risk factors indicative of the diagnosis. The analysis of the amount of drugs given revealed no correlation between the total doses applied for either gemcitabine or bleomycin and the occurrence of lung toxicity. A cumulative dose effect as postulated for single drug-related toxicity was not obvious in our trial. Apart from the patient with additional PCP, all other patients improved after omitting gemcitabine. The unexpected frequency of pulmonary toxicity led to the early termination of this trial. Based on personal communication and our early reports (American Society of Hematology meeting, 2001), the European Organization for Research and Treatment of Cancer stopped a gemcitabine-based ABVD-variant.33 Another recently reported phase I study conducted in the United States with a gemcitabine-containing ABVD variant (ABVG) also reported substantial pulmonary toxicity.34 Of 12 patients, five developed significant pulmonary toxicity after four, five, and six cycles, respectively. Eight patients received the planned number of six cycles of ABVG. Two patients had early relapses. Thus, this study underscores the risk of pulmonary sequelae when gemcitabine is combined with bleomycin. Together with the European Organization for Research and Treatment of Cancer, the GHSG has developed a novel combination regimen containing prednisone, vinblastine, doxorubicin, and gemcitabine, which is currently undergoing clinical evaluation in patients with advanced-stage of HD in order to re-evaluate the potential of gemcitabine as part of a multidrug regimen in patients with HD. In summary, a modified BEACOPP variant employing gemcitabine instead of etoposide results in unacceptable pulmonary toxicity in patients with advanced-stage HD.
The authors indicated no potential conflicts of interest.
Authors' disclosures of potential conflicts of interest are found at the end of this article.
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Copyright © 2004 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
75 kg body weight) was applied subcutaneously once daily from days 8 to 13 of each cycle. Following each cycle, dose-limiting toxicity (DLT) defined as leukopenia WHO grade 4 for more than 4 days, thrombocytopenia WHO grade 4 on at least one day, infectious disease WHO grade 4, any other WHO grade 4 toxicity, as well as treatment delay for more than 14 days due to insufficient hematopoietic recovery, was documented. 
