- Email: [email protected]
Hodgkin's disease: The salvage of radiation treatment failures
Inr. J. Radiation
Oncology Biol. Phys..
1977,
Vol. 2. pp
1035-1037.
Pergamon Press.
Printed in the U.S.A.
??Editorial
HODGKIN’S
DISEASE: THE SALVAGE OF RADIATION TREATMENT FAILURES
VINCENT T. DEVITA, JR., M.D. Director, Division of Cancer Treatment, Clinical Director, National Cancer Institute, Bethesda, MD 20014, U.S.A. Hodgkin’s disease, Radiation treatment failures-salvage
of, Combined
chemotherapy
(MOPP).
disease. Given a complete remission rate of 70% using MOPP at Stanford, this figure represents a disease-free survival of approximately 50% in MOPP treated radiation failures who achieved a complete remission, a third time around; this hits the average disease-free survival achievable with MOPP. Six additional patients were treated on first relapse with MOPP plus radiotherapy and 5 (83%) remained continuously free of disease. Thus, the authors seem to show that cross over to systemic treatment at first relapse offers a potentially better chance of a second durable remission than staying with regional treatment. A recent presentation by the same group at the American Society of Clinical Oncology meeting in Denver,‘j considering all sites of extension after radiation therapy, makes this point more forcefully, 50% of patients who were treated with MOPP chemotherapy, as the only treatment, were successfully salvaged. These data reconfirm both the initial reports using MOPP chemotherapy and a subsequent report by Canellos et ~1.~which showed that the response to MOPP chemotherapy was not compromised by prior exposure to radiotherapy. Even when relapse occurred after extensive total nodal irradiation, the complete response rate and ultimate relapse free survival of MOPP salvaged patients, were comparable to that in patients who were treated per primum with MOPP. Broadly interpreted, this means that one might expect relapse-free survivals in at least 60% of all MOPP treated radiation failures with an overall survival 10% to 15% higher, a figure double what is now achieved with radiotherapy alone as retreatment, as Weller and colleagues succinctly summarize after a review of the available literature.’ Does this mean that we should recommend combination chemotherapy as the salvage treatment of choice for all patients who develop extensions after treatment with radiotherapy? Unfortunately, the answer to this question is not simple. We do tend to behave too reflexively in selecting our salvage
The therapy of all stages of Hodgkin’s disease has improved dramatically in the past decade with the advent of more refined staging, radiotherapy, and combination chemotherapy. However, although the situation is far better than a mere decade ago, all is not well; the therapy works, it cures, but it is morbid and needs improvement. A significant fraction of patients treated primarily with either radiotherapy for Stages I and II disease or combination chemotherapy for Stages III and IV still relapse (about 30% of the former and 45% of the: latter): more investigators are appropriately turning their attention to the proper approach to salvage of the relapsing patient. The available data, in toto, suggests that those patients who relapse do not fare as well with retreatment with the same mode of therapy as patients with an equivalent volume (stage) of tumor treated per primum. While the reasons for this less dramatic response to second treatment with the same type of therapy are not entirely clear, it is easy to speculate that more widespread relatively silent dissemination of residual tumor is possible before redetection occurs. This is particularly true in areas that are difficult to examine, as in retrograde transdiaphragmatic extension to the retroperitoneal lymph nodes in patients who presented initially with supradiaphragmatic Hodgkin’s disease and were treated with only involved field or mantle field radiotherapy. Such is the case in the study’ relported by Weller et al. from Stanford in this issue of the journal.* Only 34% of their 40 patients with transdiaphragmatic extension were continuously free of disease in their second remission, three years after retreatment. Of particular interest are 28 patients who were retreated with radiotherapy alone, as. the second treatment; only 7 (25%) were rendered continuously free of Hodgkin’s disease. In Table 6 of the paper it appears that of the remaining 17 patients, not treated yet a third time with radiotherapy, 6 (:35%) treated with combination chemotherapy (MOPP) were alive and free of 1035
IO30
Radiation
Oncology
0
Biology 0
Physics
