Hodgkin’s Lymphoma: The Hazards of Success

Joseph M. Connors

Journal of Clinical Oncology, Vol 21, Issue 18 (September), 2003: 3388-3390

Chairman, Lymphoma Tumor Group, Clinical Professor, Division of Medical Oncology, University of British Columbia and the British Columbia, Cancer Agency, Vancouver, British Columbia, Canada

In line with the theme of carefully identifying and characterizing late toxicities in the hope of finding strategies to reduce or eliminate them, two studies in this issue of the Journal of Clinical Oncology address the late consequences of effective intervention for Hodgkin’s lymphoma. In the first of the two studies, Aleman  from the Netherlands Cancer Institute and the Dr Daniel den Hoed Cancer Centre examined the long-term mortality of 1,261 patients who were 40 years or younger at the time of diagnosis of Hodgkin’s lymphoma, treated at their institutions between 1965 and 1987. With a minimum potential follow-up of more than 15 years, these data provide some of the most mature results available anywhere in the medical literature. A key observation from this study was the fact that 55% of the 534 deaths were due to Hodgkin’s lymphoma, documenting in their experience that failure to cure the disease, and resultant death from the lymphoma, remains the greatest single threat to the well-being of patients with Hodgkin’s lymphoma. However, the cause of the excess risk of death switched from Hodgkin’s lymphoma during the first 10 years after diagnosis to secondary cancers and cardiovascular disease beyond that. Indeed, the risk of death from Hodgkin’s lymphoma became negligible after 20 years. However, the excess deaths from other causes, with approximately two-thirds being from secondary cancers and one-third from cardiovascular disease, still lingered more than 30 years from diagnosis. In keeping with one’s intuition, requiring a second course of treatment because of relapse of Hodgkin’s disease was strongly associated with an increased risk of death from secondary cancers, especially solid tumors. Finally, and perhaps most intriguing, was that the greatest excess risk from these causes of death other than Hodgkin’s lymphoma was seen in the youngest patients, those below the age of 21 years at diagnosis.

Some aspects of this important study are crucially relevant to its interpretation, indicating that it is primarily of historical interest. Overall, almost all patients (more than 97%) included in this study received radiation that most likely consisted of mantle or even more extended fields of treatment. Although details of the chemotherapy are not provided, it is quite likely that most patients received regimens that included the agents in MOPP-type combinations. Very few of the patients accounted for in this study received secondary treatment with high-dose chemotherapy and stem cell transplantation because that technique became broadly available only after the mid 1980s. Most importantly, the treatment technique for delivery of the radiation to 70% of the patients in the study was abandoned after the 1970s. Only in retrospect was it appreciated that this approach was associated with an increased risk of cardiovascular disease. Thus, although the results of this study remain of considerable interest, it must be remembered that the observations are based on the long-term effects of therapeutic approaches that are no longer used. One must especially keep in mind that considerably wider fields of radiation were given to a much larger proportion of the patients than would be considered optimal practice today, and the chemotherapy employed has been largely replaced by less leukemogenic and possibly less carcinogenic regimens such as doxorubicin, bleomycin, vinblastine and dacarbazine (ABVD).

The second study, by Josting from the German Hodgkin’s Lymphoma Study Group, documents the remarkable research program into the treatment of Hodgkin’s lymphoma that this group has been able to undertake during the past two decades. An extraordinary 5,411 patients were entered onto prospective clinical trials, an effort unequaled elsewhere in the world. With these large numbers, even relatively uncommon events can be examined. In particular, this study has focused on the incidence of secondary acute leukemia and myelodysplastic syndrome and the consequences of the development of these most serious complications of treatment. They show that cases of such secondary hematologic disease have been observed in widely varying patient groups regardless of specific treatment, stage of disease or age at treatment, with an overall risk of this complication for the entire group of approximately 1%. The outcome for patients who developed secondary leukemia or myelodysplasia was quite disappointing, with freedom from treatment failure falling to 2% and overall survival to 8% at 2 years. Eighty-five percent of patients had died within 1 year of documentation of this complication.

While the observation that the treatment of secondary leukemia or myelodysplasia is largely ineffective is solidly documented by this important study, certain other points must be interpreted cautiously. Both the Aleman and Jostinget al studies confirm the observation that almost all cases of leukemia or myelodysplasia after treatment for Hodgkin’s lymphoma are seen in the first decade of followup. However, it is not until that decade has fully passed that the overall impact of this complication becomes clear. Hence, there is need for caution interpreting the study by Josting et al, because of shorter follow-up in the groups of greatest interest. While some of the observations concerning radiation alone, ABVD, and cyclophosphamide, vincristine, procarbazine and prednisone (COPP) plus ABVD are mature enough to be solidly believable, with median follow-up between 7 and 10 years, all of the observations concerning the BEACOPP regimens are still tentative, with median follow-up only slightly longer than 3 years. It is important to remember that escalated BEACOPP incorporates dose-intense alkylating agents, procarbazine, hematopoietic growth factors (with the potential to stimulate cell division coincident with exposure to the carcinogenic agents), and radiation for most patients. Any complete assessment of the potential for such treatment to induce leukemia or myelodysplasia and the magnitude of this associated risk must await considerably longer follow-up.

What are the most important lessons that we can take from these two landmark studies focusing on the late complications of effective treatment for Hodgkin’s lymphoma? From the study by Aleman we have solid confirmation that the use of extended field radiation is strongly linked to the development of both secondary cancers and cardiovascular disease, and that these two effects linger in excess of three decades. However, it is important to maintain some perspective on relative risks for these patients. Of the excess deaths that occurred, more than twice as many more were due to Hodgkin’s lymphoma than to secondary cancers, and five and a half times as many excess deaths were due to Hodgkin’s lymphoma as to cardiovascular disease. In addition, it is clear that the single most productive maneuver for reducing overall excess deaths must remain improvement in the effectiveness of the primary treatment. Indeed, such improvements, if achieved without dramatic intensification of the treatment, should provide the twin benefits of reduction of excess deaths from Hodgkin’s lymphoma and, in addition, reduction of excess deaths from secondary cancers by avoidance of the negative impact of requiring secondary treatment. Some documentation of achievement of the first goal is already provided by the data from Aleman et al. The 20-year disease-specific survival results show that in the earliest era from 1965 to 1972, risk of death from Hodgkin’s lymphoma was approximately 35%, which fell to 13% from 1980 to 1987. We can also hope that other changes already widely adopted in the treatment of Hodgkin’s lymphoma will result in fewer nonlymphoma related excess deaths. Most clinicians have abandoned MOPP-based chemotherapy in favor of regimens such as ABVD, which carry a lower risk of inducing leukemia and myelodysplasia while at the same time improving cure rates from the primary course of chemotherapy. Outside of clinical trials, most clinicians now use substantially reduced radiation fields for the typical patient with Hodgkin’s lymphoma. It is reasonable to hope that such reductions in the physical extent of the radiation, coupled with improved dosimetry and radiation delivery, will further reduce excess deaths from nonlymphoma-related causes. The question as to whether the potential therapeutic gains of moving to more intensified regimens such as escalated BEACOPP or Stanford V might not be counterbalanced by the negative effects of the intensified chemotherapy and radiation for most patients can only be answered through longer follow-up of completed and ongoing clinical trials. An alarming trend is already obvious in the data from Josting  with a four- to six-fold increase in the incidence of secondary leukemia or myelodysplasia as one moves from radiation or ABVD, for which we have mature follow-up, to escalated BEACOPP, for which the follow-up is still unfolding.