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Standard and high dose chemotherapy for advanced soft tissue sarcomas
Annals of Oncology 3 (Suppl. 2): S81-S83, 1992. © 1992 Kluwer Academic Publishers. Primed in the Netherlands.
Original article Standard and high dose chemotherapy for advanced soft tissue sarcomas S. Patel & R. S. Benjamin U.T.M.D. Anderson Cancer Center, Houston, TX, U.S.A.
tionship of alkylating agents and adriamycin constitutes the theoretical rationale for use of higher doses of chemotherapy, which have become feasible, with the advent of growth factors for bone marrow support. While this approach seems promising in its infancy, with improved complete and overall response, its ultimate effect on survival is anxiously awaited. The limited experience available in the literature with even more aggressive approaches like marrow ablative doses of chemotherapy followed by bone marrow transplantation, have been uniformly disappointing, with extremely short lived responses and extremely high morbidity and cost. As clinical research continues to improve our understanding and ability to implement the currently available therapeutic armamentarium, the search for newer and better drugs needs to continue. Patients should be encouraged to enroll in experimental protocols, if we are to answer relevant questions and hopefully impact on this otherwise lethal problem.
Significant improvements have been made in overall phamide to doxorubicin based regimens, however, failed management and outcome of localized soft tissue sar- to show any beneficial effect [10-12]. It was based on comas over the last decade, however, progress in the these studies that, doxorubicin and DTIC based prooverall outcome of advanced soft tissue sarcomas has grams became front line chemotherapy options for apbeen less than impressive. Resection of pulmonary propriate patients with advanced soft tissue sarcomas. metastases is indeed a valid option for a select group of The issues of dose inensity and schedule of administrapatients with a favorable prognosis [1, 2]. This tion were also studied [13-15]. Regimens including >70 approach has been reported to result in a 5 year sur- mg/m2 of doxorubicin have revealed better responses vival of 10%-30% [3, 4]. However, for the remaining compared to those using doxorubicin at lower doses. majority of patients, combination chemotherapy con- While response rates were identical to either bolus or intinues to be the only available treatment modality. This fusional schedule of administration, cardiotoxicity was article will include a brief overview of the results of significantly less with the latter mode. some of the traditional standard, and the more recent, experimental high dose chemotherapy regimens, used Table I. Chemotherapy of soft tissue sarcomas. alone or in conjunction with bone marrow support. %RR Several commercially available chemotherapeutic agents have been tested in soft tissue sarcomas with Ifosfamide 30 single agent response rates ranging up to 30% (Table 1). Doxorubicin 26 21 Doxorubicin used to be the single most active agent in MTX, standard dose 17 the pre-ifosfamide era. While dimethyl triazeno imida- Decarbazine (DTIC) Actinomycin-D 16 zole carboxamide (DTIC) has only modest activity as a MTX high dose 13 single agent, its combination with doxorubicin was 5-fluoracil 12 reported to result in a response rate of 42% [5]. Several Vincristine 12 12 other prospective randomized trials also confirmed the Cisplatin 8 superiority of doxorubicin and DTIC combination over Cyclophosphamide Etoposide 8 single agent doxorubicin, in soft tissue sarcomas [6-9]. 6 Bleomycin Similar studies evaluating the addition of cyclophos-
Downloaded from http://annonc.oxfordjournals.org/ at Harvard University on July 1, 2015
Summary. While significant improvements have been made in the management of localized soft tissue sarcomas, enabling the realization of better functional results and a better overall outcome, progress in metastatic disease has been less than impressive. Adriamycin and DTIC based chemotherapy programs have resulted in response rates of upto 50%, with a small but finite cure fraction, especially in conjunction with surgical resection of residual abnormalities. The decade of the 80s experienced a considerable amount of enthusiasm in exploring the role of ifosfamide and mesna, and identified its definite usefullness as an effective salvage regimen with response rates of approximately 25%-30% in adriamycin failures. Studies evaluating the role of ifosfamide as upfront line agent in combination with adriamycin have met with increased toxicities without a significant additive therapeutic benefit, probably as a result of compromised dose intensity of each individual agent. The steep linear logdose response rela-
82
