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Combined modality therapy for the treatment of invasive bladder cancer
112
Radiation Oncology, Biology, Physics
FRIDAY,
Volume 24, Supplement 1
NOVEMBER 7:15
- 8:45
13, 1992 a.m.
5OlC FRACTIONATION Jack F. Fowler, Department
IN RADIATION
THERAPY
Ph.D. and Paul M. Harari,
of Human Oncology,
University
- PART II
RADIOBIOLOGICAL
EMPHASIS
M.D. of Wisconsin
Comprehensive
Cancer Center, Madison,
Worldwide variations from “conventional” fractionation schedules regard to radiobiological rationale and a brief summary of clinical results.
WI 53792
of 1.8-2 Gy “daily” (5F/wk)
for 6-7 weeks will be presented;
with
Overall Time: Late Effects Prolongation does not spare late effects. Shortening does not make late effects worse (with possible exception of bladder). Overall Time: Tumor and Earlv Normal-Tissue Effects Prolongation reduces these effects (at &JIJI 50 cGy per day). Shortening enhances damage to both tumors and early normal-tissue reactions. Overall Time: Biolow of cell and Tissue Kinetics . It is the kinetics of cell proliferation that determine the effect of altering overall time in radiotherapy. * Late-responding tissues, in which late complications occur, are slowly proliferating tissues; in which compensatory proliferation does not occur until after the end of a radiotherapy schedule. Early-responding tissues, and most tumors, proliferate rapidly. Doubling times of only a few days become effective within 2 or 3 weeks after starting radiotherapy. * This is the rationale for Accelerated Fractionation. ?? ??
??
??
??
Dose oer Fraction: Radiobiology For a constant total dose and overall time, the effect of changing dose-per-fraction is greater on late-responding than on early-responding tissues and tumors. As characterized by different a/O ratios: small for late (2-4 Gy) but large for early (2 10 Gy) effects. These values are holding up well as clinical data accumulate. Smaller Doses ner Fraction The LQ formula will be described (with time factor) Spare late complications more than tumor damage. and simple examples given. This is the rationale for hvnerfractionation. Biologically Effective Dose and ERD will be explained. Larger Doses ner Fraction Enhance late complications more than tumor cell kill. To be avoided, except for very small volumes (stereotaxic or brachytherapy) or palliation. ??
??
?? ??
?? ??
Ontimum Fractionation Shorter overall times, but not so short that total dose must be reduced below 70 Gy. Smaller doses-per-fraction than 2 Gy, so as not to cause excessive late complications Therefore use 2 fractions per day to avoid prolongation: (1.2-l .6 Gy). The minimum intervals must be at least 6 hours. (This is difficult with 3F/day.) ??
??
(keep below 117 Gys).
?? ??
502 NON-RADIATION
THERAPY
Anna T. Meadows,
M.D.
The Children’s
Hospital
LATE EFFECT OF CANCER
of Philadelphia,
University
TREATMENT
of Pennsylvania
IN CHILDREN
School of Medicine,
Philadelphia,
PA 19104
As long-term survival after cancer in childhood now is approaching 70% overall, the concern for late morbidity and studies dealing with these concerns are increasing. By the year 2000 one in every 1000 young adults will be a survivor of childhood cancer. Major concerns specific while concern regarding vital organ dysfunction and for children are those dealing with growth, development and sexual maturation, carcinogenesis are shared by children and adults, Treatment and genetic predisposition are the major etiologic categories responsible for late occurring disabilities. Other environmental and life-style factors will undoubtedly assume greater importance in children as more survive beyond the third and fourth decades of life. Growth appears development, cognition offender. Methotrexate and become chronic.
