Pediatric Rhabdomyosarcoma Treatment & Management

Treatment in patients with rhabdomyosarcoma (RMS) involves a combination of surgery, chemotherapy, and radiation therapy. Because the treatment plan is complicated and prolonged and because many medical issues are unique to pediatric oncology, all patients should be referred (at least initially) to a center with personnel who are skilled in caring for children with cancer.

At present, patients are categorized according to their risk, which takes into account the location of the tumor and the histologic and surgical results. Low-risk patients are those who have the best prognosis, whereas intermediate-risk or high-risk patients have an increased risk of having relapses and incurable disease. To separate the features into meaningful categories, patients are assigned to both a surgicopathologic clinical group (Roman numeral) and a stage (Arabic numeral). All patients with metastatic disease (group IV, stage 4) are considered high risk, except children and adolescents younger than 14 years with embryonal rhabdomyosarcoma (ERMS). In some studies, these patients appear to do better than others, for unknown reasons. Although all patients require chemotherapy, regimens vary depending on the stage and group.

• Surgicopathologic (clinical) group (Groups I-III are for localized disease).

  • Group I - Tumor completely removed

  • Group II - Microscopic residual tumor, involved regional nodes, or both

  • Group III - Gross residual tumor

  • Group IV - Distant metastatic disease

• Tumor, nodes, and metastases (TNM) staging system

  • Tumor - Confined to the site of origin (T1) or extends beyond the site of origin (T2)

  • Node - No regional node involvement (N0), regional node involvement (N1), or nodes unknown (NX)

  • Metastasis - No metastasis (M0), or metastases present at diagnosis (M1)

• RMS staging system

  • Stage 1 - Orbit, head, and/or neck (not parameningeal) involvement, and involvement of the GU tract (not bladder or prostate)

  • Stage 2 - Other locations, N0 or NX

  • Stage 3 - Other locations, N1 if the tumor is less than 5 cm or N0 or NX if the tumor more than 5 cm

  • Stage 4 - Any site with distant metastases

• Low-risk patients are those with the following embryonal histology:

  • Stages 1-3 in groups I-II (or III for only orbital involvement)

  • Stage 1 in group III

A study by Weigel et al that enrolled 109 patients, mostly 20 years of age or younger, with stage IV (metastatic) rhabdomyosarcoma, looked to improve outcome of patients with metastatic rhabdomyosarcoma by dose intensification with interval compression, use of the most active agents determined in phase II window studies, and use of irinotecan as a radiation sensitizer. The study reported a 3-year event-free survival (EFS) rate of 38%, and an overall survival rate of 56% which was below the primary objective to improve the 3-year EFS to 55%. Despite those setbacks, the study did find that patients with metastatic rhabdomyosarcoma with one or no Oberlin risk factor had an improved 3-year EFS of 69% on ARST0431 compared with a historical cohort from pooled European and US studies. ^{[24, 25]}

In a phase II trial of 87 patients with rhabdomyosarcoma who had experienced a first relapse or disease progression and whose prognosis was unfavorable, temsirolimus (Torisel) proved superior to bevacizumab (Avastin) as add-on therapy. At 6 months, event-free survival in these patients, whose prognosis was unfavorable, was 65% with temsirolimus versus 50% with bevacizumab, when these agents were added to a chemotherapy regimen of vinorelbine and cyclophosphamide. ^{[26, 27]}  At 6 months, the response rate also favored temsirolimus (47.4% vs 27.5%) as did the number of complete responses (5 vs 4) and the number of partial responses (13 vs 7). The rate of progressive disease was also better with temsirolimus (28% vs 10%). ^{[26, 27]}

In a second study of 461 children with intermediate-risk rhabdomyosarcoma, adding irinotecan to combination treatment with vincristine, dactinomycin, and cyclophosphamide (VAC) did not improve overall or event-free survival. However, the regimen containing irinotecan resulted in a lower rate of hematologic toxicity and cumulative dose of cyclophosphamide. ^{[26, 28]}

