David A. Rodeberg

Update on rhabdomyosarcoma

Rhabdomyosarcoma (RMS) is a malignant childhood tumor of mesenchymal origin that currently has a greater than 70% overall 5-year survival. Multimodality treatment is determined by risk stratification according to pretreatment stage, postoperative group, histology, and site of the primary tumor. Pretreatment staging is dependent on primary tumor site, size, regional lymph node status, and presence of metastases. Unique to RMS is the concept of postoperative clinical grouping that assesses the completeness of disease resection and takes into account lymph node evaluation. At all tumor sites, the clinical grouping, and therefore completeness of resection, is an independent predictor of outcome. Overall, the prognosis for RMS is dependent on primary tumor site, patient age, completeness of resection, extent of disease, including the presence and number of metastatic sites and histology and biology of the tumor cells. Therefore, the surgeon plays a vital role in RMS by contributing to risk stratification for treatment, local control of the primary tumor, and outcome. The current state-of-the-art treatment is determined by treatment protocols developed by the Soft Tissue Sarcoma Committee of the childrens Oncology Group.

Prognostic Significance and Tumor Biology of Regional Lymph Node Disease in Patients With Rhabdomyosarcoma: A Report From the Children's Oncology Group

PURPOSEnRegional lymph node disease (RLND) is a component of the risk-based treatment stratification in rhabdomyosarcoma (RMS). The purpose of this study was to determine the contribution of RLND to prognosis for patients with RMS.nnnPATIENTS AND METHODSnPatient characteristics and survival outcomes for patients enrolled onto Intergroup Rhabdomyosarcoma Study IV (N = 898, 1991 to 1997) were evaluated among the following three patient groups: nonmetastatic patients with clinical or pathologic negative nodes (N0, 696 patients); patients with clinical or pathologic positive nodes (N1, 125 patients); and patients with a single site of metastatic disease (77 patients).nnnRESULTSnOutcomes for patients with nonmetastatic alveolar N0 RMS were significantly better than for patients with N1 RMS (5-year failure-free survival [FFS], 73% v 43%, respectively; 5-year overall survival [OS], 80% v 46%, respectively; P < .001). Patients with a single site of alveolar metastasis had even worse FFS and OS (23% FFS and OS, P = .01) when compared with patients with N1 RMS; however, the differences was not as large as the differences between patients with N0 RMS and N1 RMS. For embryonal RMS, there was no statistically significant difference in FFS or OS (P = .41 and P = .77, respectively) for patients with N1 versus N0 RMS. Gene array analysis of primary tumor specimens identified that genes associated with the immune system and antigen presentation were significantly increased in N1 versus N0 alveolar RMS.nnnCONCLUSIONnRLND alters prognosis for alveolar but not embryonal RMS. For patients with N1 disease and alveolar histology, outcomes were more similar to distant metastatic disease rather than local disease. Current data suggest that more aggressive therapy for patients with alveolar N1 RMS may be warranted.

Local control with reduced-dose radiotherapy for low-risk rhabdomyosarcoma: a report from the Children's Oncology Group D9602 study

PURPOSEnTo analyze the effect of reduced-dose radiotherapy on local control in children with low-risk rhabdomyosarcoma (RMS) treated in the Childrens Oncology Group D9602 study.nnnMETHODS AND MATERIALSnPatients with low-risk RMS were nonrandomly assigned to receive radiotherapy doses dependent on the completeness of surgical resection of the primary tumor (clinical group) and the presence of involved regional lymph nodes. After resection, most patients with microscopic residual and uninvolved nodes received 36 Gy, those with involved nodes received 41.4 to 50.4 Gy, and those with orbital primary tumors received 45 Gy. All patients received vincristine and dactinomycin, with cyclophosphamide added for patient subsets with a higher risk of relapse in Intergroup Rhabdomyosarcoma Study Group III and IV studies.nnnRESULTSnThree hundred forty-two patients were eligible for analysis; 172 received radiotherapy as part of their treatment. The cumulative incidence of local/regional failure was 15% in patients with microscopic involved margins when cyclophosphamide was not part of the treatment regimen and 0% when cyclophosphamide was included. The cumulative incidence of local/regional failure was 14% in patients with orbital tumors. Protocol-specified omission of radiotherapy in girls with Group IIA vaginal tumors (n = 5) resulted in three failures for this group.nnnCONCLUSIONSnIn comparison with Intergroup Rhabdomyosarcoma Study Group III and IV results, reduced-dose radiotherapy does not compromise local control for patients with microscopic tumor after surgical resection or with orbital primary tumors when cyclophosphamide is added to the treatment program. Girls with unresected nonbladder genitourinary tumors require radiotherapy for postsurgical residual tumor for optimal local control to be achieved.

