Our patient had multiple poor prognostic indicators: alveolar histology, PAX3-FKHR gene fusion, tumor location (extremity), tumor >5 cm, metastatic disease at presentation, and multiple local and distant recurrences [4,5]. She was Stage 4 or Clinical Group 4 at the time of diagnosis and within the very high risk treatment group.
The alveolar subtype accounts for 20% of rhabdomyosarcoma cases and approximately 44-50% of extremity RMS tumors have alveolar histology [1,3]. The distal portion of an extremity and the lower extremities are the more common extremity locations . ARMS is located on the extremities in approximately 20% of RMS cases and typically follows a very aggressive course with an unfavorable outcome . Of the 127 patients with metastatic disease in the IRS-IV trial, the most common sites of metastases were the lungs (39%), bone marrow (32%), lymph nodes (30%), and bones (27%) . Of note, our patient had presumed or confirmed metastatic disease within all four of these locations throughout the course of her disease. In primary extremity disease, the rate of regional lymph node involvement is high, more so with recurrence; 38% of patients who had relapsing disease in IRS-IV had disease recurrence in lymph nodes . Although biopsy of her inguinal nodes at initial presentation were negative for metastases, new PET positive illiac nodes were observed with the first recurrence. Distal recurrence was presumed to have occurred in these lymph nodes; however, a biopsy was never done since these lymph nodes responded to therapy.
Patients with metastatic or stage IV ARMS have up to a 25% 5-year overall survival. Disease recurrence of ARMS is frequent with approximately 30% of patients experiencing disease relapse, commonly in lung and bone marrow [1,3]. Recurrence imparts a significant decrease in the rate of overall survival, which falls below 10% . Among patients with the alveolar subtype and one or more recurrences, as in this patient, 5-year overall survival was as low as 5% with median survival typically less than 10 months from first recurrence .
The majority of ARMS patients have a PAX-FKHR fusion positive tumor. 23% of ARMS tumors are fusion negative, 55% are PAX3-FKHR fusion positive, and 22% are PAX7-FKHR positive . In a multivariate analysis, Sorenson, et al. showed that patients with metastatic disease and PAX3-FKHR fusion positive tumors had significantly decreased estimated 4-year overall survival of 8% when compared to 75% overall survival with metastatic PAX7-FKHR fusion positive tumors . When taken with the prevalence of the PAX3-FKHR fusion, a significant number of patients with metastatic disease will have very poor overall survival . It has been postulated that fusion gene status in lower risk groups is an independent predicting factor of both disease recurrence and death, with decreased 5-year event free survival and overall survival . However, it was found that fusion positive status plays less of a role than clinical features when staging and risk-stratifying patients with metastatic disease .
New chemotherapy regimens for rhabdomyosarcoma are frequently evaluated. VAC is the typical backbone, with newer regimens substituting or adding additional cycles of chemotherapeutic agents. Newer multiagent therapy regimens, such as ARST0431, with more toxic agents, have failed to show significant improvement in ARMS 5 year event free survival when compared to IRS-IV trials . In patients with recurrence, ARST0921 using temsirolimus has shown promising results due to increased event free and overall survival when combined with vinorelbine and cyclophosphamide . Temsirolimus is active against the mammalian target of rapamycin (mTOR) pathway activated in RMS and ARST0921 represents the tangible benefits of targeted molecular therapy in conjunction with cytotoxic therapy in treatment resistant disease .
Cases of relapsing and refractory RMS are typically treated with different regimens . For this patient’s second recurrence, agents that she had not been previously exposed to were chosen. Second salvage therapy followed the Italian Soft Tissue Sarcoma Committee’s (STSC) regimen involving two upfront cycles of topotecan-carboplatin and then six total cycles of alternating between topotecan-cyclophosphamide and carboplatin-etoposide . This regimen had shown 5-year overall survival rates of 17%, a slight increase when compared to 10% 5-year overall survival observed in patients with relapsing disease . After completion of the Italian STSC regimen for refractory RMS, she was placed on maintenance therapy. Per European Pediatric Soft Tissue Sarcoma Study Group (EpSSG), in high risk patients with alveolar histology and without metastasis, maintenance therapy consisting of vinorelbine and cyclophosphamide improved 5-year overall survival compared to no further treatment . Although studies to evaluate merit of maintenance therapy in patients with metastatic disease are still in progress, the above maintenance regimen had shown promise in our patient with no evidence of disease for at least 6 months. This 6-month window afforded her the opportunity to return to school and normalize some aspects of her life. Although imaging had confirmed absence of macroscopic disease and the resolution of the left lung nodule during maintenance therapy, this sarcoma is extremely aggressive as demonstrated by the rapid progression of disease. Multiple new metastases had progressed within the two months between cycle 4 and 6 of her maintenance therapy.
Salvage therapy with gemcitabine and docetaxel has shown promise in pediatric patients with relapse or refractory sarcomas . Higher dose gemcitabine (1,000 mg/m2) and docetaxel (100 mg/m2) demonstrated an objective response rate of 50% with relapsed/refractory pediatric sarcomas, although most cases were of Ewing sarcoma and none of rhabdomyosarcoma . However, when using the gemcitabine and docetaxel at lower doses, 675 mg/m2 and 75 mg/m2, respectively; only 1 out of 5 patients with rhabdomyosarcoma had progression of his or her disease . In patients with rhabdomyosarcoma treated with gemcitabine and docetaxel salvage therapy, there was overall clinical benefit in more than half of the patients, considering stable disease to be of clinical benefit . After her confirmed third recurrence, our patient was placed on this regimen combined with radiation therapy. A priority influencing this treatment strategy was to maintain her current quality of life, something this regimen has demonstrated .
