- Email: [email protected]
Conservative management of uterine pediatric rhabdomyosarcoma: A report from the intergroup rhabdomyosarcoma study III and IV pilot
Conservative Management of Uterine Pediatric Rhabdomyosarcoma: A Report From the Intergroup Rhabdomyosarcoma Study III and IV Pilot By Cynthia A. Corpron,
Richard J. Andrassy, Daniel M. Hays, R. Beverly Rsney, Eugene Walter Lawrence, Thorn E Lobe, and Harold M. Maurer Houston,
S. Wiener,
Texas
R
a Previous studies have suggested that women with uterine rhabdomyosarcomas (RMS) represent a distinct group of patients who present at an older age, are less responsive to treatment, and have a poorer prognosis than patients with vaginal RMS. During the intergroup Rhabdomyosarcoma Study (IRS) Ill and the IRS IV pilot study, 14 patients were registered with uterine primary RMS. Three patients presented with cervical tumors that were completely removed (group 1). Eight patients had initial biopsies with gross residual disease (group 3). and 3 had metastatic disease at presentation (group 4). Of the 5 patients treated with primary chemotherapy or chemotherapy and radiation, 2 had delayed hysterectomy and vaginectomy, 1 had no further surgery, and 2 had exploratory laparotomy with no evidence of disease. There were no relapses or deaths in this group. One patient underwent initial resection of a broad ligament mass, experienced an early (3-week) recurrence of the mass while on chemotherapy, and progressed to developing distant metastases and death. Four patients died of chemotherapy toxicity or sepsis, one after achieving a complete response from chemotherapy and hysterectomy. This primary chemotherapy or chemotherapy and radiotherapy regimen resulted in 8 of 9 (89%) patients (not including those who died of chemotoxicity) surviving between 1.6 and 6 years without evidence of disease. Of the surviving patients, 2 had hysterectomy and vaginectomy, but pathological specimens showed only localized microscopic residual tumor. This report suggests that less vigorous operative resection may be possible in combination with primary chemotherapy when treating uterine rhabdomyosarcomas. However, evaluation of the excellent response to chemotherapy must include consideration of the 4 patients who died of sepsis or treatment complications. Copyright o 1995 by W. B. Saunders Company
EVIEW OF THE Intergroup Rhabdomyosarcoma (RMS) Studies (IRS) I and II1-3 suggested that patients with primary tumors of the uterus were a distinct group, distinguished from those with primary tumors arising in the vagina by older age, propensity to local recurrence, and a poorer prognosis. Before 1972, most children with uterine RMS were treated with radical surgery. Beginning in 1976, the IRS used initial surgery followed by chemotherapy for cervical polypoid lesions and biopsy followed by chemotherapy with or without radiotherapy for nonpolypoid lesions. The response to chemotherapy for the second group was unimpressive, and none survived.2,3 This introduction of combined modality therapy led to attempts to decrease the extent of surgery. Beginning in 1984, IRS III patients with uterine primaries underwent a regimen that included Adriamycin (ADR) (Adria Laboratories, Inc, Columbus, OH) as well as cisplatin (CPDD), vincristine (VCR), dactinomycin (AMD), and cyclophosphamide. In 1989 this regimen was modified to allow comparison of several newer drugs including ifosfamide and etoposide. These therapies have allowed less extensive resections and less irradiation with an excellent local and distant control of disease. This review includes all patients with uterine primaries registered in either the IRS III or the IRS IV pilot.
INDEX
All evaluable patients with uterine primary tumors entered on the IRS III (1985 to 1988) and the IRS IV pilot (1989 to 1990) were included. Distinction between primary vaginal and uterine sites was made by pretreatment examination findings and by examination of surgical specimens and were reviewed for site by the IRS Study Committee. Tumors were classified on histological review by the IRS pathologists. All patients were initially treated on IRS protocols. The Clinical Groups used in the IRS are defined in Table 1.
WORDS:
Rhabdomyosarcoma,
uterine,
pediatric.