treatment, and too often follow the party line, so to speak. If the name of the game is relapse-free survival the first, second, or third time around, then it appears that modern chemotherapy offers more prospects for producing a permanent remission after extension; a patient presenting as a radiation failure is response to MOPP no worse off uis-a-vis potential than a brand new previously untreated patient. However, one can interpret both the data reported by Canellos et al.* and Weller et aI.* another way. In both studies, the extent of radiotherapy prior to MOPP did not compromise the subsequent response to MOPP. Thus, in the Stanford study, although the number of patients was small and not backed up by a substantial followup, MOPP as the third alternative (after two tries at radiotherapy) seemed to fare pretty well. Second, we are bothered continuously by the spectre of the carcinogenic effect of both MOPP and extensive radiotherapy used together.’ Thus, the risk of a late cancer must be balanced against the risk of premature and unnecessary death; however, if one can exhaust the usefulness of radiotherapy with curative intent, before turning to systemic therapy, without compromising the latter, one can spare a small but significant fraction of patients exposure to both treatments. We are faced with the same dilemma in selecting salvage treatment as we are with the question of using both radiotherapy and chemotherapy together, rather than in sequence, as primary treatment. In neither case do we yet have a firm answer. There are other points to consider as well in selecting treatment. The data on MOPP chemotherapy at the NC1 continue to show that those patients with nodular sclerosing Hodgkin’s disease, ultimately do not fare as well in respect to relapsefree survival although they have remission rates equivalent to patients with other histologic subtypes.3 Based on these data, we continue to recommend, for example, the use of both radiotherapy and MOPP chemotherapy for the first treatment of stage IIIB disease rather than MOPP alone as some prefer (some still even prefer radiation therapy alone). No data were provided by Weller et al. on the influence of histology on disease-free survival; and surprisingly little data are available in the literature. While we simply do not have sufficient data to make absolute recommendations, there does seem to be a basis for general guidelines. The apparent success of the Stanford group in irradiating the liver, notwithstanding (as reported by Weller et al.) any patient who develops an extension to viscera or has a nodal extension with systemic symptoms would appear to have the best chance of subsequent relapsefree survival by treatment with MOPP combination chemotherapy alone, since the suspicion of systemic
September-October
1977, Volume
2, No. 9 and No.
10
spread in such patients is high. To this I would add radiotherapy to nodal extensions (or even the liver) in such patients who have nodular sclerosing Hodgkin’s disease, based on our experience (mentioned above). One might also consider as evidence of systemic spread, conversion from a lymphocyte predominant or mixed cellular histology to lymphocyte depletion; patients with the latter histologic subtype, treated per primum with local or regional treatment alone, rarely stay free of disease. This leaves those patients with good histologic subtypes (nodular sclerosing and lymphocyte predominant, and maybe mixed cellular Hodgkin’s disease) who have extentions to lymph nodes, but remain asymptomatic, to be retreated with radiotherapy; chemotherapy would be held in reserve for subsequent failure, if it occurs. Obviously, we can use more data on these points, but it doesn’t seem likely we will get it in the shape of a formal study since investigators do not like to plan studies on how to treat failures. One final obvious point is worthy of reemphasis. The most successful approach to salvage is to prevent relapse. Thus, for clinically staged patients, Weller et al. mention, but do not emphasize enough, that involved field or mantle field radiotherapy does not appear to be enough. This also has been clearly demonstrated in the national study of Hodgkin’s disease, at least in reference to relapse-free survival.5 Total nodal radiotherapy at least to the pelvic brim (including the spleen and splenic nodes) appears to be the treatment of choice in such patients (avoiding the issue, of course, of the role of drug therapy at this point). In my view, we do not yet know with any assurance, whether in patients staged using laparotomy, more limited radiotherapy for presumed limited disease, determined by negative lymph node biopsies at laparotomy, will be associated with long term relapse-free survival equal to the use of total nodal irradiation for the equivalent clinical stage; (keep in mind many of today’s stage PS IIIA and B patients were yesterday’s CS IIA and B). The jury is still out; and probably will be for at least another 5 years. Clearly, our research effort in clinical trials with Hodgkin’s disease should continue to be in the area of examining ways to prevent relapse and obviate the need for discussions of how to salvage primary treatment failures. This is the intent of the excellent studies now being conducted at Stanford exploring the use of chemotherapy and radiotherapy simultaneously.’ Approaches to salvaging patients who relapse after primary drug treatment are also being examined.4 However, not enough work, in my view, is being devoted to the prevention of relapse of drug treated stage III and IV Hodgkin’s disease by the use of tandem non-cross resistant drug combinations.
Hodgkin’s
disease:
the salvage
of radiation
Rather too much effort, it seems, is being devoted to developing just another variation of the MOPP program instead. The answer to some of these questions will be forthcoming in the next few years as the study at Stanford matures fu:rther. In that study lies the
treatment
failures
0 V. T. DEVITA, JR.
I037
answer to the question of the relative risks or benefits of using two very different but effective therapies in sequence. These data will also be applicable to the question of how to salvage patients who fail, if we still need to know.
