Annals of Oncology 3 (Suppl. 4): S67-S68, 1992. O 1992 Kluwer Academic Publishers. Printed in the Netherlands.
Commentary Current therapeutic strategies in Hodgkin's disease G. P. Canellos Harvard Medical School, Dana-Farber Cancer Institute, Boston, MA, USA
Localized disease The approach to localized HD is difficult to change radically as the overall results with radiation therapy have been excellent. The overall progression-free survival in patients PS I-IIA is in the range of 80 percent with variation due to other prognosic factors, such as age, histology (mixed cellularity) and elevated erythrocyte sedimentation rate, especially post therapy. In the latter circumstance chemotherapy originally vinblastine alone but more recently various forms of combination chemotherapy have abrogated the higher relapse rate in such patients. Since 20 to 30 percent of patients with CS I-IIA disease will have cryptic abdominal involvement the addition of chemotherapy rather than undergoing a laparotomy should correct the uncertainty of treating with radiation alone without a laparotomy. The current Stanford trial of VBM (vinblastine, bleomycin,
methotrexate) plus limited radiation and no laparotomy should help define the value of this regimen which is untested in advanced disease but relatively non-toxic. The long-term follow-up data from Milan suggest that, at 10 years, PS IIA have only a 59 percent freedom from progression, especially with bulky disease. Such patients are recommended to receive systemic therapy in addition at the time of initial therapy. The issue of systemic therapy alone for early stage has been raised by the recent NCI series using MOPP alone for I/II disease which shows superiority over radiation therapy as primary treatment. This result could not be reproduced in the Rome series which showed a radically inferior experience from MOPP. It is clear, however, that this extreme form of systemic therapy will not replace current standard approaches which include radiation. This does not preclude further research with newer and hopefully less toxic systemic therapy which could replace radiation therapy. The goals of future clinical research in early stage HD revolve around: (1) identification of biologic prognostic factors which will more accurately predict the benefits of primary radiation therapy; (2) the development of a relatively non-toxic tolerable systemic regimen which will obviate laparotomy and relapse with unfavorable prognostic features; (3) the long-term hazard of in-the-field second neoplasms following radiation therapy. These steps are only now being appreciated and the careful decrease in the dosage of extended-field radiation from 40 Gy to 30 Gy (HD4 of the German Hodgkin Study Group) is a step in that direction. Advanced stages Intermediate stages of HD, such as IIB, IIA/B and HE disease, are likely candidates for combined modality therapy and regardless of the systemic regimen the results are excellent and generally similar. The issues in so-called combined modality therapy, where a full or modified course of systemic chemotherapy is given, is the need for the radiation therapy at all. Thus far, the results of the German Hodgkin Study Group trial, HD 3 , fail to support the use of involved field radiation
Downloaded from http://annonc.oxfordjournals.org/ at McMaster University Library on June 30, 2015
The unique biologic and clinical aspects of Hodgkin's disease (HD) has attracted an interest in the disease in excess of its incidence compared to epithelial cancers. The therapeutic leads achieved in HD have been successfully applied in the treatment of the large cell lymphomas and continue to tested in other solid tumors. A number of therapeutic issues were reviewed at the Second International Symposium on Hodgkin's disease. It was clear that a large number of successfully-treated patients are in all likelihood overtreated either by the extent of radiation fields; the use of combined modality therapy in clinical situations where there is an uncertainty as to the effectiveness of radiation alone; and the duration and composition of chemotherapy regimens administered alone, alternating, in sequence or 'hybridized' in a multi-drug program. The inability to define clear prognostic subgroups except at the extreme ends of the risk/stage scale has impaired analysis of retrospective trials and limited the definition of 'high-risk' group for newer more intensive treatments. New molecular and biologic leads will be needed as well as more sensitive imaging techniques. Circulation of immunologically defined antigens which are presumed to reflect the tumor mass may permit a more objectively quantifiable measure of prognosis.