From the Intergroup Rhabdomyosarcoma Study Committee of the Pediatric Oncology Group, The Children’s Cancer Group, and the Charles Bagwell, Pediatric Intergroup Statistical Ofi ce, including: William Crist, Sarah Donaldson, Christopher Fryer, Edmund Gehan, Denman Hammond, Ruth Heyn, William Newton, Jorge Ortega, Abdel Ragab, Frederick Ruymann, Malcolm Smith, Melvin Te#t, Timothy Triche, Teresa Ketti, Bruce Webber, and Moody Wharam. Presented at the 1994 Annual Meeting of the Section on Surgery of the American Academy of Pediatrics, Dallas, Texas, October 21-23, 1994. Supported by USPHS Grants CA-24507, CA-13539, CA-29139, CA-30138, and CA-30969. Address reprint requests to Richard J. Andrassy, MD, 6431 Fannin, Suite 6.264, Houston, TX 77030. Copyright o 1995 by W. B. Saunders Company
0022-3468/95/3007-0007$03.00/O 942
MATERIALS
AND METHODS
RESULTS
Fourteen (mean age, 5.5 years; range, 4 months to 17 years) were registered with uterine RMS. Three of these patients (mean age, 9 years) presented with cervical tumors. Patients presented with vaginal bleeding and/or abdominal masses. Biopsy of these lesions showed embryonal (botryoid in three) pathology in 13 JournalofPedietric
Surgery,
Vol30,
No 7 (July),
1995:
pp 942-944
UTERINE
RMS:
CONSERVATIVE
Table
1. Uterine
RMS:
MANAGEMENT
Clinical
Group
IRS Ill and Chnical Group (At Presentation)
1. Complete 2. Resection or lymph
Classification
and Outcome
IV Pilot Number of Patients
surgical resection with positive margins nodes
3. Gross residual after biopsy or partial surgical resectlon 4. Metastatic disease
943
No Evidence of Disease
Dead
3
3
0
0
0
0
8 3
3 3
5 0
14
9
5
only
Total
patients and alveolar pathology in 1 patient. Initial operation was polypectomy with complete resection of tumor (group 1) in 3 patients, and biopsy or partial resection with gross residual tumor (group 3) in 8 patients. Three patients presented with metastatic disease (group 4). Eight patients underwent initial biopsy, then chemotherapy or chemotherapy and radiation, and 2 patients underwent primary tumor resection (1 as resection of a broad ligament mass and 1 by hysterectomy). At 20 weeks, a second-look operation was mandated by protocol. Of the group 3 and 4 patients, 1 patient had no operation, 3 patients subsequently had hysterectomy and vaginectomy, and 3 had exploration with no evidence of tumor. Three patients died of sepsis before second-look surgery. Of the 3 patients who underwent hysterectomy and vaginectomy, pathology showed only localized microscopic residual tumor in 2 patients. One patient presented with a broad ligament mass and had an early local recurrence after initial resection and 3 weeks of chemotherapy. This patient had distant metastasis and died of tumor progression. Three patients had initial biopsy and then died of chemotherapy toxicity or sepsis before the surgical second-look procedure. One patient had a complete response, had second-look hysterectomy and vaginectomy (with no residual tumor in the specimen), and then died of sepsis after development of renal failure during chemotherapy. All the group 1 patients survived. Of the 8 group 3 patients, 4 died of chemotherapy toxicity, 1 died of tumor progression, 2 survived after hysterectomy and vaginectomy, and 1 survived after biopsy with no further resection. All 3 group 4 patients survived without further resection after biopsy. The 5 patients who died all died while still undergoing chemotherapy, only 1 of whom achieved a complete response. Chemotherapy regimens are outlined in the report of IRS III by Crist et a1.4Follow-up for 1.5 to 6 years is available for the surviving patients. DISCUSSION
Uterine RMS present either as cervical tumors with a vaginal mass or bleeding, or as tumors of the
