- Email: [email protected]
The radiation therapy oncology group: An update of clinical research activities
In: J, Radialion 0nCO/Og13 Bud Phyr., Vol. 20. pp. I383Printed I” the U.S.A. All rights reserved.
I39
I Copyright
0360-3016191 $3.00 t 03 0 199 Pergamon Press plc
I
??Rapid Communication
THE RADIATION THERAPY ONCOLOGY GROUP: AN UPDATE OF CLINICAL RESEARCH ACTIVITIES TODD
H. WASSERMAN,
STANLEY
M.D.,
E. ORDER,
ELAINE
M.D.,
PAKURIS,
THEODORE CARLOS
LUTHER
L. PHILLIPS, A. PEREZ,
W. BRADY,
M.D.,
AND JAMES D. Cox,
M.D.,
M.D.,
GERALD
THOMAS
STEVEN
E. HANKS,
F. PAJAK,
M.D.,
PH.D.,
A. LEIBEL, M.D.
M.D.
Radiation Therapy Oncology Group, Philadelphia, PA This paper provides an introduction into the clinical activities of the RTOG (Radiation Therapy Oncology Group), its goals, its organization, its format for protocol development, and presents major areas of achievement. It provides an organizational chart of the group, a disease site modality cross-reference for protocols, and appendices which provide the key published results of the Group’s clinical activities. This paper presents an important overview of the RTOG clinical research activities, which are designed to improve the role of radiation therapy. Radiation Therapy Oncology Group, Clinical research. INTRODUCIION
rative and palliative results of cancer management; (c) to conduct clinical trials to advance the knowledge of radiation oncology; (d) to reduce the morbidity of radiation therapy while maintaining its efficacy; (e) to enhance cooperation among oncology specialists in providing multimodality treatment and to evaluate these in clinical trials; (f) to translate ideas from preclinical disciplines, such as, radiation and tumor biology, radiation physics, and pharmacology into clinical trials; (g) to collect long-term clinical information on patients treated in a consistent manner in order to identify potential new prognostic factors which may influence the interpretation of treatment results and aid in the design of future trials.
The Radiation Therapy Oncology Group (RTOG) is a North American clinical cooperative group with the goal of defining the optimum role of radiation therapy alone or in combination with other treatment modalities for cancer. Organized in 1968, it has grown since, in terms of the number of participating institutions, active studies, patients accessioned into clinical trials per year, and publications resulting from these clinical trials (l-4). The RTOG involves the cooperation and input of many individuals to achieve its goals. This brief paper will review the organization of the group and provide an important reference source for: the publications of the group and the current or recently closed protocols by scientific areas of interest within each disease site. The funds for participating institutions, headquarters, and other activities have come predominantly from the National Cancer Institute (grant No. CA2 166 l), through grants to the American College of Radiology, which have undergone periodic peer reviews. Some corporate sources of funding have also been obtained including Varian Corp. The RTOG is the main radiation therapy research arm of the ACR.
ORGANIZATION The organization of the RTOG consists of full-time employees, consultants, funded members and affiliates, and voluntary member institutions. The member institutions of the RTOG have varied somewhat over the past 22 years with some institutions having been continuous members. There have been a total of 4 12 institutions as members with 138 currently active. Full member institutions have a principal investigator, who a committee to deal with the scientific, logistical, and financial aspects of the group. Member and affiliate institutions, include academic cancer centers, and community-based oncology programs (through the cancer control program and the
GOALS The goals of the RTOG are (a) to increase survival of patients with local-regional cancer; (b) to increase the cuReprint requests to: Todd H. Wasserman, M.D., FACR, Radiation Therapy Oncology Group, 1101 Market St., 14th Floor, Philadelphia, PA 19 107.
Accepted for publication
1383
27 February 199 1.
1384
I. J. Radiation Oncology 0 Biology 0 Physics
community oncology program). Participants in the group from the member institutions include members from radiation oncology, medical oncology, surgical pathology, surgical oncology, gynecologic oncology, and other oncologic disciplines. Individual physicians, nurses, and data managers attend semiannual meetings, and between these participate in group activities via other meetings, telephone or mail communications. The RTOG Headquarters and the RTOG Statistical Center are located in Philadelphia, Pennsylvania. The American College of Radiology serves as the fiscal agent for the RTOG grants. Within the RTOG structure there is a series of committees, including standing committees, modality or scientific theme subcommittees, and disease site subcommittees. The RTOG organization is outlined in Figure 1 and Table 1. The RTOG’s statistical center collaborates with the RTOG investigators to provide efficient study design, careful monitoring of ongoing trials, timely and appropriate analysis of trials, and prompt reports of results. This collaboration is achieved through the assignment of a statistician to each modality, site subcommittee, and protocol. A system for quality control of protocol treatment delivery and clinical data has been established. The delivery of each treatment modality is scored in terms of compliance with the protocol design. The submitted clinical data are evaluated with respect to timeliness of the submission, accuracy, and completeness. Periodic institutional audits are done under the auspices of the Quality Control Committee to verify the validity of the clinical data as submitted to RTOG Headquarters. Extramural physics support for reviews is provided by the Radiologic Physics Center in Houston, Texas.
June 199 1, Volume 20, Number 6
PROTOCOL
DEVELOPMENT
Phase I and II protocols, which involve new research themes in radiation oncology or in multimodality treatment, yield data on feasibility, toxicity, and preliminary efficacy. These studies are organized in new modality subcommittees (Table 1). Ideas generated from these Phase I and II studies, or from other sources of information, are subsequently tested in Phase III trials in disease specific sites, where they are compared to the current best therapy applied in clinical practice. These trials are under the auspices of the disease site subcommittees, which set priorities for the ideas to be tested. The major research themes are highlighted in Table 1 and organized as to disease sites in which they have been tested by Phase III studies. Trials are only undertaken if the patient accession can be completed within an appropriate time frame, if the endpoints can be reliably measured, and if meaningful improvements in treatment can be expected. Information regarding appropriate prognostic factors, which are used to stratify patients prior to randomization, comes from past analysis of patient groups in these disease-specific protocols as well as from other sources of information. The Research Strategy Committee is composed of all chairmen of other committees, the group’s scientific vice chairmen, group chairmen, and statisticians. All research ideas and protocols are centrally coordinated by this committee (Fig. 1). Case Accession The RTOG has continued to maintain a high level of case accession in the face of ever-increasing complexity of the protocols and decreased real dollar funding (Fig. 2).
CHAIRMAN
DEPUTY
CHAIRMAN
VICE CHAIRMAN
MEMBERSHIP EVALUATION COMMITTEE
VICE CHAIRMAN
PUBLICATIONS COMMITTEE
HEADOUARTERS
OTHER STANDING COMMITTEES
VICE CHAIRMAN
Organization
of the RTOG.
-
I385
RTOC: update of clinical research activities 0 T. H. WASSERMAN et al.
Table 1. Disease site-modality
Disease sites
cross reference
88-06 A
Gastrointestinal
85-01 A* 81-04 A* 88-01 C 88-l 1 c* 89-l 1 A*
Genitourinary
Chemical modifiers
Chemotherapy
Brain
85-15 P* 90-01 A*
Head & Neck
84-06 85-03 88-17 88-24
P* P* A* C
Lung
81-07 88-04 88-08 88-15
C* C A* A*
Systemic radionuclide
Hyperthermia
83-01 P 83-19 P 88-23 A
6/ l/87 and 12/l/90
Surgery/IORT
83-02 83-15 85-28 90-05 90-06
81-15 85-04 85-05 85-06 88-20 89-02 90-14
84-05 C
P* P P P A A A*
be Published,
P P C A A
85-31 A 86-10 A 84-22 C* 85-09 P
88-05 c
85-30 A*
83-13 P 88-09 c
83-21 P
89-01 A
83-11 84-03 84-07 90-15
P P c A
87-01 P
85-07 P
82-03 82-06 83-05 85-02 88-22
P P P P A
85-27 P, A
86-05 C 89-06 A
Time/dose large field
85-32 C* 88-16 A*
86-02 C
Miscellaneous
P = Published, C = Closed/To * Intergroup Study.
accrual between
86-12 P, A 89-05 A
85-12 P 88-02 C 89-03 A
Gynecology
for Phase I, I/II, III studies open to patient
81-04 84-01 84-19 87-02 87-05 89-08 90-02
P P A C C A A
A = Active.
Publications The group has expanded its publishing record and a representative bibliography by protocol number is given in Appendix A and D. The publications listed are an update of the group’s publications (3) and cover the period from June 1987 through December 1990.
of radiation oncology concepts, such as the oxygen effect, chemical modifiers, radioimmunoglobulins, combined chemotherapy and radiation therapy, neutrons, altered fractionation, hyperthermia, intraoperative radiotherapy; and (e) identification of new prognostic factors. TOTAL
YEAR 1987
CONCLUSIONS It is beyond the intent and scope of this paper to provide for discussion of the major conclusions of the RTOG clinical research. Readers are referred to the published references (Appendix A). The major accomplishments of RTOG include the following: (a) coordinated method for protocol development utilizing input from radiobiology research and physics; (b) uniformity of radiotherapy techniques through protocol specifications, workshops, and quality assurance programs; (c) identification of optimal radiotherapy dosages at selected tumor sites; (d) testing
1988
1989
1990
TOTAL CASES -PHASE
l.l/ll.ll
‘x?%?dPHASE
~PHhSE
lll_M
Isz!amANCIIlARY
Ills
CANCERCONTROL
Fig. 2. Case accrual.
