Treatment Options for Progressive or Recurrent Childhood Rhabdomyosarcoma

Surgery. Treatment for local or regional recurrence may include wide local excision or aggressive surgical removal of tumor, particularly in the absence of widespread bony metastases.[10,11] Some survivors have also been reported after surgical removal of only one or a few metastases in the lung.[10] A review examined 108 Italian children with bladder or prostate tumors who did not achieve tumor eradication after chemotherapy, with or without RT. The study found that only two factors correlated with inability to achieve progression-free survival (PFS) at 5 or more years: initial histology showing undifferentiated sarcoma (P = .008) and diameter of the surgically removed tumor exceeding 5 cm. Positive tumor margins at the salvage operation did not predict ultimate failure.[12][Level of evidence C2]

RT. RT should be considered for patients with rhabdomyosarcoma who have not already received RT in the area of recurrence, or selectively for those who have received previous RT, particularly for those in whom surgical excision is not possible. RT techniques may include external beam in fractionated or hypofractionated courses (e.g., stereotactic body radiation therapy, CyberKnife, or brachytherapy). The rationale is primarily to improve local control that can translate into a better quality of life. An impact on OS is unlikely because of the metastatic disease that often occurs. Even a benefit on local control is difficult to unequivocally demonstrate because of small patient numbers in available reports. For example, in a multi-institutional study of 23 patients with local relapse only (n = 19) or local relapse with distant failure (n = 4) who were managed with (n = 12) or without (n = 11) re-irradiation, the local failure-free survival and OS in re-irradiated versus unirradiated patients was 19.6 months versus 12.4 months (P = .1) and 26.1 months versus 18.8 months (P = .46). In this report, patients with favorable site and Group 3 disease local (only) failure, and/or embryonal histology had improved 3-year local relapse-free survival rates with re-irradiation (62.3% vs. 40%; P = .11).[13]

Chemotherapy. A German study found that treatment with multiagent chemotherapy incorporating carboplatin and etoposide, plus RT, was efficacious for patients with embryonal rhabdomyosarcoma (5-year event-free survival [EFS] rate, 41%), but it was less effective for patients with alveolar rhabdomyosarcoma (5-year EFS rate, 25%).[14] Previously unused, active, single agents or combinations of drugs may also enhance the likelihood of disease control.

Carboplatin and etoposide.[14]

Ifosfamide, carboplatin, and etoposide.[15,16]

Cyclophosphamide and topotecan.[17]

Topotecan, carboplatin, cyclophosphamide, and etoposide.[18]

Topotecan, carboplatin, cyclophosphamide, and etoposide.[18]

In a 2018 Italian study, 38 patients with recurrent or refractory rhabdomyosarcoma were treated with topotecan, carboplatin, cyclophosphamide, and etoposide.[18][Level of evidence C1]

Topotecan, carboplatin, cyclophosphamide, and etoposide.[18] › In a 2018 Italian study, 38 patients with recurrent or refractory rhabdomyosarcoma were treated with topotecan, carboplatin, cyclophosphamide, and etoposide.[18][Level of evidence C1]

Nine of 32 patients had a complete or partial response. However, the 5-year OS rate was 17%, and the PFS rate was 14%.

Single-agent vinorelbine.[19,20]

Single-agent vinorelbine.[19,20]

In one phase II trial, 4 of 11 patients with recurrent rhabdomyosarcoma responded to single-agent vinorelbine.[19]

Single-agent vinorelbine.[19,20]

In another trial, 6 of 12 young patients (aged 9–29 years) had a partial response.[20]

Single-agent vinorelbine.[19,20]

In a meta-analysis of five studies, patients with relapsed alveolar rhabdomyosarcoma responded better to vinorelbine, either alone or in combination with other agents, than patients with relapsed embryonal and unclassified rhabdomyosarcoma.[21]

Vinorelbine and cyclophosphamide.[22,23]

Vinorelbine and cyclophosphamide.[22,23]

In a pilot study, three of nine patients with rhabdomyosarcoma had an objective response.[22]

Vinorelbine and cyclophosphamide.[22,23]

In a phase II study in France (N = 50), children with recurrent or refractory rhabdomyosarcoma were treated with vinorelbine and low-dose oral cyclophosphamide.[23][Level of evidence C3]

Vinorelbine and cyclophosphamide.[22,23] › In a phase II study in France (N = 50), children with recurrent or refractory rhabdomyosarcoma were treated with vinorelbine and low-dose oral cyclophosphamide.[23][Level of evidence C3]

Four complete responses and 14 partial responses were observed, for an objective response rate of 36%.