unaffected by chemotherapy, although steroids and methotrexate have been shown to affect bone density. Intellectual and related scholastic achievement are affected by chemotherapy, parenteral methotrexate being the most common can also affect the liver, gastrointestinal trace and lungs, and, in appropriate doses and duration, dysfunction may persist
Proceedings of the 34th Annual ASTRO Meeting
113
The most serious long-term organ toxicities likely to be related to cancer chemotherapy are those involving the heart and the kidney, the former incriminating the anthracylines, such as daunorubicin and doxorubicin, and the latter implicating the platinum compounds and ifosfamide. Alkylating agents have been shown to affect gonadal function, perhaps less so in the young and differentially in the sexes. Drugs in this class also behave as leukemogens with varying degrees of efficiency, and this seems unrelated to age. Another recently identified leukemogen, etoposide, seems relatively specific to the leukemia produced (M4 with llq23 abnormality) and follows a particular schedule of drug administration. Second solid tumor malignancies are primarily related to radiation therapy and may take decades to become manifest. Secondary leukemias occur within 10 years in anuroximatelv 4% of individuals heavily treated with certain alkvlators. Of the agents used in children, nitrogen mustard, procarbazine (as in MOPPj, and the nitrosoureas are the most common. Cyclophosphamide appears less leukemogenic and it is &early to tell what will develop in ifosfamide-treated patients. Since many children are treated with ifosfamide and etoposide simultaneously together, the relative contributions of each to new leukemia generation will be obscured. Genetic susceptibility to certain second neoplasms may exert a more powerful influence than any therapeutic modality. The most common of these are neurofibromatosis, the genetic form of retinoblastoma, and the Li-Fraumeni syndrome. In each of these conditions, recognition of some individuals at risk is provided by the clinical presentation. The genes responsible for all three conditions have been identified. Questions regarding appropriate means of counseling and surveillance for second cancers and other late effects in these and other survivors are the subject of intense study.
503 LOWER GASTROINTESTlNAL MALIGNANCIES Bruce D. Minsky, M.D. Department of Radiation Oncology Memorial Sloan-Kettering Cancer Center, New York, NY 10021 Radiation therapy has a significant role in the adjuvant treatment of lower gastrointestinal malignancies. Furthermore, there are data to suggest that radiation therapy is an integral component of the conservative management (organ preservation) of rectal and anal cancers. This refresher course will review the current knowledge as well as ongoing and future research strategies in lower gastrointestinal malignancies. 1. Colon Cancer. The standard adjuvant treatment for node positive or high risk transmural colon cancer is post-operative 5FU/Levamisole. There are retrospective data to suggest that certain subsets of high risk patients may benefit from post-operative radiation therapy. 2. Rectal Cancer. Randomized trials have revealed a significant increase in local control and survival with the combination of post-operative radiation therapy plus chemotherapy in patients with uansmural and/or node positive resectable rectal cancer. Despite these improvements, post-operative combined modality therapy is associated with an approximately 35% incidence of Grade 3+ toxicity. Recent data suggest that the use of pre-operative combined modality therapy may be associated with less toxicity as well as an increased chance of sphincter preservation. In patients with locally advanced/unresectable rectal cancer, the addition of intraoperative radiation therapy may further improve local control. 3. Anal Cancer. The use of combined 5FU/Mitomycin -C and radiation therapy is effective in the treatment of squamous cell carcinoma of the anus. The RTQG has recently completed a randomized trial addressing the question of the effectiveness and toxicity of Mitomycin-C. Future intergroup Phase II trials are in the planning stages and will be presented.
504 COMBINED MODALITY THERAPY FOR THE TREATMENT OF INVASIVE BLADDER CANCER William U. Shipley, M.D. and Anthony L. Zietman, M.D. Department of Radiation Oncology, Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA 02114 Chemo-radiotherapy can lx integrated with transurethral surgery for local cure of the cancer in the bladder in SO-70% of patients. Because local cure will not be achieved in all patients with invasive bladder cancer due to the heterogeneity in the biology of these tumors, how can patients who are likeliest to succeed be appropriately selected? Can this be achieved without compromising patient survival? The answers, insofar as they are available, to these and other important questions with patients presenting with this heterogeneous disease will be reviewed based on the experience available as of 1991. The sta$ard,treatment for patients with muscle-invading bladder cancer in the U.S. is radical cystectomy with or without radiation therapy and in Europe ts radical radiotherapy. The results of such treatment have been generally unsatisfactory with 40% or more patients developing systemtc disease with a 5 year survival rate of less than 50%. Combination chemotherapy regimens will be reviewed (using cisplatin and methouexate) which can provide a 30-50% clinical complete response rate (negative biopsy, negative urine cytology) of the primary tumor. However, even in clinically complete responding patients, 40% of
Radiation Oncology, Biology, Physics
FRIDAY,
Volume 24, Supplement 1
NOVEMBER 7:15
- 8:45
13, 1992 a.m.
