Stesura Seveso Archivio Italiano di Urologia e Andrologia 2023; 95(4):11642 1 ORIGINAL PAPER the recent multiagent chemotherapy protocols and high sensitivity of imaging techniques. Management strategy includes high inguinal orchiectomy with or without retro-peritoneal nodal dissection and mul- tiagent chemotherapy depending on the stage and group of disease (4). Patients with no sampling of para-aortic nodes are managed as stage III disease. In our institute, retro-peri- toneal nodal sampling is not widely adopted and radiation therapy to para-aortic chain is used as an alternative. Herein, we review our experience and clinico-epidemio- logical factors were studied as well as treatment strategies potentially influencing disease-free survival (DFS) in addi- tion to overall survival (OS) and loco regional recurrence (LRR).we aim to explore treatment outcomes with radia- tion therapy instead of retro-peritoneal nodal dissection. PATIENTS AND METHODS This is a retrospective study involving all patients with para-testicular RMS presented to NCI, Cairo University in the period from 2005 till 2020. IRB approval was obtained before data collection from ethical committee of Faculty of Medicine, Cairo University. No consents were required given the retrospective nature of the study. Patients' records were reviewed to extract clinico-epi- demiological data including age, pathological subtype, tumor size , risk stratification, staging and treatment data including type of surgery (biopsy or resection, para-aor- tic lymph node dissection), chemotherapy regimen and radiotherapy details (dose, overall period of treatment, radiation technique and timing of radiation),and patterns of failure. Patients with incomplete treatment records were excluded from data analysis. All patients were diagnosed by initial biopsy (high inguinal orchiectomy or trans-scrotal). Patients who underwent complete surgical staging were staged according to IRSG Postsurgical Grouping Classification (5) (Table 1), while those who underwent orchiectomy only without nodal assess- ment or those with clinical positive nodes were managed as Background: Para-testicular Rhabdomyosarcoma (PT-RMS) has a favor- able treatment outcome adopting multidisciplinary management; resection, namely high inguinal orchiectomy ± retro-peritoneal lymph node dissection (RPLND) followed by standard or inten- sive chemotherapy ± adjuvant radiation therapy. Patients and methods: This is a retrospective study including all patients with pathologically proven PT-RMS, presented to the National Cancer Institute, Cairo University, during the period from 2005 to 2020. Endpoints included overall survival, disease free survival and patterns of failure of different treatment modalities. Results: Forty one patients were identified. Median age in our cohort was 15 years (range: 2-54 years). After a median follow up of 26 months (range, 3-75 months) ,two and five years OS were 100% and 91.7% respectively and median survival was not reached. Patients who underwent retro-peritoneal nodal dissec- tion had a 5-year DFS rate of 100% versus 73% for those who received radiation to para-aortic nodes (p = 0.185). Limitations include retrospective nature and deviation from COG protocol. Conclusions: This study shows promising results suggesting that less aggressive local treatment modalities including radiation to para-aortic chain could be an option in PT-RMS, given the excellent results of this subtype. However further validation in a prospective study is warranted. KEY WORDS: Para-testicular rhabdomyosarcoma; Retro-peritoneal dissection; Radiation therapy. Submitted 5 August 2023; Accepted 31 August 2023 INTRODUCTION Paratesticular rhabdomyosarcoma (PT-RMS) is a special entity of rhabdomyosarcoma with an estimated incidence around 7% of all patients with RMS (1). The prognosis for patients with localized disease is excel- lent, owing to early detection of the tumor given its spe- cial location and a predominance of paired box gene (PAX)-fusion negative RMS (2, 3). This allows for using less aggressive local