It is quite apparent from the data that we have reviewed so far, that, chemotherapy used in standard doses has not made any significant and meaningful impact on the survival of patients with metastatic soft tissue sarcomas. The major thrust of clinical research therefore, over the last few years has been focused around dose intensification of the commercially available agents, with continued but unrewarding efforts at identification of newer, more effective agents. The basic rationale for trials evaluating higer dose intensity lies in the apparent dose response relationship established with doxorubicin, and the steep linear log-dose response relationship described with alkylating agents. The ultimate goal that one would hope to achieve is obviously, an increment in the response rate and improvement in the quality of response, sufficient enough to impact favorably on the disease free and overall survival. One of the major problems that one encounters with this approach is prolonged life threatening myelosuppression. This particular side effect can now be significantly minimized by the use of growth factors. Several studies have proven the efficacy of these compounds in shortening the duration and decreasing the intensity of chemotherapy induced absolute neutropenia [25-27]. Our experience with granulocytemacrophage colony-stimulating factor (GM-CSF) in conjuction with dose intensive chemotherapy including cyclophosphamide, doxorubicin and dacarbazine, also corroborates with the evidence in the literature [28|. We also observed a significant improvement in the absolute neutrophil count (ANC), the duration of ANC less than 500 cells/cu.mm; and an earlier recovery of the neutrophil count to 1500 so as to enable early retreatment. With regards to tumor response rates, the preliminary results of the EORTC study evaluating
doxorubicin and ifosfamide in conjunction with GMCSF, in a subset of patients reveals an impressive 50% overall response rate in a multicenter cooperative group trial [29]. While this strategy of dose intensification with growth factor support seems very promising in its early infancy, its ultimate effect on survival is anxiously awaited. The enthusiasm for marrow ablative doses of chemotherapy with or without total body radiation, followed by autologous bone marrow transplant seems to be weaning off. The results of the earlier studies performed in the mid to late 80s have been uniformly disappointing with very short durations of response, significantly high cost and treatment related morbidity and mortality and an obvious lack of improvement in survival [30, 31]. Among others, the most apparent reason seems to be the lack of an effective cytoreductive regimen with minimal non-myelosuppressive toxicities. In conclusion then, it is fair to state that our efforts so far, at improving the results of systemic therapy have been far less than rewarding. The current areas of research including dose intensification with growth factor support seem quite promising. While we continue our endeavours at better implementation of the currently available therapeutic armamentarium, and improve our understanding to put the various growth factors to better use, the search for newer and more effective drugs needs to continue. Patients should be encouraged to participate in research protocols to help answer relevant questions, so as to impact on this otherwise lethal problem.
References 1. Putnam JG Jr, Roth JA, Wesley MN et al. Analysis of Prognostic Factors in Patients Undergoing Resection of Pulmonary Metastasis from Soft Tissue Sarcomas. Journal of Thoracic Cardiovascular Surgery 1984; 87: 260-8. 2. Joseph WL, Morton DL, Adkins PC. Prognostic significant of tumor doubling time and evaluating operability in pulmonary metastatic disease. Journal of Thoracic and Cardiovascular Surgery 1971:61:23-32. 3. Putnam JA, Wesley MN. Deferring determinants of prognosis following resection of pulmonary metastasis from osteogenic and soft tissue sarcoma patients. Cancer 1985; 55: 1361-6. 4. Creagan ET, Fleming TR, Edmonson JH et al. Pulmonary resection for metastatic non-osteogenic sarcoma. Cancer 1979; 44: 1908-12. 5. Gottlieb JA, Baker LH, Quagliana JM et al. Chemotherapy of sarcomas with a combination of adriamycin and DTIC. Cancer 1972; 30: 1632-8. 6. Omura G, Major F, Blessing J et al. A randomized study of adriamycin with and without DTIC in advanced uterine sarcomas. Cancer 1983; 52:626-32. 7. Lerner H, Amato D, Stephens C et al. Leiomyosarcoma; ECOG experience with 222 patients. Proceedings of American Association of Cancer Research 1983; 24: 142. 8. Benjamin R, Gottlieb J, Baker L. CYVADIC VS CYVADACT a randomized trial of cyclophosphamide, vincristine and adriamycin plus either dacarbazine or actinomycin D in metastatic sarcomas. Proceedings of American Association. 1976; 17:256. 9. Borden E, Amato D, Enterline H et al. Randomized comparison of adriamycin regimens for treatment of metastatic soft tissue sarcomas. Journal of Clinical Oncology 1987; 5: 840-50.
