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The intergroup rhabdomyosarcoma study II: Objectives and study design
ANNOUNCEMENTS
371
November 16-22, 1980 Florian6polis VIII B R A Z I L I A N CONGRESS OF PEDIATRIC S U R G E R Y III B R A Z I L I A N CONGRESS OF PEDIATRIC RADIOLOGY III N A T I O N A L SYMPOSIUM OF INTENSIVE CARE IN PEDIATRICS For information: Dr. Peter Goldberg, General Secretary of the Congresses, Hospital Infantil Joana de Gusmao, Rua Ruy Barbosa, 88000--Florian6polis, Santa Catarina, Brazil.
ANNOUNCEMENT
The Intergroup Rhabdomyosarcoma Study II: Objectives and Study Design Harold M. Maurer, M.D. For the Intergroup Rhabdomyosarcoma Study Committee*
We previously announced in this Journal the objectives, clinical grouping (staging) classification, and study design of the Intergroup Rhabdomyosarcoma Study, a prospective study of childhood rhabdomyosarcoma initiated by the three cooperative cancer study groups concerned with pediatric tumors (Cancer and Leukemia Group B, Children's Cancer Study Group, and Southwest Oncology Group). l In 1978, after accruing nearly 800 patients in 6 yr, the study was closed to patient entry. The preliminary results have been reported. 2'3 We now wish to announce the
*Representing Cancer and Leukemia Group B, Children's Cancer Study Group and Southwest Oneology Group: William M. Crist, M.D., Milton Donaldson, M.D., Edmund A. Gehan, PH.D., Denman Hammond, M.D., Daniel M. Hays, M.D., Walter Lawrence, Jr., M.D., Robert Lindberg, M.D., William Newton, M.D., Abdelsalam H. Ragab, M.D., R. Beverly Raney, M.D., Frederick B. Ruymann, M.D., Edward H. Soule, M.D., W. W. Sutow, M.D., and Melvin Tefft, M.D. Supported by U.S. Public Health Service Grant Numbers: CA 24507 CA 03735, CA 04646, CA 12014, CA 16943, CA 13539, and CA 16118. Address reprints requests to Harold M. Maurer, M.D., Department o f Pediatrics, Medical College o f Virginia, Richmond, Va. 23298.
activation of a successor intergroup study, IRSII, open to entry as of November 1, 1978. The clinical grouping (staging) classification employed in this study and its predecessor are indentical. OBJECTIVES AND STUDY DESIGN
(1) In patients in whom there has been complete excision of a localized tumor, pathologically confirmed (Group I), the study proposes to determine whether chemotherapy can be limited to vincristine (VCR) and dactinomycin (AMD) without jeopardizing disease control. No patient in this Group will receive postoperative radiation as IRS-I demonstrated that it did not affect results. Patients will be randomized between two regimens: (A) VCR (2mg/m 2 i.v. qw x 12), AMD (0.015 m g / k g / d a y x 5; course repeated x 4 in 48 wk) and cyclophosphamide (CPM) (2.5 m g / k g / d a y p.o. from day 42 to 2 yr), i.e., VAC; or (B) VCR and AMD in the same schedule as (A). (2) In patients with microscopic residual tumor following surgical excision for local or regional disease, or patients with apparently totally resected regional disease (Group II), the
372
ANNOUNCEMENT
study proposes to compare the disease control produced by a regimen of VCR and AMD versus that produced by a more intensive regimen composed of repetitive "pulses" of VAC. All patients will receive radiotherapy. The randomization will be between: (A) VCR (2mg/m 2 i.v. qw x 6; 6 courses in 48 wk), AMD (0.015 m g / k g / d a y i.v. x 5; course repeated x 5 in 45 wk), and postoperative radiation; or (B) VCR ( 2 m g / m 2 i.v. qw x 12), A M D (0.015 m g / k g / d a y • 5), and CPM (10 m g / k g / d a y i.v. x 3, and then 20 mg/kg/i.v, on days 21, 42, and 63) followed by pulse VAC courses (VCR, 2 m g / m 2 i.v. days 0 and 4, A M D , 0.015 m g / k g / d a y i.v. • 5; CPM, 10 m g / k g / d a y i.v. x 3) given repetitively every 4 wk from week 12 through week 52. The tumor bed is irradiated after 6 wk of chemotherapy in (B). (3) In patients with gross residual disease following surgery (Group III) or with metastatic disease at diagnosis (Group IV), the study will compare repetitive pulse VAC courses, given for 2 yr, versus the same drug combination substituting adriamycin (30 m g / m 2 i.v. on days 0, 1, 21, and 22 initially, and then on days 0 and 1 of each VADRC course) for dactinomycin in alternate courses for the first year of treatment. The tumor bed and sites of metastases are irradiated after 6 wk of chemotherapy. (4) All patients with extremity tumors requiring amputation or having alveolar histology, both of which are unfavorable prognostic factors, will be treated with repetitive pulse VAC courses and those with Groups II-IV disease will also receive radiation to the tumor bed, with the aim of improving disease control. (5) In patients with head and neck tumors (nasopharynx, nasal cavity, middle ear, paranasal sinuses) at risk of meningeal extension, the study proposes to determine whether "prophylactic" local meningeal radiation will prevent this almost uniformly fatal complication. Patients who show erosion of the base of the skull, signs of intracranial tumor, or positive CSF cytology or spinal cord block will be treated