REFERENCES 1. Canellos, G.P., DeVita, V.T., Arseneau, J.C., WhangPeng, J., and Johnson, R.C.: Second malignancies complicating Hodgkin’s disease in remission. Lancer 7913, 947-979, April 1975. 2. Canellos, G.P., Young, R.C., and DeVita, V.T.: Combination chemotherapy for advanced Hodgkin’s disease in relapse following Clin. extensive radiotherapy. Pharmacol.
Ther. 13: 750-754,
1972.
3. DeVita, V.T., Canellos, G.P., Hubbard, S., Chabner, B., and Young, R.C.: Chemotherapy of Hodgkin’s disease with MOPP: A 10 year progress report. Proc. Amer. Sot. Clin. One. 17: 269, 1976. 4. Fisher, R.I., DeVita, V.T., Hubbard, S.M., and Young, R.C.: Prolonged disease-free survival in Hodgkin’s disease following reinduction with MOPP. Proc. Am. Sot. Clin. One. 18: 318, May 1977. 5. Hutchinson, G.B.: Survival and complications of
radiotherapy following involved and extended field therapy of Hodgkin’s disease stages I and II. Cancer 38: 288-305, 1976. 6. Portlock, C.S., Rosenberg, S.A., Glatstein, E., Levy, R., and Kaplan, H.S.: Failure of initial therapy for Stages I, II and III Hodgkin’s disease: Salvage management. Proc. Amer. Sot. Clin. One. 18: 342, May 1977. 7. Rosenberg, S.A., Kaplan, H.S., and Glatstein, E.: The role of adjuvant MOPP in the radiation therapy of Hodgkin’s disease: A progress report at eight years of the Stanford trials. Proc. Amer. Sot. Clin. One. 18: 342, May 1977. 8. Weller, S.A., Glatstein, E., Castellino, R.A., Kaplan, H.S., and Rosenberg, S.A.: Initial relapse in previously treated Hodgkin’s disease--II retrograde transdiaphragmatic extension. Int. J. of Rad. One. Biol. and Phys. 2: 863-872,
1977.
Oncology Biol. Phys..
1977,
Vol. 2. pp
1035-1037.
Pergamon Press.
Printed in the U.S.A.
??Editorial
HODGKIN’S
DISEASE: THE SALVAGE OF RADIATION TREATMENT FAILURES
VINCENT T. DEVITA, JR., M.D. Director, Division of Cancer Treatment, Clinical Director, National Cancer Institute, Bethesda, MD 20014, U.S.A. Hodgkin’s disease, Radiation treatment failures-salvage
of, Combined
chemotherapy
(MOPP).
disease. Given a complete remission rate of 70% using MOPP at Stanford, this figure represents a disease-free survival of approximately 50% in MOPP treated radiation failures who achieved a complete remission, a third time around; this hits the average disease-free survival achievable with MOPP. Six additional patients were treated on first relapse with MOPP plus radiotherapy and 5 (83%) remained continuously free of disease. Thus, the authors seem to show that cross over to systemic treatment at first relapse offers a potentially better chance of a second durable remission than staying with regional treatment. A recent presentation by the same group at the American Society of Clinical Oncology meeting in Denver,‘j considering all sites of extension after radiation therapy, makes this point more forcefully, 50% of patients who were treated with MOPP chemotherapy, as the only treatment, were successfully salvaged. These data reconfirm both the initial reports using MOPP chemotherapy and a subsequent report by Canellos et ~1.~which showed that the response to MOPP chemotherapy was not compromised by prior exposure to radiotherapy. Even when relapse occurred after extensive total nodal irradiation, the complete response rate and ultimate relapse free survival of MOPP salvaged patients, were comparable to that in patients who were treated per primum with MOPP. Broadly interpreted, this means that one might expect relapse-free survivals in at least 60% of all MOPP treated radiation failures with an overall survival 10% to 15% higher, a figure double what is now achieved with radiotherapy alone as retreatment, as Weller and colleagues succinctly summarize after a review of the available literature.’ Does this mean that we should recommend combination chemotherapy as the salvage treatment of choice for all patients who develop extensions after treatment with radiotherapy? Unfortunately, the answer to this question is not simple. We do tend to behave too reflexively in selecting our salvage
