The Role of Surgical Resection When Combined withChemotherapy and Radiation in the Management of

Pelvic Rhabdomyosarcoma

IRVIN D. FLEMING, M.D., ERLINDA ETCUBANAS, M.D., RICHARD PATTERSON, M.D., BHASKAR RAO, M.D.,CHARLES PRATT, M.D., OMAR HUSTU, M.D., MAHESH KUMAR, M.D.

With the development of combined chemotherapy and radiationtherapy for embryonal rhabdomyosarcoma, the role and extentof surgical resection of these pelvic tumors need to be defined.Thirty-six children with pelvic genitourinary rhabdomyosarcomaseen at St. Jude Children's were managed on protocols combiningsurgical resection and radiation, and chemotherapy. Ten childrenpresented with cervical-vaginal tumors, which were managedwith combined therapy; the surgical resection was histovagi-nectomy in eight and pelvic exenteration in one. Eight of theten are free of disease from 1 to 14 years. Twelve childrenpresented with bladder and prostate tumors, which were resectedwith segmental cystectomy in four cases, biopsy in five, andpelvic exenteration in three. All received combination therapyand six of the twelve are surviving free of disease from 6 monthsto 16 years. Fourteen children presented with paratesticularrhabdomyosarcoma. Chemotherapy was combined with radicalorchiectomy in all cases. Retroperitoneal node dissection wasdone in nine and five had inguinal node dissection. Nine of the14 are surviving NED from 2 to 16 years. One patient died,free of disease, with complications of combination therapy. Theresults of this review supports the approach of combining che-motherapy, radiation, and complete surgical resection.

R HABDOMYOSARCOMA is the most frequently en-countered pediatric soft tissue sarcoma.' While

rhabdomyosarcoma occurs in a variety of primary sites,approximately 20% of the cases are seen in the geni-tourinary system, specifically, vagina (Sarcoma Botry-oides), bladder, prostate, and paratesticular regions (Table1). Prior to the development of effective chemotherapy,the treatment of localized genitourinary rhabdomyosar-coma was radical resection and radiation therapy. In manycases, this necessitated pelvic exenteration yielding a sur-vival rate of about 20%. 1,2Now that effective chemotherapy and radiation therapy

are available, it is important to clearly define the role of

Presented at the Ninety-Fifth Annual Meeting ofthe Southern SurgicalAssociation, December 5-7, 1983, Hot Springs, Virginia.

Reprint requests: Irvin D. Fleming, M.D., St. Jude Children's ResearchHospital, 332 N. Lauderdale, Memphis, TN 38101.

Submitted for publication: December 21, 1983.

From St. Jude Children's Research Hospital and theDepartment of Surgery, University of Tennessee Center for

the Health Sciences, Memphis, Tennessee

surgical resection.35 It is not the intent of the authors toreview in detail the chemotherapy and radiation therapyfor rhabdomyosarcoma, but to attempt to define the extentof surgical resection necessary to afford the best possibilityfor cure, preserving function whenever possible.

Material and Methods

Thirty-six children with genitourinary rhabdomyo-sarcoma have been seen and treated at St. Jude Children'sResearch Hospital between 1962 and 1983. The primarysites were: vaginal wall/cervix (N = 1O), bladder/prostate(N = 12), and paratesticular (N = 14) (Table 2). Therewere 11 girls and 25 boys whose ages ranged from 3months to 17 years. The median age was 5 years for thevaginal tumor, 3 years for the bladder/prostate, and 6years for the paratesticular. In addition to routine studies,pretreatment clinical evaluation included appropriate en-doscopy and biopsy, abdominal and pelvic computerizedtomography, intravenous pyelography, bone scan andbone marrow study. Two children presented with local-ized, easily resectable disease (stage I) and four childrenpresented with disseminated metastates (stage III). Themajority of the cases presented as extensive local or re-gional disease (stage II) (Table 3). With the exception offive children not treated by protocol, 31 patients weremanaged on one of the St. Jude rhabdomyosarcoma pro-tocols, combining multiple drug chemotherapy, surgery,and radiation therapy (Tables 4-6). All patients receivedchemotherapy and 29 of the 36 children received pre-operative or postoperative radiation therapy with dosageranging from 2500 to 5500 rads. The factors of therapydepending on the age of the child, site of tumor, andextent of disease (Table 7).