Gemcitabine and docetaxel.[24]

Gemcitabine and docetaxel.[24]

In a single-institution trial, two patients (N = 5) with recurrent rhabdomyosarcoma achieved an objective response.[24]

Sirolimus.[25]

Topotecan, vincristine, and doxorubicin.[26][Level of evidence C3]

Vincristine, irinotecan, and temozolomide.[27-29]

Vincristine, irinotecan, and temozolomide.[27-29]

One of four patients with recurrent alveolar rhabdomyosarcoma had a complete radiographic response sustained for 27 weeks with no grade 3 or 4 toxicities.[27]; [28][Level of evidence C2]

Vincristine, irinotecan, and temozolomide.[27-29]

A group of 15 patients with relapsed rhabdomyosarcoma were treated with vincristine, irinotecan, and temozolomide. Many of the patients had received previous relapse therapy.[29][Level of evidence C1]

Vincristine, irinotecan, and temozolomide.[27-29] › A group of 15 patients with relapsed rhabdomyosarcoma were treated with vincristine, irinotecan, and temozolomide. Many of the patients had received previous relapse therapy.[29][Level of evidence C1]

There were no complete or partial remissions; four patients had stable disease, and 11 patients had progressive disease.

Vincristine, irinotecan, doxorubicin, cyclophosphamide, etoposide, ifosfamide, and tirapazamine.[30]

Vincristine, irinotecan, doxorubicin, cyclophosphamide, etoposide, ifosfamide, and tirapazamine.[30]

In 2019, the Children's Oncology Group (COG) reported three trials of patients with recurrent or refractory rhabdomyosarcoma with specific criteria for eligibility. Unfavorable-risk patients with measurable disease could undergo a 6-week phase II window study of vincristine and irinotecan (VI). Patients with at least a partial response then received 44 weeks of assigned chemotherapy. Unfavorable-risk patients without measurable disease, no radiographic response, or refusal to go on window therapy received 31 weeks of multiagent chemotherapy plus tirapazamine.[30][Level of evidence C1]

Vincristine, irinotecan, doxorubicin, cyclophosphamide, etoposide, ifosfamide, and tirapazamine.[30] › In 2019, the Children's Oncology Group (COG) reported three trials of patients with recurrent or refractory rhabdomyosarcoma with specific criteria for eligibility. Unfavorable-risk patients with measurable disease could undergo a 6-week phase II window study of vincristine and irinotecan (VI). Patients with at least a partial response then received 44 weeks of assigned chemotherapy. Unfavorable-risk patients without measurable disease, no radiographic response, or refusal to go on window therapy received 31 weeks of multiagent chemotherapy plus tirapazamine.[30][Level of evidence C1]

Favorable-risk patients had a 3-year failure-free survival (FFS) rate of 79% and an OS rate of 84%.

Vincristine, irinotecan, doxorubicin, cyclophosphamide, etoposide, ifosfamide, and tirapazamine.[30] › In 2019, the Children's Oncology Group (COG) reported three trials of patients with recurrent or refractory rhabdomyosarcoma with specific criteria for eligibility. Unfavorable-risk patients with measurable disease could undergo a 6-week phase II window study of vincristine and irinotecan (VI). Patients with at least a partial response then received 44 weeks of assigned chemotherapy. Unfavorable-risk patients without measurable disease, no radiographic response, or refusal to go on window therapy received 31 weeks of multiagent chemotherapy plus tirapazamine.[30][Level of evidence C1]

Thirty patients with unfavorable-risk disease who were not treated with VI had a 3-year FFS rate of 21% and an OS rate of 39%.

Irinotecan with or without vincristine and with or without temozolomide.[31-36]

Irinotecan with or without vincristine and with or without temozolomide.[31-36]

A COG prospective, randomized, up-front window trial, COG-ARST0121, compared VI (20 mg/m2/d) daily × 5 days for 4 weeks per 6-week treatment cycle (Regimen 1A) and irinotecan (50 mg/m2/d) daily × 5 days for 2 weeks per 6-week treatment cycle (Regimen 1B) in poor-risk patients with relapsed or progressive rhabdomyosarcoma.[35][Level of evidence A1]

Irinotecan with or without vincristine and with or without temozolomide.[31-36] › A COG prospective, randomized, up-front window trial, COG-ARST0121, compared VI (20 mg/m2/d) daily × 5 days for 4 weeks per 6-week treatment cycle (Regimen 1A) and irinotecan (50 mg/m2/d) daily × 5 days for 2 weeks per 6-week treatment cycle (Regimen 1B) in poor-risk patients with relapsed or progressive rhabdomyosarcoma.[35][Level of evidence A1]

At 1 year after initiation of treatment for recurrence, the FFS rate was 37% and the OS rate was 55% for Regimen 1A.