A randomized, controlled study by Bisogno et al demonstrated that the addition of 6 months of maintenance chemotherapy with low-dose vinorelbine/cyclophosphamide improved the 5-year overall survival rate for patients with high-risk RMS from 73.7% to 86.5%, or an absolute 13% increase. Over a 10-year period, 371 patients aged 6 months to 21 years were enrolled in the trial. ^{[29, 30]}

Surgical management of rhabdomyosarcoma varies depending on the location of the tumor. If feasible, remove tumors promptly and without unacceptable disfigurement or loss of function. Even if metastatic disease is present, surgical excision of the primary site should be performed, if possible. The surgical result helps determine the clinical grouping to be used for treatment stratification.

Surgical guidelines for the various sites can be found in the protocols of the Children's Oncology Group Soft Tissue Sarcoma Committee (formerly, Intergroup Rhabdomyosarcoma Study Group [IRSG]) and are beyond the scope of this article. However, common principles are noteworthy and described below.

• Primary tumor

  • Because relapses often occur at the site of the original primary tumor, adequate local control is essential.

  • Data from Europe suggest that chemotherapy alone can be effective for achieving adequate local control in some patients who have a complete response of the primary tumor. However, surgery and/or irradiation are needed for local control of residual disease.

  • If possible, complete excision of the lesion should be performed with a wide (2-cm) margin of healthy tissue. Wide margins of normal tissue often are impossible to achieve at certain sites, such as the head and neck. If margins are narrow, obtain several biopsy specimens from the surrounding tissue to assess for residual local disease.

  • For tumors that cannot be excised at diagnosis, a second-look procedure may be appropriate after a period of chemotherapy (usually 12 wk).

• Lymph nodes

  • Regional lymph nodes that appear to be clinically or radiographically involved should be sampled to determine the clinical group and the need for later radiation therapy.

  • Radical node dissection is not appropriate.

  • Axillary and femoral node sampling should be performed for lesions in the extremities, even if clinical findings are negative because of the high prevalence of metastatic disease arising from extremity lesions.

  • The use of sentinel node biopsy instead of lymph node sampling is being explored. ^[31]

The care of patients with rhabdomyosarcoma is complicated and extensive and touches all aspects of their lives. Initial evaluation and treatment should be undertaken at a center with a comprehensive program for children with cancer.

• Radiotherapist

  • Most patients with rhabdomyosarcoma require radiotherapy to achieve adequate local control, though radiotherapy is not usually performed until after initial surgical resection and the start of chemotherapy. Exceptions are patients with parameningeal primary tumors, for which initial radiotherapy has been shown to be beneficial.

  • A radiotherapist familiar with the requirements for clinical trials should be consulted at diagnosis for most patients in North America to determine if they have any special needs for treatment planning.

  • In initial studies, new techniques such as intensity-modulated radiotherapy (IMRT) and proton-beam radiotherapy appear to achieve adequate tumor control with reduced exposure to normal tissues. ^{[32, 33]}

  • There is a high risk of local recurrence in patients with group II disease (microscopic residual disease) if prescribed radiotherapy is omitted or reduced, as demonstrated by Million et al. ^[34] They noted that more than half the patients who relapsed at the original tumor site received nonstandard radiation therapy, and, of these, three quarters died of their disease.

• Psychosocial team: The psychosocial team is critical for helping patients and families cope with the stresses associated with the diagnosis and treatment of cancer. The social worker usually plays an intimate role in helping families navigate complicated insurance and financial issues.

• Dentist: A thorough dental evaluation is required to identify potential problems that may arise during chemotherapy.

• Pediatric therapists: Activities and therapy can be critical in helping the patient through the phases of medical therapy.

Diet

No specific dietary recommendations are needed. However, patients may require nasogastric feedings or parenteral nutrition during some phases of chemotherapy. This is especially true for patients with primary tumors in head and neck, who may have severe mucositis after radiation therapy.

Activity

No specific activity limitations are required. The patient's activity is restricted only as the location of the tumor and the adverse effects of treatment dictate.