1 Servicio de Oncología, Hospital Clínico Universitario, Málaga; 2 Servicio de Oncología, Hospital Sant Joan, Reus; 3 Servicio de Oncología, Hospital Universitario, Tenerife; 4 Servicio de Oncología, Hospital General, Alicante; 5 Unidad de Hematología, Hospital Costa del Sol, Marbella; 6 Servicio de Medicina Interna, Hospital Básico de la Serranía, Ronda, Spain
* Correspondence to: Dr A. Rueda Domínguez, Servicio de Oncología, Hospital Clínico Universitario, Campus de Teatinos s/n, 29010 Málaga, Spain. Tel: +34-951-032467; Fax: +34-952-279407; Email: ruedom{at}yahoo.com
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Abstract |
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Patients and methods: From January 1990 to June 2002, 95 patients with stage I and II Hodgkin's lymphoma were treated with six ABVD cycles. Fifteen patients who met the criteria for mediastinal bulky disease also received further radiotherapy on the mediastinum.
Results: After six cycles, 89 patients (94%) showed a complete response (CR) and six patients (6%) showed a partial response (PR). These PRs became CRs after radiotherapy. After a median follow-up of 78 months, 14 patients had relapsed and three had died. Overall survival and progression-free survival rates at 7 years were 96% and 84%, respectively. For patients with stage IA and IIA without mediastinal bulky disease, the survival rates were 97% and 88%, respectively.
Conclusions: The administration of six ABVD cycles is an effective and safe treatment in patients with stage I and II Hodgkin's lymphoma.
Key words: ABVD chemotherapy, early Hodgkin's lymphoma
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Introduction |
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The increase of specific survival and the early age of the patients diagnosed with Hodgkin's lymphoma has resulted in the finding of other severe pathologies occurring with a incidence higher than that observed in population subgroups of similar age. About 46% of patients die from causes not directly related to lymphoma: these include secondary neoplasias, cardiovascular events and other toxicities secondary to the treatment administered [2]. This percentage is even higher in patients with early-stage Hodgkin's lymphoma. Recently, Ng et al. [3
] reported that late toxicity is the main cause of mortality in patients <50 years diagnosed with stage I or II Hodgkin's lymphoma. In this study, mortality unrelated to lymphoma was twice that directly caused by the disease in patients with early-stage disease and a good prognosis [3
].
Some late toxic deaths are due to the use of alkylating chemotherapeutic agents, most of which are specifically related to the MOPP schedule (mechlorethamine, vincristine, procarbazine and prednisone) or derived compounds. Treatment with alkylating agents without radiotherapy is associated with increased lung cancer risk [4]. However, late toxicities leading to higher mortality are attributed to radiotherapy [5
, 6
]. Those patients irradiated by mantle field have a risk of suffering myocardial infarction three times higher than patients who receive no myocardial irradiation [7
].
Far more relevant is the continuous and growing risk of developing a second solid tumor, found in patients treated with radiotherapy: this risk increases for at least 25 years after treatment [2, 8
]. A population-based study analyzed 32 591 patients and found a relative risk of 22% of having a second solid tumor 25 years after the diagnosis of Hodgkin's lymphoma [9
]. The magnitude of this problem is even more evident if we consider the risk of developing breast cancer in women that have undergone mantle field irradiation. In this particular case, the relative risk is twice that of the overall population [9
]. However, in women treated under the age of
25 years, the picture is very different. In this population the absolute excess risk of breast cancer (per 10 000 female patients per year of follow-up) has ranged from 16.7 (for patients followed for less than 14 years) to 169 (follow-up longer than 15 years) [5
].
A logical way to avoid the late effects of radiotherapy might be to avoid its use. However, this would require alternative therapies that have a similar efficacy to therapies that include radiotherapy. Furthermore, these alternative treatments should not induce severe or potentially lethal late toxic effects. The results of a small randomized study conducted by the American National Cancer Institute were reported in 1991 [10]. This study suggested that the administration of six cycles of MOPP chemotherapy was equally or even more effective than extended field radiotherapy in patients with pathological stage I or II Hodgkin's lymphoma. However, in a similar Italian trial the survival rate was significantly higher in patients treated with radiation therapy [11
]. Acute toxicities, infertility and the risk of myeloid leukemia induced by MOPP schedule led to an overall rejection of this therapeutic alternative.