This case report detailed the clinical course of a very resilient, young patient with a very poor prognosis from initial evaluation. She had metastatic disease of an aggressive sarcoma with multiple distant and local recurrences. After 2 recurrences, chemotherapy and radiation were able to localize gross disease creating the opportunity for local surgical control. She had no evidence of disease for at least 6 months after knee disarticulation, over three years from initial presentation. Every treatment effort was made throughout the course of treatment, but her clinical course underlines the extremely aggressive and unremitting nature of alveolar rhabdomyosarcoma.
 Paulino AC, Okcu MF. Rhabdomyosarcoma. Curr Probl Cancer 2008;32(1):7-34.
 Bisogno G, et al; European paediatric Soft tissue sarcoma Study Group. Vinorelbine and continuous low-dose cyclophosphamide as maintenance chemotherapy in patients with high-risk rhabdomyosarcoma (RMS 2005): a multicentre, open-label, randomised, phase 3 trial. The Lancet Oncol. 2019;20(11):1566-75.
 LaQuaglia MP. Extremity rhabdomyosarcoma : biological principles, staging, and treatment. Seminars in surgical oncology. 1993;9(6):510-9.
 Sorensen PHB, Lynch JC, Qualman SJ, Tirabosco R, Lim JF, Maurer HM, Bridge JA, Crist WM, Triche TJ, Barr FG. PAX3-FKHR and PAX7-FKHR gene fusions are prognostic indicators in alveolar rhabdomyosarcoma: a report from the children's oncology group. J Clin Oncol. 2002;20(11):2672-9.
 Mascarenhas L, Chi Y-Y, Hingorani P, Anderson JR, Lyden ER, Rodeberg DA, et al. Randomized Phase II Trial of Bevacizumab or Temsirolimus in Combination With Chemotherapy for First Relapse Rhabdomyosarcoma: A Report From the Children's Oncology Group. J Clin Oncol. 2019;37(31):2866-74.
 Breneman JC, Lyden E, Pappo AS, Link MP, Anderson JR, Parham DM, Qualman SJ, et al. Prognostic factors and clinical outcomes in children and adolescents with metastatic rhabdomyosarcoma--a report from the Intergroup Rhabdomyosarcoma Study IV. J Clin Oncol. 2003;21(1):78-84.
 Rodeberg DA, Garcia-Henriquez N, Lyden ER, Davicioni E, Parham DM, Skapek SX, Hayes-Jordan AA, et al. Prognostic significance and tumor biology of regional lymph node disease in patients with rhabdomyosarcoma: a report from the Children's Oncology Group. J Clin Oncol. 2011;29(10):1304-11.
 Pappo AS, Anderson JR, Crist WM, Wharam MD, Breitfeld PP, Hawkins D, Raney RB, Womer RB, Parham DM, Qualman SJ, Grier HE. Survival after relapse in children and adolescents with rhabdomyosarcoma: A report from the Intergroup Rhabdomyosarcoma Study Group. J Clin Oncol. 1999;17(11):3487-93.
 Gallego S, Zanetti I, Orbach D, Francotte N, Van Noesel M, Kelsey A, Casanova M, et al. Fusion status in patients with lymph node-positive (N1) alveolar rhabdomyosarcoma is a powerful predictor of prognosis: Experience of the European Paediatric Soft Tissue Sarcoma Study Group (EpSSG). Pediatr Blood Cancer. 2018;124(15):3201-9.
 Rudzinski ER, Anderson JR, Chi Y-Y, Gastier-Foster JM, Astbury C, Barr FG, Skapek SX, Hawkins DS, , et al. Histology, fusion status, and outcome in metastatic rhabdomyosarcoma: A report from the Children's Oncology Group. Pediatr Blood Cancer. 2017;64(12):10.1002/pbc.26645.
 Weigel BJ, Lyden E, Anderson JR, Meyer WH, Parham DM, Rodeberg DA, et al. Intensive Multiagent Therapy, Including Dose-Compressed Cycles of Ifosfamide/Etoposide and Vincristine/Doxorubicin/Cyclophosphamide, Irinotecan, and Radiation, in Patients With High-Risk Rhabdomyosarcoma: A Report From the Children's Oncology Group. J Clin Oncol. 2016;34(2):117-22.
 Compostella A, Affinita MC, Casanova M, Milano GM, Scagnellato A, Dall'Igna P, Chiaravalli S, Pierobon M, Manzitti C, Zanetti I, Schiavetti A, Sorbara S, et al. Topotecan/carboplatin regimen for refractory/recurrent rhabdomyosarcoma in children: Report from the AIEOP Soft Tissue Sarcoma Committee. Tumori. 2019;105(2):138-43.
 Mora J, Cruz CO, Parareda A, de Torres C. Treatment of relapsed/refractory pediatric sarcomas with gemcitabine and docetaxel. J Pediatr Hematol Oncol. 2009;31(10):723-9.
 Rapkin L, Qayed M, Brill P, Martin M, Clark D, George BA, Olson TA, Wasilewski-Masker K, Alazraki A, Katzenstein HM. Gemcitabine and docetaxel (GEMDOX) for the treatment of relapsed and refractory pediatric sarcomas. Pediatr Blood Cancer. 2012;59(5):854-8.