509

510TABLE 1. Primary Site and Distribution ofPediatric

Rhabdomyosarcoma

Primary Site Number of Patients (%)

Head and neck 73 (34)Trunk 64 (29)Genitourinary 36 (18)Extremity 30 (14)Unknown primary 10 ( 5)

Total 213 (100)

FLEMING AND OTHERS

TABLE 2. Primary Site and Distribution of GenitourinaryRhabdomyosarcoma

Primary Site Number of Patients (%)

Vaginal 10 (27)Bladder/prostate 12 (35)Testicular/paratesticular 14 (38)

Total 36 (100)

Vaginal Rhabdomyosarcoma (N = 10)

The presenting symptoms were vaginal discharge orvaginal mass. One child presented with a small cervicalpolypoid tumor that was managed by hystovaginectomyand chemotherapy only. The other patients presentedwith large polypoid lesions of the vaginal wall (Fig. IA)and were given preoperative chemotherapy (Fig. 1 B). Ra-diation therapy was used before surgery if a large masswas present (Fig. IC), or after surgery if residual diseasewas suspected. Postoperative chemotherapy was contin-ued by protocol. One of the patients resected with hys-

TABLE 3. Distribution ofStage (Extent ofDisease) in Children withGenitourinary Rhabdomyosarcoma

Stage I Stage II Stage IIIPrimary Site (Local Resected) (Regional) (Metastatic)

Vaginal 1 9 0Bladder/prostate 0 11 1Paratesticular 1 10 3

TABLE 4. Schema ofRhabdomyosarcoma Protocol Studies I to IVfor Local and Regional Disease*

RMS I (1968)Surgery + dactinomycin, vincristine, cyclophosphamide+ radiation therapy

RMS II (1973)Surgery + dactinomycin, vincristine, cyclophosphamide,

adriamycin + radiation therapyRMS III (1977)

Surgery + dactinomycin, vincristine, cyclophosphamide,adriamycin + (?)radiation therapy + (?)surgery

RMS IV (1981)Surgery + adriamycin, DTICt, dactinomycin, vincristine,

cyclophosphamide + (?)surgery + (?)radiation therapy+ (?)surgery

Ann. Surg. - May 1984

tovaginectomy had surgery delayed while disease pro-gressed because of difficulty obtaining parental consent.The surgical procedure was hystovaginectomy in eightcases. One child had a pelvic exenteration prior to beingreferred to St. Jude, and one child's parents refused surgery(Table 8). Despite preoperative therapy, all patients hadresidual gross or microscopic tumor at the time of surgicalresection (Fig. 2).

Bladder/Prostate Rhabdomyosarcoma (N = 12)Presenting symptoms were dysuria or urinary retention,

rectal symptoms, or a perineal mass. One patient wasreferred to St. Jude following a total cystectomy and ilealconduit and received postoperative chemotherapy andradiation. Four patients, with bladder sarcomas, weretreated before surgery with chemotherapy and radiationand were resected with a partial cystectomy, preservingbladder function. One child was given preoperative che-motherapy and radiation and, when re-explored, no tumorwas found with multiple biopsies and therefore no re-section was done. Four patients had biopsy only andcombination therapy. Two patients underwent pelvic ex-enteration and ileal conduit in an attempt at salvage afterlocal failure with radiation and chemotherapy (Table 9).

Paratesticular Rhabdomyosarcoma (N = 14)Clinical presentation was that of a scrotal mass. All

underwent radical orchiectomy and combination che-motherapy. Five children underwent re-excision of thecord and genitoinguinal area because of suspicion of in-

TABLE 5. Distribution ofRhabdomyosarcoma Protocol Studies inChildren Managed with Genitourinary Tumors

RMS I RMS II RMS III RMS IVPrimary Site (1968) (1973) (1977) (1981) None

Vaginal 4 1 1 2 2Bladder/prostate 2 4 4 1 1Paratesticular 3 2 7 0 2

TABLE 6. Rhabdomyosarcoma IV Protocol Schema of Treatment

Surgical resectionDTIC-adriamycin X 3 courses

Cyclophosphamide, dactinomycin, vincristine x 3 coursesSurgical reevaluation

Radiation therapy reevaluationCyclophosphamide, dactinomycin, vincristine X 4 courses