68
Transplantation
One technique to overcome relative resistance of tumor cells to cytotoxic agents is to administer megadoses as is currently being done with autologous bone marrow or peripheral stem cell support. The early results have been encouraging enough to warrant expansion of the experience. The ablative regimens have varied from total body irradiation and cyclophosphamide to various high dose regimens such as CBV (cyclophosphamide, BCNU and etoposide, VP-16) and BEAM (BCNU, etoposide, ara-C and melphalan). The results may be enhanced by additive involved-field irradiation. A major question is the timing of ABMT in patients who relapse from primary systemic therapy. The mass of data on the impact of second-line systemic therapy as a salvage for relapse suggests that the later the relapse the more likely the achievement prolongation of a second CR which can be durable over years. Patients
who relapse from a CR which lasts less than 12 months or who fail to achieve CR with initial therapy are in a particularly unfavorable prognostic situation. Any new and intense therapy would be indicated in this situation. The results of pilot series composed of relatively small numbers of patients with early evaluation would suggest that somewhere between 30 to 40 percent of a highly selected population of patients may be free from progression at five years when the data are dissected from the many series it would appear that only patients in a drug-sensitive relapse who have a good performance status and have not been heavily pre-treated (two or less prior regimens) are likely to benefit. It is also true that in a patient who has relapsed after a CR of over 12 months, second-line treatment can achieve approximately 80 percent second CR which can be durable enough to result in a 40 to 50 percent second progression-free interval at three to five years. It would appear that the value of ABMT with its inherent ten percent or greater treatment-induced toxic deaths might be difficult to assess in that setting. The more appropriate indication is the induction failure with initial therapy, relapse within 12 months, and multiplyrelapsed even after a long initial CR. Pilot ABMT series which take patients from the initial point of relapse prior to the use of salvage chemotherapy to assess chemo-sensitivity show that only about 20 to 25 percent of such a cohort of patients will be free of disease at three years. Selection in referral to centers has confused interpretation of transplant data. A preliminary assessment of ABMT as currently performed suggests that it is not likely to salvage the unfortunate clinical situation of primary refractoriness. Innovation is clearly needed with the ablative treatments used in ABMT. These have assumed the form of multiple high-dose treatments with the use of hemopoietic growth factors and peripheral stem cells. The likelihood of developing the technology which will very significantly ameliorate the myelosuppressive aspects of high-dose therapy is very real. Whether dose alone or sequential high dose programs will overcome cellular/tissue resistance remains to be seen. There is a spectrum of drug sensitivity of all human cancers. Hodgkin's disease will likely continue to excite the interest and efforts of clinical cancer researchers as it continues to provide the leads in therapeutic research.
Correspondence to: George P. Canellos, M.D. William Rosenberg Professor of Medicine Harvard Medical School Chief, Division of Medical Oncology Dana-Farber Cancer Institute Boston, Massachusetts 02115 USA
Downloaded from http://annonc.oxfordjournals.org/ at McMaster University Library on June 30, 2015
of 20 Gy after achieving a chemotherapy-induced CR in advanced IIIB or IV patients. The same group showed, in HD,, that following systemic therapy for patients with bulk disease in stage I-IHA, 40 Gy extended field was no more effective than 20 Gy except perhaps at bulk sites. Thus, it appears that with systemic therapy less radiation (20 Gy) or perhaps none is needed to extended uninvolved fields except to the involved bulky site itself. Advanced Hodgkin's disease has been treated with a large variety of regimens, all of which are variations of MOPP and/or ABVD in various sequences or hybridized regimens. There is likely to be little or no difference amongst these programs, but a number of randomized trials are evaluating the Vancouver MOPP ABV hybrid compared to ABVD alone (Intergroup) or MOPP alternating with ABVD. The CALGB trial (8251) showed no advantage of MOPP alternating with ABVD over ABVD alone. Unless a radically new systemic agent becomes available then current trials are likely to show only small differences in overall survival at best. Surrogate endpoints, such as failure-free survival, have been more frequently used as early end points since survival can be prolonged with second- or third-line measures. The likelihood of resistance-failure appears to correlate with bulk and extent of disease. This raises issues of extent and degree of perfusion of tumor tissues by cytotoxic agents. The role of hypoxia and its possible impact as well as molecular drug resistance mechanism have not been well explored. The difficulties are enhanced by the uniquely heterogeneous histologic appearance of HD where the majority of cells appear to be reactive rather than neoplastic.