1386
1. J. Radiation Oncology 0 Biology 0 Physics
Specific major achievements include: 1. Demonstrating increased survival with concomitant cisplatin and 5fluorouracil and moderate dose radiation therapy over high dose radiation therapy alone in localized, unresectable carcinoma of the esophagus; 2. demonstrating increased survival with extended-field external radiation therapy plus brachytherapy over standard, pelvic radiation therapy plus brachytherapy in moderately advanced carcinoma of the cervix; 3. investigating hyperfractionated radiation therapy with total doses 15% to 30% above standard fractionation; identifying appropriate total doses to compare with standard fractionation and other experimental treatments for non-small cell carcinomas of the lung, carcinomas of the head and neck, and malignant gliomas; 4. conducting Phase III trials directed at organ-preservation for carcinomas of the anal canal and bladder, and established the basis for such trials in carcinoma of the rectum and larynx/hypopharynx; 5. conducting large Phase III trials of hormonal therapy as adjuvants to radiation therapy for carcinoma of the prostate; 6. conducting Phase III trials of hypoxic radiation sen-
June 1991, Volume 20, Number 6
sitizing drug (SR 2508) for inoperable carcinomas of the head and neck; and, 7. identifying pretreatment characteristics which obscure efficacy of therapy and adopting strategies to allocate favorable patients to Phase III trials and unfavorable patients to pilot studies. The future clinical research plan of the RTOG is beyond the scope of this paper. Background information regarding recently closed or current protocols (Appendix B, C) can be solicited from the group’s headquarters. The RTOG represents an international resource which is making important contributions to the assessment of innovative treatment programs for cancer management. The group has acted as a forum for the discussion, testing, and implementation of the latest advances in radiation therapy. From this has come contemporary, optimal, standard treatment programs, the objective of which is to maximize the potential for cancer cure with minimal complications. The group has sought to implement basic radiation oncology data into clinical practice. The investigative efforts of the RTOG are leading to improved cancer control.
REFERENCES
Brady, L. W. Gold Medal Address: The Radiation Therapy Oncology Group-1987. Int. J. Radiat. Oncol. Biol. Phys. 15:537-542; 1988. Brady, L. W.; Davis, L. W. Radiation oncology. JAMA 254: 2328-2392; 1985. Brady, L. W.; Kramer, S.; Wasserman, T. H.; Keiser, M.;
Davis, L. W.; Pajak, T. F.; Cox, J.; Rubin, P.; Griffin, T.; Perez, C. A.; Phillips, T.; Seydel, H. G. The Radiation Therapy Oncology Group: an outline of clinical research activities. Int. J. Radiat. Oncol. Biol. Phys. 14:S3-SlO; 1988. 4. Davis, L. W.; Gelber, R.; Kramer, S.; Zellen, M.; Rubin, P. The Radiation Therapy Oncology Group: a progress report. Cancer Clin. Trials 1(2):83-88; 1978.
APPENDIX A
Radiation Therapy Oncology Group: Bibliography of selected publications for studies which were open to patient accrual between 6/I/87 and 12/l/90 81-04: Perez, C. A.; Pajak, T.; Emami, B.; Hornback, N. B.; Tupchong, L.; Rubin, P. Randomized phase III study comparing irradiation and hyperthermia with irradiation alone in superficial measurable tumors. Final report by the Radiation Therapy Oncology Group. Am. J. Clin. Oncol. (In Press) 81-15: Sause, W. T.; Martz, K. L.; Noyes D.; Dobelbower, R. R.; Fischbach, A. J.; Doggett, S.; Mohiuddin, M. RTOG 8 I- 15 ECOG 83-23 evaluation of preoperative radiation therapy inoperable rectal carcinoma. Int. J. Radiat. Oncol. Biol. Phys. 19(1):179[105]; 1990. 82-03: Constine, L.; Zagars, G.; Rubin, P.; Kligerman, M. Protection by WR272 1 of human bone marrow function following irradiation. Int. J. Radiat. Oncol. Biol. Phys. 12:1505-1508; 1986. 82-06: Poulter, C. A.; Cosmatos, D.; Rubin, P.; Urtasun, R.; Cooper, J. S.; Perez, C. A.; Hornback, N.; Coughlin, C.; Weigensberg, I.; Rotman, M. A ,preliminary report of RTOG 8206 phase III study of whether the addition of single dose hemibody irradiation to standard fractionated local field irradiation is more effective than local field irradiation alone in the treatment of symptomatic oss mets. Int. J. Radiat. Oncol. Biol. Phys. 17(1):192[147]; 1989. 83-01: Stillwagon, G. B.; Order, S. E.; Guse, C.; Klein, J. L.; Leichner, P. K.; Leibel, S. A.; Fishman, E. K. 194 Hepatocellular cancers treated by radiation and che-
RTOG: update of clinical research activities 0 T. H. WASSERMANet al.
motherapy combinations: toxicity and response: a Radiation Therapy Oncology Group study. Int. J. Radiat. Oncol. Biol. Phys. 17(6): 1223-1229; 1989. 83-02: Nelson, D. F.; Cm-ran, W. J.; Nelson, J. S.; Weinstein, A. S.; Martz, K. L.; Ahmad, K.; Keller, J. W.; Murray, K.; Hanks, G. E. Hyperfmctionation in malignant glioma, report on a dose searching phase I/II protocol of the Radiation Therapy Oncology Group (RTOG). Proceedings of the 26th Annual Meeting of ASCO 9[350]: 90; 1990. 83-05: Sause, W. T.; Cooper, J. S.; Rush, S.; Ago, C. T.; Cosmatos, D.; Coughlin, C. T. RTOG 83-05: A Randomized trial evaluating fraction size in external beam radiation therapy. Proceedings of ASCO 8:283[ 11041; 1989. 83- 11: Cox, J. D.; Azarnia, N.; Byhardt, R. W.; Shin, K. H.; Emami, B.; Pajak, T. A Randomized Phase I/II Trial of hyperfractionated radiation therapy with total dose of 60. 0 Gy to 79. 2 Gy-possible survival benefit with 269.6 Gy in favorable patients with Radiation Therapy Oncology Group Stage III non-small cell lung carcinoma. Report of Radiation Therapy Oncology Group 83-l 1. J. Clin. Oncol. 8:1543-1555; 1990. 83-13: Cox, J. D.; Pajak, T. F.; Martial, V. A.; Hanks, G. E.; Mohiuddin, M.; Fu, K. K.; Byhardt, R. W.; Rubin, P. Dose-response for local control with hyperfractionated radiation therapy in advanced carcinomas of the upper aerodigestive tracts. Preliminary report of Radiation Therapy Oncology Group protocol 83- 13. Int. J. Radiat. Oncol. Biol. Phys. 18:5 15-521; 1990. 83-l 5: Nelson, D.; Martz, K.; Bonner, H.; Nelson, J.; Newall, J.; Kerman, H.; Thomson, J.; Murray, K. Definitive radiation therapy in the treatment of primary nonHodgkin’s lymphoma of the central nervous system (CNS): preliminary report of RTOG study 83 15. J. Neuro. Surg. (In press) 83-19: Order, S.; Pajak, T. F.; Leibel, S. A.; Asbell, S.; Leichner, P.; Ettinger, D.; Stillwagon, G.; Herpst, J.; Haulk, T.; Kopher, K.; Frazier, C.; Klein, J. A randomized prospective trial comparing full dose chemotherapy to I31antiferritin in non-randomized hepatoma: an RTOG study. Int. J. Radiat. Oncol. Biol. Phys. 20:953963; 1991. 83-2 1: Asbell, S. 0.; Pajak, T.; Seydel, H. G.; Brady, L.; Mohiuddin, N.; Weigensberg, I.; Montesano, A. T. Phase III RTOG double blind lung cancer trial of xrt and subsequent thymosin or placebo. Proceedings of ASCO 26th Annual Mtg 9:242[937]; 1990. 84-O 1: Myerson, R. J.; Emami, B.; Pereza, C. A.; Gibbs, F.; Lee, C.; Pajak, T. Phase I/II study, combination of radiotherapy and hyperthermia in patients with deepseated malignant tumors: report of a pilot study by the Radiation Therapy Oncology Group. Int. J. Radiat. Oncol. Biol. Phys. 17( 1):204[ 1701; 1989. 84-03: Russell, A. H.; Pajak, T. F.; Selim, H. M.; Paradelo, J. C.; Murray, K.; Bansal, P.; Cooper, J. S.; Silverman, S.; Clement, J. A. Prophylactic cranial irradiation (PCI) for selected lung cancer patients at high risk for development of cerebral metastasis: results of a prospective randomized trial. Int. J. Radiat. Oncol. Biol. Phys. 19( 1): 146[44], 1990. 84-06: Haselow, R. E.; Warshaw, M. G.; Oken, M. M.; Adams, G. L.; Aughey, J. L.; Cooper, J. S.; Schuller, D. E.; Jacobs, C. D. Radiation alone versus radiation with weekly low dose cisplatinum in unresectable cancer of the head and neck. Head and Neck Cancer, Toronto, B. C. Decker Inc., Vol. II: 279-28 1, 1990. 85-02: Spanos, W.; Guse, C.; Perez, C.; Grigsby, P.; Doggett, R. L. S.; Poulter, C. Phase II study of multiple daily fractionations in the palliation of advanced pelvic malignancies: preliminary report of RTOG 8502. Int. J. Radiat. Oncol. Biol. Phys. 17:659-661, 1989. 85-03: Schuller, D. E.; Laramore, G. E.; Al-Sarraf, M.; Jacobs, J.; Pajak, T. F. Combined therapy for resectable head and neck cancer. A phase III intergroup study. Arch. Otolaryngol. Head. Neck Surg. 115:364-368, 1989. 85-04-09: Calvo, F. A.; Hanks, G. E. Intraoperative trials. Int. J. Radiat. Oncol. Biol. Phys. 14:Sll l-S1 17, 1988. 85-l 2: Tester, W.; Porter, A.; Asbell, S.; Coughlin, C.; Heaney, J.; Martz, K.; Venner,