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

PURPOSEnPatients with metastatic rhabdomyosarcoma (RMS), except those younger than 10 years with embryonal RMS, have an estimated long-term event-free survival (EFS) of less than 20%. The main goal of this study was to improve outcome of patients with metastatic RMS 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.nnnPATIENTS AND METHODSnPatients with metastatic RMS received 54 weeks of therapy: blocks of therapy with vincristine/irinotecan (weeks 1 to 6, 20 to 25, and 47 to 52), interval compression with vincristine/doxorubicin/cyclophosphamide alternating with etoposide/ifosfamide (weeks 7 to 19 and 26 to 34), and vincristine/dactinomycin/cyclophosphamide (weeks 38 to 46). Radiation therapy occurred at weeks 20 to 25 (primary) but was also permitted at weeks 1 to 6 (for intracranial or paraspinal extension) and weeks 47 to 52 (for extensive metastatic sites).nnnRESULTSnOne hundred nine eligible patients were enrolled, with a median follow-up of surviving patients of 3.8 years (3-year EFS for all patients, 38% [95% CI, 29% to 48%]; survival, 56% [95% CI, 46% to 66%]). Patients with one or no Oberlin risk factor (age > 10 years or < 1 year, unfavorable primary site of disease, ≥ three metastatic sites, and bone or bone marrow involvement) had a 3-year EFS of 69% (95% CI, 52% to 82%); high-risk patients with two or more risk factors had a 3-year EFS of 20% (95% CI, 11% to 30%). Toxicity was similar to that on prior RMS studies.nnnCONCLUSIONnPatients with metastatic RMS with one or no Oberlin risk factor had an improved 3-year EFS of 69% on ARST0431 compared with an historical cohort from pooled European and US studies; those with two or more risk factors have a dismal prognosis, and new approaches are needed for this very-high-risk group.

Delayed primary excision with subsequent modification of radiotherapy dose for intermediate-risk rhabdomyosarcoma: a report from the Children's Oncology Group Soft Tissue Sarcoma Committee.

The majority of intermediate‐risk rhabdomyosarcoma (RMS) patients have gross residual disease (Group III) after their first operative procedure. It is currently not known if local control rates can be maintained when, following induction chemotherapy, the radiation therapy (RT) dose is decreased after a delayed primary excision (DPE). To answer this question we evaluated patients enrolled on COG D9803 (1999–2005) who had Group III tumors of the bladder dome, extremity or trunk (thorax, abdomen and pelvis) were candidates for DPE at Week 12 if the primary tumor appeared resectable. RT dose was then adjusted by the completeness of DPE: no evidence of disease 36 Gy, microscopic residual 41.4 Gy and gross residual disease (GRD) 50.4 Gy. A total of 161 Group III patients were evaluated (24 bladder dome, 63 extremity and 74 trunk). Seventy‐three patients (45%) underwent DPE which achieved removal of all gross disease in 61 (84%) who were then eligible for reduced RT dose (43/73 received 36 Gy, 19/73 received 41.4 Gy). The local 5‐year failure rate (0% for bladder dome, 7% for extremity and 20% for trunk) was similar to IRS‐IV, which did not encourage DPE and did not allow for DPE adapted RT dose reduction. In conclusion, DPE was performed in 45% of Group III RMS patients with tumors at select anatomic sites (bladder dome, extremity and trunk) and 84% of those who had DPE were eligible for RT dose reduction. Local control outcomes were similar to historic results with RT alone.

