|
Advertisement |
|
|
||
 |
|
|||||
|
|||||
|
 |
||||||
|
||||||
|
||||||
|
Originally published as JCO Early Release 10.1200/JCO.2003.07.001 on August 4 2003 © 2003 American Society for Clinical Oncology
Hodgkin’s Lymphoma: The Hazards of SuccessChairman, Lymphoma Tumor Group, Clinical Professor, Division of Medical Oncology, University of British Columbia and the British Columbia, Cancer Agency, Vancouver, British Columbia, Canada THE STEADY improvement in overall outcome for patients with Hodgkin’s lymphoma has become a proverbial example of the achievements of modern oncology. In the first 120 years after the initial description of this lymphoma, a foundation was put in place that included detailed refinement of the histopathologic identification of the disease and the observation that it would regress when exposed to ionizing radiation. However, it has only been in the last half century that dramatic improvement in treatment has occurred, beginning at the end of the 1950s when cure with radiation was documented.1–3 An equally important observation was made during the 1960s when chemotherapeutic agents were combined into regimens capable of eradicating even disseminated disease.4 The 1970s and 1980s consolidated these gains with the frequent use of combined-modality therapy, most often consisting of variations of mechlorethamine, vincristine, procarbazine, and prednisone (MOPP) chemotherapy and wide-field irradiation, usually a mantle field or mantle plus para-aortic lymph nodes. The most modern era, beginning in the 1990s, has focused on twin goals. On the one hand, reducing toxicity has become a theme of clinical investigation, focusing on reduced duration of chemotherapy and size of radiation fields and elimination of staging laparotomy and lymphangiography, with a shift to reliance on more sophisticated but less invasive imaging techniques. Conversely, some investigators have concentrated on determining the possibility of increased cure rates of even more intensified chemotherapy—often combined with radiation—as exemplified by such regimens as escalated bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (BEACOPP)5,6 or mechlorethamine, doxorubicin, vinblastine, vincristine, bleomycin, etoposide, and prednisone (Stanford V).7,8 An alternate form of dose intensification is high-dose chemotherapy and hematopoietic stem cell transplantation, a technique documented to cure otherwise resistant disease.9–11 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 et al12 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).13–16 The second study, by Josting et al17 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 et al12 and Josting17 et 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 et al12 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 myelodysplasia15 while at the same time improving cure rates from the primary course of chemotherapy.14,15 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 et al17, 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. Viewed together, these two studies support some even broader observations. First of all, large studies are imperative to permit valid observations, especially when the focus is on uncommon events. The admirable efforts of these two groups to gather mature data describing outcomes for large numbers of patients provide clear standards to which other clinical investigators should aspire. The other important observation is that, as in many areas of medicine, prevention is the best policy. Once established, secondary leukemia or myelodysplasia is exceptionally difficult to eradicate. Likewise, the greatest benefit to Hodgkin’s lymphoma patients comes from more effectively eliminating the lymphoma with the first treatment, as long as this can be achieved without overly dangerous intensification of treatment. For those already treated with regimens similar to the ones described by these two groups of investigators, we can offer informed counseling and targeted surveillance. The study by Aleman et al12 provides encouraging results that this may be reducing mortality from breast cancer. Even more importantly, for our future patients, we need to carefully adjust the treatment strategy for each patient to properly balance high effectiveness of early treatment with minimization of the late hazards of that same treatment. Our patients deserve our careful attention to thetype of experience reported in these two important reports to help us meet that challenge. AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The authors indicated no potential conflicts of interest. REFERENCES 1. Peters MV: A study in survival of Hodgkin’s disease treated radiologically. Am J Roentgenol Radium Ther 63:299–311, 1950[Medline] 2. Kaplan HS: The radical radiotherapy of regionally localized Hodgkin’s disease. Radiology 78:553–561, 1962[Medline] 3. Kaplan HS: Evidence for a tumoricidal dose level in the radiotherapy of Hodgkin’s disease. Cancer Res 26:1221–1224, 1966[Medline] 4. De Vita VT, Serpick A, Carbone PP: Combination chemotherapy in the treatment of Hodgkin’s disease. Ann Intern Med 73:881–895, 1970[Medline]
5. Diehl V, Sieber M, Ruffer U, et al: BEACOPP: An intensified chemotherapy regimen in advanced Hodgkin’s disease—The German Hodgkin’s Lymphoma Study Group. Ann Oncol 8:143–148, 1997
6. Diehl V, Franklin J, Hasenclever D, et al: BEACOPP, a new dose-escalated and accelerated regimen, is at least as effective as COPP/ABVD in patients with advanced-stage Hodgkin’s lymphoma: Interim report from a trial of the German Hodgkin’s Lymphoma Study Group. J Clin Oncol 16:3810–3821, 1998 7. Bartlett NL, Rosenberg SA, Hoppe RT, et al: Brief chemotherapy, Stanford V, and adjuvant radiotherapy for bulky or advanced-stage Hodgkin’s disease: A preliminary report. J Clin Oncol 13:1080–1088, 1995[Abstract]
8. Horning SJ, Hoppe RT, Breslin S, et al: Stanford V and radiotherapy for locally extensive and advanced Hodgkin’s disease: Mature results of a prospective clinical trial. J Clin Oncol 20:630–637, 2002 9. Schmitz N, Pfistner B, Sextro M, et al: Aggressive conventional chemotherapy compared with high-dose chemotherapy with autologous haemopoietic stem-cell transplantation for relapsed chemosensitive Hodgkin’s disease: A randomised trial. Lancet 359:2065–2071, 2002[CrossRef][Medline] 10. Linch DC, Winfield D, Goldstone AH, et al: Dose intensification with autologous bone-marrow transplantation in relapsed and resistant Hodgkin’s disease: Results of a BNLI randomised trial. Lancet 341:1051–1054, 1993[CrossRef][Medline]
11. Constans M, Sureda A, Terol MJ, et al: Autologous stem cell transplantation for primary refractory Hodgkin’s disease: Results and clinical variables affecting outcome. Ann Oncol 14:745–751, 2003
12. Aleman BMP, van den Belt-Dusebout AW, Klokman WJ, et al: Long-term cause-specific mortality of patients treated for Hodgkin’s disease. J Clin Oncol 21:3431–3439, 2003 13. Bonadonna G, Zucali R, Monfardini S, et al: Combination chemotherapy of Hodgkin’s disease with Adriamycin, bleomycin, vinblastine, and imidazole carboxamide versus MOPP. Cancer 36:252–259, 1975[CrossRef][Medline] 14. Canellos GP, Anderson JR, Propert KJ, et al: Chemotherapy of advanced Hodgkin’s disease with MOPP, ABVD, or MOPP alternating with ABVD. N Engl J Med 327:1478–1484, 1992[Abstract]
15. Duggan DB, Petroni GR, Johnson JL, et al: Randomized comparison of ABVD and MOPP/ABV hybrid for the treatment of advanced Hodgkin’s disease: report of an intergroup trial. J Clin Oncol 21:607–614, 2003
16. Valagussa P, Santoro A, Fossati-Bellani F, et al: Second acute leukemia and other malignancies following treatment for Hodgkin’s disease. J Clin Oncol 4:830–837, 1986 17. Josting A, Wiedenmann S, Franklin J, et al: Secondary Myeloid Leukemia and Myelodysplastic Syndromes in Patients Treated for Hodgkin’s Disease: A Report From the German Hodgkin’s Lymphoma Study Group. J Clin Oncol 21:10.1200/JCO.2003.07.160 This article has been cited by other articles:
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|
|||||||||||
|
|||||||||||
|
|
Copyright © 2003 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
|
