The goal of therapy for patients with advanced-stage Hodgkin lymphoma is to ensure that as many patients as possible are healthy and free of disease decades after completing treatment. To achieve this, the treating physician needs to select the most effective therapeutic regimen, but also needs to choose a treatment strategy that limits long-term toxicity. One approach to achieve this is to use a less intense combination, such as ABVD chemotherapy, as initial treatment and intensify therapy only in those patients who do not become PET negative or who subsequently relapse.
Key points
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Approximately 65% to 75% of advanced-stage Hodgkin lymphoma patients have a complete response to initial therapy with ABVD chemotherapy.
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The 5-year failure-free survival for advanced-stage Hodgkin lymphoma patients treated with ABVD is 70% to 75%.
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ABVD can be given to patients less than 60 years and patients with a poorer performance score.
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Although more intensive combinations, such as escalated BEACOPP, result in higher response rates and improved failure-free survival, the short- and long-term complications are greater.
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When all therapy including salvage therapy after initial treatment is considered, the outcomes of patients initially treated with ABVD or escalated BEACOPP were similar in a randomized trial. A network meta-analysis however showed a survival benefit with escalated BEACOPP.
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Because many patients are cured, exposing all patients to early intensive therapy increases the long-term complication risk in everyone. Reserving intensification for only those patients who need it decreases complications without clearly compromising overall outcome.
Introduction: nature of the problem
Hodgkin lymphoma is a B-cell malignancy that has been shown to be highly sensitive to chemotherapy. The overall response rates to combination chemotherapy are in excess of 70% and most patients are cured with standard therapy. Patients with advanced-stage disease commonly have a higher risk of disease relapse than limited stage patients and often present with more poor prognostic features. Despite this, the percentage of patients who are cured by initial therapy is typically 70% to 75%.
ABVD chemotherapy (Adriamycin, Bleomycin, Vinblastine, and Dacarbazine) is a standard therapy for patients with Hodgkin lymphoma and is often used in North America to treat patients with advanced-stage disease. Typically patients receive 6 to 8 cycles of therapy, and provided they have had a complete response to the treatment that is PET negative, they will then be observed without further therapy. Some patients may have disease that proves to be resistant to this initial therapy and may require further treatment intensification. Other patients may subsequently relapse and then will receive salvage chemotherapy followed by high-dose chemotherapy with an autologous stem cell transplant.
A difference in opinion regarding optimal management of patients with advanced-stage Hodgkin lymphoma has developed over time. Some physicians think that an intensive approach as early as possible should be considered. Groups advocating this position commonly administer escalated BEACOPP (Bleomycin, Etoposide, Adriamycin, Cyclophosphamide, vincristine, Procarbazine, and Prednisone) chemotherapy for 6 cycles of treatment. They argue that an intensive approach will decrease the number of patients having an inadequate response to initial treatment and result in a greater percentage of patients who remain in remission and do not require further salvage chemotherapy. However, the more intensive escalated BEACOPP approach may be associated with a greater frequency of initial toxicities and treatment-related mortality, and a greater prevalence of long-term toxicities.
Those advocating for initially treating patients with less intense ABVD chemotherapy reason that the response rates are high with ABVD chemotherapy and the combination is substantially less toxic. ABVD chemotherapy can also be administered to older patients as well as those with a poor performance score at diagnosis, many of whom do not tolerate the more intensive approach. The minority of patients who fail this less intense initial treatment approach would then proceed to be treated in an intensive fashion with salvage chemotherapy followed by high-dose chemotherapy and an autologous stem cell transplant. Those physicians favoring the limited late intensification approach argue that most patients are not exposed to more intense chemotherapy and therefore the short-term and long-term complications are substantially less for most patients.
This concern about exposing all patients who generally have a very favorable prognosis to intensive therapy is illustrated by a study by Biasoli and colleagues that looked at a Groupe d’Etudes des Lymphomes de l’Adulte/European Organisation for Research and Treatment of Cancer clinical trial randomizing patients between ABVD chemotherapy and escalated BEACOPP. They found that only one-half of the patients that were considered for the study at one of the participating centers were enrolled. The remaining patients chose not to participate. The choice not to participate was due to both patient and physician concerns. The main reason for patient’s refusal was that they preferred the standard treatment (ABVD chemotherapy) and were concerned about toxicity in the experimental arm (escalated BEACOPP). When questioned further, the patient’s main concern was the high incidence of anticipated infertility in the BEACOPP arm. Similarly, physicians chose not to enroll patients in the study because of their concerns with increased toxicity in the escalated BEACOPP arm. Subsequent studies by this group however have used escalated BEACOPP as initial therapy, suggesting that these attitudes may have changed over time.