Chemotherapy with the ABVD schedule (doxorubicin, bleomycin, vinblastine and dacarbacine) is the standard treatment for advanced-stage Hodgkin's lymphoma: ABVD has been found to be more efficacious than MOPP [12] and less toxic than the hybrid chemotherapy MOPP/ABV (mechlorethamine, vincristine, procarbazine, prednisone, doxorubicin, bleomycin and vinblastine) [13
]. Moreover, ABVD does not cause sterility [14
], and its potential for inducing second solid or hematological neoplasias seems to be lower than the observed with radiation therapy or MOPP [5
, 15
]. All these facts also support the use of ABVD schedule in patients with early disease stages.
In 1997 we published the first study evaluating the administration of six ABVD cycles as exclusive treatment of patients with stage I or II Hodgkin's lymphoma [16]. In the present work, we report the results of this study after a long-term follow-up period (maximum 14 years) and in a larger cohort of patients (95 versus 23).
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Patients and methods |
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Clinical staging of the disease was done according to Cotswold's criteria [17]. A complete physical examination was conducted, together with the following complementary explorations: full hematological and biochemical screening, determination of erythrosedimentation rate, computed axial tomography of chest, abdomen and pelvis, and unilateral biopsy of bone marrow. Other radiological or radioisotopic analyses were carried out only if indicated by signs or symptoms. Two patients with infradiaphragmatic disease and no inguinal affectation were subjected to laparotomy for node biopsy, but Kaplan's laparotomy was not used. Infection by HIV was ruled out.
Cardiorespiratory function was not routinely monitored in all patients. During treatment, pulmonary toxicity was excluded by a careful anamnesis together with posteroanterior and lateral chest radiographies. Respiratory function tests were performed only if suggestive symptoms were present. From September 1996, respiratory function tests and echocardiography to determine the left ventricle ejection fraction (LVEF) were conducted 1824 months after the completion of chemotherapy. Respiratory function tests included the spirometric evaluation of forced vital capacity (FVC), the forced expiratory volume in the first second (FEV1) and carbon monoxide diffusing capacity (DLCO). Cardiorespiratory evaluation was performed in 15 patients before and 1824 months after chemotherapy.
The fertility of patients after treatment was not routinely evaluated. Seminogram was done only in male patients who relapsed in order to check fertility prior to cryopreserving their semen.
Chemotherapy and other treatments
Patients with clinical stage I and II disease, no previous cardiopulmonary disease, and good bone marrow, liver and kidney function were treated with six cycles of ABVD: doxorubicin 25 mg/m2, bleomycin 10 mg/m2, vinblastine 6 mg/m2 and dacarbacine 375 mg/m2. All drugs were given intravenously on days 1 and 15. The treatment was repeated every 4 weeks.
Secondary prophylaxis with granulocyte colony-stimulating factor (G-CSF; filgrastim) was given from 1991, as previously described [18], in those patients with febrile neutropenia or showing treatment delay on day 1 or 15 of the chemotherapy cycle due to grade 3/4 neutropenia.
Complementary radiotherapy was administered on mediastinum and supraclavicular fossae (3645 Gy) after the six chemotherapy cycles in case of mediastinal bulky disease, according to Cotswold's criteria [17].
Evaluation of response, toxicity and survival
All patients were included in the analysis of efficacy, toxicity and survival (intention-to-treat analysis). Response to treatment was evaluated after the third or fourth cycle and after the sixth cycle, following Cotswold's criteria [17]. In patients who also received radiotherapy, response was assessed 2 months later. It was documented on the basis of the clinical situation and the results of the tests and imaging investigation that were abnormal at presentation. A complete response (CR) was considered when, after treatment, the patient has no clinical, radiological or other evidence of Hodgkin's lymphoma. Partial response (PR) was defined as a decrease by at least 50% in the sum of the products of the largest perpendicular diameters of all measurable lesions and a objective improvement in non-evaluable but clinically evident malignant disease. Patients with a remission of >75% of all measurable lesions, and with no changes between the computed axial tomography performed after the third and the sixth cycle, were considered to be in unconfirmed CR (uCR). Post-chemotherapy nuclear medicine studies were not carried out routinely.
Toxicity was evaluated according to WHO criteria [19]. Dose intensity was calculated as mg x m2 of body surface x week. Relative dose intensity was also calculated by dividing the real dose by the theoretical dose.
Progression-free survival was calculated from the date of beginning chemotherapy to the date of progression or relapse or to the date of last control. Overall survival was calculated from the date of beginning chemotherapy to the date of death by any cause or to the date of last control. Survival curves were estimated using the KaplanMeier method [20], and differences between survival curves were evaluated using the log-rank test [21
]. The prognostic influence of the following variables was evaluated: gender, disease stage, histology, B symptoms and presence of mediastinal bulky disease. Moreover, in order to compare the present results with those obtained in other European studies, the patients were classified into two groups according to the criteria of favorable or unfavorable disease established by the European Organization for Research and Treatment of Cancer (EORTC) [22
].