1387
1388
I. J. Radiation Oncology 0 Biology 0 Physics
June 1991, Volume 20, Number 6
P.; Hammond, E. Combined modality program with possible organ preservation for invasive bladder carcinoma. Proceedings of ASCO 8: 14 1[548]; 1989. 85-15: John, M.; Flam, N.; Sikic, B.; Rotman, M.; Cooper, J.; Malec, M.; Hannigan, J.; Phillips, T. Preliminary results of concurrent radiotherapy and chemotherapy in advanced cervical carcinoma: a phase I/II prospective intergroup NCOG-RTOG study. Gyn. Oncol. 34: 1-5; 1990. 85-27: Lee, D. J.; Wasserman, T.; Coleman, N.; Phillips, T.; Davis, L.; Martial, V.; Scott, C. A progress report of the RTOG head and neck SR-2508 trial. Int. J. Radiat. Oncol. Biol. Phys. 17( 1): 133[36]; 1989. 86-12: Urtasun, R. C.; Fulton, D. S.; Lester, S. G.; Silverstein, M.; Kinsella, T.; Wasserman, T.; Martz, K. A phase I RTOG study of iododeoxyuridine (IUdR) and radiotherapy in the treatment of primary malignant brain tumors. Int. J. Radiat. Oncol. Biol. Phys. 17( I):22 1[ 10241; 1989. 87-O 1: Vriesendorp, H. M.; Blum, J. E.; Herpst, J. M.; Germack, M. A.; Leichner, P. K.; Klein, J. L.; Kopher, K. A.; Order, S. E. Refractory Hodgkin’s disease: treatment with polyclonal yttrium labeled antiferritin. Proceedings of the 26th Annual Mtg. of ASCO 9[990]:256; 1990. General
Brady, L. W.; Kramer, S.; Wasserman, T. H.; Keiser, M.; Davis, L. W.; Pajak, T. F.; Cox, J.; Griffin, T.; Perez, C.; Phillips, T.; Rubin, P.; Seydel, H. G. The radiation therapy oncology group: an outline of clinical research activities. Int. J. Radiat. Oncol. Biol. Phys. 14:S3-SlO; 1988. Davis, L. W.; Bauer, M. Research plan for radiation oncology-1987: design and analysis of clinical trials. Am. J. Clin. Oncol. (CCT) 11(3):404-410; 1988. Martial, V.; Pajak, T.; Kramer, S.; Davis, L.; Stetz, J.; Laramore, G.; Jacobs, J.; AlSarraf, M.; Brady, L. Radiation Therapy Oncology Group (RTOG) studies in head and neck cancer. Seminars in Oncology 15( 1):39-60; 1988. Pajak, T.; Fazekas, J.; Davis, L.; Martial, V. Analysis of the RTOG head and neck database: identification of prognostic factors and the re-evaluation of AJC stages. In Vogl, S., ed. Head and Neck Cancer. Churchill Livingston, New York, pg. 4164, 1988. Perez, C. A.; Gillespie, B.; Pajak, T.; Hornback, N. B.; Emami, B.; Rubin, P. Quality assurance problems in clinical hyperthermia and their impact on therapeutic outcome: a report by the Radiation Therapy Oncology Group. Int. J. Radiat. Oncol. Biol. Phys. 16:551-558; 1989. Rubin, P.; Wasserman, T. H. The late effects of toxicity scoring. Int. J. Radiat. Oncol. Biol. Phys. 14:S29-S38; 1988. Shrivastava, P.; Luk, K.; Oleson, J.; Dewhirst, M.; Pajak, T.; Paliwal, B.; Perez, C.; Sapareto, S.; Saylor, T.; Steeves, R. Hyperthermia quality assurance guidelines. Int. J. Radiat. Oncol. Biol. Phys. 16:571-587; 1989. Wallner, P. E.; Lustig, R. A.; Pajak, T. F.; Robinson, G.; Davis, L. W.; Perez, C. A.; Seydel, H. G.; Martial, V. A.; Laramore, G. E. Impact of initial quality control review on study outcome in lung and head/neck cancer studies-review of the Radiation Therapy Oncology Group Experience. Int. J. Radiat. Oncol. Biol. Phys. 17:893-900; 1989. APPENDIX
B
Radiation Therapy Oncology Group: Closed Studies Pending Publication 84-05:
Phase I/II Dose Escalating Trial of Accelerated Fractionation in the Palliative Irradiation of Hepatic Metastases 84-07: A Phase I/II Pilot Study to Evaluate Accelerated Fractionation via Concomitant Boost for Squamous, Adeno, and Large Cell Carcinoma of the Lung 84-22: Treatment of Patients with Sub-Optimal (“Bulky”) Stage IB Carcinoma of the Cervix: A Randomized Comparison of Radiation Therapy vs. Radiation Therapy Plus Adjuvant Extrafascial Hysterectomy (Phase III)
RTOG: update of clinical research activities 0 T. H. WASSERMANet a/.
85-28: A Phase I/II Protocol for the Evaluation of Accelerated Fractionation in the Treatment of Patients with Supratentorial Brain Metastases 85-32: Treatment of Intracranial Ependymomas, A Pediatric Oncology Group Phase III Study 86-02: Phase III Study of Pentosanpolysulfate (PPS) in Radiation Cystitis and Hematuria 86-05: A Phase I Trial of Continuous Infusion SR-2508 with Interstitial and Intracavitary Radiation 87-02: Phase I Clinical Trial of Hyperthermia Plus Cisplatinum Chemotherapy for Refractory Superficial Malignancies 87-05: A Non-Randomized Phase I-II Study of Efficacy of Radiation and Hyperthermia (45°C for 15 Minutes) in the Treatment of some Measurable Superficial Human Tumors 88-01: Phase I/II Study of Prophylactic Hepatic Irradiation with Local Irradiation and Systemic Chemotherapy for Adenocarcinoma of the Pancreas 88-02: Phase I/II Study of Neoadjuvant Combined Modality Treatment with Selective Bladder Preservation for Patients with Invasive Bladder Cancer 88-04: Phase I/II Study of Sequential and Concurrent Radiation Therapy and Chemotherapy for Patients with Non-Small Cell Lung Cancer 88-05: Phase II Study of a Twice Daily Fractionation Schedule with External Irradiation and Intracavitary Brachytherapy in Bulky Stage IB, Stage II, III or WA Carcinoma of the Cervix 88-09: A Phase I/II Study to Evaluate Twice Daily Accelerated Hyperfractionation vs. Concomitant Boost Radiotherapy for Squamous Cell Carcinoma of the Upper Respiratory and Digestive Tracts 88-24: Phase II Trial to Determine the Feasibility of Post-Operative Concurrent Cisplatin and Radiotherapy in Patients with Resected Head and Neck Cancers
APPENDIX
C
Radiation Therapy Oncology Group: Active Studies as of 121l/90 84-19: A Randomized Phase III Study of Interstitial Thermoradiotherapy (43°C) Compared with Interstitial Radiotherapy Alone in the Treatment of Recurrent or Persistent Human Tumors 85-O1: Phase III Prospective Trial for Localized Cancer of the Esophagus: Comparing Radiation as a Single Modality to the Combination of Radiation Therapy and Chemotherapy 85-27: A Two Phase Study for the Evaluation of the Effectiveness of the Hypoxic Cell Sensitizer SR-2508 Combined with Conventional Radiotherapy in Patients with Locally Advanced Head and Neck Squamous Carcinomas 85-30: A Phase III Study of the Role of Cricopharyngeal Myotomy in the Treatment of Dysphagia Following Major Head and Neck Surgery 85-3 1: Phase III Study of Zoladex Adjuvant to Radiotherapy in Unfavorable Prognosis Carcinoma of the Prostate 86- 10: Phase III Study of Zoladex and Flutamide Used as Cytoreductive Agents in Locally Advanced Carcinoma of the Prostate Treated with Definitive Radiotherapy 86- 12: Phase I Study of Iododeoxyuridine (IUdR) and Radiotherapy in the Treatment of Primary Malignant Brain Tumors 87-04: A Phase III Randomized Study Employing 5 Fluorouracil, Mitomycin-C and Radiotherapy in Carcinoma of the Anal Canal 88-06: Phase I/II Protocol for the Treatment of Primary Central Nervous System Lymphomas 88-08: Phase III Study of Radiation Therapy Alone or in Combination with Chemotherapy for Patients with Non-Small Cell Lung Cancer 88- 15: A Phase III Study of Cisplatin Plus Etoposide Combined with Standard Fractionation Thoracic Radiotherapy versus Cisplatin Plus Etoposide Combined with