treatment modalities especially with Treatment results of Para-Testicular Rhabdomyosarcoma (PT-RMS) using radiation as an alternative to retro-peritoneal nodal dissection: A single Institution experience Yasser A. Abdelazim 1, Monika F. Zaki 1, Mohsen M. Abdel Mohsen 2, Reem M. Emad 1, Heba G. Mohamad 3, Dalia Abdelfatah 4, Ehab M. Kalil 1 1 Department of Radiation Oncology, National Cancer Institute, Cairo University, Egypt; 2 Department of Clinical Oncology, Faculty of medicine, Cairo University, Egypt; 3 Department of Surgical Oncology, National Cancer Institute, Cairo University, Egypt; 4 Department of Cancer epidemiology & biostatistics. National Cancer Institute, Cairo University, Egypt. DOI: 10.4081/aiua.2023.11642 Summary Archivio Italiano di Urologia e Andrologia 2023; 95(4):11642 Y.A. Abdelazim, M.F. Zaki, M.M. Abdel Mohsen, et al. 2 group III. Pretreatment clinical staging was per IRSG pre- surgical staging (5) (Table 2). Work up included scrotal U/S, MRI of the pelvis, CT of chest and abdomen with con- trast and bone scan. PET-CT was done for 5 patients for ini- tial staging and/or post chemotherapy to assess the treat- ment response in last two years (2019-2020). Lymph node evaluation was done using staging CT of the abdomen and pelvis in all cases. Surgical nodal staging was done in only 4 cases. Treatment details All patients underwent surgery for the primary testicular tumor (most of them were by inguinal approach); only 4 patients underwent therapeutic retroperitoneal lymph node dissection (RPLND) for grossly enlarged nodes on CT. Postoperative chemotherapy was used according to the Intergroup Rhabdomyosarcoma Study IRS- IV chemother- apy protocol (vincristine, dactinomycin, and cyclophos- phamide) (6) for 42 weeks. A flow chart of the protocol is provided in Figure 1. Hemi-scrotum irradiation was used in cases of scrotal vio- lation (trans-scrotal approach). Iliac and inguinal nodal radiation was used with para-aor- tic nodal radiation in cases of presence of clinically involved nodes in these stations. Regarding radiation therapy planning, patients were fixed with a mattress during CT simulation. CT cuts were taken with a slice thickness of 3 mm from level of suprasternal notch down to mid-thighs. A three-dimensional conformal radiotherapy technique was commonly used for treatment. Starting from year 2020, Intensity- Modulated Radiation Therapy (IMRT) technique was used for better sparing of organs at risk. Radiotherapy doses were dependent on the completeness of surgical resection of the primary tumor (Clinical Group) and presence or absence of involved regional lymph nodes. After resection, patients with complete resection and stage I alveolar histology were treated to 36 Gy, those with stage II and uninvolved nodes received 41.4 Gy, those with patho- logically involved nodes received 41.4 Gy and patients with positive gross nodes in planning CT received 50.4 Table 1. IRSG Postsurgical Grouping Classification. Group 1 Localized disease, completely resected, no microscopic residual A Confined to site of origin, completely resected B Extends beyond site of origin, completely resected Group 2 Gross total resection A Residual microscopic disease ( positive margins) B Involved regional nodes, completely resected C Microscopic local and/or regional residual disease Group 3 Incomplete resection or biopsy with gross residual Group 4 Distant metastasis Figure 1. Diagrammatic scheme of IRS-IV protocol. Table 2. IRSG Pre-surgical Staging Classification. Stage Sites Tumor (T) Size Node (N) Metastases (M) I Orbit, head and neck T1 a N0, M0 (excluding PM), or or b N1 GU: non-bladder/non-prostate T2 or Nx II Bladder/prostate, extremity, T1 or T2 a N0 or Nx M0 cranial, PM other (includes trunk, retroperitoneum, and so on) III Bladder/prostate, extremity, T1 or T2 a N1 M0 cranial, PM, other (includes trunk, b N0, N1 or Nx retroperitoneum, and so on) IV All Any Any Any M1 Tumor: T1, confined to anatomic site of origin, (a) < 5 cm in diameter, (b) > 5 cm in diameter; T2, extension and/or fixative to surrounding