Early response as assessed by anatomic imaging does not predict failure-free survival among patients with Group III rhabdomyosarcoma: A report from the Children’s Oncology Group

BACKGROUNDnThe prognostic significance of response to induction therapy for rhabdomyosarcoma (RMS) by anatomic imaging [computerised tomographic (CT) or magnetic resonance imaging (MRI) scan] is controversial. We previously reported no relationship between early response and failure-free survival (FFS) on Intergroup Rhabdomyosarcoma Study (IRS)-IV. We repeated the same analysis using a more recent clinical trial as an independent cohort of patients with non-metastatic, initially unresected RMS.nnnMETHODSnA total of 338 patients enrolled in Childrens Oncology Group (COG) study D9803 met the inclusion criteria for this analysis: (1) non-metastatic, initially unresected (Group III); (2) embryonal (ERMS) or alveolar (ARMS) histology; (3) documented protocol week 12 response to induction chemotherapy (excluding progressive disease) based on anatomic imaging (CT/MRI) and (4) documented protocol therapy beyond week 12. Response at week 12 was determined by the treating institution as complete response (CR), partial response (PR) or no response (NR). FFS was estimated using the Kaplan-Meier method and comparisons between patient subsets were made using the log-rank test.nnnRESULTSnOverall objective response rate (CR+PR) at week 12 of therapy was 85% and was similar between ERMS and ARMS. FFS was similar among all patients with CR, PR or NR (p=0.49). Restricting the analysis to either ERMS or ARMS, there was no difference in FFS by response within either histology subset (p=0.89 and p=0.08, respectively).nnnCONCLUSIONSnThese findings provide additional evidence that anatomic imaging to assess early response to therapy among patients with RMS does not predict outcome and has questionable use in tailoring subsequent therapy.

Local Control for Intermediate-Risk Rhabdomyosarcoma: Results From D9803 According to Histology, Group, Site, and Size: A Report From the Children's Oncology Group

PURPOSEnTo determine local control according to clinical variables for patients with intermediate-risk rhabdomyosarcoma (RMS) treated on Childrens Oncology Group protocol D9803.nnnPATIENTS AND METHODSnOf 702 patients enrolled, we analyzed 423 patients with central pathology-confirmed group III embryonal (n=280) or alveolar (group III, n=102; group I-II, n=41) RMS. Median age was 5 years. Patients received 42 weeks of VAC (vincristine, dactinomycin, cyclophosphamide) or VAC alternating with VTC (T = topotecan). Local therapy with 50.4 Gy radiation therapy with or without delayed primary excision began at week 12 for group III patients. Patients with group I/II alveolar RMS received 36-41.4 Gy. Local failure (LF) was defined as local progression as a first event with or without concurrent regional or distant failure.nnnRESULTSnAt a median follow-up of 6.6 years, patients with clinical group I/II alveolar RMS had a 5-year event-free survival rate of 69% and LF of 10%. Among patients with group III RMS, 5-year event-free survival and LF rates were 70% and 19%, respectively. Local failure rates did not differ by histology, nodal status, or primary site, though there was a trend for increased LF for retroperitoneal (RP) tumors (P=.12). Tumors ≥5 cm were more likely to fail locally than tumors <5 cm (25% vs 10%, P=.0004). Almost all (98%) RP tumors were ≥5 cm, with no difference in LF by site when the analysis was restricted to tumors ≥5 cm (P=.86).nnnCONCLUSIONnLocal control was excellent for clinical group I/II alveolar RMS. Local failure constituted 63% of initial events in clinical group III patients and did not vary by histology or nodal status. The trend for higher LF in RP tumors was related to tumor size. There has been no clear change in local control over RMS studies, including IRS-III and IRS-IV. Novel approaches are warranted for larger tumors (≥5 cm).

Age-related toxicity in patients with rhabdomyosarcoma: A report from the children's oncology group

On the Fourth Intergroup Rhabdomyosarcoma study, older children experienced excessive neurotoxicity, whereas younger children had increased myelosuppression. The purpose of this study was to determine whether the same pattern of toxicity was seen on the successor study when use of growth factor was required and dosing of chemotherapy was different by performing a retrospective cohort analysis on patients treated on Children’s Oncology Group protocol D9803. Toxicity data were analyzed by stratifying children into 4 age groups. The frequency of grade 3/4 neurotoxicity, myelosuppression, infection, and mucositis was predicted for each age group. The cumulative doses of vincristine and cyclophosphamide administered were measured as percent of protocol-prescribed dose. Adolescents (aged 15+) were more likely to experience neurotoxicity compared with younger patients (odds ratio, 3.6; P<0.0001). There was no difference in myelosuppression, infection, or mucositis. The mean percent protocol-prescribed doses administered for vincristine and cyclophosphamide did not differ much by age group. Adolescents experienced more neurotoxicity with vincristine compared with younger patients. No differences in other toxicities were observed between age groups. As adolescents received at least 85% of protocol-prescribed doses of vincristine, it is difficult to attribute the poorer survival in this age group to inadequate protocol-delivered therapy.