1389
1390
I. J. Radiation Oncology 0 Biology 0 Physics
June 1991, Volume 20, Number 6
Multiple Daily Fractionated Thoracic Radiotherapy for Limited Stage Small Cell Lung Cancer 88-16: Low Grade Glioma Phase III: Surgery and Immediate Radiotherapy vs. Surgery and Delayed Radiotherapy 88-17: A Phase III Study of Radiotherapy with or without Concurrent Cisplatin in Patients with Nasopharyngeal Cancer 88-20: Phase III Protocol for the Treatment of Residual or Unresectable Carcinoma of the Rectum and Rectosigmoid or Pelvic Recurrence Following Primary Colorectal Resection: External Beam Radiation Therapy + 5+luorouracil/Leucovorin with or without IORT Electron Boost 88-22: A Phase I/II Study to Evaluate the Effect of Fractionated Hemi-Body Irradiation in the Treatment of Osseous Metastases 88-23: Phase I/II Integrated Intra-Arterial Cisplatin and Intravenous 13’1Antiferritin in the Treatment of Non-Resectable Hepatocellular Cancer 89-O1: Phase III Study Comparing Combination Chemotherapy and Radiation Therapy with Preoperative Chemotherapy and Surgical Resection in Patients with NonSmall Cell Lung Cancer (NSCLC) with Spread to Mediastinal Lymph Nodes (N2) 89-02: Phase I/II Study of Sphincter Sparing Local Excision Combined with Post Operative Radiation Therapy and Concurrent 5-FU in the Treatment of Limited Adenocarcinoma of the Rectum 89-03: A Phase III Trial to Study the Role of Neoadjuvant MCV Chemotherapy Combined with Transurethral Surgery Plus Cisplatin with Radiation Therapy for Selective Bladder Preservation in Patients with Muscle-Invading Bladder Cancer 89-05: A Randomized Phase III Study of Conventional Radiation Therapy versus Conventional Radiation Therapy and Bromodeoxyuridine (BUdR) for Tumors Metastatic to the Brain 89-06: A Phase I Pilot Study to Evaluate Intraoperative Radiation Therapy and the Hypoxic Cell Sensitizer SR-2508 in Patients with Locally Advanced Malignancies 89-08: A Phase I/II Study to Evaluate Radiation Therapy and Hyperthermia for DeepSeated Tumors 89- 11: A Phase III Intergroup Trial: A Prospective Randomized Comparison of Combined Modality Therapy for Squamous Carcinoma of the Esophagus: Chemotherapy Plus Surgery versus Surgery Alone for Patients with Local Regional Disease 90-O1: Phase III Randomized Study: Pelvic Radiation with Concurrent Chemotherapy versus Pelvic and Para-Aortic Radiation for High Risk Cervical Carcinoma 90-02: A Randomized Phase III Research Study Using Irradiation Alone or Combined with Hyperthermia for Treatment of Localized Chest Wall Recurrences of Breast Carcinoma 90-05: Phase I Study of Small Field Stereotactic External Beam Irradiation for the Treatment of Recurrent Primary Brain Tumors and CNS Metastases 90-06: A Phase III Comparison of Hyperfractionated Radiation Therapy (RT) with BCNU and Conventional RT with BCNU for Supratentorial Malignant Glioma 90-14: Intergroup Rectal Adjuvant Protocol, A Phase III Study 90-15: Phase I/II Study of Concurrent Radiation Therapy and Chemotherapy for Patients with Non-Small Cell Lung Cancer APPENDIX
D
Radiation Therapy Oncology Group: Bibliography of selected publication for studies which were closed to patient accrual since 61 I/87 75-06/77-06: Lai, P. P.; Pilepich, M. V.; IQ-all, J. M.; Asbell, S. 0.; Hanks, G. E.; Perez, C. A.; Rubin, P.; Sause, W. T.; Cox, J. C. The effect of overall treatment time on the outcome of definitive radiotherapy for localized prostate carcinoma: the Radiation Therapy Oncology Group 75-06 and 77-06 experience. Int. J. Radiat. Oncol. Biol. Phys. (In Press) 76-19: Cooper, J. S.; Pajak, T. F.; Rubin, P.; Tupchong, L.; Brady, L. W.; Leibel, S. A.; Laramore, G. A.; Marcial, V. A.; Davis, L. W.; Cox, J. D. Second malignancies
RTOG: update of clinical research activities 0 T. H. WASSERMANet al.
in patients who have head and neck cancers: incidence, effect on survival and implications based on the RTOG experience. Int. J. Radiat. Oncol. Biol. Phys. 17: 449-456; 1989. 77-06: Asbell, S. 0.; Krall, J. M.; Pilepich, M. V.; Baerwald, H.; Sause, W. T.; Hanks, G. E.; Perez, C. A. Elective pelvic irradiation in stage A2, B carcinoma of the prostate-analysis of RTOG 77-06. Int. J. Radiat. Oncol. Biol. Phys. 15: 1307- 13 16; 1988. 79- 15: Fazekas, J. T.; Scott, C.; Martial, V.; Davis, L. W.; Wasserman, T.; Cooper, J. S. The role of hemoglobin concentration in the outcome of misonidazole-sensitized radiotherapy of head and neck cancers: based on RTOG trial #79- 15. Int. J. Radiat. Oncol. Biol. Phys. 17(6):1177-l 181; 1989. 79-16: Diener-West, M.; Dobbins, T. W.; Phillips, T. L.; Nelson, D. F. Identification of an optimal subgroup for treatment evaluation of patients with brain metastases using RTOG study 7916. Int. J. Radiat. Oncol. Biol. Phys. 16:669-673; 1989. 79-20: Rotman, M.; Choi, K.; Guse, C.; Marcial, V.; Hornback, N. Prophylactic irradiation of the para-aortic lymph node chain in stage 2B and bulky stage IB carcinoma of the cervix, initial treatment results of RTOG 79-20. Int. J. Radiat. Oncol. Biol. Phys. 17(1):151[71]; 1989. 80-02: Kligerman, M.; Turrisi, A.; Urtasun, R.; Norfleet, L.; Phillips, T.; Barkley, T.; Rubin, P. Final report on phase I trial of WR-2721 before protracted fractionated radiation therapy. Int. J. Radiat. Oncol. Biol. Phys. 14: 1119-l 122; 1988. 80-07: Laramore, G.; Deiner-West, M.; Griffin, T.; Griem, M.; Thomas, F.; Hendrickson, F.; Nelson, J.; Griffin, B.; Myrianthopoulos, L.; Saxton, J. Randomized neutron dose searching study for malignant gliomas of the brain: result of an RTOG study. Int. J. Radiat. Oncol. Biol. Phys. 14:1093-l 102; 1988. 83-08: Cox, J. D.; Guse, C.; Asbell, S.; Rubin, P.; Sause, W. T. Tolerance of pelvic normal tissues to hyperfractionated radiation therapy: results of protocol 83-08 of the Radiation Therapy Oncology Group. Int. J. Radiat. Oncol. Biol. Phys. 15: 133 l1336; 1988. 83-10: Sause, W. T.; Crowley, J. J.; Townsend, J. J.; Rotman, M.; Ager-Mowry, P.; Bouzaglou, A.; Borst, J. R.; Selim, H. Solitary brain metastasis: results of an RTOG/ SWOG protocol evaluation: surgery + rt vs. rt alone. J. Clin. Oncol. (Submitted for publication) 83-12: Emami, B.; Perez, C. A.; Herskovic, A.; Hederman, M. A. Phase I/II study of treatment of locally advanced (T3T4) non-oat cell lung cancer with high dose radiotherapy (rapid fractionation): Radiation Therapy Oncology Group Study. Int. J. Radiat. Oncol. Biol. Phys. 15:1021-1025; 1988. 85- 19: Pilepich, M. V.; Al-Sarraf, M.; John, M. J.; McGowan, D.; Hwang, Y. S.; Perez, C. A.; Krall, J. M. Phase II RTOG study of hormonal cytoreduction with flutamide and zoladex in locally advanced carcinoma of the prostate treated with definitive radiotherapy. Am. J. Clin. Oncol. (Submitted for publication). General
Leibel, S. A.; Scott, C. B.; Mohiuddin, M.; Marcial, V. A.; Coia, L. R.; Davis, L. W.; Fuks, Z. Does local-regional control affect distant metastatic spread in squamous cell carcinoma of the head and neck? Results of an RTOG analysis. Accepted to ASTRO for October 1990 meeting in Florida, 5/90.