Downloaded from http://annonc.oxfordjournals.org/ at Harvard University on July 1, 2015
The advent of mesna in 1982 resulted in resurgeance of isfosfamide. This combination has since been extensively studied as a salvage regimen in patients who had failed prior doxorubicin based chemotherapy, resulting in response rates of 25%-30% [16-19]. Several investigators attempted to capitalize on these promising results by combining ifosfamide with other agents achieving varying degrees of succes. The combination of ifosfamide and doxorubicin with or without DTIC was of particular interest to 'optimize' front line therapy by combining the two best available agents [2022]. The Dana Farber Cancer Institute study revealed increased response rates of 47%, however, the preliminary analyses of the EORTC study [20] and the multi institutional study [21] failed to confirm the additive beneficial effect of ifosfamide to doxorubicin. Two large cooperative group trials randomizing patients to doxorubicin versus doxorubicin plus ifosfamide are currently in progress. The preliminary results of the EORTC study [23] indicate no difference in response rates to either single agent doxorubicin and ifosfamide. The intergroup study however, does reveal an improved response rate for the combination, but there is no statistically significant difference in survival [24].
83
23.
24.
25.
26.
27.
28.
29.
30. 31.
with advanced sarcoma. Seminars in Oncology 1990; 17 (2 Supplement 4): 41-9. Santoro A, Rouesse J, Stewart W et al. A randomized EORTC study in advanced soft tissue sarcomas adriamycin vs adriamycin plus ifosfamide vs CYVADIC. Proceedings of American Society of Clinical Oncology 1990; 9 (309): 1196. Antman KH, Baker L, Balcerzak S et al. An inter-group phase III randomized study of doxorubicin and dacarbazine with or without Ifosfamide and MESNA in advanced soft tissue and bone sarcomas. Proceedings of American Society of Clinical Oncology 1990; 9 (311): 1203. Gabrilove JL, Jakubowski A, Sher H et al. Effect of granulocyte colony stimulating factor on neutropenia and associated morbidity due to chemotherapy for transitional cell carcinoma of urothelium. New England Journal of Medicine 1988; 318: 1414-22. Crawford J, Ozer H, Stoller R et al. Reduction granulocyte colony stimulating factor of the fever and neutropenia induced by chemotherapy in patients with small cell lung cancer. New England Journal of Medicine 1991; 325: 164-70. Antman KH, Griffin JD, Elias A et al. Effect of recombinant human granulocyte macrophage colony stimulating factor on chemotherapy induced myelosuppression. New England Journal of Medicine 1988; 319: 593-8. Vadhan-Raj S, Broxmeyer H, Hittleman WN et al. Abrogating chemotherapy induced myelosuppression by GM-CSF; optimizing the schedule. Proceedings of ASCO 1991; 10 (349): 1241. Steward WP, Verweij J, Somers R et al. High dose chemotherapy with two schedules of recombinant human granulocyte macrophage colony stimulating factor in the treatment of soft tissue sarcomas. Proceeding of ASCO 1991; 10(349): 1240. Cheson BD, Lacerna L, Leyland-Jones B et al. Autologous bone marrow transplantation current status in future directions. Annuals of Internal Medicine 1989; 110:51-65. Antman KH, Paul Eder J, Frei E. High dose chemotherapy with bone marrow support for solid tumors. Advances in Oncology 1987; 221-35.
Correspondence to: Patel Shreyaskumar, M.D. Dept. of Medical Oncology MD Anderson Cancer Center 1515HolcombeBlvd. Houston, TX 77030 U.S.A.
