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Protection of bone marrow by WR-2721 after fractionated irradiation
908
I. J. Radiation
Oncology
0 Biology 0 Physics
discreet, very superficial mucosal ulcers without clinical evidence of infection. These were located bilaterally on the lateral borders of the tongue and buccal mucosa, and on the hard palate adjacent to gold dental work in the left posterior maxilla (Fig. I). Lateral tongue involvement was greater on the right where the gold crowns were on both the first and second lower molars. This pattern indicated that his severe mucosal reaction to chemotherapy must have been due, in part, to a radiation recall phenomenon. During subsequent visits he was noted to develop additional small lesions in the mid hard palate at some distance from his dental work. He was managed throughout with careful oral care and liquid dietary supplements with which he was able to maintain his weight. The patient experienced some clinical improvement after treatment with beta-methasone syrup and minimal improvement with hyperbaric oxygen treatment. In June and July, 1988, the patient underwent surgical grafting of the remaining defects. These have healed well, the patient is resuming a more normal diet and continues to be free of lymphoma. A number of chemotherapeutic agents have been implicated in the induction of “radiation recall” reactions involving lung, skin, mucosa and other normal tissues (1,2,4.7). The drugs most commonly implicated are doxorubicin and actinomycin-D although radiation-drug interactions have also been reported with bleomycin, cyclophosphamide, methotrexate and others (5). Oral mucositis is the most frequent dose-limiting toxicity of prolonged high-dose methotrexate infusion (8). The regimen MACOPB has been associated with particularly severe acute mucosal reactions with a 50-60% incidence of moderate and 20-30% incidence of severe, mucositis in patients who have not received irradiation (6). Severe reactions appear to be more common in patients over 60 years of age (6). Clearly several drugs could have contributed to the acute reaction and/ or the apparant “recall” in this patient. Steroid withdrawal has also been reported to activate latent radiation injury in the lung and heart (3). and the timing of this patient’s post-treatment deterioration suggests that steroid withdrawal could also have played a role in the patient’s course. Although doxorubicin is the most likely agent to have caused this patient’s recall reaction, we feel that it was the combination of drug-induced. radiation-recall, a highly aggressive, mucosally toxic multi-drug regimen, and. possibly. the added effect of steroid withdrawal that caused this unusual and severe reaction. Since MACOP-B alone has been associated with severe mucositis. it would have been difficult to implicate this patient’s radiation therapy without the peculiar pattern of his chronic superficial ulceration. Clinical radiation oncologists have long been familiar with the increased mucosal reactions which may occur adjacent to gold crowns and fillings in patients receiving photon irradiation to the oral cavity. Measurements using thermo-luminescent dosimetry suggest that the absorbed dose within I2 mm of the gold may be as high as 180% of the prescribed photon dose (9). Although this patient had wet gauze packed around his gold dental work during most of his radiation therapy and suffered minimal mucositis during treatment, he clearly received a somewhat higher dose to mucosa adjacent to his gold crowns. This was not apparent clinically until I year later when salvage chemotherapy induced a “recall” mucositis. It is, of course. standard radiotherapeutic practice to cover metallic dental work with a material which will shield mucosa from secondary electrons. This case illustrates, however. that the acute mucosal reaction (or lack thereof) experienced by a patient under treatment is not an adequate indicator of the effectiveness of the technique being employed. particularly if doxorubicin or mucosally-toxic chemotherapy may be required in the future. In light of this experience, we recommend that any patient treated with radiation therapy for Waldeyer’s ring lymphoma have capping of all gold dental work with a non-metallic material (such as dental wax) which will comp/efelJ~ and consistently separate the mucosa from all gold surfaces. If MACOP-B is ultimately determined to be a superior regimen for the treatment of non-Hodgkin’s lymphoma, then it should be delivered to patients with a prior history of Waldeyer’s irradiation with extreme caution. If not. consideration should be given to using other effective regimens which have been associated with less mucosal toxicity.