5OlC FRACTIONATION Jack F. Fowler, Department
IN RADIATION
THERAPY
Ph.D. and Paul M. Harari,
of Human Oncology,
University
- PART II
RADIOBIOLOGICAL
EMPHASIS
M.D. of Wisconsin
Comprehensive
Cancer Center, Madison,
Worldwide variations from “conventional” fractionation schedules regard to radiobiological rationale and a brief summary of clinical results.
WI 53792
of 1.8-2 Gy “daily” (5F/wk)
for 6-7 weeks will be presented;
with
Overall Time: Late Effects Prolongation does not spare late effects. Shortening does not make late effects worse (with possible exception of bladder). Overall Time: Tumor and Earlv Normal-Tissue Effects Prolongation reduces these effects (at &JIJI 50 cGy per day). Shortening enhances damage to both tumors and early normal-tissue reactions. Overall Time: Biolow of cell and Tissue Kinetics . It is the kinetics of cell proliferation that determine the effect of altering overall time in radiotherapy. * Late-responding tissues, in which late complications occur, are slowly proliferating tissues; in which compensatory proliferation does not occur until after the end of a radiotherapy schedule. Early-responding tissues, and most tumors, proliferate rapidly. Doubling times of only a few days become effective within 2 or 3 weeks after starting radiotherapy. * This is the rationale for Accelerated Fractionation. ?? ??
??
??
??
Dose oer Fraction: Radiobiology For a constant total dose and overall time, the effect of changing dose-per-fraction is greater on late-responding than on early-responding tissues and tumors. As characterized by different a/O ratios: small for late (2-4 Gy) but large for early (2 10 Gy) effects. These values are holding up well as clinical data accumulate. Smaller Doses ner Fraction The LQ formula will be described (with time factor) Spare late complications more than tumor damage. and simple examples given. This is the rationale for hvnerfractionation. Biologically Effective Dose and ERD will be explained. Larger Doses ner Fraction Enhance late complications more than tumor cell kill. To be avoided, except for very small volumes (stereotaxic or brachytherapy) or palliation. ??
??
?? ??
?? ??
Ontimum Fractionation Shorter overall times, but not so short that total dose must be reduced below 70 Gy. Smaller doses-per-fraction than 2 Gy, so as not to cause excessive late complications Therefore use 2 fractions per day to avoid prolongation: (1.2-l .6 Gy). The minimum intervals must be at least 6 hours. (This is difficult with 3F/day.) ??
??
(keep below 117 Gys).
?? ??
502 NON-RADIATION
THERAPY
Anna T. Meadows,
M.D.
The Children’s
Hospital
LATE EFFECT OF CANCER
of Philadelphia,
University
TREATMENT
of Pennsylvania
IN CHILDREN
School of Medicine,
Philadelphia,
PA 19104
As long-term survival after cancer in childhood now is approaching 70% overall, the concern for late morbidity and studies dealing with these concerns are increasing. By the year 2000 one in every 1000 young adults will be a survivor of childhood cancer. Major concerns specific while concern regarding vital organ dysfunction and for children are those dealing with growth, development and sexual maturation, carcinogenesis are shared by children and adults, Treatment and genetic predisposition are the major etiologic categories responsible for late occurring disabilities. Other environmental and life-style factors will undoubtedly assume greater importance in children as more survive beyond the third and fourth decades of life. Growth appears development, cognition offender. Methotrexate and become chronic.