1391
I39
I Copyright
0360-3016191 $3.00 t 03 0 199 Pergamon Press plc
I
??Rapid Communication
THE RADIATION THERAPY ONCOLOGY GROUP: AN UPDATE OF CLINICAL RESEARCH ACTIVITIES TODD
H. WASSERMAN,
STANLEY
M.D.,
E. ORDER,
ELAINE
M.D.,
PAKURIS,
THEODORE CARLOS
LUTHER
L. PHILLIPS, A. PEREZ,
W. BRADY,
M.D.,
AND JAMES D. Cox,
M.D.,
M.D.,
GERALD
THOMAS
STEVEN
E. HANKS,
F. PAJAK,
M.D.,
PH.D.,
A. LEIBEL, M.D.
M.D.
Radiation Therapy Oncology Group, Philadelphia, PA This paper provides an introduction into the clinical activities of the RTOG (Radiation Therapy Oncology Group), its goals, its organization, its format for protocol development, and presents major areas of achievement. It provides an organizational chart of the group, a disease site modality cross-reference for protocols, and appendices which provide the key published results of the Group’s clinical activities. This paper presents an important overview of the RTOG clinical research activities, which are designed to improve the role of radiation therapy. Radiation Therapy Oncology Group, Clinical research. INTRODUCIION
rative and palliative results of cancer management; (c) to conduct clinical trials to advance the knowledge of radiation oncology; (d) to reduce the morbidity of radiation therapy while maintaining its efficacy; (e) to enhance cooperation among oncology specialists in providing multimodality treatment and to evaluate these in clinical trials; (f) to translate ideas from preclinical disciplines, such as, radiation and tumor biology, radiation physics, and pharmacology into clinical trials; (g) to collect long-term clinical information on patients treated in a consistent manner in order to identify potential new prognostic factors which may influence the interpretation of treatment results and aid in the design of future trials.
The Radiation Therapy Oncology Group (RTOG) is a North American clinical cooperative group with the goal of defining the optimum role of radiation therapy alone or in combination with other treatment modalities for cancer. Organized in 1968, it has grown since, in terms of the number of participating institutions, active studies, patients accessioned into clinical trials per year, and publications resulting from these clinical trials (l-4). The RTOG involves the cooperation and input of many individuals to achieve its goals. This brief paper will review the organization of the group and provide an important reference source for: the publications of the group and the current or recently closed protocols by scientific areas of interest within each disease site. The funds for participating institutions, headquarters, and other activities have come predominantly from the National Cancer Institute (grant No. CA2 166 l), through grants to the American College of Radiology, which have undergone periodic peer reviews. Some corporate sources of funding have also been obtained including Varian Corp. The RTOG is the main radiation therapy research arm of the ACR.
ORGANIZATION The organization of the RTOG consists of full-time employees, consultants, funded members and affiliates, and voluntary member institutions. The member institutions of the RTOG have varied somewhat over the past 22 years with some institutions having been continuous members. There have been a total of 4 12 institutions as members with 138 currently active. Full member institutions have a principal investigator, who a committee to deal with the scientific, logistical, and financial aspects of the group. Member and affiliate institutions, include academic cancer centers, and community-based oncology programs (through the cancer control program and the
GOALS The goals of the RTOG are (a) to increase survival of patients with local-regional cancer; (b) to increase the cuReprint requests to: Todd H. Wasserman, M.D., FACR, Radiation Therapy Oncology Group, 1101 Market St., 14th Floor, Philadelphia, PA 19 107.
Accepted for publication
1383
27 February 199 1.
1384
I. J. Radiation Oncology 0 Biology 0 Physics
community oncology program). Participants in the group from the member institutions include members from radiation oncology, medical oncology, surgical pathology, surgical oncology, gynecologic oncology, and other oncologic disciplines. Individual physicians, nurses, and data managers attend semiannual meetings, and between these participate in group activities via other meetings, telephone or mail communications. The RTOG Headquarters and the RTOG Statistical Center are located in Philadelphia, Pennsylvania. The American College of Radiology serves as the fiscal agent for the RTOG grants. Within the RTOG structure there is a series of committees, including standing committees, modality or scientific theme subcommittees, and disease site subcommittees. The RTOG organization is outlined in Figure 1 and Table 1. The RTOG’s statistical center collaborates with the RTOG investigators to provide efficient study design, careful monitoring of ongoing trials, timely and appropriate analysis of trials, and prompt reports of results. This collaboration is achieved through the assignment of a statistician to each modality, site subcommittee, and protocol. A system for quality control of protocol treatment delivery and clinical data has been established. The delivery of each treatment modality is scored in terms of compliance with the protocol design. The submitted clinical data are evaluated with respect to timeliness of the submission, accuracy, and completeness. Periodic institutional audits are done under the auspices of the Quality Control Committee to verify the validity of the clinical data as submitted to RTOG Headquarters. Extramural physics support for reviews is provided by the Radiologic Physics Center in Houston, Texas.
June 199 1, Volume 20, Number 6
PROTOCOL
DEVELOPMENT
Phase I and II protocols, which involve new research themes in radiation oncology or in multimodality treatment, yield data on feasibility, toxicity, and preliminary efficacy. These studies are organized in new modality subcommittees (Table 1). Ideas generated from these Phase I and II studies, or from other sources of information, are subsequently tested in Phase III trials in disease specific sites, where they are compared to the current best therapy applied in clinical practice. These trials are under the auspices of the disease site subcommittees, which set priorities for the ideas to be tested. The major research themes are highlighted in Table 1 and organized as to disease sites in which they have been tested by Phase III studies. Trials are only undertaken if the patient accession can be completed within an appropriate time frame, if the endpoints can be reliably measured, and if meaningful improvements in treatment can be expected. Information regarding appropriate prognostic factors, which are used to stratify patients prior to randomization, comes from past analysis of patient groups in these disease-specific protocols as well as from other sources of information. The Research Strategy Committee is composed of all chairmen of other committees, the group’s scientific vice chairmen, group chairmen, and statisticians. All research ideas and protocols are centrally coordinated by this committee (Fig. 1). Case Accession The RTOG has continued to maintain a high level of case accession in the face of ever-increasing complexity of the protocols and decreased real dollar funding (Fig. 2).
CHAIRMAN
DEPUTY
CHAIRMAN
VICE CHAIRMAN
MEMBERSHIP EVALUATION COMMITTEE
VICE CHAIRMAN
PUBLICATIONS COMMITTEE
HEADOUARTERS
OTHER STANDING COMMITTEES
VICE CHAIRMAN
Organization
of the RTOG.
-
I385
RTOC: update of clinical research activities 0 T. H. WASSERMAN et al.
Table 1. Disease site-modality
Disease sites
cross reference
88-06 A
Gastrointestinal
85-01 A* 81-04 A* 88-01 C 88-l 1 c* 89-l 1 A*
Genitourinary
Chemical modifiers
Chemotherapy
Brain
85-15 P* 90-01 A*
Head & Neck
84-06 85-03 88-17 88-24
P* P* A* C
Lung
81-07 88-04 88-08 88-15
C* C A* A*
Systemic radionuclide
Hyperthermia
83-01 P 83-19 P 88-23 A
6/ l/87 and 12/l/90
Surgery/IORT
83-02 83-15 85-28 90-05 90-06
81-15 85-04 85-05 85-06 88-20 89-02 90-14
84-05 C
P* P P P A A A*
be Published,
P P C A A
85-31 A 86-10 A 84-22 C* 85-09 P
88-05 c
85-30 A*
83-13 P 88-09 c
83-21 P
89-01 A
83-11 84-03 84-07 90-15
P P c A
87-01 P
85-07 P
82-03 82-06 83-05 85-02 88-22
P P P P A
85-27 P, A
86-05 C 89-06 A
Time/dose large field
85-32 C* 88-16 A*
86-02 C
Miscellaneous
P = Published, C = Closed/To * Intergroup Study.
accrual between
86-12 P, A 89-05 A
85-12 P 88-02 C 89-03 A
Gynecology
for Phase I, I/II, III studies open to patient
81-04 84-01 84-19 87-02 87-05 89-08 90-02
P P A C C A A
A = Active.
Publications The group has expanded its publishing record and a representative bibliography by protocol number is given in Appendix A and D. The publications listed are an update of the group’s publications (3) and cover the period from June 1987 through December 1990.
of radiation oncology concepts, such as the oxygen effect, chemical modifiers, radioimmunoglobulins, combined chemotherapy and radiation therapy, neutrons, altered fractionation, hyperthermia, intraoperative radiotherapy; and (e) identification of new prognostic factors. TOTAL
YEAR 1987
CONCLUSIONS It is beyond the intent and scope of this paper to provide for discussion of the major conclusions of the RTOG clinical research. Readers are referred to the published references (Appendix A). The major accomplishments of RTOG include the following: (a) coordinated method for protocol development utilizing input from radiobiology research and physics; (b) uniformity of radiotherapy techniques through protocol specifications, workshops, and quality assurance programs; (c) identification of optimal radiotherapy dosages at selected tumor sites; (d) testing
1988
1989
1990
TOTAL CASES -PHASE
l.l/ll.ll
‘x?%?dPHASE
~PHhSE
lll_M
Isz!amANCIIlARY
Ills
CANCERCONTROL
Fig. 2. Case accrual.