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Results |
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G-CSF was required as secondary prophylaxis in 61 patients (63%): 48 (50%) of them received G-CSF after the first or second chemotherapy cycles. As a result of this prophylactic policy, treatment delay or dose reduction was avoided in 85% of patients who required G-CSF, and the relative dose intensity was >90% in 84 of 95 patients (88%).
After six cycles of chemotherapy, 89 patients (94%) showed complete response (CR confirmed or uCR). Six patients showed a PR: five of them had mediastinal bulky disease at diagnosis and received complementary radiotherapy. Only one patient without mediastinal bulky disease did not show CR/CRu; this patient was treated with radiotherapy on the areas of residual disease (mediastinum and left supraclavicular fossa).
All patients receiving complementary radiotherapy (15 patients because of mediastinal bulky disease at diagnosis and one due to lack of CR after the six ABVD cycles) showed CR or CRu in the evaluation carried out 2 months after the completion of radiotherapy.
To date, we have observed 14 relapses (10 in patients treated solely with chemotherapy and four in patients treated with chemotherapy followed by radiotherapy). The median time to relapse was 18 months (range 968). Ten relapses occurred during the first 2 years of follow-up. Eleven patients showed relapse in the same nodal areas affected in the initial diagnosis. No patients with mixed cellularity histology relapsed; 11 patients had nodular sclerosis subtype and three patients had lymphocytic predominance.
The median follow-up from rescue treatment for the 14 relapsed patients was 56 months (range 35124). At present, 12 patients are free from disease and two patients have died due to progression of their disease. One patient, who was 73 years old, died due to a secondary bilateral pneumonia caused by multiresistant Enterococcus faecium 1 month after completing the six chemotherapy cycles; no hematological toxicities were reported. No pathological evidence of Hodgkin's lymphoma was found at necropsy.
Up to 31 March 2004, 85 and 93 patients have been followed-up for more than 3 and 2 years, respectively. With a median follow-up of 78 months (range 22168), the actuarial progression-free survival and overall survival at 7 years and for the whole group were 84% and 96%, respectively (Figure 1). Survival curves for 65 patients without B symptoms and without mediastinal bulky disease (stage IA and IIA) are shown in Figure 2. In this group of patients, the actuarial progression-free survival and overall survival at 7 years were 88% and 97%, respectively.
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The cardiorespiratory function was evaluated in 40 patients 1824 months after completing the treatment. No abnormal decreases in LVEF, FVC, FEV1 or DLCO were detected. In the 15 patients evaluated previously and subsequently to treatment, no significant decreases were found in these parameters compared with baseline (i.e. >5%).
To date, we have not observed any second solid tumor. One stage IIx patient, who relapsed after ABVD plus radiotherapy, developed an acute myeloid leukemia after treatment with three chemotherapeutic regimens and bone marrow transplantation.
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Discussion |
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There are considerable retrospective data supporting the notion that larger field irradiation is associated with a higher second tumor risk [25, 26
]. For second solid tumors there is no question that involved field irradiation has far less tissue in the field than extended field irradiation, and that the cancer risks should be reduced. However, data from the British National Lymphoma Investigation Group (BNLI) have led to the suggestion that radiotherapy on the involved field might not decrease the incidence of second neoplasias as significantly as was expected. Recently, the BNLI reported long-term results of a study comparing localized radiotherapy versus extended radiotherapy in patients with early-stage Hodgkin's lymphoma [27
]. Surprisingly, the actuarial rates of second neoplasias were the same in both treatment groups: 20% at 25 years.
We cannot assume that reduction of irradiated dose below 3036 Gy might dramatically decrease the incidence of second solid neoplasias, at least in the case of breast cancer. The administration of 20 Gy on breast tissue increases more than four-fold the relative risk of suffering breast cancer [28, 29
], and doses as small as 4 Gy substantially increase this risk [30
]. The risk of radioinduced breast cancer seems to increase linearly from 4 to 40 Gy, with no evidence of risk reduction at the levels of therapeutic irradiation usually received by patients with Hodgkin's lymphoma [28
].
The most logical strategy for maximally reducing the risk of late toxicity in patients with early-stage Hodgkin's lymphoma is the administration of ABVD chemotherapy as sole treatment [31]. ABVD not only is the standard treatment for advanced disease [12
, 13
], but also shows a favorable late toxicity profile: ABVD does not produce sterility [14
], and its potential to induce second neoplasias is expected to be low [5
, 15
]. However, it is surprising that mature results from comparatively large studies evaluating the efficacy of ABVD as first-line treatment of patients with early stages of Hodgkin's lymphoma are still not available.