Introduction: nature of the problem
Hodgkin lymphoma is a B-cell malignancy that has been shown to be highly sensitive to chemotherapy. The overall response rates to combination chemotherapy are in excess of 70% and most patients are cured with standard therapy. Patients with advanced-stage disease commonly have a higher risk of disease relapse than limited stage patients and often present with more poor prognostic features. Despite this, the percentage of patients who are cured by initial therapy is typically 70% to 75%.
ABVD chemotherapy (Adriamycin, Bleomycin, Vinblastine, and Dacarbazine) is a standard therapy for patients with Hodgkin lymphoma and is often used in North America to treat patients with advanced-stage disease. Typically patients receive 6 to 8 cycles of therapy, and provided they have had a complete response to the treatment that is PET negative, they will then be observed without further therapy. Some patients may have disease that proves to be resistant to this initial therapy and may require further treatment intensification. Other patients may subsequently relapse and then will receive salvage chemotherapy followed by high-dose chemotherapy with an autologous stem cell transplant.
A difference in opinion regarding optimal management of patients with advanced-stage Hodgkin lymphoma has developed over time. Some physicians think that an intensive approach as early as possible should be considered. Groups advocating this position commonly administer escalated BEACOPP (Bleomycin, Etoposide, Adriamycin, Cyclophosphamide, vincristine, Procarbazine, and Prednisone) chemotherapy for 6 cycles of treatment. They argue that an intensive approach will decrease the number of patients having an inadequate response to initial treatment and result in a greater percentage of patients who remain in remission and do not require further salvage chemotherapy. However, the more intensive escalated BEACOPP approach may be associated with a greater frequency of initial toxicities and treatment-related mortality, and a greater prevalence of long-term toxicities.
Those advocating for initially treating patients with less intense ABVD chemotherapy reason that the response rates are high with ABVD chemotherapy and the combination is substantially less toxic. ABVD chemotherapy can also be administered to older patients as well as those with a poor performance score at diagnosis, many of whom do not tolerate the more intensive approach. The minority of patients who fail this less intense initial treatment approach would then proceed to be treated in an intensive fashion with salvage chemotherapy followed by high-dose chemotherapy and an autologous stem cell transplant. Those physicians favoring the limited late intensification approach argue that most patients are not exposed to more intense chemotherapy and therefore the short-term and long-term complications are substantially less for most patients.
This concern about exposing all patients who generally have a very favorable prognosis to intensive therapy is illustrated by a study by Biasoli and colleagues that looked at a Groupe d’Etudes des Lymphomes de l’Adulte/European Organisation for Research and Treatment of Cancer clinical trial randomizing patients between ABVD chemotherapy and escalated BEACOPP. They found that only one-half of the patients that were considered for the study at one of the participating centers were enrolled. The remaining patients chose not to participate. The choice not to participate was due to both patient and physician concerns. The main reason for patient’s refusal was that they preferred the standard treatment (ABVD chemotherapy) and were concerned about toxicity in the experimental arm (escalated BEACOPP). When questioned further, the patient’s main concern was the high incidence of anticipated infertility in the BEACOPP arm. Similarly, physicians chose not to enroll patients in the study because of their concerns with increased toxicity in the escalated BEACOPP arm. Subsequent studies by this group however have used escalated BEACOPP as initial therapy, suggesting that these attitudes may have changed over time.
Clinical outcomes
Overall Results with ABVD Chemotherapy
Most patients have an excellent outcome after treatment with ABVD chemotherapy. Multiple studies evaluating the efficacy of ABVD chemotherapy have shown that on average 65% to 75% of advanced-stage Hodgkin lymphoma patients have a complete response to initial therapy with ABVD chemotherapy. Studies that have evaluated interim positron emission tomography (PET) scans have shown approximately 75% of patients to be PET-negative after 2 to 3 cycles of ABVD chemotherapy, further confirming the high response rate. The 5-year failure-free survival for advanced-stage Hodgkin lymphoma treated with ABVD chemotherapy in multiple studies has been shown to be 70% to 75%. The following studies confirm the above-mentioned results:
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In the recently reported Eastern Cooperative Oncology Group clinical trial of ABVD chemotherapy compared with Stanford V chemotherapy (E2496), 854 patients were treated and 395 of these patients received ABVD chemotherapy. The complete response rate for those receiving ABVD chemotherapy was 73% and the 5-year failure-free survival was 67% for advanced-stage patients receiving ABVD.