uterine body with an abdominal mass. Diagnosis is made by incisional or excisional biopsy (usually by dilatation and curettage and transvaginal biopsy). Most uterine tumors show embryonal histology.5 In addition to biopsy, staging requires a metastatic work-up including pelvic examination and computed tomography (CT) scans of the pelvis, abdomen, and chest, examination of the bone marrow by biopsy or aspiration, cystoscopy, and vaginoscopy. Before 1972, treatment for uterine RMS included radical surgery before chemotherapy and radiation. Stimulated by the report of Ortega et al,‘j treatment shifted to primary chemotherapy with delayed operations for locally advanced or distantly metastatic uterine RMS in an attempt to improve the survival and local response rates while limiting radical surgical resection. A major goal of IRS II was to preserve a functional distal urinary tract after treatment of pelvic tumors.7 It has been suggested in previous studies’” that patients with uterine RMS present at an older age and have a worse prognosis than do those patients who present with vaginal rhabdomyosarcomas. Hays et aP3 reviewed 10 patients with primary uterine RMS from IRS I and II. These patients presented at a mean age of 14.2 years. Five of the 10 patients were placed in clinical group 1 after cervical polypectomy or hysterectomy and vaginectomy. No irradiation was used. All 5 patients survived without relapse. Five patients presented with intramural involvement of the uterus and extensive local disease. Two of these had distant metastases. One of these group 3 and 4 patients was treated with a regimen including Adriamycin (and one had Adriamytin added after progression on pulse VAC). One of these patients died of infection after 2 months of chemotherapy, and the other 4 died of progression of disease, none living longer than 14 months. In contrast, the present series is composed of a mostly younger group of patients (mean age, 5.5 years), of which 3 presented with cervical polypoid lesions and the remainder presented with large ( > 5 cm) masses and intramural involvement. In the group 3 and group 4 patients, only 1 has had a relapse and died of tumor, whereas 4 died of sepsis or chemotherapy complications. The patient that had local recurrence and death was very unusual in that the initial tumor presented as a broad ligament mass and had the only alveolar histology in the series. Only 2 of 7 surviving patients required hysterectomy and vaginectomy. Only 3 patients underwent irradiation, and 2 of these patients have survived; the other patient had the unusual broad ligament tumor referred to above. Initial radical resection would no longer seem justified because it appears that biopsy and initial chemo-
944
CORPRON
therapy or chemotherapy and radiotherapy allow a high percentage of these patients to avoid having resection. A portion of these patients may be able to avoid having radiation. Only 1 patient with uterine RMS had local progression and/or relapse during IRS III and IV pilot (the patient with the broad ligament tumor who had no clear involvement of the uterus and may thus represent a different site of tumor). This review suggests that age of presentation and prognosis in uterine and vaginal RMS may be more similar than previously suggested in earlier series1-3 and that primary chemotherapy and radiotherapy may be as effective in uterine tumors as it has been in vaginal tumors. With this type of regimen, the prognosis in uterine RMS may be less ominous than previously described. Long-term follow-up for late recurrences and sequelae of treatment is required and continues in these patients. The response of patients with locally advanced or metastatic (group 3
ET AL
and 4) uterine RMS to primary chemotherapy followed by radiation and/or operative resection shows an 86% (6 of 7) survival rate (not including deaths from toxicity or sepsis) at 1.5 to 6 years of follow-up. This is significantly improved over the 20% survival reported for these patients in IRS I and II, whereas the group 1 patients continue to do well with a 100% (3 of 3) survival rate. Only one group 4 patient died of sepsis during IRS I, but during the IRS III and IV pilot, 4 of 14 (29%) patients died of chemotherapy toxicity or sepsis. Although the number of patients in this series is small and does not allow for conclusions about therapy, the results suggest that although primary chemotherapy may allow less surgical resection and thus preservation of pelvic organs, it may lead to an unacceptably high rate of chemotoxicity and sepsis-related deaths. The optimal combination of surgery, chemotherapy, and radiation for treatment of uterine RMS has yet to be determined.
