This Article Abstract Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Stewart, R. J. Articles by Stevens, M. C.G. Search for Related Content PubMed PubMed Citation Articles by Stewart, R. J. Articles by Stevens, M. C.G. Social Bookmarking                            What's this?

Treatment of Children With Nonmetastatic Paratesticular Rhabdomyosarcoma: Results of the Malignant Mesenchymal Tumors Studies (MMT 84 and MMT 89) of the International Society of Pediatric Oncology

From the Queen’s Medical Centre, Nottingham, and Royal Hospital for Children, Bristol, United Kingdom; Bicêtre Hospital, Le Kremlin-Bicêtre, and Institut Gustave Roussy, Villejuif, France; and Marciniak Hospital, Wroclaw, Poland.

Address reprint requests to Hélène Martelli, MD, PhD, Department of Paediatric Surgery, Bicêtre Hospital, 78, rue du Général Leclerc, 94275 Le Kremlin, Bicêtre Cedex, France; email: helene.martelli{at}bct.ap-hop-paris.fr.

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX REFERENCES

 
Purpose: To report the results of the Malignant Mesenchymal Tumors studies (MMT 84 and 89) of the International Society of Pediatric Oncology (SIOP) in males with nonmetastatic paratesticular rhabdomyosarcoma.

Patients and Methods: From 1984 to 1994, 96 males were treated in SIOP protocols. Radical inguinal orchidectomy was recommended, but initial retroperitoneal lymph node dissection was not performed. Disease was staged according to the SIOP tumor-node-metastasis staging system. Treatment was stratified by stage. In the MMT 89 study, males with completely resected tumors at diagnosis received less chemotherapy (vincristine and dactinomycin) than patients in the MMT 84 study (ifosfamide, vincristine, and dactinomycin).

Results: Median age at diagnosis was 65 months. Thirty-one tumors were larger than 5 cm, and 13 males were older than 10 years with a tumor larger than 5 cm. At a median follow-up of 7 years, 87 patients were alive; 79 were in first complete remission and eight were in second complete remission. Relapse occurred in 16 patients (17%). At 5 years, the overall survival (OS) rate was 92%, with an event-free survival (EFS) rate of 82%. OS and EFS were significantly worse for males with tumors greater than 5 cm and for males older than 10 years at diagnosis.

Conclusion: Males with paratesticular RMS have an excellent prognosis except for a selected group of patients older than 10 years or with tumor greater than 5 cm. Intensified chemotherapy incorporating alkylating agents for this subgroup may be preferred to the use of systematic lymphadenectomy to improve survival while minimizing the burden of therapy.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX REFERENCES

 
PATIENTS WITH paratesticular tumors account for 6%¹ of children and adolescents with rhabdomyosarcoma (RMS) and, with current management, have an excellent prognosis. Survival rates of more than 90% are reported in most series.^2–5 Controversies remain about the role of lymph node evaluation by lymphadenectomy at diagnosis and the identification of the small number of children who are at increased risk of treatment failure.⁶ Results from early International Society of Pediatric Oncology (SIOP) studies indicated that para-aortic lymphadenectomy was not necessary in the treatment of localized paratesticular RMS.⁷ Furthermore, at this site where complete surgical resection at diagnosis is frequent, attempts have been made to decrease the burden of therapy by reducing the intensity and duration of chemotherapy.^3,5 The aim of this article is to report the results of the Malignant Mesenchymal Tumors studies (MMT 84 and MMT 89) protocols in males with localized (nonmetastatic) paratesticular RMS.

