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Controlling multiple myeloma
909
Correspondence
I. Coia, L.; Brown, D. Q.; Hardiman, J. WR-2721 as cytotoxic and radioprotective agent in treatment of murine lymphoma with total body irradiation. NC1 Monogr. 6:235-239; 1988. 2. Travis, E.; Fang, M. Z.; Basic, I. Protection of mouse bone marrow by WR-2721 after fractionated irradiation. Int. J. Radiat. Oncol. Biol. Phys. 15:377-382; 1988.
2. McIntyre, R. 0.; Telft, M.; Propert, K.; Wolf, D. J.; Coleman. Leone, L.; Cooper, M. R.; Eaton, W.; Zimmer, B. Melphalan prednisone plus total marrow irradiation for multiple myeloma. J. Radiat. Oncol. Biol. Phys. 16:1007-1012; 1988.
RESPONSE CONTROLLING
MULTIPLE
MYELOMA
To the Editor: While reading the article by Dr. McIntyre, et al. (2) describing the failure of total bone marrow irradiation to contribute to the control of multiple myeloma. I wondered why radiation failed. Was it because the dose was too low or that the authors failed to cover all marrow sites? The more likely reason is the spread of myeloma cells through the vasculature. If this is the case, the tumor volume is the entire circulatory system. Treating only part of that volume at a time allows repopulation by cells arriving from untreated areas. We have seen previous examples of this in the failure of sequential hemi-body radiation to improve cure rates in small cell carcinoma of the lung and neuroblastoma. The peritoneal cavity is another large compartment of circulation where treating piecemeal has gained favor among radiation oncologists. It is well known that material injected into the peritoneal cavity will quickly find its way to the subdiaphragmatic lymphatics ( 1). A downward circulation explains Kruckenberg tumors and Blumer’s shelf. Any tumor cells adherent to small bowel will have some movement unless anchored by adhesions. The moving strip technique treats small segments of the peritoneum, from the bottom up, in sequential steps. It is analagous to treating a flask of cultured tumor cells by first treating the bottom of the flask, the next day treating the middle of the flask and on another day treating the top. The results are moot. Sequentially treating areas of tumor infiltrated bone marrow is the hematopoietic equivalent of the moving strip technique. If cells circulating in a compartment represent a significant method for spread of myeloma (and other tumor) cells, should studies, such as this one, that treat only part of that compartment at time, be pursued? Instead of trying to find ways to mix chemotherapy with piecemeal total marrow irradiation, we should spend our time and limited resources on more fruitful endeavors. F. R. ELLWANGER, M.D. 3900 Belmoor Dr. Palm Harbor, FL 34685
1. Feldman, G. B.: Knapp, R. C. Lymphatic drainage of the peritoneal cavity and its significance in ovarian cancer. Am. J. Obstet. Gynecol. 119:991-994: 1974.
TO LETTER
M.; and Int.
BY DR. ELLWANGER
To the Editor: Dr. Ellwanger’s letter suggests a reason for the failure of our sequential total bone marrow irradiation trial to produce a clinical benefit in patients with multiple myeloma. In the design of our protocol, we considered the issue that is raised by Dr. Ellwanger in his letter (namely that myeloma cells circulate), and hypothesized that normal marrow might repopulate the irradiated marrow segments more rapidly and effectively than myeloma cells. Our negative result is evidence against this hypothesis, but does not disprove it. Now, several years after the study was completed, methods for enumerating peripheral blood myeloma stem cells are available (1) and the ratios of tumor cells to normal colony-forming cells have been determined. This ratio varies considerably from patient to patient. There is a wealth of information from experimental systems which provides insight as to whether or not a circulating tumor cell will take up residence in a given tissue and proliferate. In fact, the example of Kruckenberg tumors. which Dr. Ellwanger uses, may be an example in which proliferation of tumor cells is influenced by factors more complex than gravity sedimentation. Obviously, it would be an advantage to treat the entire tumor volume simultaneously. Our protocol explored the possibility that radiation to sequential segments would allow a therapeutic radiation dose to be given without the need for bone marrow transplantation. Dr. Ellwanger suggests that we should spend our time and limited resources on more fruitful endeavors, an easy thing to say after a negative study has been reported. In myeloma, a disease where therapeutic advances have come slow and hard, it is presumptuous to predict what will or will not work, or from what direction the next advance in our knowledge will come. 0. R. MCINTYRE. M.D.
Norris Cotton Cancer Hanover, NH 03756
Center
Greipp, P. R.: Ahmann, G.; Katzmann, J. A.; Witzig, T. E.; Carton. J. P.: Gertz, M. A.; Solberg. L. A.: Goncheroff. Kyle, R. A. Peripheral blood as a source of stem cells in myeloma. Blood 72(Suppl. 1):243; 1988.