REFERENCES 5. Palmer NF, Foulkes M: Histopathology and prognosis in the 1. Hays DM, Raney RB, Lawrence W, et al: Rhabdomyosarcoma of the female urogenital tract. J Pediatr Surg 16:828-834,1981 second Intergroup Rhabdomyosarcoma Study (IRS-II). Proc Am Sot Oncol2:229,1983 (abstr) 2. Hays DM, Shimada H, Raney RB, et al: Sarcomas of the vagina and uterus: The Intergroup Rhabdomyosarcoma Study. J 6. Ortega JA: A therapeutic approach to childhood pelvic rhabdomyosarcoma without pelvic exenteration. J Pediatr 94:205Pediatr Surg 20:718-724, 1985 3. Hays DM, Shimada H, Raney RB, et al: Clinical staging and 209,1979 treatment in rhabdomyosarcoma of the female genital tract among 7. Raney RB, Gehan EA, Hays DM, et al: Primary chemotherchildren and adolescents. Cancer 61:1893-1903,1988 apy with or without radiation therapy and/or surgery for children 4. Crist W, Gehan EA, Ragab AH, et al: The third Intergroup with localized sarcoma of the bladder, prostate, vagina, uterus, and Rhabdomyosarcoma Study. J Clin Oncol13:610-630,1995 cervix. Cancer 66:2072-2081.1990
Discussion C. Bagwell (Richmond, VA): I appreciate the opportunity to comment on the paper and the authors sending me the text to review. I think most of us agree with your conclusions; namely, that optimum treatment is evolving and that surgery is a facet in the multimodal treatment of these tumors. We also agree that conservative resection is probably best, but it may require a surgical resection for a second-look operation, as was suggested by Drs Grosfeld and Clatworthy some years ago. However, I’m not sure if the data here really support these conclusions. The data really should exclude the three patients who are stage 1, in whom polyploid tumors result in a uniformly good prognosis. The three patients with metastatic disease should also be excluded. That leaves eight in the group 3 series, of whom four suffered very significant complications from chemotherapy with an overall 50% mortality rate. This is unacceptable, and should be put in perspective when we think about the report of Dan Hays in
1988, who reported from IRS I and II, 10 patients with uterine primary tumors, all of whom were treated at that time with available chemotherapy, and all of whom died, but of progressive disease. Have we traded a death of tumor progression for chemotherapy-related toxic death? In the meantime, the updates from the IRS series, especially with a variance like this, certainly indicate that it’s necessary to refine a treatment, that refinement will include not only surgical but chemotherapy and radiation therapy refinements as well. From the Floor: Half your patients in group 3 went on to have vaginectomy and hysterectomy. Was that because of local recurrence or was that part of a staged plan up front? CA. Corpron (response):That was part of a staged second-look operation. Two of the three that had hysterectomy after chemotherapy actually had very minimal microscopic disease, so they probably could have had a smaller resection at the time of secondlook surgery.
Richard J. Andrassy, Daniel M. Hays, R. Beverly Rsney, Eugene Walter Lawrence, Thorn E Lobe, and Harold M. Maurer Houston,
S. Wiener,
Texas
R
a Previous studies have suggested that women with uterine rhabdomyosarcomas (RMS) represent a distinct group of patients who present at an older age, are less responsive to treatment, and have a poorer prognosis than patients with vaginal RMS. During the intergroup Rhabdomyosarcoma Study (IRS) Ill and the IRS IV pilot study, 14 patients were registered with uterine primary RMS. Three patients presented with cervical tumors that were completely removed (group 1). Eight patients had initial biopsies with gross residual disease (group 3). and 3 had metastatic disease at presentation (group 4). Of the 5 patients treated with primary chemotherapy or chemotherapy and radiation, 2 had delayed hysterectomy and vaginectomy, 1 had no further surgery, and 2 had exploratory laparotomy with no evidence of disease. There were no relapses or deaths in this group. One patient underwent initial resection of a broad ligament mass, experienced an early (3-week) recurrence of the mass while on chemotherapy, and progressed to developing distant metastases and death. Four patients died of chemotherapy toxicity or sepsis, one after achieving a complete response from chemotherapy and hysterectomy. This primary chemotherapy or chemotherapy and radiotherapy regimen resulted in 8 of 9 (89%) patients (not including those who died of chemotoxicity) surviving between 1.6 and 6 years without evidence of disease. Of the surviving patients, 2 had hysterectomy and vaginectomy, but pathological specimens showed only localized microscopic residual tumor. This report suggests that less vigorous operative resection may be possible in combination with primary chemotherapy when treating uterine rhabdomyosarcomas. However, evaluation of the excellent response to chemotherapy must include consideration of the 4 patients who died of sepsis or treatment complications. Copyright o 1995 by W. B. Saunders Company
EVIEW OF THE Intergroup Rhabdomyosarcoma (RMS) Studies (IRS) I and II1-3 suggested that patients with primary tumors of the uterus were a distinct group, distinguished from those with primary tumors arising in the vagina by older age, propensity to local recurrence, and a poorer prognosis. Before 1972, most children with uterine RMS were treated with radical surgery. Beginning in 1976, the IRS used initial surgery followed by chemotherapy for cervical polypoid lesions and biopsy followed by chemotherapy with or without radiotherapy for nonpolypoid lesions. The response to chemotherapy for the second group was unimpressive, and none survived.2,3 This introduction of combined modality therapy led to attempts to decrease the extent of surgery. Beginning in 1984, IRS III patients with uterine primaries underwent a regimen that included Adriamycin (ADR) (Adria Laboratories, Inc, Columbus, OH) as well as cisplatin (CPDD), vincristine (VCR), dactinomycin (AMD), and cyclophosphamide. In 1989 this regimen was modified to allow comparison of several newer drugs including ifosfamide and etoposide. These therapies have allowed less extensive resections and less irradiation with an excellent local and distant control of disease. This review includes all patients with uterine primaries registered in either the IRS III or the IRS IV pilot.