	PATIENTS AND METHODS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX REFERENCES

 
All males with nonmetastatic paratesticular RMS diagnosed from 1984 to 1994 and treated in the MMT 84 and MMT 89 SIOP studies were the subject of this analysis. Both protocols had been submitted to ethical committees, and patients or their parents signed an informed consent before participating in the studies. Radical inguinal orchidectomy was recommended as initial surgery, with primary re-excision⁸ (excision of the cord at the deep inguinal ring) with or without hemiscrotectomy if the initial orchidectomy was not undertaken via the inguinal route. Ipsilateral retroperitoneal node sampling or lymphadenectomy was not performed, and the status of lymph node involvement was determined by radiologic examination (ultrasound and abdominal computed tomography scan). Histopathology of all tumors was centrally reviewed by an international panel of pathologists and classified according to the new international classification for RMS.⁹

The extent of disease at diagnosis was defined according to the SIOP tumor-node-metastasis pre- and postsurgical staging system (Table 1).¹⁰ Treatment was stratified according to clinical stage and postsurgical stage (Table 2). Treatment schedules used in the MMT 84 and MMT 89 studies have already been reported^3,11 and are indicated in Table 2. The standard first-line chemotherapy for all patients in MMT 84 was combination therapy with ifosfamide, vincristine, and dactinomycin. In the MMT 89 study, an attempt was made to avoid alkylating agents for those patients in whom tumors had been completely resected at primary surgery (stage I pT1). These patients received only vincristine and dactinomycin. The ifosfamide, vincristine, and dactinomycin regimen was used for patients with residual disease, although in MMT 89, this included ifosfamide at 9 g/m²/course in contrast to 6 g/m²/course in MMT 84. An intensified six-drug combination (incorporating carboplatin, epirubicin, vincristine, ifosfamide, dactinomycin, and etoposide) was given to patients with stage III (node-positive) disease in MMT 89.

	RESULTS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX REFERENCES

 
Ninety-six males with nonmetastatic paratesticular RMS were registered in these two studies, 27 in MMT 84 and 69 in MMT 89.

Histology and Age at Diagnosis
The Pathology Review Committee classified 78 tumors (81%) as embryonal, 15 (16%) as leiomyomatoid, and three (3%) as alveolar. The median age at diagnosis was 65 months (range, 3 months to 18 years). Twenty-five males were 10 years of age or older.

Clinical (presurgical) Staging
Clinical staging confirmed that the majority of tumors (n = 80) were localized (stage I). Twelve were stage II, and four were stage III (node-positive). Thirty-one tumors (32%) were larger than 5 cm. Size of the primary tumor was correlated with age; 25% of the males less than 10 years had a tumor 5 cm compared with 52% of the males 10 years of age or older (P = .02).

Surgery
All patients had initial surgery. Fifty patients (52%) underwent a radical inguinal orchidectomy. Twenty-seven patients (28%) had primary scrotal incisions; of these, 12 patients had scrotal orchidectomies, eight patients had scrotal tumorectomies, four patients with local scrotal invasion required scrotal resection with tumorectomy, two patients with large tumors required a scrotal incision for delivery of the tumor, and one patient had transscrotal biopsy. In 17 patients, the surgical approach was not specified. Finally, two patients had only tumorectomies, one via inguinal and one via unspecified approach. Primary re-excision was performed in 20 patients, 17 of whom underwent excision of the cord at the deep ring, and an additional three patients underwent a hemiscrotectomy. One patient underwent an ipsilateral lymphadenectomy concurrent with primary re-excision of the cord.

Postsurgical Staging
Seventy-six patients had a microscopically complete primary excision (pT1, pT2). Eighteen patients had evidence of microscopic residual disease (pT3a), and two patients had macroscopic residual disease (pT3b) after primary surgical resection.