with craniospinal radiation and receive intrathecal courses of cytosine arabinoside, hydrocortisone, and methotrexate for 18 to 24 too. (6) In patients with tumors localized to the vagina, uterus, bladder or prostate, the study proposes to compare a primary chemotherap y / r a d i o t h e r a p y approach to the classical primary surgery approach with the hope of avoiding the disability associated with radical surgery while maintaining a high rate of disease control and survival. In the former case only a biopsy is taken and then the patient is started on pulse VAC chemotherapy. After 4 courses (16 wk), surgery is carried out to remove any residual tumor. If there is no microscopic residual and positive nodes are completely excised, the patient is returned to the pulse VAC regimen, given every 4 wk. If gross or microscopic residual remains following surgery, the tumor bed and involved nodes are irradiated as well. If on the other hand no response or progressive disease is noted at the 8 wk evaluation, surgery should be carried out and the tumor excised. If the excision is complete, the patient is then placed on repetitive pulse VADRC chemotherapy. If the tumor is incompletely removed the patient is then to receive radiation as well. If at any time excision would require exenteration, an option is to employ radiotherapy to the known extent of the tumor. (7) Special histopathology studies will be performed on all cases in an attempt to develop a pathologic staging classification for rhabdomyosarcoma. (8) Lastly, we are studying the ability to modify the dose and volume of radiation for children who are receiving concomitant intensive chemotherapy, in order to minimize damage to normal growing tissues. From November 1, 1978 to August 31, 1979, a total of 158 patients have been entered on IRS-II. The initial accrual rate of 15.8 patients per month is slightly higher than that observed in IRS-I, indicating a substantial continuing interest in these studies.
REFERENCES
1. Maurer HM: The Intergroup Rhabdomyosarcoma Study (NIH): Objectivesand clinicalstaging classification. J Pediatr Surg 10:977, 1975 2. Maurer HM, Moon T, Donaldson M, et al: The Inter-
group Rhabdomyosarcoma Study: A preliminary report. Cancer 40:2015, 1977 3. Maurer HM, Donaldson M, Gehan EA, et al: The Intergroup RhabdomyosarcomaStudy: Update--November 1978. J Natl Cancer Inst (in press)
371
November 16-22, 1980 Florian6polis VIII B R A Z I L I A N CONGRESS OF PEDIATRIC S U R G E R Y III B R A Z I L I A N CONGRESS OF PEDIATRIC RADIOLOGY III N A T I O N A L SYMPOSIUM OF INTENSIVE CARE IN PEDIATRICS For information: Dr. Peter Goldberg, General Secretary of the Congresses, Hospital Infantil Joana de Gusmao, Rua Ruy Barbosa, 88000--Florian6polis, Santa Catarina, Brazil.
ANNOUNCEMENT
The Intergroup Rhabdomyosarcoma Study II: Objectives and Study Design Harold M. Maurer, M.D. For the Intergroup Rhabdomyosarcoma Study Committee*
We previously announced in this Journal the objectives, clinical grouping (staging) classification, and study design of the Intergroup Rhabdomyosarcoma Study, a prospective study of childhood rhabdomyosarcoma initiated by the three cooperative cancer study groups concerned with pediatric tumors (Cancer and Leukemia Group B, Children's Cancer Study Group, and Southwest Oncology Group). l In 1978, after accruing nearly 800 patients in 6 yr, the study was closed to patient entry. The preliminary results have been reported. 2'3 We now wish to announce the
*Representing Cancer and Leukemia Group B, Children's Cancer Study Group and Southwest Oneology Group: William M. Crist, M.D., Milton Donaldson, M.D., Edmund A. Gehan, PH.D., Denman Hammond, M.D., Daniel M. Hays, M.D., Walter Lawrence, Jr., M.D., Robert Lindberg, M.D., William Newton, M.D., Abdelsalam H. Ragab, M.D., R. Beverly Raney, M.D., Frederick B. Ruymann, M.D., Edward H. Soule, M.D., W. W. Sutow, M.D., and Melvin Tefft, M.D. Supported by U.S. Public Health Service Grant Numbers: CA 24507 CA 03735, CA 04646, CA 12014, CA 16943, CA 13539, and CA 16118. Address reprints requests to Harold M. Maurer, M.D., Department o f Pediatrics, Medical College o f Virginia, Richmond, Va. 23298.