INDEX
All evaluable patients with uterine primary tumors entered on the IRS III (1985 to 1988) and the IRS IV pilot (1989 to 1990) were included. Distinction between primary vaginal and uterine sites was made by pretreatment examination findings and by examination of surgical specimens and were reviewed for site by the IRS Study Committee. Tumors were classified on histological review by the IRS pathologists. All patients were initially treated on IRS protocols. The Clinical Groups used in the IRS are defined in Table 1.
WORDS:
Rhabdomyosarcoma,
uterine,
pediatric.
From the Intergroup Rhabdomyosarcoma Study Committee of the Pediatric Oncology Group, The Children’s Cancer Group, and the Charles Bagwell, Pediatric Intergroup Statistical Ofi ce, including: William Crist, Sarah Donaldson, Christopher Fryer, Edmund Gehan, Denman Hammond, Ruth Heyn, William Newton, Jorge Ortega, Abdel Ragab, Frederick Ruymann, Malcolm Smith, Melvin Te#t, Timothy Triche, Teresa Ketti, Bruce Webber, and Moody Wharam. Presented at the 1994 Annual Meeting of the Section on Surgery of the American Academy of Pediatrics, Dallas, Texas, October 21-23, 1994. Supported by USPHS Grants CA-24507, CA-13539, CA-29139, CA-30138, and CA-30969. Address reprint requests to Richard J. Andrassy, MD, 6431 Fannin, Suite 6.264, Houston, TX 77030. Copyright o 1995 by W. B. Saunders Company
0022-3468/95/3007-0007$03.00/O 942
MATERIALS
AND METHODS
RESULTS
Fourteen (mean age, 5.5 years; range, 4 months to 17 years) were registered with uterine RMS. Three of these patients (mean age, 9 years) presented with cervical tumors. Patients presented with vaginal bleeding and/or abdominal masses. Biopsy of these lesions showed embryonal (botryoid in three) pathology in 13 JournalofPedietric
Surgery,
Vol30,
No 7 (July),
1995:
pp 942-944
UTERINE
RMS:
CONSERVATIVE
Table
1. Uterine
RMS:
MANAGEMENT
Clinical
Group
IRS Ill and Chnical Group (At Presentation)
1. Complete 2. Resection or lymph
Classification
and Outcome
IV Pilot Number of Patients
surgical resection with positive margins nodes
3. Gross residual after biopsy or partial surgical resectlon 4. Metastatic disease
943
No Evidence of Disease
Dead
3
3
0
0
0
0
8 3
3 3
5 0
14
9
5
only
Total
patients and alveolar pathology in 1 patient. Initial operation was polypectomy with complete resection of tumor (group 1) in 3 patients, and biopsy or partial resection with gross residual tumor (group 3) in 8 patients. Three patients presented with metastatic disease (group 4). Eight patients underwent initial biopsy, then chemotherapy or chemotherapy and radiation, and 2 patients underwent primary tumor resection (1 as resection of a broad ligament mass and 1 by hysterectomy). At 20 weeks, a second-look operation was mandated by protocol. Of the group 3 and 4 patients, 1 patient had no operation, 3 patients subsequently had hysterectomy and vaginectomy, and 3 had exploration with no evidence of tumor. Three patients died of sepsis before second-look surgery. Of the 3 patients who underwent hysterectomy and vaginectomy, pathology showed only localized microscopic residual tumor in 2 patients. One patient presented with a broad ligament mass and had an early local recurrence after initial resection and 3 weeks of chemotherapy. This patient had distant metastasis and died of tumor progression. Three patients had initial biopsy and then died of chemotherapy toxicity or sepsis before the surgical second-look procedure. One patient had a complete response, had second-look hysterectomy and vaginectomy (with no residual tumor in the specimen), and then died of sepsis after development of renal failure during chemotherapy. All the group 1 patients survived. Of the 8 group 3 patients, 4 died of chemotherapy toxicity, 1 died of tumor progression, 2 survived after hysterectomy and vaginectomy, and 1 survived after biopsy with no further resection. All 3 group 4 patients survived without further resection after biopsy. The 5 patients who died all died while still undergoing chemotherapy, only 1 of whom achieved a complete response. Chemotherapy regimens are outlined in the report of IRS III by Crist et a1.4Follow-up for 1.5 to 6 years is available for the surviving patients. DISCUSSION