Outcome
Five-year OS was 92% (95% confidence interval, 84% to 96%) for the whole group, with a 5-year EFS of 82% (95% confidence interval, 74% to 89%; Fig 1). At a median follow-up of 7 years (range, 37 to 141 months), 87 patients were alive; 79 were in first complete remission and eight were in second complete remission. Nine patients died, eight after relapse, including one who subsequently developed a secondary acute myeloblastic leukemia. There was one toxic death in a 6-month-old child who experienced dactinomycin-induced hepatotoxicity. Relapse occurred in 16 patients at a median interval of 11 months from diagnosis (range, 7 to 25 months). All had undergone radical orchidectomy, and none had had evidence of lymph node involvement at diagnosis. Fourteen of the relapsing patients had clinical stage I disease, and two had stage II disease. Postsurgical staging confirmed complete local excision in 14 patients (among 41 stage I pT1 patients who received vincristine and dactinomycin in the MMT 89 study, 12 patients relapsed) and microscopic residual disease in two patients. None had alveolar pathology (14 were typical embryonal, and two had the leiomyomatoid subtype). Fourteen of the 16 patients relapsed in para-aortic nodes, four of whom subsequently developed pulmonary metastases at 2, 5, 9, and 12 months, respectively, after their local relapse. One patient relapsed in inguinal and iliac nodes and one relapsed with pulmonary metastases alone. All relapsed patients received second-line chemotherapy followed by additional local therapy (lymphadenectomy and/or radiation therapy). Second complete remission was maintained in eight patients who were alive with a median follow-up of 54 months (range, 43 to 91 months) from their relapse. These included six of those patients who had had para-aortic nodal relapse, the patient with inguinal and iliac relapse, and the patient with metastatic relapse. Eight patients died, four after para-aortic node relapse and four after para-aortic relapse and subsequent pulmonary metastases.

View larger version (19K): [in this window] [in a new window]   Fig 1. Event-free survival and overall survival of the whole population.

Prognostic Factors
Results from the MMT 84 and MMT 89 studies are separately listed in Table 3. Univariate analysis (Table 4) showed that both age and size of the primary tumor had an impact on EFS and OS. Patients with large tumors ( 5 cm) were at increased risk of relapse compared with those with small tumors (P < .001). Their OS was also significantly lower than the survival of patients with tumors less than 5 cm. (P < .001). Males aged 10 years were at higher risk of relapse (P < .001) and had a significantly lower OS than that of children less than 10 years of age (P < .003). The combination of a large primary tumor and age 10 years had a significantly adverse impact on both OS and EFS (Figs 2 and 3). Among the 13 patients who met both criteria (three patients in MMT 84 and 10 patients in MMT 89), only five were stage I pT1 (all were in the MMT 89 study and received only vincristine and dactinomycin; two are in first complete remission, one is in second complete remission, and two died), two were stage I pT2 patients (one is in first complete remission and one died), and two were stage I pT3a patients (one is in first complete remission and one died); two stage II patients died, and two stage III patients are in first complete remission.

View larger version (29K): [in this window] [in a new window]   Fig 2. Event-free survival according to the size of the tumor and age at diagnosis.

View larger version (28K): [in this window] [in a new window]   Fig 3. Overall survival according to the size of the tumor and age at diagnosis.

Others factors, including tumor status, clinical stage, surgical approach (ideal inguinal approach v others with scrotal incision), postsurgical staging, and histology were not independently significant prognostic factors.

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX REFERENCES

 
Our findings support previous reports of the excellent prognosis for patients with nonmetastatic paratesticular RMS. The 5-year OS of 92% compares with the 95% 5-year OS reported by the recently published Italian and German studies⁵ and the 3-year survival rates reported in the Intergroup Rhabdomyosarcoma Study (IRS) III (96%) and IRS IV (92%).^2,4