Downloaded from http://annonc.oxfordjournals.org/ at Harvard University on July 1, 2015
10. Schoenfeld DA, Rosenbaum C, Horton J et al. A comparison of adriamycin vs vincristine and adriamycin and cyclophosphamide vs vincristine actinomycin D and cyclophosphamide for advanced sarcoma. Cancer 1982; 50: 2757-62. 11. Baker LH, Frank J, Fine G et al. Combination chemotherapy using adriamycin, DTIC, cyclophosphamide and actinomycin D for advanced soft tissue sarcomas; a randomized competitive trial. A phase III, SWOG study. Journal of Clinical Oncology 5: 851-61. 12. Muss H, Bundy B, Di Saia P et al. Treatment of recurrent advanced uterine sarcomas - a randomized trial of doxorubicin vs doxorubicin in cyclophosphamide. Cancer 1985; 55: 164853. 13. Pinedo H, Bramwell B, Mouridson M et al. CYVAD1C in advanced soft tissue sarcoma - a randomized study comparing two schedules. A study of the EORTC soft tissue and bone sarcoma group. Cancer 1984; 53: 1825-32. 14. Bodey G, Rodriguez W et al. PEPA program for malignant sarcomas randomized trial during remission induction chemotherapy. Cancer 1981; 47: 2422-9. 15. Baker L, Green S, Ryan J et al. Combined mortality for disseminated soft tissue sarcoma phase III. Proceeding of American Society of Clinical Oncology 1987; 6: 138. 16. Antman KH, Ryan K, Elias A et al. Response to Ifosfamide and MESNA: 124 previously treated patients with metastatic unresectable sarcoma. Journal of Clinical Oncology 1989; 7: 126-31. 17. Scheulen M, Eiderlen, Bremer K et al. Efficacy of Ifosfamide and refractory malignant diseases and uroprotection by MESNA: Results of a clinical phase II study with 151 patients. Cancer Treatment Reviews 1983; 10 (Supplement A): 91-101. 18. Magrath I, Sandlund J, Rayner A et al. Treatment of recurrent sarcomas with Ifosfamide. Proceeding of American Society of Clinical Oncology 1985; 4: 136. 19. Klein H, Wickramanayake P, Coerper C et al. High dose Ifosfamide and MESNA as continuous infusion over 5 days-a phase I-II trial. Cancer Treatment Review 1983; 10 (Supplement A): 671-3. 20. Schutte J, Mouridsen HT, Stewart W et al. Ifosfamide plus doxorubicin in previously untreated patients with advanced soft tissue sarcoma. European Journal of Cancer 1990; 26 (5): 558-61. 21. Loehrer J Sr., Sledge GW Jr., Nicaise C et al. Ifosfamide with doxorubicin in metastatic adult sarcomas: multi-institutional phase II trial. Journal of Clinical Oncology 1989; 7: 1655-9. 22. Elias A, Ryan L, Aisner J et al. MESNA, Doxorubicin, Ifosfamide, Dacarbazine (MAID) complete regimens for adults
Original article Standard and high dose chemotherapy for advanced soft tissue sarcomas S. Patel & R. S. Benjamin U.T.M.D. Anderson Cancer Center, Houston, TX, U.S.A.
tionship of alkylating agents and adriamycin constitutes the theoretical rationale for use of higher doses of chemotherapy, which have become feasible, with the advent of growth factors for bone marrow support. While this approach seems promising in its infancy, with improved complete and overall response, its ultimate effect on survival is anxiously awaited. The limited experience available in the literature with even more aggressive approaches like marrow ablative doses of chemotherapy followed by bone marrow transplantation, have been uniformly disappointing, with extremely short lived responses and extremely high morbidity and cost. As clinical research continues to improve our understanding and ability to implement the currently available therapeutic armamentarium, the search for newer and better drugs needs to continue. Patients should be encouraged to enroll in experimental protocols, if we are to answer relevant questions and hopefully impact on this otherwise lethal problem.