Uterine RMS present either as cervical tumors with a vaginal mass or bleeding, or as tumors of the
uterine body with an abdominal mass. Diagnosis is made by incisional or excisional biopsy (usually by dilatation and curettage and transvaginal biopsy). Most uterine tumors show embryonal histology.5 In addition to biopsy, staging requires a metastatic work-up including pelvic examination and computed tomography (CT) scans of the pelvis, abdomen, and chest, examination of the bone marrow by biopsy or aspiration, cystoscopy, and vaginoscopy. Before 1972, treatment for uterine RMS included radical surgery before chemotherapy and radiation. Stimulated by the report of Ortega et al,‘j treatment shifted to primary chemotherapy with delayed operations for locally advanced or distantly metastatic uterine RMS in an attempt to improve the survival and local response rates while limiting radical surgical resection. A major goal of IRS II was to preserve a functional distal urinary tract after treatment of pelvic tumors.7 It has been suggested in previous studies’” that patients with uterine RMS present at an older age and have a worse prognosis than do those patients who present with vaginal rhabdomyosarcomas. Hays et aP3 reviewed 10 patients with primary uterine RMS from IRS I and II. These patients presented at a mean age of 14.2 years. Five of the 10 patients were placed in clinical group 1 after cervical polypectomy or hysterectomy and vaginectomy. No irradiation was used. All 5 patients survived without relapse. Five patients presented with intramural involvement of the uterus and extensive local disease. Two of these had distant metastases. One of these group 3 and 4 patients was treated with a regimen including Adriamycin (and one had Adriamytin added after progression on pulse VAC). One of these patients died of infection after 2 months of chemotherapy, and the other 4 died of progression of disease, none living longer than 14 months. In contrast, the present series is composed of a mostly younger group of patients (mean age, 5.5 years), of which 3 presented with cervical polypoid lesions and the remainder presented with large ( > 5 cm) masses and intramural involvement. In the group 3 and group 4 patients, only 1 has had a relapse and died of tumor, whereas 4 died of sepsis or chemotherapy complications. The patient that had local recurrence and death was very unusual in that the initial tumor presented as a broad ligament mass and had the only alveolar histology in the series. Only 2 of 7 surviving patients required hysterectomy and vaginectomy. Only 3 patients underwent irradiation, and 2 of these patients have survived; the other patient had the unusual broad ligament tumor referred to above. Initial radical resection would no longer seem justified because it appears that biopsy and initial chemo-
944
CORPRON
therapy or chemotherapy and radiotherapy allow a high percentage of these patients to avoid having resection. A portion of these patients may be able to avoid having radiation. Only 1 patient with uterine RMS had local progression and/or relapse during IRS III and IV pilot (the patient with the broad ligament tumor who had no clear involvement of the uterus and may thus represent a different site of tumor). This review suggests that age of presentation and prognosis in uterine and vaginal RMS may be more similar than previously suggested in earlier series1-3 and that primary chemotherapy and radiotherapy may be as effective in uterine tumors as it has been in vaginal tumors. With this type of regimen, the prognosis in uterine RMS may be less ominous than previously described. Long-term follow-up for late recurrences and sequelae of treatment is required and continues in these patients. The response of patients with locally advanced or metastatic (group 3
ET AL