1386
1. J. Radiation Oncology 0 Biology 0 Physics
Specific major achievements include: 1. Demonstrating increased survival with concomitant cisplatin and 5fluorouracil and moderate dose radiation therapy over high dose radiation therapy alone in localized, unresectable carcinoma of the esophagus; 2. demonstrating increased survival with extended-field external radiation therapy plus brachytherapy over standard, pelvic radiation therapy plus brachytherapy in moderately advanced carcinoma of the cervix; 3. investigating hyperfractionated radiation therapy with total doses 15% to 30% above standard fractionation; identifying appropriate total doses to compare with standard fractionation and other experimental treatments for non-small cell carcinomas of the lung, carcinomas of the head and neck, and malignant gliomas; 4. conducting Phase III trials directed at organ-preservation for carcinomas of the anal canal and bladder, and established the basis for such trials in carcinoma of the rectum and larynx/hypopharynx; 5. conducting large Phase III trials of hormonal therapy as adjuvants to radiation therapy for carcinoma of the prostate; 6. conducting Phase III trials of hypoxic radiation sen-
June 1991, Volume 20, Number 6
sitizing drug (SR 2508) for inoperable carcinomas of the head and neck; and, 7. identifying pretreatment characteristics which obscure efficacy of therapy and adopting strategies to allocate favorable patients to Phase III trials and unfavorable patients to pilot studies. The future clinical research plan of the RTOG is beyond the scope of this paper. Background information regarding recently closed or current protocols (Appendix B, C) can be solicited from the group’s headquarters. The RTOG represents an international resource which is making important contributions to the assessment of innovative treatment programs for cancer management. The group has acted as a forum for the discussion, testing, and implementation of the latest advances in radiation therapy. From this has come contemporary, optimal, standard treatment programs, the objective of which is to maximize the potential for cancer cure with minimal complications. The group has sought to implement basic radiation oncology data into clinical practice. The investigative efforts of the RTOG are leading to improved cancer control.
REFERENCES
Brady, L. W. Gold Medal Address: The Radiation Therapy Oncology Group-1987. Int. J. Radiat. Oncol. Biol. Phys. 15:537-542; 1988. Brady, L. W.; Davis, L. W. Radiation oncology. JAMA 254: 2328-2392; 1985. Brady, L. W.; Kramer, S.; Wasserman, T. H.; Keiser, M.;
Davis, L. W.; Pajak, T. F.; Cox, J.; Rubin, P.; Griffin, T.; Perez, C. A.; Phillips, T.; Seydel, H. G. The Radiation Therapy Oncology Group: an outline of clinical research activities. Int. J. Radiat. Oncol. Biol. Phys. 14:S3-SlO; 1988. 4. Davis, L. W.; Gelber, R.; Kramer, S.; Zellen, M.; Rubin, P. The Radiation Therapy Oncology Group: a progress report. Cancer Clin. Trials 1(2):83-88; 1978.
APPENDIX A
Radiation Therapy Oncology Group: Bibliography of selected publications for studies which were open to patient accrual between 6/I/87 and 12/l/90 81-04: Perez, C. A.; Pajak, T.; Emami, B.; Hornback, N. B.; Tupchong, L.; Rubin, P. Randomized phase III study comparing irradiation and hyperthermia with irradiation alone in superficial measurable tumors. Final report by the Radiation Therapy Oncology Group. Am. J. Clin. Oncol. (In Press) 81-15: Sause, W. T.; Martz, K. L.; Noyes D.; Dobelbower, R. R.; Fischbach, A. J.; Doggett, S.; Mohiuddin, M. RTOG 8 I- 15 ECOG 83-23 evaluation of preoperative radiation therapy inoperable rectal carcinoma. Int. J. Radiat. Oncol. Biol. Phys. 19(1):179[105]; 1990. 82-03: Constine, L.; Zagars, G.; Rubin, P.; Kligerman, M. Protection by WR272 1 of human bone marrow function following irradiation. Int. J. Radiat. Oncol. Biol. Phys. 12:1505-1508; 1986. 82-06: Poulter, C. A.; Cosmatos, D.; Rubin, P.; Urtasun, R.; Cooper, J. S.; Perez, C. A.; Hornback, N.; Coughlin, C.; Weigensberg, I.; Rotman, M. A ,preliminary report of RTOG 8206 phase III study of whether the addition of single dose hemibody irradiation to standard fractionated local field irradiation is more effective than local field irradiation alone in the treatment of symptomatic oss mets. Int. J. Radiat. Oncol. Biol. Phys. 17(1):192[147]; 1989. 83-01: Stillwagon, G. B.; Order, S. E.; Guse, C.; Klein, J. L.; Leichner, P. K.; Leibel, S. A.; Fishman, E. K. 194 Hepatocellular cancers treated by radiation and che-
RTOG: update of clinical research activities 0 T. H. WASSERMANet al.
motherapy combinations: toxicity and response: a Radiation Therapy Oncology Group study. Int. J. Radiat. Oncol. Biol. Phys. 17(6): 1223-1229; 1989. 83-02: Nelson, D. F.; Cm-ran, W. J.; Nelson, J. S.; Weinstein, A. S.; Martz, K. L.; Ahmad, K.; Keller, J. W.; Murray, K.; Hanks, G. E. Hyperfmctionation in malignant glioma, report on a dose searching phase I/II protocol of the Radiation Therapy Oncology Group (RTOG). Proceedings of the 26th Annual Meeting of ASCO 9[350]: 90; 1990. 83-05: Sause, W. T.; Cooper, J. S.; Rush, S.; Ago, C. T.; Cosmatos, D.; Coughlin, C. T. RTOG 83-05: A Randomized trial evaluating fraction size in external beam radiation therapy. Proceedings of ASCO 8:283[ 11041; 1989. 83- 11: Cox, J. D.; Azarnia, N.; Byhardt, R. W.; Shin, K. H.; Emami, B.; Pajak, T. A Randomized Phase I/II Trial of hyperfractionated radiation therapy with total dose of 60. 0 Gy to 79. 2 Gy-possible survival benefit with 269.6 Gy in favorable patients with Radiation Therapy Oncology Group Stage III non-small cell lung carcinoma. Report of Radiation Therapy Oncology Group 83-l 1. J. Clin. Oncol. 8:1543-1555; 1990. 83-13: Cox, J. D.; Pajak, T. F.; Martial, V. A.; Hanks, G. E.; Mohiuddin, M.; Fu, K. K.; Byhardt, R. W.; Rubin, P. Dose-response for local control with hyperfractionated radiation therapy in advanced carcinomas of the upper aerodigestive tracts. Preliminary report of Radiation Therapy Oncology Group protocol 83- 13. Int. J. Radiat. Oncol. Biol. Phys. 18:5 15-521; 1990. 83-l 5: Nelson, D.; Martz, K.; Bonner, H.; Nelson, J.; Newall, J.; Kerman, H.; Thomson, J.; Murray, K. Definitive radiation therapy in the treatment of primary nonHodgkin’s lymphoma of the central nervous system (CNS): preliminary report of RTOG study 83 15. J. Neuro. Surg. (In press) 83-19: Order, S.; Pajak, T. F.; Leibel, S. A.; Asbell, S.; Leichner, P.; Ettinger, D.; Stillwagon, G.; Herpst, J.; Haulk, T.; Kopher, K.; Frazier, C.; Klein, J. A randomized prospective trial comparing full dose chemotherapy to I31antiferritin in non-randomized hepatoma: an RTOG study. Int. J. Radiat. Oncol. Biol. Phys. 20:953963; 1991. 83-2 1: Asbell, S. 0.; Pajak, T.; Seydel, H. G.; Brady, L.; Mohiuddin, N.; Weigensberg, I.; Montesano, A. T. Phase III RTOG double blind lung cancer trial of xrt and subsequent thymosin or placebo. Proceedings of ASCO 26th Annual Mtg 9:242[937]; 1990. 84-O 1: Myerson, R. J.; Emami, B.; Pereza, C. A.; Gibbs, F.; Lee, C.; Pajak, T. Phase I/II study, combination of radiotherapy and hyperthermia in patients with deepseated malignant tumors: report of a pilot study by the Radiation Therapy Oncology Group. Int. J. Radiat. Oncol. Biol. Phys. 17( 1):204[ 1701; 1989. 84-03: Russell, A. H.; Pajak, T. F.; Selim, H. M.; Paradelo, J. C.; Murray, K.; Bansal, P.; Cooper, J. S.; Silverman, S.; Clement, J. A. Prophylactic cranial irradiation (PCI) for selected lung cancer patients at high risk for development of cerebral metastasis: results of a prospective randomized trial. Int. J. Radiat. Oncol. Biol. Phys. 19( 1): 146[44], 1990. 84-06: Haselow, R. E.; Warshaw, M. G.; Oken, M. M.; Adams, G. L.; Aughey, J. L.; Cooper, J. S.; Schuller, D. E.; Jacobs, C. D. Radiation alone versus radiation with weekly low dose cisplatinum in unresectable cancer of the head and neck. Head and Neck Cancer, Toronto, B. C. Decker Inc., Vol. II: 279-28 1, 1990. 85-02: Spanos, W.; Guse, C.; Perez, C.; Grigsby, P.; Doggett, R. L. S.; Poulter, C. Phase II study of multiple daily fractionations in the palliation of advanced pelvic malignancies: preliminary report of RTOG 8502. Int. J. Radiat. Oncol. Biol. Phys. 17:659-661, 1989. 85-03: Schuller, D. E.; Laramore, G. E.; Al-Sarraf, M.; Jacobs, J.; Pajak, T. F. Combined therapy for resectable head and neck cancer. A phase III intergroup study. Arch. Otolaryngol. Head. Neck Surg. 115:364-368, 1989. 85-04-09: Calvo, F. A.; Hanks, G. E. Intraoperative trials. Int. J. Radiat. Oncol. Biol. Phys. 14:Sll l-S1 17, 1988. 85-l 2: Tester, W.; Porter, A.; Asbell, S.; Coughlin, C.; Heaney, J.; Martz, K.; Venner,