Significant improvements have been made in overall phamide to doxorubicin based regimens, however, failed management and outcome of localized soft tissue sar- to show any beneficial effect [10-12]. It was based on comas over the last decade, however, progress in the these studies that, doxorubicin and DTIC based prooverall outcome of advanced soft tissue sarcomas has grams became front line chemotherapy options for apbeen less than impressive. Resection of pulmonary propriate patients with advanced soft tissue sarcomas. metastases is indeed a valid option for a select group of The issues of dose inensity and schedule of administrapatients with a favorable prognosis [1, 2]. This tion were also studied [13-15]. Regimens including >70 approach has been reported to result in a 5 year sur- mg/m2 of doxorubicin have revealed better responses vival of 10%-30% [3, 4]. However, for the remaining compared to those using doxorubicin at lower doses. majority of patients, combination chemotherapy con- While response rates were identical to either bolus or intinues to be the only available treatment modality. This fusional schedule of administration, cardiotoxicity was article will include a brief overview of the results of significantly less with the latter mode. some of the traditional standard, and the more recent, experimental high dose chemotherapy regimens, used Table I. Chemotherapy of soft tissue sarcomas. alone or in conjunction with bone marrow support. %RR Several commercially available chemotherapeutic agents have been tested in soft tissue sarcomas with Ifosfamide 30 single agent response rates ranging up to 30% (Table 1). Doxorubicin 26 21 Doxorubicin used to be the single most active agent in MTX, standard dose 17 the pre-ifosfamide era. While dimethyl triazeno imida- Decarbazine (DTIC) Actinomycin-D 16 zole carboxamide (DTIC) has only modest activity as a MTX high dose 13 single agent, its combination with doxorubicin was 5-fluoracil 12 reported to result in a response rate of 42% [5]. Several Vincristine 12 12 other prospective randomized trials also confirmed the Cisplatin 8 superiority of doxorubicin and DTIC combination over Cyclophosphamide Etoposide 8 single agent doxorubicin, in soft tissue sarcomas [6-9]. 6 Bleomycin Similar studies evaluating the addition of cyclophos-
Downloaded from http://annonc.oxfordjournals.org/ at Harvard University on July 1, 2015
Summary. While significant improvements have been made in the management of localized soft tissue sarcomas, enabling the realization of better functional results and a better overall outcome, progress in metastatic disease has been less than impressive. Adriamycin and DTIC based chemotherapy programs have resulted in response rates of upto 50%, with a small but finite cure fraction, especially in conjunction with surgical resection of residual abnormalities. The decade of the 80s experienced a considerable amount of enthusiasm in exploring the role of ifosfamide and mesna, and identified its definite usefullness as an effective salvage regimen with response rates of approximately 25%-30% in adriamycin failures. Studies evaluating the role of ifosfamide as upfront line agent in combination with adriamycin have met with increased toxicities without a significant additive therapeutic benefit, probably as a result of compromised dose intensity of each individual agent. The steep linear logdose response rela-
82
It is quite apparent from the data that we have reviewed so far, that, chemotherapy used in standard doses has not made any significant and meaningful impact on the survival of patients with metastatic soft tissue sarcomas. The major thrust of clinical research therefore, over the last few years has been focused around dose intensification of the commercially available agents, with continued but unrewarding efforts at identification of newer, more effective agents. The basic rationale for trials evaluating higer dose intensity lies in the apparent dose response relationship established with doxorubicin, and the steep linear log-dose response relationship described with alkylating agents. The ultimate goal that one would hope to achieve is obviously, an increment in the response rate and improvement in the quality of response, sufficient enough to impact favorably on the disease free and overall survival. One of the major problems that one encounters with this approach is prolonged life threatening myelosuppression. This particular side effect can now be significantly minimized by the use of growth factors. Several studies have proven the efficacy of these compounds in shortening the duration and decreasing the intensity of chemotherapy induced absolute neutropenia [25-27]. Our experience with granulocytemacrophage colony-stimulating factor (GM-CSF) in conjuction with dose intensive chemotherapy including cyclophosphamide, doxorubicin and dacarbazine, also corroborates with the evidence in the literature [28|. We also observed a significant improvement in the absolute neutrophil count (ANC), the duration of ANC less than 500 cells/cu.mm; and an earlier recovery of the neutrophil count to 1500 so as to enable early retreatment. With regards to tumor response rates, the preliminary results of the EORTC study evaluating
doxorubicin and ifosfamide in conjunction with GMCSF, in a subset of patients reveals an impressive 50% overall response rate in a multicenter cooperative group trial [29]. While this strategy of dose intensification with growth factor support seems very promising in its early infancy, its ultimate effect on survival is anxiously awaited. The enthusiasm for marrow ablative doses of chemotherapy with or without total body radiation, followed by autologous bone marrow transplant seems to be weaning off. The results of the earlier studies performed in the mid to late 80s have been uniformly disappointing with very short durations of response, significantly high cost and treatment related morbidity and mortality and an obvious lack of improvement in survival [30, 31]. Among others, the most apparent reason seems to be the lack of an effective cytoreductive regimen with minimal non-myelosuppressive toxicities. In conclusion then, it is fair to state that our efforts so far, at improving the results of systemic therapy have been far less than rewarding. The current areas of research including dose intensification with growth factor support seem quite promising. While we continue our endeavours at better implementation of the currently available therapeutic armamentarium, and improve our understanding to put the various growth factors to better use, the search for newer and more effective drugs needs to continue. Patients should be encouraged to participate in research protocols to help answer relevant questions, so as to impact on this otherwise lethal problem.