DTIC-adriamycinAlternate with 2 courses of cyclophosphamide, dactinomycin

Vincristine at monthly intervals

Adriamycin 60 mg/m2 IV Day IDTIC 200 mg/m2/day Day 1-5

Cyclophosphamide 200 mg/m2/day IV or PO day 1-5Vincristine 1.5 mg/M2 IV maximum 2 mg/dose Day 6

Dactinomycin 1.5 mg/M2 IV maximum 2 mg/dose Day 6

* Dimethyltriazenoimidazole carboxamide.* Note: sequence oftreatment modalities may vary with clinical setting.t Dimethyltriazenoimidazole carboxamide.

Vol. 199 * No. 5 PELVIC RHABDOMYOSARCOMA MANAGEMENT

B

FIG. IA. Large vaginal rhabdomyosarcoma in a 3-month-old child. B.Vaginal rhabdomyosarcoma with tumor reduction with initial therapywith cyclophosphamide, vincristine, and dactinomycin. C. Further re-

duction of vaginal rhabdomyosarcoma with 2500 rads preoperative ra-

diation.

C

complete resection of the primary site upon review ofthe margins of the resected tumor. Nine underwent lap-arotomy with periaortic node biopsy or dissection, fiveof whom had periaortic lymph node metastasis (Ta-ble 10).

TABLE 7. Children with Genitourinary RhabdomyosarcomaReceiving Radiation Therapy

Pre- Post-Primary Site operative operative Both None

Vaginal 4 7** 2 1 (stage I)Bladder/prostate 6* 5 1 1 (stage III)Paratesticular 0 9 0 5

* Three children received brachytherapy.

Five children with paratesticular rhabdomyosarcomaunderwent inguinal lymph node dissection because ofsuspected metastasis or extensive scrotal involvement withtumor. Two of the five had inguinal lymph node metas-tasis. Nine of the children with paratesticular rhabdo-

TABLE 8. Surgical Management and Survival of Children withVaginal Rhabdomyosarcoma (Sarcoma Botryoides)

SurvivingSurgical Procedure Number Free of Disease

Histovaginectomies 8 7Exenteration 1 IBiopsy only 1 0

Total 10 8

511

FLEMING AND OTHERS

Ti J.a1<1IA J.

FIG. 2. Surgical specimen following histovaginectomy for rhabdomyo-sarcoma after preoperative chemotherapy and radiation-note viabletumor in vaginal wall.

myosarcoma received postoperative radiation therapy toeilther the periaortic or the genitoinguinal region.

ResultsVaginal Rhabdomyosarcoma

Eight ofthe nine children treated by combination ther-apy and complete excision (seven with hystovaginectomyand one with pelvic exenteration) remain free of diseasefrom 6 months to 16 years with a median follow up ofsurvivors of 8 years. One child's parents refused surgeryand, in spite of other therapy, the child died of uncon-

trolled pelvic tumor in 20 months. A second child hadtreatment and surgery delayed and attempt at salvagewith late resection and combined therapy was unsuccessfulfor local tumor control; she died 21 months followingdiagnosis (Table 8).

Bladder/Prostate RhabdomyosarcomaThe one child referred to St. Jude following cystectomy

and conduit had one positive pelvic lymph node and wastreated with postoperative radiation therapy and che-motherapy and is alive and well at 16 years. Four childrenwere treated by biopsy, preoperative chemotherapy andradiation, and then had resection ofthe tumor with partialcystectomy, preserving bladder function. Three of thefour are alive and free of disease for 5, 6, and 7 years,

TABLE 9. Surgical Management and Survival of Children withBladder and Prostate Rhabdomyosarcoma

SurvivingSurgical Procedure Number Free of Disease

Complete excision 4 3Exenteration 3 2Biopsy only 5 1

Total 12 0

TABLE 10. Surgical Management ofChildren Treatedfor Testicularand Paratesticular Rhabdomyosarcoma