PATRICIA J. EIFEL, M.D. Dept. of Radiation
Therapy
SUZANNE MCCLURE. M.D. Dept. of Internal Medicine Division of Hematology-Oncology University of Texas Medical Branch Galveston, TX
October
1989. Volume
17, Number
4
1. Aristizabal. S. A.: Miller, R. C.; Schlichtemeier, A. L.; Jones, S. E.: Boone, M. L. M. Adriamycin-irradiation cutaneous complications. Int. J. Radiat. Oncol. Biol. Phys. 2:325-331; 1977. 2. Cassady, J. R.; Richter, M. T.; Piro, A. J.; Jaffe, N. Radiation-adriamycin interactions: preliminary clinical observations. Cancer 36: 946-949; 1975. 3. Castellino, R. A.: Glatstein, E.; Turbow. M. M.; Rosenberg, S.; Kaplan. H. S. Latent radiation injury of lungs or heart activated by steroid withdrawal. Ann. Intern. Med. 80:593-599; 1974. 4. Donaldson, S. S.; Lenon. R. A. Alterations of nutritional status: Impact of chemotherapy and radiation therapy. Cancer 43:20362052: 1979. 5. Dunagin, W. G. Dermatologic toxicity. In: Perry, M. C.. Yarbro, J. W., eds. Toxicity of chemotherapy. Orlando, FA: Grune and Stratton Inc; 1984: 125-154. 6. Klimo. P.; Connors. J. M. MACOP-B chemotherapy for the treatment of diffuse large cell Iymphoma. Ann. Intern. Med. 102:596602; 1985. 7. Mclnerney, D. P.; Bullimore, J. Reactivation of radiation pneumonitis by adriamycin. Br. J. Radiol. 50:224-227: 1977. 8. Oliff. A.: Blever. W. A.: Poolack. D. G. Methotrexate-induced oral mucosisis an-d salivary methotrexate concentrations. Cancer Chemother. Pharmacol. 2:225-226: 1979. 9. Thambi. V.: Mm-thy, A. K.: Alder. G.; Dartha, P. K. Dose perturbation resulting from gold fillings in patients with head and neck cancers. Int. J. Radiat. Oncol. Biol. Phys. 5:581-582: 1979.
PROTECTION OF BONE MARROW BY WR-2721 AFTER FRACTIONATED IRRADIATION To the Editor; In the August, 1988 issue of the Journal, Travis et al. reported that bone marrow protection by WR-2721 is dependent on dose and will be less after clinically relevant small dose fractions (2). They also pointed out, however, that sufficient protection remains and can be exoerimentallv measured even over a clinically relevant dose range of 2 Gy or less per fraction. Their results therefore encourage investieators to continue to search for protectors which do not protect tumors and can be clinicallv useful We have reported findings which support bone marrow protection at low dose. but additionallv ~ suaaest that there may be a benefit to fractionated treatment over single dose treatment due to tumor cytotoxicity of WR-273 I with minimal tumor radioprotection (1). Using LDSolxo as an endpoint and administering 365 mg/kg of WR-272 I intraperitoneally thirty minutes prior to whole body irradiation of C3H mice, we found a protection factor of 2.3 for single dose treatment and 1.45 for a five fraction reeimen. This comoares to a nrotection factor of 1.8 for a single fraction and I .3 for four fractions as reported by Travis et al. using 200 mg/kg of WR-272 I. Using a CFU survival assay at doses down to 0.51.75Gy/fraction, they also found the protection factor decreased from 2.3 for a single fraction to I .3 for four fractions. Neither their work nor ours showed any evidence of WR-272 I cytotoxicity towards the bone marrow. However using a mouse lymphoma model, we found a significant increase in tumor regrowth delay as well as a small but significant improvement in survival when WR-2721 was added to five 0.40 Gy fractions of total body irradiation (I ). We found the therapeutic gain. defined as the ratio of the protection factor for bone marrow to the protection factor for lymphoma, to be better for the fractionated treatment than for the single dose treatment primarily due to the lack of Iymphoma radioprotection plus discernable tumor cytotoxicity of WR-272 I. That effect of WR-272 I on lymphoma had not been previously reported. On the basis of these encouraging results, we have initiated a phase I clinical trial to test the use of WR-2721 given prior to whole body irradiation in patients with advanced non-Hodgkin’s lymphoma. The intent is to use WR-272 I to its greatest potential by protecting bone marrow during TBI, while keeping the number of treatments relatively small so as to avoid dose limiting toxicity.
LAWRENCE R. COIA, M.D. DARRELL Q. BROWN, PH.D. Department of Radiation Oncology School of Medicine Fox Chase Cancer Center Central and Shelmire Aves Philadelphia, PA 19 I I 1
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.