The decision not to perform routine staging lymphadenectomy in our studies was based on a desire to minimize the burden of treatment in the light of the well-recognized late sequelae of such surgery, including intestinal obstruction, loss of ejaculatory function, and lymphoedema of the leg.^14,15 However, ipsilateral nerve-sparing retroperitoneal node dissection as performed by modern-day techniques has presumably significantly decreased the late effects in, at least, the adult patients in whom it has been studied.^16,17 Previous reports from our own group⁷ and from the Italian Cooperative Studies^18,19 have indicated that staging lymphadenectomy is not normally required in this group of patients. Only four patients (4.2%) in this series had retroperitoneal lymphadenopathy on initial imaging, which is less than the 9% incidence reported in the IRS IV study in which, contrary to their previous practice, lymphadenectomy was omitted and staging was based on imaging.⁶ These data contrast with experience in IRS III, in which staging lymphadenectomy was performed systematically and 24% patients were shown to be node-positive.²⁰ Indeed, the Intergroup Rhabdomyosarcoma Study Group subsequently attributed a reduction in both 3-year failure-free survival and OS in IRS IV (86% and 92% compared with 92% and 96% in IRS III, respectively) to the failure of imaging to detect para-aortic lymph node disease at diagnosis and, hence, inappropriate downstaging and undertreatment.⁶ If we assume that the 14 patients in our study who relapsed in the para-aortic nodes (but were not identified as having nodal disease at diagnosis with imaging) could have been identified at lymphadenectomy, this would increase our node positivity rate to 19%, a figure not dissimilar to that in IRS III.

Although such experience may support the view that current imaging is not reliable in the detection of lymph node involvement at diagnosis because the OS in this series is comparable with IRS III, there is an implication that the avoidance of systematic lymphadenectomy does not compromise survival. However, it is important to address the issue of the total burden of therapy in this setting because patients who relapse receive additional chemotherapy in addition to local treatment with radiation therapy and, in some cases, lymphadenectomy. Overall, 37% of our patients were cured without exposure to elements of treatment most likely to be responsible for important late sequelae (alkylating agents, anthracyclines, radiotherapy, and lymphadenectomy).

Patient age and size of primary tumor seem to be useful predictive factors in assessing the risk of relapse in patients without overt evidence of lymph node disease at diagnosis. Our data suggest that patients aged 10 years and those with tumors 5 cm should be identified as being at higher risk. The occurrence of both of these adverse factors in the same patient (ie, an older male with a large primary tumor) certainly seems to merit more intensive therapy (Fig 2). Furthermore, duration of therapy may be a relevant factor in minimizing risk of relapse even in patients without these unfavorable factors. In MMT 89, patients with completely resected localized tumors received chemotherapy with vincristine and dactinomycin for only 8 weeks. This was half the duration of the same therapy given in a contemporaneous Italian study (Italian Cooperative Group 88).⁵ Relapse occurred in 12 of 41 stage I patients receiving vincristine and dactinomycin in MMT 89 but in only one of 36 patients receiving extended vincristine and dactinomycin in Italian Cooperative Group 88. However, the decreased relapse rate in the MMT 84 study compared with the MMT 89 study may also be related to a lesser percentage of high-risk patients in MMT 84 (26% compared with 52%, respectively).

There is no controversy regarding the recommended local surgical management of the paratesticular tumor; however, a surprisingly high number (n = 27) of patients in our studies had a primary scrotal incision with an orchidectomy, tumorectomy, or biopsy, instead of radical inguinal orchidectomy. Subsequent primary re-excision was performed with excision of the cord at the deep ring in 17 of 27 patients, but only three hemiscrotectomies were performed, despite protocol recommendations that this was required. Fortunately, this less than ideal surgery did not seem to have any adverse effect on either EFS or OS. The fact that hemiscrotectomy may not be necessary as a secondary procedure after inappropriate initial surgery has also been discussed by others.²¹

It is also of interest that none of the four patients with stage III disease or the three patients with alveolar tumors relapsed. This may also be identified as the benefit of the use of intensified chemotherapy in patients with adverse prognostic factors at diagnosis. Similar findings were also reported in IRS III, in which adolescents with recognized group II tumors experienced better 3-year failure-free survival than those with group I tumors on IRS IV (100% v 68%, respectively; P = .06), most likely as a result of receiving radiotherapy and intensified chemotherapy.⁶

Although we have been able to confirm the observation that older males ( 10 years) have a worse prognosis, particularly among those with larger ( 5 cm) tumors, there is no clear biologic reason why this should be the case. It has been postulated that younger children may present earlier as a result of parental surveillance, whereas adolescents present late because of a lack of self-awareness or a reluctance to discuss the presence of a mass in the scrotum with others. It is difficult to prove this hypothesis, although our data suggest that larger tumors are more common in older males, an observation that may support the theory of delayed presentation in older males. Delayed diagnosis may then predispose the males to the development of micrometastases and regional lymph node involvement.