References 1. Putnam JG Jr, Roth JA, Wesley MN et al. Analysis of Prognostic Factors in Patients Undergoing Resection of Pulmonary Metastasis from Soft Tissue Sarcomas. Journal of Thoracic Cardiovascular Surgery 1984; 87: 260-8. 2. Joseph WL, Morton DL, Adkins PC. Prognostic significant of tumor doubling time and evaluating operability in pulmonary metastatic disease. Journal of Thoracic and Cardiovascular Surgery 1971:61:23-32. 3. Putnam JA, Wesley MN. Deferring determinants of prognosis following resection of pulmonary metastasis from osteogenic and soft tissue sarcoma patients. Cancer 1985; 55: 1361-6. 4. Creagan ET, Fleming TR, Edmonson JH et al. Pulmonary resection for metastatic non-osteogenic sarcoma. Cancer 1979; 44: 1908-12. 5. Gottlieb JA, Baker LH, Quagliana JM et al. Chemotherapy of sarcomas with a combination of adriamycin and DTIC. Cancer 1972; 30: 1632-8. 6. Omura G, Major F, Blessing J et al. A randomized study of adriamycin with and without DTIC in advanced uterine sarcomas. Cancer 1983; 52:626-32. 7. Lerner H, Amato D, Stephens C et al. Leiomyosarcoma; ECOG experience with 222 patients. Proceedings of American Association of Cancer Research 1983; 24: 142. 8. Benjamin R, Gottlieb J, Baker L. CYVADIC VS CYVADACT a randomized trial of cyclophosphamide, vincristine and adriamycin plus either dacarbazine or actinomycin D in metastatic sarcomas. Proceedings of American Association. 1976; 17:256. 9. Borden E, Amato D, Enterline H et al. Randomized comparison of adriamycin regimens for treatment of metastatic soft tissue sarcomas. Journal of Clinical Oncology 1987; 5: 840-50.
Downloaded from http://annonc.oxfordjournals.org/ at Harvard University on July 1, 2015
The advent of mesna in 1982 resulted in resurgeance of isfosfamide. This combination has since been extensively studied as a salvage regimen in patients who had failed prior doxorubicin based chemotherapy, resulting in response rates of 25%-30% [16-19]. Several investigators attempted to capitalize on these promising results by combining ifosfamide with other agents achieving varying degrees of succes. The combination of ifosfamide and doxorubicin with or without DTIC was of particular interest to 'optimize' front line therapy by combining the two best available agents [2022]. The Dana Farber Cancer Institute study revealed increased response rates of 47%, however, the preliminary analyses of the EORTC study [20] and the multi institutional study [21] failed to confirm the additive beneficial effect of ifosfamide to doxorubicin. Two large cooperative group trials randomizing patients to doxorubicin versus doxorubicin plus ifosfamide are currently in progress. The preliminary results of the EORTC study [23] indicate no difference in response rates to either single agent doxorubicin and ifosfamide. The intergroup study however, does reveal an improved response rate for the combination, but there is no statistically significant difference in survival [24].
83
23.
24.
25.
26.
27.
28.
29.
30. 31.