1387
1388
I. J. Radiation Oncology 0 Biology 0 Physics
June 1991, Volume 20, Number 6
P.; Hammond, E. Combined modality program with possible organ preservation for invasive bladder carcinoma. Proceedings of ASCO 8: 14 1[548]; 1989. 85-15: John, M.; Flam, N.; Sikic, B.; Rotman, M.; Cooper, J.; Malec, M.; Hannigan, J.; Phillips, T. Preliminary results of concurrent radiotherapy and chemotherapy in advanced cervical carcinoma: a phase I/II prospective intergroup NCOG-RTOG study. Gyn. Oncol. 34: 1-5; 1990. 85-27: Lee, D. J.; Wasserman, T.; Coleman, N.; Phillips, T.; Davis, L.; Martial, V.; Scott, C. A progress report of the RTOG head and neck SR-2508 trial. Int. J. Radiat. Oncol. Biol. Phys. 17( 1): 133[36]; 1989. 86-12: Urtasun, R. C.; Fulton, D. S.; Lester, S. G.; Silverstein, M.; Kinsella, T.; Wasserman, T.; Martz, K. A phase I RTOG study of iododeoxyuridine (IUdR) and radiotherapy in the treatment of primary malignant brain tumors. Int. J. Radiat. Oncol. Biol. Phys. 17( I):22 1[ 10241; 1989. 87-O 1: Vriesendorp, H. M.; Blum, J. E.; Herpst, J. M.; Germack, M. A.; Leichner, P. K.; Klein, J. L.; Kopher, K. A.; Order, S. E. Refractory Hodgkin’s disease: treatment with polyclonal yttrium labeled antiferritin. Proceedings of the 26th Annual Mtg. of ASCO 9[990]:256; 1990. General
Brady, L. W.; Kramer, S.; Wasserman, T. H.; Keiser, M.; Davis, L. W.; Pajak, T. F.; Cox, J.; Griffin, T.; Perez, C.; Phillips, T.; Rubin, P.; Seydel, H. G. The radiation therapy oncology group: an outline of clinical research activities. Int. J. Radiat. Oncol. Biol. Phys. 14:S3-SlO; 1988. Davis, L. W.; Bauer, M. Research plan for radiation oncology-1987: design and analysis of clinical trials. Am. J. Clin. Oncol. (CCT) 11(3):404-410; 1988. Martial, V.; Pajak, T.; Kramer, S.; Davis, L.; Stetz, J.; Laramore, G.; Jacobs, J.; AlSarraf, M.; Brady, L. Radiation Therapy Oncology Group (RTOG) studies in head and neck cancer. Seminars in Oncology 15( 1):39-60; 1988. Pajak, T.; Fazekas, J.; Davis, L.; Martial, V. Analysis of the RTOG head and neck database: identification of prognostic factors and the re-evaluation of AJC stages. In Vogl, S., ed. Head and Neck Cancer. Churchill Livingston, New York, pg. 4164, 1988. Perez, C. A.; Gillespie, B.; Pajak, T.; Hornback, N. B.; Emami, B.; Rubin, P. Quality assurance problems in clinical hyperthermia and their impact on therapeutic outcome: a report by the Radiation Therapy Oncology Group. Int. J. Radiat. Oncol. Biol. Phys. 16:551-558; 1989. Rubin, P.; Wasserman, T. H. The late effects of toxicity scoring. Int. J. Radiat. Oncol. Biol. Phys. 14:S29-S38; 1988. Shrivastava, P.; Luk, K.; Oleson, J.; Dewhirst, M.; Pajak, T.; Paliwal, B.; Perez, C.; Sapareto, S.; Saylor, T.; Steeves, R. Hyperthermia quality assurance guidelines. Int. J. Radiat. Oncol. Biol. Phys. 16:571-587; 1989. Wallner, P. E.; Lustig, R. A.; Pajak, T. F.; Robinson, G.; Davis, L. W.; Perez, C. A.; Seydel, H. G.; Martial, V. A.; Laramore, G. E. Impact of initial quality control review on study outcome in lung and head/neck cancer studies-review of the Radiation Therapy Oncology Group Experience. Int. J. Radiat. Oncol. Biol. Phys. 17:893-900; 1989. APPENDIX
B
Radiation Therapy Oncology Group: Closed Studies Pending Publication 84-05:
Phase I/II Dose Escalating Trial of Accelerated Fractionation in the Palliative Irradiation of Hepatic Metastases 84-07: A Phase I/II Pilot Study to Evaluate Accelerated Fractionation via Concomitant Boost for Squamous, Adeno, and Large Cell Carcinoma of the Lung 84-22: Treatment of Patients with Sub-Optimal (“Bulky”) Stage IB Carcinoma of the Cervix: A Randomized Comparison of Radiation Therapy vs. Radiation Therapy Plus Adjuvant Extrafascial Hysterectomy (Phase III)
RTOG: update of clinical research activities 0 T. H. WASSERMANet a/.
85-28: A Phase I/II Protocol for the Evaluation of Accelerated Fractionation in the Treatment of Patients with Supratentorial Brain Metastases 85-32: Treatment of Intracranial Ependymomas, A Pediatric Oncology Group Phase III Study 86-02: Phase III Study of Pentosanpolysulfate (PPS) in Radiation Cystitis and Hematuria 86-05: A Phase I Trial of Continuous Infusion SR-2508 with Interstitial and Intracavitary Radiation 87-02: Phase I Clinical Trial of Hyperthermia Plus Cisplatinum Chemotherapy for Refractory Superficial Malignancies 87-05: A Non-Randomized Phase I-II Study of Efficacy of Radiation and Hyperthermia (45°C for 15 Minutes) in the Treatment of some Measurable Superficial Human Tumors 88-01: Phase I/II Study of Prophylactic Hepatic Irradiation with Local Irradiation and Systemic Chemotherapy for Adenocarcinoma of the Pancreas 88-02: Phase I/II Study of Neoadjuvant Combined Modality Treatment with Selective Bladder Preservation for Patients with Invasive Bladder Cancer 88-04: Phase I/II Study of Sequential and Concurrent Radiation Therapy and Chemotherapy for Patients with Non-Small Cell Lung Cancer 88-05: Phase II Study of a Twice Daily Fractionation Schedule with External Irradiation and Intracavitary Brachytherapy in Bulky Stage IB, Stage II, III or WA Carcinoma of the Cervix 88-09: A Phase I/II Study to Evaluate Twice Daily Accelerated Hyperfractionation vs. Concomitant Boost Radiotherapy for Squamous Cell Carcinoma of the Upper Respiratory and Digestive Tracts 88-24: Phase II Trial to Determine the Feasibility of Post-Operative Concurrent Cisplatin and Radiotherapy in Patients with Resected Head and Neck Cancers
APPENDIX
C
Radiation Therapy Oncology Group: Active Studies as of 121l/90 84-19: A Randomized Phase III Study of Interstitial Thermoradiotherapy (43°C) Compared with Interstitial Radiotherapy Alone in the Treatment of Recurrent or Persistent Human Tumors 85-O1: Phase III Prospective Trial for Localized Cancer of the Esophagus: Comparing Radiation as a Single Modality to the Combination of Radiation Therapy and Chemotherapy 85-27: A Two Phase Study for the Evaluation of the Effectiveness of the Hypoxic Cell Sensitizer SR-2508 Combined with Conventional Radiotherapy in Patients with Locally Advanced Head and Neck Squamous Carcinomas 85-30: A Phase III Study of the Role of Cricopharyngeal Myotomy in the Treatment of Dysphagia Following Major Head and Neck Surgery 85-3 1: Phase III Study of Zoladex Adjuvant to Radiotherapy in Unfavorable Prognosis Carcinoma of the Prostate 86- 10: Phase III Study of Zoladex and Flutamide Used as Cytoreductive Agents in Locally Advanced Carcinoma of the Prostate Treated with Definitive Radiotherapy 86- 12: Phase I Study of Iododeoxyuridine (IUdR) and Radiotherapy in the Treatment of Primary Malignant Brain Tumors 87-04: A Phase III Randomized Study Employing 5 Fluorouracil, Mitomycin-C and Radiotherapy in Carcinoma of the Anal Canal 88-06: Phase I/II Protocol for the Treatment of Primary Central Nervous System Lymphomas 88-08: Phase III Study of Radiation Therapy Alone or in Combination with Chemotherapy for Patients with Non-Small Cell Lung Cancer 88- 15: A Phase III Study of Cisplatin Plus Etoposide Combined with Standard Fractionation Thoracic Radiotherapy versus Cisplatin Plus Etoposide Combined with