Commentary Current therapeutic strategies in Hodgkin's disease G. P. Canellos Harvard Medical School, Dana-Farber Cancer Institute, Boston, MA, USA
Localized disease The approach to localized HD is difficult to change radically as the overall results with radiation therapy have been excellent. The overall progression-free survival in patients PS I-IIA is in the range of 80 percent with variation due to other prognosic factors, such as age, histology (mixed cellularity) and elevated erythrocyte sedimentation rate, especially post therapy. In the latter circumstance chemotherapy originally vinblastine alone but more recently various forms of combination chemotherapy have abrogated the higher relapse rate in such patients. Since 20 to 30 percent of patients with CS I-IIA disease will have cryptic abdominal involvement the addition of chemotherapy rather than undergoing a laparotomy should correct the uncertainty of treating with radiation alone without a laparotomy. The current Stanford trial of VBM (vinblastine, bleomycin,
methotrexate) plus limited radiation and no laparotomy should help define the value of this regimen which is untested in advanced disease but relatively non-toxic. The long-term follow-up data from Milan suggest that, at 10 years, PS IIA have only a 59 percent freedom from progression, especially with bulky disease. Such patients are recommended to receive systemic therapy in addition at the time of initial therapy. The issue of systemic therapy alone for early stage has been raised by the recent NCI series using MOPP alone for I/II disease which shows superiority over radiation therapy as primary treatment. This result could not be reproduced in the Rome series which showed a radically inferior experience from MOPP. It is clear, however, that this extreme form of systemic therapy will not replace current standard approaches which include radiation. This does not preclude further research with newer and hopefully less toxic systemic therapy which could replace radiation therapy. The goals of future clinical research in early stage HD revolve around: (1) identification of biologic prognostic factors which will more accurately predict the benefits of primary radiation therapy; (2) the development of a relatively non-toxic tolerable systemic regimen which will obviate laparotomy and relapse with unfavorable prognostic features; (3) the long-term hazard of in-the-field second neoplasms following radiation therapy. These steps are only now being appreciated and the careful decrease in the dosage of extended-field radiation from 40 Gy to 30 Gy (HD4 of the German Hodgkin Study Group) is a step in that direction. Advanced stages Intermediate stages of HD, such as IIB, IIA/B and HE disease, are likely candidates for combined modality therapy and regardless of the systemic regimen the results are excellent and generally similar. The issues in so-called combined modality therapy, where a full or modified course of systemic chemotherapy is given, is the need for the radiation therapy at all. Thus far, the results of the German Hodgkin Study Group trial, HD 3 , fail to support the use of involved field radiation
Downloaded from http://annonc.oxfordjournals.org/ at McMaster University Library on June 30, 2015
The unique biologic and clinical aspects of Hodgkin's disease (HD) has attracted an interest in the disease in excess of its incidence compared to epithelial cancers. The therapeutic leads achieved in HD have been successfully applied in the treatment of the large cell lymphomas and continue to tested in other solid tumors. A number of therapeutic issues were reviewed at the Second International Symposium on Hodgkin's disease. It was clear that a large number of successfully-treated patients are in all likelihood overtreated either by the extent of radiation fields; the use of combined modality therapy in clinical situations where there is an uncertainty as to the effectiveness of radiation alone; and the duration and composition of chemotherapy regimens administered alone, alternating, in sequence or 'hybridized' in a multi-drug program. The inability to define clear prognostic subgroups except at the extreme ends of the risk/stage scale has impaired analysis of retrospective trials and limited the definition of 'high-risk' group for newer more intensive treatments. New molecular and biologic leads will be needed as well as more sensitive imaging techniques. Circulation of immunologically defined antigens which are presumed to reflect the tumor mass may permit a more objectively quantifiable measure of prognosis.