Irinotecan with or without vincristine and with or without temozolomide.[31-36] › A COG prospective, randomized, up-front window trial, COG-ARST0121, compared VI (20 mg/m2/d) daily × 5 days for 4 weeks per 6-week treatment cycle (Regimen 1A) and irinotecan (50 mg/m2/d) daily × 5 days for 2 weeks per 6-week treatment cycle (Regimen 1B) in poor-risk patients with relapsed or progressive rhabdomyosarcoma.[35][Level of evidence A1]

At 1 year after initiation of treatment for recurrence, the FFS rate was 38% and OS rate was 60% for Regimen 1B.

Irinotecan with or without vincristine and with or without temozolomide.[31-36] › A COG prospective, randomized, up-front window trial, COG-ARST0121, compared VI (20 mg/m2/d) daily × 5 days for 4 weeks per 6-week treatment cycle (Regimen 1A) and irinotecan (50 mg/m2/d) daily × 5 days for 2 weeks per 6-week treatment cycle (Regimen 1B) in poor-risk patients with relapsed or progressive rhabdomyosarcoma.[35][Level of evidence A1]

The Soft Tissue Sarcoma Committee of the COG recommended the more convenient Regimen 1B for further investigation.

Irinotecan with or without vincristine and with or without temozolomide.[31-36]

In a European Soft Tissue Sarcoma Study Group study, 120 patients with recurrent or refractory rhabdomyosarcoma were randomly assigned to receive either VI or vincristine, irinotecan, and temozolomide (VIT).[37][Level of evidence A1]

Irinotecan with or without vincristine and with or without temozolomide.[31-36] › In a European Soft Tissue Sarcoma Study Group study, 120 patients with recurrent or refractory rhabdomyosarcoma were randomly assigned to receive either VI or vincristine, irinotecan, and temozolomide (VIT).[37][Level of evidence A1]

The objective response rate was 44% (24 of 55 evaluable patients) for patients who received VIT, compared with 31% (18 of 58) for patients who received VI.

Irinotecan with or without vincristine and with or without temozolomide.[31-36] › In a European Soft Tissue Sarcoma Study Group study, 120 patients with recurrent or refractory rhabdomyosarcoma were randomly assigned to receive either VI or vincristine, irinotecan, and temozolomide (VIT).[37][Level of evidence A1]

The patients in the VIT arm achieved significantly better OS (adjusted hazard ratio [HR], 0.55; 95% confidence interval [CI], 0.35–0.84; P = .006), than patients on the VI arm, with consistent PFS results (adjusted HR, 0.68; 95% CI, 0.46–1.01; P = .059).

Irinotecan with or without vincristine and with or without temozolomide.[31-36] › In a European Soft Tissue Sarcoma Study Group study, 120 patients with recurrent or refractory rhabdomyosarcoma were randomly assigned to receive either VI or vincristine, irinotecan, and temozolomide (VIT).[37][Level of evidence A1]

Overall, patients experienced grade 3 or greater adverse events more frequently with VIT than VI (98% vs. 78%, respectively; P = .009), including a significant excess of hematological toxicity (81% vs. 61%; P = .025).

Temsirolimus, irinotecan, and temozolomide.[38]

Temsirolimus, irinotecan, and temozolomide.[38]

In a phase I trial of these agents, four patients had rhabdomyosarcoma.[38]

Temsirolimus, irinotecan, and temozolomide.[38] › In a phase I trial of these agents, four patients had rhabdomyosarcoma.[38]

The regimen was well tolerated.

Temsirolimus, irinotecan, and temozolomide.[38] › In a phase I trial of these agents, four patients had rhabdomyosarcoma.[38]

One patient had a partial response, and another patient had stable disease.