tissue, (a) < 5 cm in diameter, (b) > 5 cm in diameter; regional nodes: N0, regional nodes clinically negative; N1, regional nodes clinicallypositive; Nx, clinical status is unknown; metastasis: M0, no distant metastasis; M1, metastasis present. GU, genitourinary; PM, para-meningeal. Archivio Italiano di Urologia e Andrologia 2023; 95(4):11642 3 Radiation role in in PT-RMS Gy. The gross tumor volume (GTV) was defined as any gross nodal disease on planning CT or post-chemotherapy PET- CT. The clinical target volume (CTV) was defined as 1.5 cm expansion on aorta and inferior vena cava (IVC) from level of 11th dorsal vertebra (DV11) down to bifurcation, exclud- ing bowel, bone and muscles. The planning target volume (PTV) was defined as an additional 1 cm margin to CTV. Kidneys, bowel and spinal cord were delineated as organs at risk. PTV coverage of minimum 95% of dose to 95% of volume was required for plan acceptance. Dmax of cord was limited to < 45 Gy and bilateral kidney V24 was lim- ited to < 50%. Radiation therapy was started at week 13 in patients with Low Risk (14 patients) whereas in other cases it was usu- ally given at week 20 as per protocol. Statistical analysis Data was analyzed using IBM SPSS advanced statistics (Statistical Package for Social Sciences), version 21 (SPSS Inc., Chicago, IL). Numerical data was described as mean and standard devi- ation or median and range as appropriate, while qualitative data were described as number and percentage. Endpoints were the disease-free survival, metastasis-free survival, loco-regional control and overall survival. Overall survival was defined as the time from primary diagnosis date to death (all-cause). Time to loco-regional recurrence was defined as time from primary treatment to recurrence at the primary tumor site or regional lymph nodes, whichever comes first; distant recurrences and deaths that occur before local events were ignored. Distant recurrence was defined as recurrences outside these loco-regional sites; deaths and loco-regional recur- rences that occur before distant events were ignored. Disease-free survival (DFS) was defined as the time from primary treatment to loco-regional recurrence, distant recurrence, whichever comes first. Comparisons between the two groups were made using either Chi- square test or Fishers exact test for categorical data. For quantitative data comparison between 2 groups was done using either parametric or non-parametric t-test as appropriate. Survival analysis was done using Kaplan-Meier method and comparison between survival curves was done using Log rank test. A p-value less than 0.05 was considered statistically significant. All tests were two tailed. RESULTS Forty one patients with pathologically proven PT RMS were identified in the period from January 2005 till December 2020. The Median age in our cohort was 15 years (range: 2-54 years). Children below 10 years constituted 24% of the total population. Thirty seven (90%) patients had embry- onal histology. Retroperitoneal lymph node involvement was present in twelve (29%) patients by CT evaluation (four patients < 10 years and eight patients > 10 years). Ten patients presented with initially metastatic disease (eight patients to lungs and two patients to supra-clavic- ular lymph nodes). Demographic and pathological char- acteristics of the patients are summarized in Table 3. Treatment related characteristics Thirty-nine (95%) patients were surgically excised com- pletely by high inguinal orchiectomy and high cord liga- tion at the internal ring prior to tumor mobilization as per international guidelines; only 2 patients (5%) were man- aged by trans-scrotal approach. Thirty seven (90%) patients did not undergo retroperi- toneal lymph node dissection (RPLND), while four (10%) patients underwent inguinal orchiectomy with RPLND (all were > 10 years), Patients were treated according to Intergroup Rhabdomyosarcoma Study IRS-IV protocol. All patients were treated by systemic chemotherapy (VAC based regi- mens) for 42 weeks. Radiotherapy was adopted for local control