The therapy of all stages of Hodgkin’s disease has improved dramatically in the past decade with the advent of more refined staging, radiotherapy, and combination chemotherapy. However, although the situation is far better than a mere decade ago, all is not well; the therapy works, it cures, but it is morbid and needs improvement. A significant fraction of patients treated primarily with either radiotherapy for Stages I and II disease or combination chemotherapy for Stages III and IV still relapse (about 30% of the former and 45% of the: latter): more investigators are appropriately turning their attention to the proper approach to salvage of the relapsing patient. The available data, in toto, suggests that those patients who relapse do not fare as well with retreatment with the same mode of therapy as patients with an equivalent volume (stage) of tumor treated per primum. While the reasons for this less dramatic response to second treatment with the same type of therapy are not entirely clear, it is easy to speculate that more widespread relatively silent dissemination of residual tumor is possible before redetection occurs. This is particularly true in areas that are difficult to examine, as in retrograde transdiaphragmatic extension to the retroperitoneal lymph nodes in patients who presented initially with supradiaphragmatic Hodgkin’s disease and were treated with only involved field or mantle field radiotherapy. Such is the case in the study’ relported by Weller et al. from Stanford in this issue of the journal.* Only 34% of their 40 patients with transdiaphragmatic extension were continuously free of disease in their second remission, three years after retreatment. Of particular interest are 28 patients who were retreated with radiotherapy alone, as. the second treatment; only 7 (25%) were rendered continuously free of Hodgkin’s disease. In Table 6 of the paper it appears that of the remaining 17 patients, not treated yet a third time with radiotherapy, 6 (:35%) treated with combination chemotherapy (MOPP) were alive and free of 1035
IO30
Radiation
Oncology
0
Biology 0
Physics
treatment, and too often follow the party line, so to speak. If the name of the game is relapse-free survival the first, second, or third time around, then it appears that modern chemotherapy offers more prospects for producing a permanent remission after extension; a patient presenting as a radiation failure is response to MOPP no worse off uis-a-vis potential than a brand new previously untreated patient. However, one can interpret both the data reported by Canellos et al.* and Weller et aI.* another way. In both studies, the extent of radiotherapy prior to MOPP did not compromise the subsequent response to MOPP. Thus, in the Stanford study, although the number of patients was small and not backed up by a substantial followup, MOPP as the third alternative (after two tries at radiotherapy) seemed to fare pretty well. Second, we are bothered continuously by the spectre of the carcinogenic effect of both MOPP and extensive radiotherapy used together.’ Thus, the risk of a late cancer must be balanced against the risk of premature and unnecessary death; however, if one can exhaust the usefulness of radiotherapy with curative intent, before turning to systemic therapy, without compromising the latter, one can spare a small but significant fraction of patients exposure to both treatments. We are faced with the same dilemma in selecting salvage treatment as we are with the question of using both radiotherapy and chemotherapy together, rather than in sequence, as primary treatment. In neither case do we yet have a firm answer. There are other points to consider as well in selecting treatment. The data on MOPP chemotherapy at the NC1 continue to show that those patients with nodular sclerosing Hodgkin’s disease, ultimately do not fare as well in respect to relapsefree survival although they have remission rates equivalent to patients with other histologic subtypes.3 Based on these data, we continue to recommend, for example, the use of both radiotherapy and MOPP chemotherapy for the first treatment of stage IIIB disease rather than MOPP alone as some prefer (some still even prefer radiation therapy alone). No data were provided by Weller et al. on the influence of histology on disease-free survival; and surprisingly little data are available in the literature. While we simply do not have sufficient data to make absolute recommendations, there does seem to be a basis for general guidelines. The apparent success of the Stanford group in irradiating the liver, notwithstanding (as reported by Weller et al.) any patient who develops an extension to viscera or has a nodal extension with systemic symptoms would appear to have the best chance of subsequent relapsefree survival by treatment with MOPP combination chemotherapy alone, since the suspicion of systemic
September-October
1977, Volume
2, No. 9 and No.