I. J. Radiation
Oncology
0 Biology 0 Physics
discreet, very superficial mucosal ulcers without clinical evidence of infection. These were located bilaterally on the lateral borders of the tongue and buccal mucosa, and on the hard palate adjacent to gold dental work in the left posterior maxilla (Fig. I). Lateral tongue involvement was greater on the right where the gold crowns were on both the first and second lower molars. This pattern indicated that his severe mucosal reaction to chemotherapy must have been due, in part, to a radiation recall phenomenon. During subsequent visits he was noted to develop additional small lesions in the mid hard palate at some distance from his dental work. He was managed throughout with careful oral care and liquid dietary supplements with which he was able to maintain his weight. The patient experienced some clinical improvement after treatment with beta-methasone syrup and minimal improvement with hyperbaric oxygen treatment. In June and July, 1988, the patient underwent surgical grafting of the remaining defects. These have healed well, the patient is resuming a more normal diet and continues to be free of lymphoma. A number of chemotherapeutic agents have been implicated in the induction of “radiation recall” reactions involving lung, skin, mucosa and other normal tissues (1,2,4.7). The drugs most commonly implicated are doxorubicin and actinomycin-D although radiation-drug interactions have also been reported with bleomycin, cyclophosphamide, methotrexate and others (5). Oral mucositis is the most frequent dose-limiting toxicity of prolonged high-dose methotrexate infusion (8). The regimen MACOPB has been associated with particularly severe acute mucosal reactions with a 50-60% incidence of moderate and 20-30% incidence of severe, mucositis in patients who have not received irradiation (6). Severe reactions appear to be more common in patients over 60 years of age (6). Clearly several drugs could have contributed to the acute reaction and/ or the apparant “recall” in this patient. Steroid withdrawal has also been reported to activate latent radiation injury in the lung and heart (3). and the timing of this patient’s post-treatment deterioration suggests that steroid withdrawal could also have played a role in the patient’s course. Although doxorubicin is the most likely agent to have caused this patient’s recall reaction, we feel that it was the combination of drug-induced. radiation-recall, a highly aggressive, mucosally toxic multi-drug regimen, and. possibly. the added effect of steroid withdrawal that caused this unusual and severe reaction. Since MACOP-B alone has been associated with severe mucositis. it would have been difficult to implicate this patient’s radiation therapy without the peculiar pattern of his chronic superficial ulceration. Clinical radiation oncologists have long been familiar with the increased mucosal reactions which may occur adjacent to gold crowns and fillings in patients receiving photon irradiation to the oral cavity. Measurements using thermo-luminescent dosimetry suggest that the absorbed dose within I2 mm of the gold may be as high as 180% of the prescribed photon dose (9). Although this patient had wet gauze packed around his gold dental work during most of his radiation therapy and suffered minimal mucositis during treatment, he clearly received a somewhat higher dose to mucosa adjacent to his gold crowns. This was not apparent clinically until I year later when salvage chemotherapy induced a “recall” mucositis. It is, of course. standard radiotherapeutic practice to cover metallic dental work with a material which will shield mucosa from secondary electrons. This case illustrates, however. that the acute mucosal reaction (or lack thereof) experienced by a patient under treatment is not an adequate indicator of the effectiveness of the technique being employed. particularly if doxorubicin or mucosally-toxic chemotherapy may be required in the future. In light of this experience, we recommend that any patient treated with radiation therapy for Waldeyer’s ring lymphoma have capping of all gold dental work with a non-metallic material (such as dental wax) which will comp/efelJ~ and consistently separate the mucosa from all gold surfaces. If MACOP-B is ultimately determined to be a superior regimen for the treatment of non-Hodgkin’s lymphoma, then it should be delivered to patients with a prior history of Waldeyer’s irradiation with extreme caution. If not. consideration should be given to using other effective regimens which have been associated with less mucosal toxicity.