in thirty one (75%) patients, while 8 patients did not receive radio- therapy as they were low risk group (stage I, group I, embryonal histology). One patient did not receive radia- tion due to his guardian’s refusal and one patient did not receive local treatment due to progression during chemotherapy and he was shifted to second line chemotherapy Ifosfamide/Carboplatin/Etoposide (ICE), with good response. Patients who received radiation to scrotum were due to scrotal violation during surgery and those who received radiation to inguinal and ipsilateral iliac nodes was due to presence of gross disease at these sites at presentation. The timing of radiotherapy in COG Protocol was in week 13 in all risk groups. Patients in low risk group received radiotherapy at week 12 and some patients were delayed to week 20. The median radiotherapy dose was 36Gy Table 3. Demographic and pathological characteristics of patients in this study. N = 41 (%) Age Median (range) 15 (2-54) ≤ 10 10 (24) > 10 31 (76) Histological type Alveolar 2 (4.9) Embryonal 37 (90.2) Pleomorphic 2 (4.9) Staging Stage 1 23 (56.1) Stage 2 4 (9.8) Stage 3 4 (9.8) Stage 4 10 (24.4) Grouping Group 1 8 (19.5) Group 2 13 (31.7) Group 3 20 (48.8) Risk stratification Low risk 14 (34.1) Intermediate risk 14 (34.1) High risk 13 (31.7) Archivio Italiano di Urologia e Andrologia 2023; 95(4):11642 Y.A. Abdelazim, M.F. Zaki, M.M. Abdel Mohsen, et al. 4 (range, 19.5- 50.4 Gy). Treatment related characteristics are summarized in Table 4. Patterns of failure One patient had distant failure in lung, one patient had distant failure in bones and seven patients had nodal fail- ure, three of them in ilio-inguinal nodes and 4 patients had para-aortic failure. In patients who underwent RPLND, one patient had para-aortic failure. Survival analysis Overall survival (OS) After a median follow up of 26 months (range, 3-75 months), two and five years OS were 100% and 91.7% respectively and median survival was not reached (Figure 2). Five year survival rate for patients < 10 years were 100% versus 86% for patients above 10 years of age (p = 0.390). Disease Free Survival (DFS) Five years disease free survival for the whole group was 77 percent (Figure 3). Patients who underwent retro-peri- toneal nodal dissection had a 5-year DFS rate of 100% ver- sus 73% for those who received radiation to para-aortic nodes (p = 0.185). Five years DFS was 100% for patients < 10 years versus 71% for those > 10 years (p = 0.106). No difference in DFS between patients who had positive para-aortic nodes at presentation (n = 12) and those with negative para-aortic nodes (n = 29), with a 5-year DFS rate 90 percent vs. 72 percent, respectively (p = 0.287). Local control (LC) The one-year LC is 85% for whole study group while the five-year LC is 71.2%. No difference in LC between patients with posi- tive para-aortic nodes at presentation and those with negative nodes at 5 years (89 per- cent vs. 60 percent, respectively, p = 0.158). DISCUSSION This retrospective study included 41 patients with para-testicular Rhabdomyosarcoma (PT RMS) who presented to NCI - Cairo University in the period from 2005 to 2020. The median age of the study patients group was 15 years which is comparable to other studies showing a median age of 16.5 years (7). The embryonal pathological subtype consti- tuted 90% of the study group. Similar results were reported in the literature with predominance of the embryonal histology representing 70% (7). Regarding the surgical and clinical group, the majority of the studied patients were catego- rized as Group 3 (50%) which is consistent with the analysis of PT RMS patients treated in IRS II through IV in which surgical group 3 was reported in (40%) of cases (7). Regarding the IRSG stage, 56% of studied patients presented in stage I while 25% of Figure 2. KM curve representing overall survival for the whole study group. Figure 3. Kaplan Meier curve representing DFS for the whole study group. Table 4. Treatment related characteristics in this study. Surgical approach n = 41 (%) Inguinal 39 (95) Scrotal 2 (5) PALN dissection Yes 4 (10) No 37 (90) PALN status Positive 12 (29) Negative 29 (71) Type of CTH VAC 32 (78) VAC-ICE 6 (15) VAC-ICE-IE 1 (2.4) VCR 2 (5) Archivio Italiano di Urologia e Andrologia 2023; 95(4):11642 5 Radiation role in in PT-RMS patients had stage IV disease. Findings are in agreement with other studies which reported stage I and IV diseases in 40% and 40% of cases respectively (7). Approximately 29% of patients with PT-RMS presented with retroperitoneal lymph node disease which is compa- rable to another study in which approximately 25% of patients with PT-RMS had Positive retroperitoneal lymph node disease (6). The treatment of the patients in this study followed the international guidelines regarding the surgical approach for the primary tumor (high inguinal orchiectomy) which was followed by standard chemotherapy protocol. As for the nodal regional control in positive retroperitoneal lymph nodes, radiotherapy was used in most of the patients (90%) instead of RPLND which was only done in four patients (10%). This policy adapted by our institute is contradictory to the current protocol for Children's Oncology Group (COG) adapting ipsilateral staging RPLND for all boys aged 10 years or more and for those with enlarged lymph nodes suspicious for metastatic dis- ease on CT scan, or patients with alveolar histology irre- spective of the age (8). Retro-peritoneal nodal dissection carries a high post-operative morbidity rates between 5- 20% at high-volume centers. The most common compli- cations being small bowel obstruction, retrograde ejacu- lation, lower extremity lymphedema, hydronephrosis and chylous ascites (9-11). These complications are consid- ered more significant compared for nodal irradiation complications which include radiation dermatitis, gastro- enteritis, and myelosuppresion (12). Despite these low rates of para-aortic nodal dissection in our study, median OS was not reached and the calculat- ed one and five year OS rates were 100% and 91.7% respectively, reflecting the excellent prognosis of the dis- ease regardless of the nodal regional treatment modality used. These results are comparable to similar studies which reported overall survival rates ranging between 81 and 95 percent (6, 13, 14). The retroperitoneal lymph node positivity at presentation (whether clinical or pathological) did not influence the outcome as there was no difference in treatment related outcomes between patients with positive and negative para-aortic nodes at presentation, reflecting the excellent outcome despite less intensive treatment in our study. In terms of DFS, 5-year DFS rate was 73% in patients who received radiotherapy to para-aortic chain versus 100% for those who underwent retro-peritoneal nodal dissection with no significant difference between both groups statistically (p = 0.185). Only one patient (2.7%) out of 37 patients in our study experienced isolated regional failure in para-aortic chain. This is comparable to another study which was held by SIOP 2016 which reported 5-year DFS 83% in patients who underwent Radical inguinal orchiectomy without RPLND (15). In summary, our study shows a favorable outcome in PT- RMS patients managed with radiation to para-aortic chain instead of surgery. This might be attributed to the indo- lent nature of the disease itself or the efficacy of radiation. However, a prospective study may be warranted. To our knowledge, this is the first work addressing radiation as an alternative to surgery in PT-RMS. Limitations of this study include its retrospective nature which makes it subjected to selection bias, small sample size, lack of toxicity scoring and quality of life (QoL) assessment of the patients, lack of PET-CT staging which might have underestimated the real incidence of clinical- ly positive retro-peritoneal nodes and deviation from the current COG protocol. However in such rare diagnosis where prospective trials are difficult to conduct, institu- tional series remain instructive. REFERENCES 1. Stewart LH, Lioe TF, Johnston SR. Thirty-year review of intrascrotal rhabdomyosarcoma. Br J Urol. 1991; 68:418-20. 