1389
1390
I. J. Radiation Oncology 0 Biology 0 Physics
June 1991, Volume 20, Number 6
Multiple Daily Fractionated Thoracic Radiotherapy for Limited Stage Small Cell Lung Cancer 88-16: Low Grade Glioma Phase III: Surgery and Immediate Radiotherapy vs. Surgery and Delayed Radiotherapy 88-17: A Phase III Study of Radiotherapy with or without Concurrent Cisplatin in Patients with Nasopharyngeal Cancer 88-20: Phase III Protocol for the Treatment of Residual or Unresectable Carcinoma of the Rectum and Rectosigmoid or Pelvic Recurrence Following Primary Colorectal Resection: External Beam Radiation Therapy + 5+luorouracil/Leucovorin with or without IORT Electron Boost 88-22: A Phase I/II Study to Evaluate the Effect of Fractionated Hemi-Body Irradiation in the Treatment of Osseous Metastases 88-23: Phase I/II Integrated Intra-Arterial Cisplatin and Intravenous 13’1Antiferritin in the Treatment of Non-Resectable Hepatocellular Cancer 89-O1: Phase III Study Comparing Combination Chemotherapy and Radiation Therapy with Preoperative Chemotherapy and Surgical Resection in Patients with NonSmall Cell Lung Cancer (NSCLC) with Spread to Mediastinal Lymph Nodes (N2) 89-02: Phase I/II Study of Sphincter Sparing Local Excision Combined with Post Operative Radiation Therapy and Concurrent 5-FU in the Treatment of Limited Adenocarcinoma of the Rectum 89-03: A Phase III Trial to Study the Role of Neoadjuvant MCV Chemotherapy Combined with Transurethral Surgery Plus Cisplatin with Radiation Therapy for Selective Bladder Preservation in Patients with Muscle-Invading Bladder Cancer 89-05: A Randomized Phase III Study of Conventional Radiation Therapy versus Conventional Radiation Therapy and Bromodeoxyuridine (BUdR) for Tumors Metastatic to the Brain 89-06: A Phase I Pilot Study to Evaluate Intraoperative Radiation Therapy and the Hypoxic Cell Sensitizer SR-2508 in Patients with Locally Advanced Malignancies 89-08: A Phase I/II Study to Evaluate Radiation Therapy and Hyperthermia for DeepSeated Tumors 89- 11: A Phase III Intergroup Trial: A Prospective Randomized Comparison of Combined Modality Therapy for Squamous Carcinoma of the Esophagus: Chemotherapy Plus Surgery versus Surgery Alone for Patients with Local Regional Disease 90-O1: Phase III Randomized Study: Pelvic Radiation with Concurrent Chemotherapy versus Pelvic and Para-Aortic Radiation for High Risk Cervical Carcinoma 90-02: A Randomized Phase III Research Study Using Irradiation Alone or Combined with Hyperthermia for Treatment of Localized Chest Wall Recurrences of Breast Carcinoma 90-05: Phase I Study of Small Field Stereotactic External Beam Irradiation for the Treatment of Recurrent Primary Brain Tumors and CNS Metastases 90-06: A Phase III Comparison of Hyperfractionated Radiation Therapy (RT) with BCNU and Conventional RT with BCNU for Supratentorial Malignant Glioma 90-14: Intergroup Rectal Adjuvant Protocol, A Phase III Study 90-15: Phase I/II Study of Concurrent Radiation Therapy and Chemotherapy for Patients with Non-Small Cell Lung Cancer APPENDIX
D
Radiation Therapy Oncology Group: Bibliography of selected publication for studies which were closed to patient accrual since 61 I/87 75-06/77-06: Lai, P. P.; Pilepich, M. V.; IQ-all, J. M.; Asbell, S. 0.; Hanks, G. E.; Perez, C. A.; Rubin, P.; Sause, W. T.; Cox, J. C. The effect of overall treatment time on the outcome of definitive radiotherapy for localized prostate carcinoma: the Radiation Therapy Oncology Group 75-06 and 77-06 experience. Int. J. Radiat. Oncol. Biol. Phys. (In Press) 76-19: Cooper, J. S.; Pajak, T. F.; Rubin, P.; Tupchong, L.; Brady, L. W.; Leibel, S. A.; Laramore, G. A.; Marcial, V. A.; Davis, L. W.; Cox, J. D. Second malignancies
RTOG: update of clinical research activities 0 T. H. WASSERMANet al.
in patients who have head and neck cancers: incidence, effect on survival and implications based on the RTOG experience. Int. J. Radiat. Oncol. Biol. Phys. 17: 449-456; 1989. 77-06: Asbell, S. 0.; Krall, J. M.; Pilepich, M. V.; Baerwald, H.; Sause, W. T.; Hanks, G. E.; Perez, C. A. Elective pelvic irradiation in stage A2, B carcinoma of the prostate-analysis of RTOG 77-06. Int. J. Radiat. Oncol. Biol. Phys. 15: 1307- 13 16; 1988. 79- 15: Fazekas, J. T.; Scott, C.; Martial, V.; Davis, L. W.; Wasserman, T.; Cooper, J. S. The role of hemoglobin concentration in the outcome of misonidazole-sensitized radiotherapy of head and neck cancers: based on RTOG trial #79- 15. Int. J. Radiat. Oncol. Biol. Phys. 17(6):1177-l 181; 1989. 79-16: Diener-West, M.; Dobbins, T. W.; Phillips, T. L.; Nelson, D. F. Identification of an optimal subgroup for treatment evaluation of patients with brain metastases using RTOG study 7916. Int. J. Radiat. Oncol. Biol. Phys. 16:669-673; 1989. 79-20: Rotman, M.; Choi, K.; Guse, C.; Marcial, V.; Hornback, N. Prophylactic irradiation of the para-aortic lymph node chain in stage 2B and bulky stage IB carcinoma of the cervix, initial treatment results of RTOG 79-20. Int. J. Radiat. Oncol. Biol. Phys. 17(1):151[71]; 1989. 80-02: Kligerman, M.; Turrisi, A.; Urtasun, R.; Norfleet, L.; Phillips, T.; Barkley, T.; Rubin, P. Final report on phase I trial of WR-2721 before protracted fractionated radiation therapy. Int. J. Radiat. Oncol. Biol. Phys. 14: 1119-l 122; 1988. 80-07: Laramore, G.; Deiner-West, M.; Griffin, T.; Griem, M.; Thomas, F.; Hendrickson, F.; Nelson, J.; Griffin, B.; Myrianthopoulos, L.; Saxton, J. Randomized neutron dose searching study for malignant gliomas of the brain: result of an RTOG study. Int. J. Radiat. Oncol. Biol. Phys. 14:1093-l 102; 1988. 83-08: Cox, J. D.; Guse, C.; Asbell, S.; Rubin, P.; Sause, W. T. Tolerance of pelvic normal tissues to hyperfractionated radiation therapy: results of protocol 83-08 of the Radiation Therapy Oncology Group. Int. J. Radiat. Oncol. Biol. Phys. 15: 133 l1336; 1988. 83-10: Sause, W. T.; Crowley, J. J.; Townsend, J. J.; Rotman, M.; Ager-Mowry, P.; Bouzaglou, A.; Borst, J. R.; Selim, H. Solitary brain metastasis: results of an RTOG/ SWOG protocol evaluation: surgery + rt vs. rt alone. J. Clin. Oncol. (Submitted for publication) 83-12: Emami, B.; Perez, C. A.; Herskovic, A.; Hederman, M. A. Phase I/II study of treatment of locally advanced (T3T4) non-oat cell lung cancer with high dose radiotherapy (rapid fractionation): Radiation Therapy Oncology Group Study. Int. J. Radiat. Oncol. Biol. Phys. 15:1021-1025; 1988. 85- 19: Pilepich, M. V.; Al-Sarraf, M.; John, M. J.; McGowan, D.; Hwang, Y. S.; Perez, C. A.; Krall, J. M. Phase II RTOG study of hormonal cytoreduction with flutamide and zoladex in locally advanced carcinoma of the prostate treated with definitive radiotherapy. Am. J. Clin. Oncol. (Submitted for publication). General
Leibel, S. A.; Scott, C. B.; Mohiuddin, M.; Marcial, V. A.; Coia, L. R.; Davis, L. W.; Fuks, Z. Does local-regional control affect distant metastatic spread in squamous cell carcinoma of the head and neck? Results of an RTOG analysis. Accepted to ASTRO for October 1990 meeting in Florida, 5/90.
1391