10
spread in such patients is high. To this I would add radiotherapy to nodal extensions (or even the liver) in such patients who have nodular sclerosing Hodgkin’s disease, based on our experience (mentioned above). One might also consider as evidence of systemic spread, conversion from a lymphocyte predominant or mixed cellular histology to lymphocyte depletion; patients with the latter histologic subtype, treated per primum with local or regional treatment alone, rarely stay free of disease. This leaves those patients with good histologic subtypes (nodular sclerosing and lymphocyte predominant, and maybe mixed cellular Hodgkin’s disease) who have extentions to lymph nodes, but remain asymptomatic, to be retreated with radiotherapy; chemotherapy would be held in reserve for subsequent failure, if it occurs. Obviously, we can use more data on these points, but it doesn’t seem likely we will get it in the shape of a formal study since investigators do not like to plan studies on how to treat failures. One final obvious point is worthy of reemphasis. The most successful approach to salvage is to prevent relapse. Thus, for clinically staged patients, Weller et al. mention, but do not emphasize enough, that involved field or mantle field radiotherapy does not appear to be enough. This also has been clearly demonstrated in the national study of Hodgkin’s disease, at least in reference to relapse-free survival.5 Total nodal radiotherapy at least to the pelvic brim (including the spleen and splenic nodes) appears to be the treatment of choice in such patients (avoiding the issue, of course, of the role of drug therapy at this point). In my view, we do not yet know with any assurance, whether in patients staged using laparotomy, more limited radiotherapy for presumed limited disease, determined by negative lymph node biopsies at laparotomy, will be associated with long term relapse-free survival equal to the use of total nodal irradiation for the equivalent clinical stage; (keep in mind many of today’s stage PS IIIA and B patients were yesterday’s CS IIA and B). The jury is still out; and probably will be for at least another 5 years. Clearly, our research effort in clinical trials with Hodgkin’s disease should continue to be in the area of examining ways to prevent relapse and obviate the need for discussions of how to salvage primary treatment failures. This is the intent of the excellent studies now being conducted at Stanford exploring the use of chemotherapy and radiotherapy simultaneously.’ Approaches to salvaging patients who relapse after primary drug treatment are also being examined.4 However, not enough work, in my view, is being devoted to the prevention of relapse of drug treated stage III and IV Hodgkin’s disease by the use of tandem non-cross resistant drug combinations.
Hodgkin’s
disease:
the salvage
of radiation
Rather too much effort, it seems, is being devoted to developing just another variation of the MOPP program instead. The answer to some of these questions will be forthcoming in the next few years as the study at Stanford matures fu:rther. In that study lies the
treatment
failures
0 V. T. DEVITA, JR.
I037
answer to the question of the relative risks or benefits of using two very different but effective therapies in sequence. These data will also be applicable to the question of how to salvage patients who fail, if we still need to know.
REFERENCES 1. Canellos, G.P., DeVita, V.T., Arseneau, J.C., WhangPeng, J., and Johnson, R.C.: Second malignancies complicating Hodgkin’s disease in remission. Lancer 7913, 947-979, April 1975. 2. Canellos, G.P., Young, R.C., and DeVita, V.T.: Combination chemotherapy for advanced Hodgkin’s disease in relapse following Clin. extensive radiotherapy. Pharmacol.
Ther. 13: 750-754,
1972.
3. DeVita, V.T., Canellos, G.P., Hubbard, S., Chabner, B., and Young, R.C.: Chemotherapy of Hodgkin’s disease with MOPP: A 10 year progress report. Proc. Amer. Sot. Clin. One. 17: 269, 1976. 4. Fisher, R.I., DeVita, V.T., Hubbard, S.M., and Young, R.C.: Prolonged disease-free survival in Hodgkin’s disease following reinduction with MOPP. Proc. Am. Sot. Clin. One. 18: 318, May 1977. 5. Hutchinson, G.B.: Survival and complications of
radiotherapy following involved and extended field therapy of Hodgkin’s disease stages I and II. Cancer 38: 288-305, 1976. 6. Portlock, C.S., Rosenberg, S.A., Glatstein, E., Levy, R., and Kaplan, H.S.: Failure of initial therapy for Stages I, II and III Hodgkin’s disease: Salvage management. Proc. Amer. Sot. Clin. One. 18: 342, May 1977. 7. Rosenberg, S.A., Kaplan, H.S., and Glatstein, E.: The role of adjuvant MOPP in the radiation therapy of Hodgkin’s disease: A progress report at eight years of the Stanford trials. Proc. Amer. Sot. Clin. One. 18: 342, May 1977. 8. Weller, S.A., Glatstein, E., Castellino, R.A., Kaplan, H.S., and Rosenberg, S.A.: Initial relapse in previously treated Hodgkin’s disease--II retrograde transdiaphragmatic extension. Int. J. of Rad. One. Biol. and Phys. 2: 863-872,
1977.