Quality assessment of lymph node sampling in rhabdomyosarcoma: A surveillance, epidemiology, and end results (SEER) program study

BACKGROUNDnLymph node sampling is integral in the management of extremity and paratesticular rhabdomyosarcoma (RMS). The aim of this study was to determine overall surgical compliance with treatment protocols and impact of nodal sampling outcomes in these tumors.nnnMETHODSnA query of the surveillance, epidemiology, and end results program (SEER) database was performed from 2003 to 2008 for patients <19years of age with RMS. Data obtained included demographics, five-year survival and rate of nodal sampling. Analysis was performed utilizing chi-squared, Kaplan-Meier and hazard ratio modeling.nnnRESULTSnOf 537 patients with extremity RMS, nodal sampling was performed in 25.7% (n=138). This lack of nodal sampling had a negative outcome on survival (p=0.004). Sixty five patients with paratesticular RMS aged greater than 10 were identified and also displayed low rates of lymph node sampling (47.7%, n=31). For paratesticular patients, a similar increase in survival was seen in patients who underwent nodal evaluation (p=0.024).nnnCONCLUSIONnLymph node sampling is the standard of care in RMS. However, surgical compliance with treatment protocols is poor. Nodal evaluation correlated significantly with overall survival. These findings suggest a need for improved education among surgeons and oncologists regarding the need lymph node assessment in pediatric oncology patients. Evidence rating/classification: Prognosis study, Level III.

Treatment Approach and Outcomes in Infants with Localized Rhabdomyosarcoma: A Report from the Soft Tissue Sarcoma Committee of the Children's Oncology Group

PURPOSEnFor infants with localized rhabdomyosarcoma who were enrolled on Childrens Oncology Group ARST0331 and ARST0531, local therapy guidelines were provided, but adherence was not mandated because of toxicity concerns. We examined adherence to protocol for local therapy guidelines, treatment variations, and outcomes for these patients.nnnMETHODSnChildren aged ≤24xa0months who were enrolled on ARST0331 and ARST0531 were evaluated. Data were verified through radiologic, surgical, pathologic, and clinical records. Local therapy was assessed for adherence to protocol guidelines, with variations termed individualized local therapy. The subdistribution hazards model assessed local failure, the Kaplan-Meier product limit method assessed event-free survival (EFS) and overall survival, and the log-rank test was used to evaluate prognostic impact.nnnRESULTSnThe median age of the patients was 14xa0months, and 124 patients were eligible. Common primary sites were genitourinary (40%), parameningeal (14%), and the extremities (11%). Most patients had unresected disease (group 3, 64%) and embryonal histology (73%). Fifty-eight percent of patients received radiation therapy at a median of week 12 (weeks 1-45). The median radiation dose was 48.6xa0Gy (30.6-54xa0Gy). Forty-three percent of patients received individualized local therapy (outside protocol guidelines), typically omission or delay of radiation therapy. Delayed primary excision was performed in 28% at a median of week 14 (weeks 7-34). With a median follow-up of 5.6xa0years, the 5-year local failure, EFS, and overall survival rates were 24%, 68%, and 82%, respectively. Local failure was significantly higher (35%) in patients receiving individualized local therapy than in patients who received protocol-specified local therapy (16%; Pxa0=xa0.02). The site of failure was local in 64% of patients, local and distant in 5%, and distant only in 23%. EFS was significantly higher among patients who were aged 12 to 24xa0months, had tumors ≤5xa0cm, had group 1/2 disease, and underwent protocol-specified therapy.nnnCONCLUSIONSnLocal recurrence was the predominant pattern of failure and was more common in those receiving individualized local therapy. De-escalation of effective therapies because of concerns about treatment toxicity should be considered cautiously.