with advanced sarcoma. Seminars in Oncology 1990; 17 (2 Supplement 4): 41-9. Santoro A, Rouesse J, Stewart W et al. A randomized EORTC study in advanced soft tissue sarcomas adriamycin vs adriamycin plus ifosfamide vs CYVADIC. Proceedings of American Society of Clinical Oncology 1990; 9 (309): 1196. Antman KH, Baker L, Balcerzak S et al. An inter-group phase III randomized study of doxorubicin and dacarbazine with or without Ifosfamide and MESNA in advanced soft tissue and bone sarcomas. Proceedings of American Society of Clinical Oncology 1990; 9 (311): 1203. Gabrilove JL, Jakubowski A, Sher H et al. Effect of granulocyte colony stimulating factor on neutropenia and associated morbidity due to chemotherapy for transitional cell carcinoma of urothelium. New England Journal of Medicine 1988; 318: 1414-22. Crawford J, Ozer H, Stoller R et al. Reduction granulocyte colony stimulating factor of the fever and neutropenia induced by chemotherapy in patients with small cell lung cancer. New England Journal of Medicine 1991; 325: 164-70. Antman KH, Griffin JD, Elias A et al. Effect of recombinant human granulocyte macrophage colony stimulating factor on chemotherapy induced myelosuppression. New England Journal of Medicine 1988; 319: 593-8. Vadhan-Raj S, Broxmeyer H, Hittleman WN et al. Abrogating chemotherapy induced myelosuppression by GM-CSF; optimizing the schedule. Proceedings of ASCO 1991; 10 (349): 1241. Steward WP, Verweij J, Somers R et al. High dose chemotherapy with two schedules of recombinant human granulocyte macrophage colony stimulating factor in the treatment of soft tissue sarcomas. Proceeding of ASCO 1991; 10(349): 1240. Cheson BD, Lacerna L, Leyland-Jones B et al. Autologous bone marrow transplantation current status in future directions. Annuals of Internal Medicine 1989; 110:51-65. Antman KH, Paul Eder J, Frei E. High dose chemotherapy with bone marrow support for solid tumors. Advances in Oncology 1987; 221-35.
Correspondence to: Patel Shreyaskumar, M.D. Dept. of Medical Oncology MD Anderson Cancer Center 1515HolcombeBlvd. Houston, TX 77030 U.S.A.
Downloaded from http://annonc.oxfordjournals.org/ at Harvard University on July 1, 2015
10. Schoenfeld DA, Rosenbaum C, Horton J et al. A comparison of adriamycin vs vincristine and adriamycin and cyclophosphamide vs vincristine actinomycin D and cyclophosphamide for advanced sarcoma. Cancer 1982; 50: 2757-62. 11. Baker LH, Frank J, Fine G et al. Combination chemotherapy using adriamycin, DTIC, cyclophosphamide and actinomycin D for advanced soft tissue sarcomas; a randomized competitive trial. A phase III, SWOG study. Journal of Clinical Oncology 5: 851-61. 12. Muss H, Bundy B, Di Saia P et al. Treatment of recurrent advanced uterine sarcomas - a randomized trial of doxorubicin vs doxorubicin in cyclophosphamide. Cancer 1985; 55: 164853. 13. Pinedo H, Bramwell B, Mouridson M et al. CYVAD1C in advanced soft tissue sarcoma - a randomized study comparing two schedules. A study of the EORTC soft tissue and bone sarcoma group. Cancer 1984; 53: 1825-32. 14. Bodey G, Rodriguez W et al. PEPA program for malignant sarcomas randomized trial during remission induction chemotherapy. Cancer 1981; 47: 2422-9. 15. Baker L, Green S, Ryan J et al. Combined mortality for disseminated soft tissue sarcoma phase III. Proceeding of American Society of Clinical Oncology 1987; 6: 138. 16. Antman KH, Ryan K, Elias A et al. Response to Ifosfamide and MESNA: 124 previously treated patients with metastatic unresectable sarcoma. Journal of Clinical Oncology 1989; 7: 126-31. 17. Scheulen M, Eiderlen, Bremer K et al. Efficacy of Ifosfamide and refractory malignant diseases and uroprotection by MESNA: Results of a clinical phase II study with 151 patients. Cancer Treatment Reviews 1983; 10 (Supplement A): 91-101. 18. Magrath I, Sandlund J, Rayner A et al. Treatment of recurrent sarcomas with Ifosfamide. Proceeding of American Society of Clinical Oncology 1985; 4: 136. 19. Klein H, Wickramanayake P, Coerper C et al. High dose Ifosfamide and MESNA as continuous infusion over 5 days-a phase I-II trial. Cancer Treatment Review 1983; 10 (Supplement A): 671-3. 20. Schutte J, Mouridsen HT, Stewart W et al. Ifosfamide plus doxorubicin in previously untreated patients with advanced soft tissue sarcoma. European Journal of Cancer 1990; 26 (5): 558-61. 21. Loehrer J Sr., Sledge GW Jr., Nicaise C et al. Ifosfamide with doxorubicin in metastatic adult sarcomas: multi-institutional phase II trial. Journal of Clinical Oncology 1989; 7: 1655-9. 22. Elias A, Ryan L, Aisner J et al. MESNA, Doxorubicin, Ifosfamide, Dacarbazine (MAID) complete regimens for adults