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In the HD9601 trial, ABVD chemotherapy was compared with an intensive combination approach as well as with Stanford V chemotherapy. The 122 patients who received ABVD chemotherapy had a complete response rate of 89%. With long-term follow-up, the 5-year failure-free survival was 78% and the 10-year failure-free survival was 75%, suggesting that most of the patients that achieved a complete remission remained in remission and that approximately three-quarters of the patients were cured.
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In a randomized trial comparing ABVD chemotherapy with escalated BEACOPP chemotherapy conducted by Viviani and colleagues, 331 patients were treated in the study, 166 of whom received ABVD chemotherapy. In this study, the complete response rate for ABVD-treated patients was 64% with a 73% 7-year failure-free survival.
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Similar results were seen in the HD2000 trial published by Federico and colleagues. In this study, 307 patients were treated with escalated BEACOPP, an intensive combination chemotherapy regimen (cyclophosphamide, lomustine, vindesine, melphalan, prednisone, epidoxirubicin, vincristine, procarbazine, vinblastine, and bleomycin [COPPEBVCAD; CEC]), or ABVD chemotherapy. When the ABVD-treated patients are considered, the 103 patients who received ABVD chemotherapy had a complete response rate of 70% and a 5-year failure-free survival of 65%.
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Finally, in a United Kingdom study (ISRCTN64141244), 520 patients were treated with either ABVD chemotherapy or Stanford V chemotherapy. Again, a complete response rate of 67% was seen in the 252 patients receiving the ABVD chemotherapy and the 5-year progression-free survival was 76%.
All of these studies suggest that approximately three-quarters of the patients treated with ABVD chemotherapy for advanced-stage Hodgkin lymphoma have a durable remission and are potentially cured with this approach.
Results with ABVD Compared with More Dose-intense Initial Therapy
Although the clinical outcomes with ABVD chemotherapy have been very good, randomized controlled trials have shown that an early intensification approach using escalated BEACOPP results in higher response rates and an improved failure-free survival. Whether the overall survival of patients treated with escalated BEACOPP is significantly different to those treated with ABVD chemotherapy is controversial. Randomized trials have not clearly shown an overall survival advantage, but a meta-analysis by the Cochrane Group has shown that BEACOPP-treated patients have a superior overall outcome. However, the improved response rate and failure-free survival with escalated BEACOPP comes at the cost of increased toxicity and lower rates of salvage for those who relapse.
In the German Hodgkin Study Group (GHSG) HD9 trial, the failure-free survival at 10 years was 64%, 70%, or 82%, with overall response rates of 75%, 80%, or 86%, for patients treated with either COPP alternating with ABVD (arm A), baseline BEACOPP (arm B), or escalated BEACOPP (arm C), respectively ( P <.001). Similarly, in the study by Federico and colleagues, complete response rates in patients receiving ABVD chemotherapy, escalated BEACOPP chemotherapy, or the CEC regimen were 70%, 81%, and 69%, respectively. The 5-year failure-free survival in the ABVD chemotherapy-treated patients was 65% compared with 78% for those receiving escalated BEACOPP ( P = .036), suggesting that response to treatment and durability of response may be improved in those receiving escalated BEACOPP.