Surgical Surviving FreeProcedure Number of Disease

Orchiectomy only 3 3Orchiectomy+ laparotomy 9 (4 positive nodes) 4 (2 positive nodes)

Orchiectomy+ inguinal nodedissection 5* (2 positive nodes) 2 (I positive nodes)

* Three children had both laparotomy and inguinal node dissection.

while the fourth died with pulmonary metastasis after 3years. One patient explored after preoperative chemo-therapy and radiation was found to have no residual tu-mor. She remains free ofdisease at 5 years. Four childrenhad biopsy only with combination therapy. One presentedwith stage III disease (metastatic) and died with bone andlung metastasis within 6 months; the others survived 6months, 2 years, and 3 years. They developed uncontrolledpelvic tumors and three distant metastases to brain, bone,and lungs. Two children with local pelvic tumor followingfailure to control the primary tumor with radiation andchemotherapy had an attempt at salvage with pelvic ex-enteration. One, an anterior exenteration, was unsuc-cessful and the patient expired of uncontrolled pelvictumor 3 months after surgery. The other, a total exen-teration, is presently free of disease with only 6 monthsfollow up (Table 9).

Paratesticular RhabdomyosarcomaNine of the 14 children presenting with paratesticular

rhabdomyosarcoma are surviving from 2 to 16 years witha median follow up ofsurvivors of4 years. Three childrenwith localized paratesticular rhabdomyosarcoma and noevidence of retroperitoneal adenopathy on preoperativeevaluation were managed by radical orchiectomy andchemotherapy only and remain free of disease (4, 6, 16years). Nine children underwent laparotomy, with fivedemonstrating histologic evidence of periaortic metastasis.They received radiation therapy in addition to chemo-therapy. Two of these five are alive and free of diseaseat 2 years and 9 years. One child died 2 years after treat-ment of complications of bowel perforation and abscessformation without evidence of recurrent tumor. The re-maining two children died with abdominal, lung, andbone metastasis at 13 months and 6 years. Five childrenunderwent inguinal lymph node dissection because ofsuspected inguinal node involvement with tumor, andtwo demonstrated histologic evidence ofmetastatic tumor.Two of the five are surviving: one with positive inguinalnodes received chemotherapy and postoperative radiationand is alive at 9 years, and the second child survivinghad negative nodes, received chemotherapy, and is aliveat 12 years. The remaining three children who had in-guinal node dissection received chemotherapy and sur-

512 Ann. SUrg. * May 1984

PELVIC RHABDOMYOSARCOMA MANAGEMENT

vived for 2 and 6 years, dying of metastasis to lung andbone. The third is the child who died ofbowel perforationand abdominal abscess probably secondary to combi-nation of chemotherapy and abdominal radiation (Ta-ble 10).

DiscussionAs reported in this series, only an occasional patient

presented with early localized tumor or clinically dissem-inated metastatic disease. The majority of the childrenpresented with extensive local or regional tumor. As re-ported by Hays, from the Intergroup Rhabdomyosarcomastudy, the incidence of regional lymph node metastasesvaried with the primary site (0/6 vaginal, 6/14 bladderand prostate, and 4/16 paratesticular.6 This correspondsto the findings in this study with one of the nine childrenwith vaginal rhabdomyosarcoma demonstrating nodaldisease when explored. However, most had received pre-operative treatment with chemotherapy and/or radiationtherapy. The same findings were true for bladder andprostate tumor. The incidence of lymph node metastasiswas higher for paratesticular rhabdomyosarcoma with fourof the nine patients explored having periaortic nodes in-volved with tumor and two of the five children with in-guinal node dissection having positive nodes.

140

100

820

70

..

Z_

1-0

FIG. 3. Patient 12 years after combination therapy and histovaginectomyfor rhabdomyosarcoma vaginal wall.

£

Chf i'"W? Ea

FIG. 4. Surgical specimen of total pelvic exenteration after combinationchemotherapy and radiation for rhabdomyosarcoma of the prostate.Viable tumor was present throughout the prostate and anteriorly.