68
Transplantation
One technique to overcome relative resistance of tumor cells to cytotoxic agents is to administer megadoses as is currently being done with autologous bone marrow or peripheral stem cell support. The early results have been encouraging enough to warrant expansion of the experience. The ablative regimens have varied from total body irradiation and cyclophosphamide to various high dose regimens such as CBV (cyclophosphamide, BCNU and etoposide, VP-16) and BEAM (BCNU, etoposide, ara-C and melphalan). The results may be enhanced by additive involved-field irradiation. A major question is the timing of ABMT in patients who relapse from primary systemic therapy. The mass of data on the impact of second-line systemic therapy as a salvage for relapse suggests that the later the relapse the more likely the achievement prolongation of a second CR which can be durable over years. Patients
who relapse from a CR which lasts less than 12 months or who fail to achieve CR with initial therapy are in a particularly unfavorable prognostic situation. Any new and intense therapy would be indicated in this situation. The results of pilot series composed of relatively small numbers of patients with early evaluation would suggest that somewhere between 30 to 40 percent of a highly selected population of patients may be free from progression at five years when the data are dissected from the many series it would appear that only patients in a drug-sensitive relapse who have a good performance status and have not been heavily pre-treated (two or less prior regimens) are likely to benefit. It is also true that in a patient who has relapsed after a CR of over 12 months, second-line treatment can achieve approximately 80 percent second CR which can be durable enough to result in a 40 to 50 percent second progression-free interval at three to five years. It would appear that the value of ABMT with its inherent ten percent or greater treatment-induced toxic deaths might be difficult to assess in that setting. The more appropriate indication is the induction failure with initial therapy, relapse within 12 months, and multiplyrelapsed even after a long initial CR. Pilot ABMT series which take patients from the initial point of relapse prior to the use of salvage chemotherapy to assess chemo-sensitivity show that only about 20 to 25 percent of such a cohort of patients will be free of disease at three years. Selection in referral to centers has confused interpretation of transplant data. A preliminary assessment of ABMT as currently performed suggests that it is not likely to salvage the unfortunate clinical situation of primary refractoriness. Innovation is clearly needed with the ablative treatments used in ABMT. These have assumed the form of multiple high-dose treatments with the use of hemopoietic growth factors and peripheral stem cells. The likelihood of developing the technology which will very significantly ameliorate the myelosuppressive aspects of high-dose therapy is very real. Whether dose alone or sequential high dose programs will overcome cellular/tissue resistance remains to be seen. There is a spectrum of drug sensitivity of all human cancers. Hodgkin's disease will likely continue to excite the interest and efforts of clinical cancer researchers as it continues to provide the leads in therapeutic research.
Correspondence to: George P. Canellos, M.D. William Rosenberg Professor of Medicine Harvard Medical School Chief, Division of Medical Oncology Dana-Farber Cancer Institute Boston, Massachusetts 02115 USA
Downloaded from http://annonc.oxfordjournals.org/ at McMaster University Library on June 30, 2015
of 20 Gy after achieving a chemotherapy-induced CR in advanced IIIB or IV patients. The same group showed, in HD,, that following systemic therapy for patients with bulk disease in stage I-IHA, 40 Gy extended field was no more effective than 20 Gy except perhaps at bulk sites. Thus, it appears that with systemic therapy less radiation (20 Gy) or perhaps none is needed to extended uninvolved fields except to the involved bulky site itself. Advanced Hodgkin's disease has been treated with a large variety of regimens, all of which are variations of MOPP and/or ABVD in various sequences or hybridized regimens. There is likely to be little or no difference amongst these programs, but a number of randomized trials are evaluating the Vancouver MOPP ABV hybrid compared to ABVD alone (Intergroup) or MOPP alternating with ABVD. The CALGB trial (8251) showed no advantage of MOPP alternating with ABVD over ABVD alone. Unless a radically new systemic agent becomes available then current trials are likely to show only small differences in overall survival at best. Surrogate endpoints, such as failure-free survival, have been more frequently used as early end points since survival can be prolonged with second- or third-line measures. The likelihood of resistance-failure appears to correlate with bulk and extent of disease. This raises issues of extent and degree of perfusion of tumor tissues by cytotoxic agents. The role of hypoxia and its possible impact as well as molecular drug resistance mechanism have not been well explored. The difficulties are enhanced by the uniquely heterogeneous histologic appearance of HD where the majority of cells appear to be reactive rather than neoplastic.