and 4) uterine RMS to primary chemotherapy followed by radiation and/or operative resection shows an 86% (6 of 7) survival rate (not including deaths from toxicity or sepsis) at 1.5 to 6 years of follow-up. This is significantly improved over the 20% survival reported for these patients in IRS I and II, whereas the group 1 patients continue to do well with a 100% (3 of 3) survival rate. Only one group 4 patient died of sepsis during IRS I, but during the IRS III and IV pilot, 4 of 14 (29%) patients died of chemotherapy toxicity or sepsis. Although the number of patients in this series is small and does not allow for conclusions about therapy, the results suggest that although primary chemotherapy may allow less surgical resection and thus preservation of pelvic organs, it may lead to an unacceptably high rate of chemotoxicity and sepsis-related deaths. The optimal combination of surgery, chemotherapy, and radiation for treatment of uterine RMS has yet to be determined.
REFERENCES 5. Palmer NF, Foulkes M: Histopathology and prognosis in the 1. Hays DM, Raney RB, Lawrence W, et al: Rhabdomyosarcoma of the female urogenital tract. J Pediatr Surg 16:828-834,1981 second Intergroup Rhabdomyosarcoma Study (IRS-II). Proc Am Sot Oncol2:229,1983 (abstr) 2. Hays DM, Shimada H, Raney RB, et al: Sarcomas of the vagina and uterus: The Intergroup Rhabdomyosarcoma Study. J 6. Ortega JA: A therapeutic approach to childhood pelvic rhabdomyosarcoma without pelvic exenteration. J Pediatr 94:205Pediatr Surg 20:718-724, 1985 3. Hays DM, Shimada H, Raney RB, et al: Clinical staging and 209,1979 treatment in rhabdomyosarcoma of the female genital tract among 7. Raney RB, Gehan EA, Hays DM, et al: Primary chemotherchildren and adolescents. Cancer 61:1893-1903,1988 apy with or without radiation therapy and/or surgery for children 4. Crist W, Gehan EA, Ragab AH, et al: The third Intergroup with localized sarcoma of the bladder, prostate, vagina, uterus, and Rhabdomyosarcoma Study. J Clin Oncol13:610-630,1995 cervix. Cancer 66:2072-2081.1990
Discussion C. Bagwell (Richmond, VA): I appreciate the opportunity to comment on the paper and the authors sending me the text to review. I think most of us agree with your conclusions; namely, that optimum treatment is evolving and that surgery is a facet in the multimodal treatment of these tumors. We also agree that conservative resection is probably best, but it may require a surgical resection for a second-look operation, as was suggested by Drs Grosfeld and Clatworthy some years ago. However, I’m not sure if the data here really support these conclusions. The data really should exclude the three patients who are stage 1, in whom polyploid tumors result in a uniformly good prognosis. The three patients with metastatic disease should also be excluded. That leaves eight in the group 3 series, of whom four suffered very significant complications from chemotherapy with an overall 50% mortality rate. This is unacceptable, and should be put in perspective when we think about the report of Dan Hays in
1988, who reported from IRS I and II, 10 patients with uterine primary tumors, all of whom were treated at that time with available chemotherapy, and all of whom died, but of progressive disease. Have we traded a death of tumor progression for chemotherapy-related toxic death? In the meantime, the updates from the IRS series, especially with a variance like this, certainly indicate that it’s necessary to refine a treatment, that refinement will include not only surgical but chemotherapy and radiation therapy refinements as well. From the Floor: Half your patients in group 3 went on to have vaginectomy and hysterectomy. Was that because of local recurrence or was that part of a staged plan up front? CA. Corpron (response):That was part of a staged second-look operation. Two of the three that had hysterectomy after chemotherapy actually had very minimal microscopic disease, so they probably could have had a smaller resection at the time of secondlook surgery.