The good results obtained by hystovaginectomy forvaginal rhabdomyosarcoma with combination therapy inthis series confirm the suggestions of Hays, Kumar, andothers that pelvic exenteration is rarely necessary.7'8 Hys-tovaginectomy following preoperative therapy to reducethe size and extent of tumor followed by postoperativechemotherapy and radiation therapy for suspected orknown residual tumor produce consistent local controland long-term survivors. This avoids mortality and mor-bidity of pelvic exenteration with colostomy or urinarydiversion (Fig. 3).The surgical management of bladder and prostatic

rhabdomyosarcoma is more complex and unsettled. Bi-opsy and combined radiation and chemotherapy havebeen reported to be successful in a small number of pa-tients in each reported series, but the majority of patientsundergo a partial response with residual clinical disease.9"0In this series only one patient was found to be free ofmicroscopic residual tumor at the time of resection. Anumber of patients with bladder tumor achieve sufficientregression with preoperative therapy to allow segmentalresection with preservation of the bladder and in thisseries three of the four children treated by preoperativetherapy and complete local excision have remained freeof disease.' 1"12

Unfortunately an occasional child with prostatic orbladder rhabdomyosarcoma with persistent active tumorfollowing initial chemotherapy and radiation will requirepelvic exenteration to obtain local tumor control and thepossibility of cure (Fig. 4).'3 It is frequently difficult byendoscopy and biopsy to detect residual microscopic tu-mor, but it is most important that resective surgery beconsidered at the earliest date of known residual tumor.Attempts at salvage exenterative surgery following treat-

Vol. 199 - No. 5 513

514 FLEMING AND OTHERS Ann. Surg. May 1984

TABLE 11. Number and Survival of Children with Pediatric Rhabdo-myosarcoma Managed with Surgery and Combination Therapy

SurvivingFree of

Primary Site Number Disease Survival (Median)

Vaginal 10 8 12 months-12 years (8 years)Bladder/prostate 12 6 6 months-16 years (7 years)Paratesticular 14 9 24 months-16 years (4 years)

Total 36 23

ment failure and gross recurrent tumor have not beensuccessful. 14

The surgical management of paratesticular rhabdo-myosarcoma is radical orchiectomy with high ligation ofthe spermatic cord and wide excision of any tumor orscrotal involvement. Periaortic lymph node metastasesare reported to be present in 25%.'0 In this series four ofnine children explored were found to have metastasis toperiaortic lymph nodes. Diagnostic imaging with ultra-sonography, computerized tomography, and lymphog-raphy may be helpful in identifying enlarged periaorticnodes, but do not rule out microscopic metastasis. Aconserative periaortic dissection aids in correctly stagingparatesticular rhabdomyosarcoma and identifying chil-dren who may benefit from postoperative radiation ther-apy. If the paratesticular tumor involves the spermaticcord or scrotum, consideration must be given to the pos-sibility of inguinal lymph node metastasis. In this seriestwo of the five children who underwent inguinal lymphnode dissection had evidence of metastasis.

Conclusion

Genitourinary rhabdomyosarcoma is a tumor that re-sponds to combination chemotherapy and radiation inmost cases. The best results in this series and most reportedseries combine surgical resection with the other thera-peutic modalities. It is therefore most important whenplanning therapy for pelvic rhabdomyosarcoma that thediagnosis be clearly established, staging be accurate, and

therapy be planned to avoid either incomplete excisionof tumor or unnecessary radical surgery.

Carefully combining chemotherapy and radiation withsurgical resection of genitourinary rhabdomyosarcomahas improved survival (Table 11). In many instances,pretreatment with chemotherapy and/or radiation therapyhas permitted more conservative resection with preser-vation of function. There are, however, still clinical set-tings in which combined therapy plus radical resectionare necessary to obtain local tumor control and cure.

References1. Lawrence W Jr, Jegge G, Foote FW Jr. Embryonal rhabdomyo-

sarcoma. A clinicopathogen study. Cancer 1964; 17:361-376.2. Daniel WW, Koss LG, Brunschwig A. Sarcoma botryoides of the

vagina. Cancer 1959; 12:74-84.3. Edland RW. Embryonal rhabdomyosarcoma. Am J Roentgen 1965;

93:671-685.4. Pratt CB. Response ofchildhood rhabdomyosarcoma to combination

chemotherapy. J. Pediat. 1969; 74:791-794.5. Pratt CB, Hustu HO, Fleming ID, Pinkel D. Coordinated treatment

ofchildhood rhabdomyosarcoma with surgery, radiotherapy andcombination chemotherapy. Cancer Res 1972; 32:606-610.