PATRICIA J. EIFEL, M.D. Dept. of Radiation
Therapy
SUZANNE MCCLURE. M.D. Dept. of Internal Medicine Division of Hematology-Oncology University of Texas Medical Branch Galveston, TX
October
1989. Volume
17, Number
4
1. Aristizabal. S. A.: Miller, R. C.; Schlichtemeier, A. L.; Jones, S. E.: Boone, M. L. M. Adriamycin-irradiation cutaneous complications. Int. J. Radiat. Oncol. Biol. Phys. 2:325-331; 1977. 2. Cassady, J. R.; Richter, M. T.; Piro, A. J.; Jaffe, N. Radiation-adriamycin interactions: preliminary clinical observations. Cancer 36: 946-949; 1975. 3. Castellino, R. A.: Glatstein, E.; Turbow. M. M.; Rosenberg, S.; Kaplan. H. S. Latent radiation injury of lungs or heart activated by steroid withdrawal. Ann. Intern. Med. 80:593-599; 1974. 4. Donaldson, S. S.; Lenon. R. A. Alterations of nutritional status: Impact of chemotherapy and radiation therapy. Cancer 43:20362052: 1979. 5. Dunagin, W. G. Dermatologic toxicity. In: Perry, M. C.. Yarbro, J. W., eds. Toxicity of chemotherapy. Orlando, FA: Grune and Stratton Inc; 1984: 125-154. 6. Klimo. P.; Connors. J. M. MACOP-B chemotherapy for the treatment of diffuse large cell Iymphoma. Ann. Intern. Med. 102:596602; 1985. 7. Mclnerney, D. P.; Bullimore, J. Reactivation of radiation pneumonitis by adriamycin. Br. J. Radiol. 50:224-227: 1977. 8. Oliff. A.: Blever. W. A.: Poolack. D. G. Methotrexate-induced oral mucosisis an-d salivary methotrexate concentrations. Cancer Chemother. Pharmacol. 2:225-226: 1979. 9. Thambi. V.: Mm-thy, A. K.: Alder. G.; Dartha, P. K. Dose perturbation resulting from gold fillings in patients with head and neck cancers. Int. J. Radiat. Oncol. Biol. Phys. 5:581-582: 1979.
PROTECTION OF BONE MARROW BY WR-2721 AFTER FRACTIONATED IRRADIATION To the Editor; In the August, 1988 issue of the Journal, Travis et al. reported that bone marrow protection by WR-2721 is dependent on dose and will be less after clinically relevant small dose fractions (2). They also pointed out, however, that sufficient protection remains and can be exoerimentallv measured even over a clinically relevant dose range of 2 Gy or less per fraction. Their results therefore encourage investieators to continue to search for protectors which do not protect tumors and can be clinicallv useful We have reported findings which support bone marrow protection at low dose. but additionallv ~ suaaest that there may be a benefit to fractionated treatment over single dose treatment due to tumor cytotoxicity of WR-273 I with minimal tumor radioprotection (1). Using LDSolxo as an endpoint and administering 365 mg/kg of WR-272 I intraperitoneally thirty minutes prior to whole body irradiation of C3H mice, we found a protection factor of 2.3 for single dose treatment and 1.45 for a five fraction reeimen. This comoares to a nrotection factor of 1.8 for a single fraction and I .3 for four fractions as reported by Travis et al. using 200 mg/kg of WR-272 I. Using a CFU survival assay at doses down to 0.51.75Gy/fraction, they also found the protection factor decreased from 2.3 for a single fraction to I .3 for four fractions. Neither their work nor ours showed any evidence of WR-272 I cytotoxicity towards the bone marrow. However using a mouse lymphoma model, we found a significant increase in tumor regrowth delay as well as a small but significant improvement in survival when WR-2721 was added to five 0.40 Gy fractions of total body irradiation (I ). We found the therapeutic gain. defined as the ratio of the protection factor for bone marrow to the protection factor for lymphoma, to be better for the fractionated treatment than for the single dose treatment primarily due to the lack of Iymphoma radioprotection plus discernable tumor cytotoxicity of WR-272 I. That effect of WR-272 I on lymphoma had not been previously reported. On the basis of these encouraging results, we have initiated a phase I clinical trial to test the use of WR-2721 given prior to whole body irradiation in patients with advanced non-Hodgkin’s lymphoma. The intent is to use WR-272 I to its greatest potential by protecting bone marrow during TBI, while keeping the number of treatments relatively small so as to avoid dose limiting toxicity.
LAWRENCE R. COIA, M.D. DARRELL Q. BROWN, PH.D. Department of Radiation Oncology School of Medicine Fox Chase Cancer Center Central and Shelmire Aves Philadelphia, PA 19 I I 1
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.