However, to truly appreciate the merits of using an intensification approach early in all patients, or later only in relapsing patients, the outcome of all therapy needs to be considered, meaning that initial therapy and subsequent salvage approaches should be considered. In a recent randomized comparison of ABVD chemotherapy versus escalated BEACOPP, 107 patients assigned to the ABVD chemotherapy group (64%) and 114 patients assigned to the escalated BEACOPP therapy (70%) had a complete response to initial therapy. The estimated 7-year rate of freedom from first progression in this population was 85% in the BEACOPP group as compared with 73% in the ABVD group, which was a significant difference of 12 percentage points ( P = .004). However, when discontinuation of treatment owing to life-threatening toxic effects or secondary leukemias was considered, the difference of 7 percentage points between the 7-year event free-survival rate (78%) in those receiving BEACOPP versus 71% in those receiving ABVD failed to reach significance ( P = .15). When the 65 patients who did not have a complete response to initial therapy or who subsequently relapsed were considered, there were 45 in the ABVD-treated group and 20 patients in the escalated BEACOPP group. Two-thirds of the patients in both groups could receive high-dose consolidation chemotherapy that included high-dose treatment followed by an autologous stem cell transplant. A similar percentage of patients in both groups were unable to start salvage treatment or did not complete the salvage regimen due to poor performance score or progressive disease. The complete response rate at the end of salvage treatment was higher among those who had initially received ABVD chemotherapy than among those who had initially received escalated BEACOPP (51% vs 35%). Of the patients who received ABVD chemotherapy, 33% remained alive and free of disease after salvage treatment compared with 15% in the escalated BEACOPP group. After completion of all of the assigned treatment in the study including subsequent salvage therapy for those required it, the estimated 7-year rate of freedom from second progression was not significantly different—88% in the escalated BEACOPP group compared with 82% in the ABVD group ( P = .12). The difference in the estimated 7-year overall survival rate (89% in the escalated BEACOPP group compared with 84% in the ABVD group) was also not statistically significant ( P = .39). However, it should be noted that this trial has been criticized for being underpowered to detect a difference in overall outcome.
Overall, escalated BEACOPP chemotherapy does induce a greater percentage of patients to achieve a complete remission and results in a higher percentage of patients who remain free from disease progression after initial therapy. However, when salvage therapy is also considered (initial therapy plus an autologous transplant if patients have resistant or progressive disease), patients who initially receive ABVD chemotherapy have a similarly favorable overall outcome to those who initially received escalated BEACOPP therapy. The overall outcome after all therapy shows a similar failure-free survival after second therapy and a similar overall survival. The main consideration therefore is whether all patients should be treated with an intensive chemotherapy approach or whether it is preferable to administer a more modest treatment initially for the three-quarters of patients that will be cured by this treatment and only expose a quarter of patients to late intensified treatment, thereby significantly minimizing the side effects of treatment.
Results with Subsequent Salvage Chemotherapy After Initial ABVD Chemotherapy
Although it could be argued that the “first shot is the best and only shot,” data would suggest that most patients who have subsequent disease progression after ABVD can be successfully salvaged with a late intensification approach. In a retrospective review of their treatment strategy, Gallamini and colleagues treated patients with ABVD chemotherapy for 2 cycles with the plan to escalate treatment to BEACOPP if a PET scan during therapy was abnormal due to persistent disease. In this review, most patients did very well with ABVD chemotherapy and 83% of the 155 patients treated had a negative interim PET scan. Most patients who were PET2-negative remained in remission and the 2-year failure-free survival of PET2-negative patients was 92%. Only 23 patients had an abnormal interim PET scan and required escalated BEACOPP treatment. Of these patients, 15 achieved a continuous complete remission confirming that initial treatment with ABVD did not significantly compromise the likelihood of a response to subsequent intensification.
In a separate study by Wannesson and colleagues, salvage chemotherapy with an autologous stem cell transplant after initial treatment was studied. Patients who initially received ABVD chemotherapy had a greater likelihood of successful salvage therapy than those who received escalated BEACOPP. When the chemosensitive Hodgkin lymphoma patients autografted after failure of escalated BEACOPP (n = 22) were compared with 22 cases of those who received a salvage autologous transplant after ABVD chemotherapy, the 5-year progression-free survival was 76% for ABVD-treated patients and 42% for those who received escalated BEACOPP ( P = .029). These data would suggest that patients who relapse after ABVD chemotherapy can successfully be salvaged in most cases with an autologous stem cell transplant.
Related posts:
Brentuximab Vedotin for the Treatment of Patients with Hodgkin Lymphoma
First Hodgkin Cell Line L428 and the CD30 Antigen
Early Intensification Treatment Approach in Advanced-stage Hodgkin Lymphoma
FDG-PET Response–adapted Therapy
Balancing Risks and Benefits of Therapy for Patients with Favorable-Risk Limited-Stage Hodgkin Lymphoma
FDG-PET Response–adapted Therapy
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