Advanced Hodgkin’s Disease: Are We Making any Progress?
Advanced Hodgkin’s Disease: Are We Making any Progress?
Special Report
In the first 30 years after mopp (nitrogen mustard, vincristine (oncovin), procarbazine, prednisone), accomplishments in the treatment of advanced Hodgkin’s disease have been modest. ABVD (Doxorubicin (adriamycin), bleomycin, vinblastine, and dacarbazine) have replaced MOPP as the standard regimen based on its reduced acute bone marrow toxicity, reduced gonadal toxicity, and reduced incidence of secondary acute leukemia. Its efficacy is similar to that of MOPP. It has been demonstrated repeatedly that maintenance chemotherapy does not prolong remissions or extend survival and, thus, the use of post-remission chemotherapy has been abandoned. The same cannot be said for post-remission radiation therapy. The data from randomized, prospective trials do not demonstrate any survival benefit associated with post-remission radiation therapy, but its use continues. In fact, three new regimens in Hodgkin’s disease from three of the most active groups in the world in this disease all claim to have superior results in advanced stage Hodgkin’s disease—yet all of them include post-remission radiation therapy to previously involved nodal sites of disease.
Stanford V from the Stanford group, dose-escalated BEACOPP (bleomycin, etoposide, doxorubicin (adriamycin), cyclophosphamide, vincristine (oncovin), procarbazine, prednisone) from the German Hodgkin’s Lymphoma Study Group, and VEBEP (etoposide (VP-16), epirubicin, bleomycin, cyclophosphamide, and prednisolone) from the National Cancer Institute (Milan) are all felt by their originators to be more effective than MOPP or ABVD. The doses and schedules are shown in the table. (See Table.)1,2,3
Stanford V is given in three four-week cycles, for a total of 12 weeks of chemotherapy. BEACOPP is given in eight three-week cycles. VEBEP is given in six to eight three-week cycles.
Stanford V is said to achieve complete responses in 99% of patients with a six-year freedom-from-progression of 89% and a six-year overall survival of 93%. The median follow-up at the time of the initial report was less than three years. The regimen was well tolerated with no effect on fertility and no other serious sequelae noted. Of course, the follow-up time is too short to detect any radiation-induced second solid tumors that would be expected to appear in the second decade of follow-up. This study included some patients with earlier stage disease. For patients with stage III and IV disease, six-year freedom-from-progression and overall survival were 84%.
Dose-escalated BEACOPP was more toxic than conventional MOPP or ABVD and required G-CSF support throughout. It was compared to COPP/ABVD and to baseline doses of BEACOPP (etoposide 100 instead of 200, doxorubicin 5 instead of 35, cyclophosphamide 650 instead of 1250) in a prospective, randomized trial. The complete response rate was 92% with dose-escalated BEACOPP and 83% with COPP/ABVD. Two-year freedom-from-progression was 84% for dose-escalated BEACOPP and 74% for COPP/ABVD, a difference that was statistically significant. However, at the early time of the report, no differences were noted in overall survival. Of some concern is the development of secondary acute leukemia in four patients on dose-escalated BEACOPP. The time of follow-up was only slightly more than two years and more late complications would be expected.
The VEBEP phase II study included patients with stage IIB disease, but the results were not influenced by disease stage. The complete response rate was 94%, the six-year freedom-from-progression was 78%, and six-year overall survival was 82%. Colony-stimulating factors were not used to support the blood counts and 85% of patients experienced grade IV neutropenia. Half of the men on the study and all women older than age 35 became infertile. No secondary acute leukemia was noted but two patients have developed second solid tumors. No cardiac toxicity was documented.
| Table-Doses and Schedules for Three Treatment Options for Advanced Hodgkin’s Disease | |||
| Agents Used | Stanford V | BEACOPP | VEBEP |
| etoposide (mg/m2) | 60 days 15,16 | 200 days 1-3 | 120 days 1, 2 |
| epirubicin or doxorubicin(mg/m2) | 25 days 1, 15 | 35 day 1 40 | days 1, 2 |
| bleomycin (mg/m2) | 5 days 8, 22 | 10 day 8 | 10 day 1 |
| cyclophosphamide | none | 250 day 1 | 500 days 1, 2 |
| prednisone | 40 qod * 12 weeks | 40 days 1-14 | 50 days 1-7 |
| vincristine (mg/m2) | 1.4 (2 max)days 8, 22 | 1.4 (2 max)day 1 | none |
| vinblastine (mg/m2) | 6 days 1, 15 | none | none |
| nitrogen mustard | 6 mg/m2 day 1 | none | none |
| procarbazine | none | 100 mg/m2 days 1-7 | none |
Commentary
The major goals of clinical research in Hodgkin’s disease treatment are to further improve its efficacy and reduce its late toxicities. At present, the standard regimens we all use are capable of curing about 70% of patients with advanced stage disease. If one uses MOPP (we are talking about only a few people here), about 2% of the patients will develop and die from acute leukemia. The peak incidence is between years three and six after treatment and if a patient has not developed leukemia in the first decade after treatment, his/her risk goes back to that of the general population. ABVD has advantages over MOPP in the arena of toxicity. It does not induce infertility. It is not leukemogenic. The main problem with ABVD is acute and chronic pulmonary toxicity. In the large Cancer and Leukemia Group B study comparing MOPP, ABVD, and MOPP/ABVD, the death rate from pulmonary toxicity on the ABVD arm was 3%, but this seems a little higher than one might encounter if one were routinely following patients with diffusion capacity assessments.