6. Hays DM, Raney RB, Lawrence W Jr, et al. Radiation to regionalnodes for rhabdomyosarcoma in genitourinary tract in children:is it necessary? Cancer 1980; 45:3065-3068.

7. Kumar M, Wrenn EL Jr, Fleming ID, et al. Combined therapy toprevent complete pelvic exenteration for rhabdomyosarcoma ofthe vagina. Cancer 1976; 37:118-122.

8. Hays DM, Raney RB, Lawrence W Jr, et al. Rhabdomyosarcomaof the female urogenital tract. J Pediatr Surg 1981; 16(3):828-834.

9. Hays DM, Raney RB, Lawrence W Jr, et al. Primary chemotherapyin the treatment of children in bladder-prostate tumors in theintergroup rhabdomyosarcoma. Study (IRS-II). J Pediatr Surg1982; 17(6):813-820.

10. Hays DM, Raney RB, Lawrence W Jr, et al. Rhabdomyosarcomaof the female urogenital tract. J Pediatr Surg 1981; 16(6):828-834.

11. Kaplan WE, Furlit CF, Berger RM. Genitourinary rhabdomyosar-coma. J Urol 1982; 130:116-119.

12. Hays DM. Pelvic rhabdomyosarcoma in childhood: Diagnosis andconcepts of management reviewed. Cancer April 1980;45(Supple): 1810-1814.

13. Hays DM, Raney RB, Lawrence W Jr, et al. Bladder and prostatictumors in the intergroup rhabdomyosarcoma study (LRS- 1).Cancer 1982; 50:1472-1482.

14. McDougal WS, Pessky L. Rhabdomyosarcoma of the bladder andprostate in children. J Urol 1980; 124:882-885.

DISCUSSIONDR. VERNON H. REYNOLDS (Nashville, Tennessee): President Cohn,

Secretary Sawyers, members and guests: I would like to congratulateDr. Fleming and his co-authors on this excellent paper and the equallyimpressive results from combining less radical operation with chemo-therapy and radiation.The number of cases of this rare tumor of childhood seen in any one

institution is small, except at hospitals like St. Jude's that specialize intreating malignancy in children. For that reason, Vanderbilt is a memberof the Intergroup Rhabdomyosarcoma Study and pools its experiencewith other institutions. Our protocol is quite similar to the one that wasoutlined by Dr. Fleming. Patients receive vincristine, actinomycin D,and cyclophosphamide every 4 weeks for two cycles. If there has beenprogression of the disease, or there has been no tumor response, thepatient has his or her tumor removed, after which the patient may ormay not receive radiation, followed by a period of maintenance che-motherapy in every case.

In the patients who show partial response, or complete response, twomore cycles of drug are given before the tumor is either removed or

biopsied. If there is no tumor present, they receive VAC, which is thevincristine, actinomycin, Cytoxan regimen, for another 2 years. Iftumoris still present, they receive radiation therapy, followed by 2 years ofthe VAC regimen.

In the Intergroup Rhabdomyosarcoma Study II, 44 patients aged 1to 17 years with a median age of 2 years were treated with VAC forsarcomas arising in the prostate, bladder, or vagina. In those patientswho received VAC alone, 50% are alive. If they had VAC plus radiationtherapy alone, 68% are alive. Of those patients who received VAC andsurgery alone, 67% are alive.

However, when VAC was combined with radiotherapy plus surgery,88% of the patients are alive. It should be noted that VAC alone wasusually insufficient to treat these patients. With the combination of allthree modalities, 70% of the patients have retained their bladder, andwe consider this very worthwhile.

DR. RICHARD PATTERSON (Closing discussion): We would like toemphasize that rhabdomyosarcoma is a disease that varies widely in itsbehavior by site, and the lessons drawn from one primary site cannotnecessarily be applied to another.