In the present study, we update the preliminary results of the first published study that evaluated the efficacy of six ABVD cycles in patients with stage I and II Hodgkin's lymphoma [16]. The progression-free and overall survival observed at 7 years (84% and 96%, respectively) confirm the efficacy of this treatment in a group of 95 patients, half of whom showed unfavorable disease according to EORTC criteria [22
]. The results obtained here are similar to those reported in 1538 stage III patients (35% with favorable disease and 65% with unfavorable disease) who received combined treatment in the H8 EORTC trials, in which progression-free and overall survival at 5 years were 86% and 94%, respectively [32
].
For patients with unfavorable disease the result of a recently reported comparative study did not differ significantly from those observed here. The HD8 study of the German Hodgkin's Study Group [33] randomized 1204 patients with unfavorable disease to receive radiotherapy of involved versus extended field radiotherapy, in both cases after two cycles of alternating COPP/ABVD chemotherapy. The patients included in the less toxic arm showed a progression-free and overall survival at 5 years of 82% and 94%, respectively.
The efficacy of six ABVD cycles also seems to be adequate in patients with good prognostic criteria. The EORTC H8F trial [34] reported results on the combination of three cycles of MOPP/ABV hybrid chemotherapy followed by radiotherapy of the involved field in 543 stage I and II patients and favorable prognosis. Progression-free and overall survival at 4 years were 99%. These results, however, were preliminary, as the median follow-up was <4 years. In the present study, the progression-free and overall survival at 7 years observed in 49 patients with EORTC criteria of favorable disease were 88% and 100%, respectively. Moreover, the progression-free and overall survival at 7 years reported in 65 patients without B symptoms or mediastinal bulky disease were 88% and 97%, respectively.
Two comparative trials evaluating the efficacy of ABVD alone in the treatment of adults patients with early stage Hodgkin's lymphoma have been recently reported. Straus et al. [35] compared, in a small randomized trial, the administration of six ABVD cycles versus the same chemotherapy followed by extended radiotherapy in 152 patients with non-bulky stages IA to IIIA. The progression-free (81% versus 86%) and overall (92% versus 97%) survival at 5 years were not significantly different between these two groups of patients. However, this study was statistically underpowered, and the authors concluded that they could only exclude a recurrence difference of
18%.
Meyer et al. [36] compared the administration of four to six cycles of ABVD with standard therapy in patients with non-bulky clinical stage IIIA. Patients randomized to standard therapy received subtotal nodal irradiation (STNI) if categorized as low-risk and combined modality ABVD (two cycles) plus STNI if categorized as high-risk. Five-year progression-free survival was significantly inferior (87% versus 93%) in patients randomized to ABVD alone; no difference in overall survival has been detected.
In our study, the plausible higher efficacy of exclusive chemotherapy in those patients with mixed cellularity histological subtype compared with patients with nodular sclerosis subtype must be interpreted with caution owing to the low number of treated patients. Nevertheless, this finding has also been reported in a small retrospective study on 35 patients with stage I and II Hodgkin's lymphoma treated with different chemotherapy schedules [37].
The safety and toxicity of chemotherapy is another relevant factor when considering its use as usual treatment. The data reported here support the safety of six ABVD cycles as treatment for patients with early-stage Hodgkin's lymphoma. No fatal respiratory toxicity, clinical cardiac toxicity or second solid neoplasias were recorded. These results agree with those reported by the Milano group concerning the low risk of cardiac and respiratory toxicity and the low risk of second neoplasias in patients treated with ABVD after a follow-up of 10 years [15, 38
, 39
]. However, late cardiac toxicity experienced >10 years after anthracycline therapy has been documented among individuals treated during childhood [40
]. Our study does not have sufficient long-term data to exclude late cardiac effects. The risk of fatal pulmonary toxicity for bleomycin is real, but minimal; moreover, this risk is conditioned by the administration of radiotherapy before or after chemotherapy but also by the age of the patient. In this sense, we must take into account that Einhorn et al. [41
] reported an incidence of 0% in 188 patients with germinal cell tumors who received a total dose of 270 or 360 U of bleomycin.
In conclusion, the administration of six ABVD cycles to patients with stage I and II Hodgkin's lymphoma is a safe therapeutic alternative that might reduce the risk of late and potentially lethal toxicity. However, in patients with favorable disease or nodular sclerosis histology, progression-free survival could be lower than that reported with the combination treatment [34, 36
], but no differences are expected in overall survival. Further follow-up of the reported trials is required to determined whether treatment with single-modality ABVD is associated with improved long-term survival through a reduced incidence of late secondary effects.
Received for publication May 3, 2004. Accepted for publication June 25, 2004.
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