The great majority of males with paratesticular RMS have localized disease and an excellent prognosis using low-intensity chemotherapy after primary surgical resection. Our experience suggests that, in most cases, it should be possible to avoid the sequelae associated with staging lymphadenectomy. The identification of older age ( 10 years) and large primary tumor ( 5 cm) as important adverse prognostic factors offers the opportunity to preselect patients who require more intensive therapy to achieve cure.

	APPENDIX

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX REFERENCES

 
The following centers included patients in the studies: centers from France: Bordeaux, Caen, Colmar, Lille (Saint-Antoine), Lille (Oscar Lambret), Lyon, Marseille, Nancy, Nantes, Paris (Curie), Rennes, Rouen (Becquerel), Strasbourg (Hautepierre), Toulouse (CHU), Villejuif (Gustave Roussy); centers from the United Kingdom: Birmingham, Cambridge, Edinburgh, Glasgow, Leeds, Liverpool, London (Great Ormond Street, Royal Marsden), Manchester, Nottingham, Newcastle, Oxford, Southampton; centers from other countries: Amsterdam, the Netherlands; Barcelona (Vall d’Hebron), Spain; Bruxelles (Queen Fabiola), Belgium; Buenos Aires, Argentina; Copenhagen, Denmark; Dublin, Ireland; Lausanne, Switzerland; Nimegue, Pampelune (Virgin del Camino).

	REFERENCES

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX REFERENCES

 
1. Raney RB Jr, Hays DM, Tefft M, et al: Rhabdomyosarcoma and the undifferentiated sarcomas, in Pizzo PA, Poplack DG (eds): Principles and Practice of Pediatric Oncology. Philadephia, PA, Lippincott-Raven Co, 1989, pp 635–658

2. Crist W, Gehan EA, Ragab AH, et al: The third Intergroup Rhabdomyosarcoma study. J Clin Oncol 13:610–630, 1995[Abstract/Free Full Text]

3. Flamant F, Rodary C, Rey A, et al: Treatment of non-metastatic rhabdomyosarcomas in childhood and adolescence: Results of the second study of the International Society of Paediatric Oncology: MMT84. Eur J Cancer 34:1050–1062, 1998[CrossRef][Medline]

4. Crist WM, Anderson JR, Meza JL, et al: Intergroup rhabdomyosarcoma study-IV: Results for patients with nonmetastatic disease. J Clin Oncol 19:3091–3102, 2001[Abstract/Free Full Text]

5. Ferrari A, Bisogno G, Casanova M, et al: Paratesticular rhabdomyosarcoma: Report from the Italian and German Cooperative Group. J Clin Oncol 20:449–455, 2002[Abstract/Free Full Text]

6. Weiner ES, Anderson JR, Ojimba JI, et al: Controversies in the management of paratesticular rhabdomyosarcomas: Is staging retroperitoneal lymph node dissection necessary for adolescents with resected paratesticular rhabdomyosarcoma? Semin Pediatr Surg 10:146–152, 2001[CrossRef][Medline]

7. Olive D, Flamant F, Zucker JM, et al: Paraaortic lymphadenectomy is not necessary in the treatment of localized paratesticular rhabdomyosarcoma. Cancer 54:1283–1287, 1984[CrossRef][Medline]

8. Hays DM, Lawrence W Jr, Wharam M, et al: Primary re-excision for patients with "microscopic residual" tumour following initial excision of sarcomas of trunk and extremity sites. J Pediatr Surg 24:5–10, 1989[CrossRef][Medline]