Correspondence
I. Coia, L.; Brown, D. Q.; Hardiman, J. WR-2721 as cytotoxic and radioprotective agent in treatment of murine lymphoma with total body irradiation. NC1 Monogr. 6:235-239; 1988. 2. Travis, E.; Fang, M. Z.; Basic, I. Protection of mouse bone marrow by WR-2721 after fractionated irradiation. Int. J. Radiat. Oncol. Biol. Phys. 15:377-382; 1988.
2. McIntyre, R. 0.; Telft, M.; Propert, K.; Wolf, D. J.; Coleman. Leone, L.; Cooper, M. R.; Eaton, W.; Zimmer, B. Melphalan prednisone plus total marrow irradiation for multiple myeloma. J. Radiat. Oncol. Biol. Phys. 16:1007-1012; 1988.
RESPONSE CONTROLLING
MULTIPLE
MYELOMA
To the Editor: While reading the article by Dr. McIntyre, et al. (2) describing the failure of total bone marrow irradiation to contribute to the control of multiple myeloma. I wondered why radiation failed. Was it because the dose was too low or that the authors failed to cover all marrow sites? The more likely reason is the spread of myeloma cells through the vasculature. If this is the case, the tumor volume is the entire circulatory system. Treating only part of that volume at a time allows repopulation by cells arriving from untreated areas. We have seen previous examples of this in the failure of sequential hemi-body radiation to improve cure rates in small cell carcinoma of the lung and neuroblastoma. The peritoneal cavity is another large compartment of circulation where treating piecemeal has gained favor among radiation oncologists. It is well known that material injected into the peritoneal cavity will quickly find its way to the subdiaphragmatic lymphatics ( 1). A downward circulation explains Kruckenberg tumors and Blumer’s shelf. Any tumor cells adherent to small bowel will have some movement unless anchored by adhesions. The moving strip technique treats small segments of the peritoneum, from the bottom up, in sequential steps. It is analagous to treating a flask of cultured tumor cells by first treating the bottom of the flask, the next day treating the middle of the flask and on another day treating the top. The results are moot. Sequentially treating areas of tumor infiltrated bone marrow is the hematopoietic equivalent of the moving strip technique. If cells circulating in a compartment represent a significant method for spread of myeloma (and other tumor) cells, should studies, such as this one, that treat only part of that compartment at time, be pursued? Instead of trying to find ways to mix chemotherapy with piecemeal total marrow irradiation, we should spend our time and limited resources on more fruitful endeavors. F. R. ELLWANGER, M.D. 3900 Belmoor Dr. Palm Harbor, FL 34685
1. Feldman, G. B.: Knapp, R. C. Lymphatic drainage of the peritoneal cavity and its significance in ovarian cancer. Am. J. Obstet. Gynecol. 119:991-994: 1974.
TO LETTER
M.; and Int.
BY DR. ELLWANGER
To the Editor: Dr. Ellwanger’s letter suggests a reason for the failure of our sequential total bone marrow irradiation trial to produce a clinical benefit in patients with multiple myeloma. In the design of our protocol, we considered the issue that is raised by Dr. Ellwanger in his letter (namely that myeloma cells circulate), and hypothesized that normal marrow might repopulate the irradiated marrow segments more rapidly and effectively than myeloma cells. Our negative result is evidence against this hypothesis, but does not disprove it. Now, several years after the study was completed, methods for enumerating peripheral blood myeloma stem cells are available (1) and the ratios of tumor cells to normal colony-forming cells have been determined. This ratio varies considerably from patient to patient. There is a wealth of information from experimental systems which provides insight as to whether or not a circulating tumor cell will take up residence in a given tissue and proliferate. In fact, the example of Kruckenberg tumors. which Dr. Ellwanger uses, may be an example in which proliferation of tumor cells is influenced by factors more complex than gravity sedimentation. Obviously, it would be an advantage to treat the entire tumor volume simultaneously. Our protocol explored the possibility that radiation to sequential segments would allow a therapeutic radiation dose to be given without the need for bone marrow transplantation. Dr. Ellwanger suggests that we should spend our time and limited resources on more fruitful endeavors, an easy thing to say after a negative study has been reported. In myeloma, a disease where therapeutic advances have come slow and hard, it is presumptuous to predict what will or will not work, or from what direction the next advance in our knowledge will come. 0. R. MCINTYRE. M.D.
Norris Cotton Cancer Hanover, NH 03756
Center
Greipp, P. R.: Ahmann, G.; Katzmann, J. A.; Witzig, T. E.; Carton. J. P.: Gertz, M. A.; Solberg. L. A.: Goncheroff. Kyle, R. A. Peripheral blood as a source of stem cells in myeloma. Blood 72(Suppl. 1):243; 1988.