2. Raney RB Jr, Tefft M, Lawrence W Jr, et al. Paratesticular sarco- ma in childhood and adolescence. A report from the Intergroup Rhabdomyosarcoma Studies I and II, 1973-1983. Cancer. 1987; 60:2337-43. 3. Raney RB, Walterhouse DO, Meza JL, et al. Results of the Intergroup Rhabdomyosarcoma Study Group D9602 protocol, using vincristine and dactinomycin with or without cyclophosphamide and radiation therapy, for newly diagnosed patients with low-risk embry- onal rhabdomyosarcoma: a report from the Soft Tissue Sarcoma Committee of the Children’s Oncology Group. J Clin Oncol. 2011; 29:1312-1318. 4. Rogers TN, Seitz G, Fuchs J, et al. Surgical management of parat- esticular rhabdomyosarcoma: A consensus opinion from the Children's Oncology Group, European pediatric Soft tissue sarcoma Study Group, and the Cooperative Weichteilsarkom Studiengruppe. Pediatr Blood Cancer. 2021; 68:e28938. 5. Crane JN, Xue W, Qumseya A, et al. Clinical group and modified TNM stage for rhabdomyosarcoma: A review from the Children's Oncology Group. Pediatr Blood Cancer. 2022; 69:e29644. 6. Crist WM, Anderson JR, Meza JL, et al. Intergroup rhab- domyosarcoma study-IV: Results for patients with nonmetastatic dis- ease. J Clin Oncol. 2001; 19:3091-3102. 7. Kumar R, Kapoor R, Khosla D, et al. Paratesticular rhab- domyosarcoma in young adults: A tertiary care institute experience. Indian J Urol. 2013; 29:110-3. 8. Rogers TN, De Corti F, Burrieza GG, et al. Paratesticular rhab- domyosarcoma—impact of locoregional approach on patient out- come: a report from the European paediatric Soft tissue sarcoma Study Group (EpSSG). Pediatr Blood Cancer. 2020; 67:e28479. 9. Heidenreich A, Albers P, Hartmann M, et al. Complications of pri- mary nerve sparing retroperitoneal lymph node dissection for clinical stage I nonseminomatous germ cell tumors of the testis: experience of the German Testicular Cancer Study Group. J Urol. 2003; 169:1710-1714. 10. Beck SD, Bey AL, Bihrle R, Foster RS. Ejaculatory status and fer- tility rates after primary retroperitoneal lymph node dissection. J Urol. 2010; 184:2078-2080. 11. Steiner H, Zangerl F, Stöhr B, et al. Results of bilateral nerve sparing laparoscopic retroperitoneal lymph node dissection for testic- ular cancer. J Urol. 2008; 180:1348-1353. 12. Gupta AA, Anderson JR, Pappo AS, et al. Patterns of chemother- apy-induced toxicities in younger children and adolescents with rhab- domyosarcoma: a report from the children's oncology group soft tis- sue sarcoma committee. Cancer. 2012;118:1130-1137. 13. LaQuaglia MP, Ghavimi F, Heller G, et al. Mortality in pediatric paratesticular rhabdomyosarcoma: a multivariate analysis. J Urol. 1989; 142:473-478. Archivio Italiano di Urologia e Andrologia 2023; 95(4):11642 Y.A. Abdelazim, M.F. Zaki, M.M. Abdel Mohsen, et al. 6 14. Lawrence W Jr, Gehan EA, Hays DM, et al. Prognostic significance of staging factors of the UICC staging system in childhood rhab- domyosarcoma: a report from the Intergroup Rhabdomyosarcoma Study (IRS II). J Clin Oncol. 1987; 5:46. 15. Stevens MC, Rey A, Bouvet N, 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. 2005; 23:2618-2628. Correspondence Yasser A. Abdelazim, MD (Corresponding Author) Yasser.anwar@nci.cu.edu.eg National Cancer Institute 1 Kasr EL Ainy Street, Cairo, Egypt, 11796 Monika Foad Zaki, MD monikafouad@icloud.com Reem Mohamad Emad, MD reem.emad@nci.cu.edu.eg Ehab Mohamad Khalil, MD ehab.khalil@nci.cu.edu.eg Department of Radiation Oncology, National Cancer Institute, Cairo University, Egypt Mohsen Mokhtar Abdel Mohsen, MD mohsenonc@hotmail.com Department of Clinical Oncology, Faculty of Medicine, Cairo University, Egypt Heba Gamal Mohamad, MD hebasurg@yahoo.com Department of Surgical Oncology, National Cancer Institute, Cairo University, Egypt Dalia Abdelfatah Mohammed, MD dalia.abdelfatah@nci.cu.edu.eg Department of Cancer Epidemiology & Biostatistics. National Cancer Institute, Cairo University, Egypt Conflict of interest: The authors declare no potential conflict of interest.