activation of a successor intergroup study, IRSII, open to entry as of November 1, 1978. The clinical grouping (staging) classification employed in this study and its predecessor are indentical. OBJECTIVES AND STUDY DESIGN
(1) In patients in whom there has been complete excision of a localized tumor, pathologically confirmed (Group I), the study proposes to determine whether chemotherapy can be limited to vincristine (VCR) and dactinomycin (AMD) without jeopardizing disease control. No patient in this Group will receive postoperative radiation as IRS-I demonstrated that it did not affect results. Patients will be randomized between two regimens: (A) VCR (2mg/m 2 i.v. qw x 12), AMD (0.015 m g / k g / d a y x 5; course repeated x 4 in 48 wk) and cyclophosphamide (CPM) (2.5 m g / k g / d a y p.o. from day 42 to 2 yr), i.e., VAC; or (B) VCR and AMD in the same schedule as (A). (2) In patients with microscopic residual tumor following surgical excision for local or regional disease, or patients with apparently totally resected regional disease (Group II), the
372
ANNOUNCEMENT
study proposes to compare the disease control produced by a regimen of VCR and AMD versus that produced by a more intensive regimen composed of repetitive "pulses" of VAC. All patients will receive radiotherapy. The randomization will be between: (A) VCR (2mg/m 2 i.v. qw x 6; 6 courses in 48 wk), AMD (0.015 m g / k g / d a y i.v. x 5; course repeated x 5 in 45 wk), and postoperative radiation; or (B) VCR ( 2 m g / m 2 i.v. qw x 12), A M D (0.015 m g / k g / d a y • 5), and CPM (10 m g / k g / d a y i.v. x 3, and then 20 mg/kg/i.v, on days 21, 42, and 63) followed by pulse VAC courses (VCR, 2 m g / m 2 i.v. days 0 and 4, A M D , 0.015 m g / k g / d a y i.v. • 5; CPM, 10 m g / k g / d a y i.v. x 3) given repetitively every 4 wk from week 12 through week 52. The tumor bed is irradiated after 6 wk of chemotherapy in (B). (3) In patients with gross residual disease following surgery (Group III) or with metastatic disease at diagnosis (Group IV), the study will compare repetitive pulse VAC courses, given for 2 yr, versus the same drug combination substituting adriamycin (30 m g / m 2 i.v. on days 0, 1, 21, and 22 initially, and then on days 0 and 1 of each VADRC course) for dactinomycin in alternate courses for the first year of treatment. The tumor bed and sites of metastases are irradiated after 6 wk of chemotherapy. (4) All patients with extremity tumors requiring amputation or having alveolar histology, both of which are unfavorable prognostic factors, will be treated with repetitive pulse VAC courses and those with Groups II-IV disease will also receive radiation to the tumor bed, with the aim of improving disease control. (5) In patients with head and neck tumors (nasopharynx, nasal cavity, middle ear, paranasal sinuses) at risk of meningeal extension, the study proposes to determine whether "prophylactic" local meningeal radiation will prevent this almost uniformly fatal complication. Patients who show erosion of the base of the skull, signs of intracranial tumor, or positive CSF cytology or spinal cord block will be treated
with craniospinal radiation and receive intrathecal courses of cytosine arabinoside, hydrocortisone, and methotrexate for 18 to 24 too. (6) In patients with tumors localized to the vagina, uterus, bladder or prostate, the study proposes to compare a primary chemotherap y / r a d i o t h e r a p y approach to the classical primary surgery approach with the hope of avoiding the disability associated with radical surgery while maintaining a high rate of disease control and survival. In the former case only a biopsy is taken and then the patient is started on pulse VAC chemotherapy. After 4 courses (16 wk), surgery is carried out to remove any residual tumor. If there is no microscopic residual and positive nodes are completely excised, the patient is returned to the pulse VAC regimen, given every 4 wk. If gross or microscopic residual remains following surgery, the tumor bed and involved nodes are irradiated as well. If on the other hand no response or progressive disease is noted at the 8 wk evaluation, surgery should be carried out and the tumor excised. If the excision is complete, the patient is then placed on repetitive pulse VADRC chemotherapy. If the tumor is incompletely removed the patient is then to receive radiation as well. If at any time excision would require exenteration, an option is to employ radiotherapy to the known extent of the tumor. (7) Special histopathology studies will be performed on all cases in an attempt to develop a pathologic staging classification for rhabdomyosarcoma. (8) Lastly, we are studying the ability to modify the dose and volume of radiation for children who are receiving concomitant intensive chemotherapy, in order to minimize damage to normal growing tissues. From November 1, 1978 to August 31, 1979, a total of 158 patients have been entered on IRS-II. The initial accrual rate of 15.8 patients per month is slightly higher than that observed in IRS-I, indicating a substantial continuing interest in these studies.
REFERENCES
1. Maurer HM: The Intergroup Rhabdomyosarcoma Study (NIH): Objectivesand clinicalstaging classification. J Pediatr Surg 10:977, 1975 2. Maurer HM, Moon T, Donaldson M, et al: The Inter-
group Rhabdomyosarcoma Study: A preliminary report. Cancer 40:2015, 1977 3. Maurer HM, Donaldson M, Gehan EA, et al: The Intergroup RhabdomyosarcomaStudy: Update--November 1978. J Natl Cancer Inst (in press)