MOPP/ABVD or MOPP-ABV hybrid programs have a number of theoretical advantages over MOPP and ABVD. However, these potential advantages have not been convincingly demonstrated to result in a higher cure rate. If one examines all the literature, it may be that the seven- and eight-drug regimens are up to 5% more effective, a difference that is difficult to validate when one is trying to go from 70-75% to 75-80% cure rates.
Clinical research in Hodgkin’s disease has been preoccupied with reducing the toxicity of therapy. In that spirit, efforts have been made to create gentler and kinder chemotherapy regimens that omit certain active drugs that are toxic or give them for shorter periods or at lower doses. However, often it is decided to add radiation therapy to the gentler and kinder chemotherapy to try to compensate for any loss of efficacy. It remains unclear whether any regimen that includes therapeutic doses of radiation therapy will be able to avoid the high rate of second solid malignancies that have been extensively documented to date. Indeed, it appears that the only safe dose of radiation therapy is none. We accept the risk of late second tumors when it is completely clear that radiation therapy is needed to optimize disease control. In Hodgkin’s disease, the main settings where radiation therapy is essential are in patients with massive mediatinal involvement and in patients who have obtained only a partial response to chemotherapy. The use of radiation therapy in patients with advanced stage disease is not supported by the available data.4 In fact, meta-analysis suggests that overall survival after 10 years is signficantly better if no radiation therapy is given.
The dilemma we face is that our usual approach to improving treatment results in the absence of new agents is to intensify the use of the old agents. In Hodgkin’s disease, it is difficult to develop new agents because, by the time any patient has been treated with all the available agents that work, he/she is usually too sick to take a new experimental agent. Despite this problem, several new active agents have appeared (e.g., gemcitabine). However, by intensifying the old agents, we are often exceeding the tolerable dose, inducing greater toxicity in a larger fraction of patients, and benefiting few of them. For example, if dose-escalated BEACOPP truly cures 84% of advanced stage patients, it is 10-14% better than conventional-dose therapy. We are exposing 100 people to the increased toxicity to benefit 10-14 patients and for at least 70% of those patients (i.e., those who would have been cured by the old treatment), the treatment is overkill.
Stanford V looks to me to be the most interesting of the new regimens. I remain skeptical of Horning and colleagues’ hope that the patients treated with combined modality therapy will not have an increased incidence of second solid tumors, but only time can address this concern. In the meantime, a large intergroup study comparing ABVD and Stanford V is planned.
If we are permitted to gaze into the future, it is certainly possible that the revolution in genetics will one day be able to help us make further progress in Hodgkin’s disease. By correlating treatment results with gene expression patterns in tumor cells (information that can be obtained using DNA microarray technology), it is possible that our pathologists will one day tell us that a particular patient’s tumor is highly likely or highly unlikely to respond to a certain treatment program. If we were able to identify in advance those individuals who are not curable with MOPP or ABVD, we could focus our treatment development efforts on those individuals who actually need it and protect the rest from errors and toxicities such research usually includes.
This goal may be closer than you think. In the current issue of Science, a group headed by Eric Lander at Massachusetts Institute of Technology has begun to apply DNA microarray technology to a new molecular classification of tumors.5 A day may come when we base our treatment on the pattern of gene expression rather than tumor histology.
References
1. Horning SJ, et al. Ann Oncol 1996;7(4):105-108.
2. Diehl V, et al. J Clin Oncol 1998;16:3810-3821.
3. Viviani S, et al. Cancer J Sci Am 1999;5:275-282.
4. Loeffler M, et al. J Clin Oncol 1998;16:818-829.
5. Golub TR, et al. Science 1999;286:531-537.
Which of the following regimens has been demonstrated to be more effective than ABVD alone in patients with advanced stage Hodgkin’s disease?
a. ABVD plus radiation therapy
b. Stanford V plus radiation therapy
c. BEACOPP plus radiation therapy
d VEBEP plus radiation therapy
e. None of the above
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