Temsirolimus, cyclophosphamide, and vinorelbine.[39]

Temsirolimus, cyclophosphamide, and vinorelbine.[39]

A COG randomized, phase II, selection-design study of patients with relapsed rhabdomyosarcoma compared bevacizumab with temsirolimus, both administered with cyclophosphamide and vinorelbine.[40][Level of evidence C2]

Temsirolimus, cyclophosphamide, and vinorelbine.[39] › A COG randomized, phase II, selection-design study of patients with relapsed rhabdomyosarcoma compared bevacizumab with temsirolimus, both administered with cyclophosphamide and vinorelbine.[40][Level of evidence C2]

Patients on the temsirolimus arm had improved EFS (P = .003). The 6-month and 12-month EFS rates in the temsirolimus arm were 65% (95% CI, 44%–79%) and 40.5% (95% CI, 25.6%–55.3%), respectively, compared with 50% (95% CI, 32%–66%) and 18.2% (95% CI, 6.8%–29.6%) in the bevacizumab arm.

Temsirolimus, cyclophosphamide, and vinorelbine.[39] › A COG randomized, phase II, selection-design study of patients with relapsed rhabdomyosarcoma compared bevacizumab with temsirolimus, both administered with cyclophosphamide and vinorelbine.[40][Level of evidence C2]

The complete response rate (complete remission plus partial remission) was higher on the temsirolimus arm (47%) than on the bevacizumab arm (28%). The difference was not statistically significant at the 0.05 level (P = .12).

Temsirolimus, cyclophosphamide, and vinorelbine.[39] › A COG randomized, phase II, selection-design study of patients with relapsed rhabdomyosarcoma compared bevacizumab with temsirolimus, both administered with cyclophosphamide and vinorelbine.[40][Level of evidence C2]

These results are the basis for the subsequent COG trial randomizing the use of temsirolimus for newly diagnosed patients with nonmetastatic rhabdomyosarcoma (ARST1431 [NCT02567435]).

Adriamycin, carboplatin, cyclophosphamide, topotecan, vincristine, and etoposide (ACCTTIVE) or topotecan, etoposide, carboplatin, and cyclophosphamide (TECC).

Adriamycin, carboplatin, cyclophosphamide, topotecan, vincristine, and etoposide (ACCTTIVE) or topotecan, etoposide, carboplatin, and cyclophosphamide (TECC).

The Cooperative Weichteilsarkom Studiengruppe (CWS) examined second-line treatment for patients who had recurrence of rhabdomyosarcoma after initial treatment. Second-line chemotherapy based on anthracyclines (ACCTTIVE) was recommended for patients in initial low-risk, standard-risk, and high-risk groups after their original treatment did not include anthracyclines. TECC was recommended for patients in the very high-risk group after their initial treatment included anthracycline-based regimens. The risk groups included low risk, standard risk, high risk, and very high risk.[41]

Adriamycin, carboplatin, cyclophosphamide, topotecan, vincristine, and etoposide (ACCTTIVE) or topotecan, etoposide, carboplatin, and cyclophosphamide (TECC). › The Cooperative Weichteilsarkom Studiengruppe (CWS) examined second-line treatment for patients who had recurrence of rhabdomyosarcoma after initial treatment. Second-line chemotherapy based on anthracyclines (ACCTTIVE) was recommended for patients in initial low-risk, standard-risk, and high-risk groups after their original treatment did not include anthracyclines. TECC was recommended for patients in the very high-risk group after their initial treatment included anthracycline-based regimens. The risk groups included low risk, standard risk, high risk, and very high risk.[41]

Initial risk stratification, pattern/time to relapse, and achievement of second complete remission were significant prognostic factors for postrelapse survival.

Adriamycin, carboplatin, cyclophosphamide, topotecan, vincristine, and etoposide (ACCTTIVE) or topotecan, etoposide, carboplatin, and cyclophosphamide (TECC). › The Cooperative Weichteilsarkom Studiengruppe (CWS) examined second-line treatment for patients who had recurrence of rhabdomyosarcoma after initial treatment. Second-line chemotherapy based on anthracyclines (ACCTTIVE) was recommended for patients in initial low-risk, standard-risk, and high-risk groups after their original treatment did not include anthracyclines. TECC was recommended for patients in the very high-risk group after their initial treatment included anthracycline-based regimens. The risk groups included low risk, standard risk, high risk, and very high risk.[41]

The 5-year OS rates were 80% (± 21%) for patients with relapsed disease in the standard-risk group, 20% (± 16%) for patients in the high-risk group, and 13% (± 23%) for patients in the very high-risk group (P = .008).