unaffected by chemotherapy, although steroids and methotrexate have been shown to affect bone density. Intellectual and related scholastic achievement are affected by chemotherapy, parenteral methotrexate being the most common can also affect the liver, gastrointestinal trace and lungs, and, in appropriate doses and duration, dysfunction may persist
Proceedings of the 34th Annual ASTRO Meeting
113
The most serious long-term organ toxicities likely to be related to cancer chemotherapy are those involving the heart and the kidney, the former incriminating the anthracylines, such as daunorubicin and doxorubicin, and the latter implicating the platinum compounds and ifosfamide. Alkylating agents have been shown to affect gonadal function, perhaps less so in the young and differentially in the sexes. Drugs in this class also behave as leukemogens with varying degrees of efficiency, and this seems unrelated to age. Another recently identified leukemogen, etoposide, seems relatively specific to the leukemia produced (M4 with llq23 abnormality) and follows a particular schedule of drug administration. Second solid tumor malignancies are primarily related to radiation therapy and may take decades to become manifest. Secondary leukemias occur within 10 years in anuroximatelv 4% of individuals heavily treated with certain alkvlators. Of the agents used in children, nitrogen mustard, procarbazine (as in MOPPj, and the nitrosoureas are the most common. Cyclophosphamide appears less leukemogenic and it is &early to tell what will develop in ifosfamide-treated patients. Since many children are treated with ifosfamide and etoposide simultaneously together, the relative contributions of each to new leukemia generation will be obscured. Genetic susceptibility to certain second neoplasms may exert a more powerful influence than any therapeutic modality. The most common of these are neurofibromatosis, the genetic form of retinoblastoma, and the Li-Fraumeni syndrome. In each of these conditions, recognition of some individuals at risk is provided by the clinical presentation. The genes responsible for all three conditions have been identified. Questions regarding appropriate means of counseling and surveillance for second cancers and other late effects in these and other survivors are the subject of intense study.
503 LOWER GASTROINTESTlNAL MALIGNANCIES Bruce D. Minsky, M.D. Department of Radiation Oncology Memorial Sloan-Kettering Cancer Center, New York, NY 10021 Radiation therapy has a significant role in the adjuvant treatment of lower gastrointestinal malignancies. Furthermore, there are data to suggest that radiation therapy is an integral component of the conservative management (organ preservation) of rectal and anal cancers. This refresher course will review the current knowledge as well as ongoing and future research strategies in lower gastrointestinal malignancies. 1. Colon Cancer. The standard adjuvant treatment for node positive or high risk transmural colon cancer is post-operative 5FU/Levamisole. There are retrospective data to suggest that certain subsets of high risk patients may benefit from post-operative radiation therapy. 2. Rectal Cancer. Randomized trials have revealed a significant increase in local control and survival with the combination of post-operative radiation therapy plus chemotherapy in patients with uansmural and/or node positive resectable rectal cancer. Despite these improvements, post-operative combined modality therapy is associated with an approximately 35% incidence of Grade 3+ toxicity. Recent data suggest that the use of pre-operative combined modality therapy may be associated with less toxicity as well as an increased chance of sphincter preservation. In patients with locally advanced/unresectable rectal cancer, the addition of intraoperative radiation therapy may further improve local control. 3. Anal Cancer. The use of combined 5FU/Mitomycin -C and radiation therapy is effective in the treatment of squamous cell carcinoma of the anus. The RTQG has recently completed a randomized trial addressing the question of the effectiveness and toxicity of Mitomycin-C. Future intergroup Phase II trials are in the planning stages and will be presented.
504 COMBINED MODALITY THERAPY FOR THE TREATMENT OF INVASIVE BLADDER CANCER William U. Shipley, M.D. and Anthony L. Zietman, M.D. Department of Radiation Oncology, Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA 02114 Chemo-radiotherapy can lx integrated with transurethral surgery for local cure of the cancer in the bladder in SO-70% of patients. Because local cure will not be achieved in all patients with invasive bladder cancer due to the heterogeneity in the biology of these tumors, how can patients who are likeliest to succeed be appropriately selected? Can this be achieved without compromising patient survival? The answers, insofar as they are available, to these and other important questions with patients presenting with this heterogeneous disease will be reviewed based on the experience available as of 1991. The sta$ard,treatment for patients with muscle-invading bladder cancer in the U.S. is radical cystectomy with or without radiation therapy and in Europe ts radical radiotherapy. The results of such treatment have been generally unsatisfactory with 40% or more patients developing systemtc disease with a 5 year survival rate of less than 50%. Combination chemotherapy regimens will be reviewed (using cisplatin and methouexate) which can provide a 30-50% clinical complete response rate (negative biopsy, negative urine cytology) of the primary tumor. However, even in clinically complete responding patients, 40% of