9. Newton WA, Gehan EA, Weber BL, et al: Classification of rhabdomyosarcomas and related sarcomas: Pathologic aspects and proposal for a new classification. An Intergroup Rhabdomyosarcoma Study. Cancer 76:1073–1085, 1995[CrossRef][Medline]

10. Rodary C, Flamant F, Donaldson SS: An attempt to use a common staging system in rhabdomyosarcoma: A report of an international workshop initiated by the International Society of Pediatric Oncology (SIOP). Med Pediatr Oncol 17:210–215, 1989[Medline]

11. Martelli H, Oberlin O, Rey A, et al: Conservative treatment for girls with nonmetastatic rhabdomyosarcoma of the genital tract: A report from the study committee of the International Society of Paediatric Oncology. J Clin Oncol 17:2117–2122, 1999[Abstract/Free Full Text]

12. Kaplan ES, Meier P: Non-parametric estimation from incomplete observation. J Am Stat Assoc 53:457–481, 1958[CrossRef]

13. Peto R, Pike MC, Armitage P, et al: Design and analysis of randomized clinical trials requiring prolonged observation of each patient. Br J Cancer 35:1–39, 1977[Medline]

14. Heyn R, Raney RB Jr, Hays DM, et al: Late effects of therapy in patients with paratesticular rhabdomyosarcoma. Intergroup Rhabdomyosarcoma Study Committee. J Clin Oncol 10:614–623, 1992[Abstract/Free Full Text]

15. Hughes LL, Baruzzi MJ, Ribeiro RC, et al: Paratesticular rhabdomyosarcoma: Delayed effects of multimodality therapy and implications for current management. Cancer 73:467–482, 1994

16. Jewett MA: Nerve-sparing technique for retroperitoneal lymphadenectomy in testis cancer. Urol Clin North Am 17:449–456, 1990[Medline]

17. Janetsche G, Hobisch A, Peschel R, et al: Laparoscopic retroperitoneal lymph node dissection of clinical stage 1 nonseminomatous testicular carcinoma: Long term outcome. J Urol 163:1793–1796, 2000[CrossRef][Medline]

18. Cecchetto G, Grotto P, De Bernardi B, et al: Paratesticular rhabdomyosarcoma in childhood: Experience of the Italian Cooperative Study. Tumori 74:645–647, 1988[Medline]

19. Gamba PG, Cecchetto G, Katende M, et al: Paratesticular rhabdomyosarcoma (RMS) and paraaortic lymphadenectomy. Eur J Pediatr Surg 4:158–160, 1994[Medline]

20. Wiener ES, Lawrence W, Hays D, et al: Retroperitoneal node biopsy in paratesticular rhabdomyosarcoma. J Pediatr Surg 29:171–178, 1994[CrossRef][Medline]

21. Dall’Igna P, Cecchetto G, Carli M, et al: Primary transcrotal excision for paratesticular RMS: Is hemiscrotectomy really mandatory? Med Pediatr Oncol 37:344, 2001

Submitted June 6, 2002; accepted November 18, 2002.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Facebook    Reddit    Technorati    Twitter    What's this?

This article has been cited by other articles:

				M. C.G. Stevens, A. Rey, N. Bouvet, C. Ellershaw, F. Flamant, J. L. Habrand, H. B. Marsden, H. Martelli, J. S. de Toledo, R. D Spicer, et al. Treatment of Nonmetastatic Rhabdomyosarcoma in Childhood and Adolescence: Third Study of the International Society of Paediatric Oncology--SIOP Malignant Mesenchymal Tumor 89 J. Clin. Oncol., April 20, 2005; 23(12): 2618 - 2628. [Abstract] [Full Text] [PDF]

This Article Abstract Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Stewart, R. J. Articles by Stevens, M. C.G. Search for Related Content PubMed PubMed Citation Articles by Stewart, R. J. Articles by Stevens, M. C.G. Social Bookmarking                            What's this?