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Local Control of Perineal Rhabdomyosarcoma: Are Current Recommendations Adequate?
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Local Control of Perineal Rhabdomyosarcoma: Are Current Recommendations Adequate? Jerrod T. Heermans MD , John H. Makari MD,FAAP, FACS , Fernando A. Ferrer Jr. MD, FAAP, FACS PII: DOI: Reference:
S0090-4295(19)31013-1 https://doi.org/10.1016/j.urology.2019.11.011 URL 21855
To appear in:
Urology
Received date: Revised date: Accepted date:
2 August 2019 10 November 2019 12 November 2019
Please cite this article as: Jerrod T. Heermans MD , John H. Makari MD,FAAP, FACS , Fernando A. Ferrer Jr. MD, FAAP, FACS , Local Control of Perineal Rhabdomyosarcoma: Are Current Recommendations Adequate?, Urology (2019), doi: https://doi.org/10.1016/j.urology.2019.11.011
This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2019 Published by Elsevier Inc.
Local Control of Perineal Rhabdomyosarcoma: Are Current Recommendations Adequate? Authors: 1.
Jerrod T. Heermans,MD – Corresponding author Division of Urologic Surgery, University of Nebraska Medical Center, Omaha, NE [email protected] ; [email protected] Home Address: 1816 N 49th Ave Omaha, NE 68104 Cell: (972) 207-0889 Work Address: 4400 Emile St. Omaha, NE 68104 (402) 559-4292
2. John H. Makari, MD,FAAP, FACS Section of Pediatric Urology, University of Nebraska Medical Center and Children’s Hospital & Medical Center, Omaha, NE 3. Fernando A. Ferrer, Jr. MD, FAAP, FACS Section of Pediatric Urology, University of Nebraska Medical Center and Children’s Hospital & Medical Center, Omaha, NE
Key Words: Perineal rhabdomyosarcoma; pediatric rhabdomyosarcoma; local control rhabdomyosarocma; soft tissue sarcoma
To whom it may concern: This case report is part of a multiple case report group invited by Dr. Stock and Dr. Nicholas Cost (Pediatric Urologic Oncology Working Group)
Abstract: Rhabdomyosarcoma (RMS) is a rare malignancy that can develop in nearly any soft-tissue of the body. Location of the primary tumor affects treatment strategy and prognosis, and RMS of the perineal areas can be especially difficult to treat successfully. RMS is treated systemically with chemotherapy. Local control options include surgical excision, radiation treatment (RT), or a combination of the two. Treating RMS with RT can be challenging due to the absence of standardized dosage protocols, along with the presence of conflicting recommendations in the literature. Each case of perineal RMS may benefit from a more individualized treatment plan.
Local Control of Perineal Rhabdomyosarcoma: Are Current Recommendations Adequate?
Background: Rhabdomyosarcoma (RMS) in the pediatric population is a rare soft-tissue malignancy that occurs at an incidence rate of 4.7 cases per million in children 0-19 (1). RMS can have a variable prognosis, although the past several decades of research has led to a significant increase in 5-year and overall cure rates. The cure rate for localized RMS was previously 25% or lower in 1970, but has improved to 70% or better with the use of multimodal treatment regimens including surgery, multiagent chemotherapy, and radiation therapy (2). Advances in treatment options and specific protocols have improved outcomes significantly over time, but there remains specific subsets of patients with poorer prognoses due to anatomic and histologic considerations. Genetic anomalies including chromosomal translocations have also been found to have prognostic value, and may predict the efficacy of specific systemic therapies (2). Additionally, the issue of the best way to attain local control remains controversial. Rhabdomyosarcoma of the perineal or perianal area is an uncommon diagnosis, and has been shown to have a much more discouraging prognosis (3). Additional factors that carry a poor prognosis for even-free and overall survival include alveolar histology, age greater than 10 years, tumor greater 5 cm at the time of diagnosis, and presence of pathologic lymph regional or distant lymph nodes at time of diagnosis (4,5,6,7). Because of the rarity and variability of each individual case of RMS, there are multiple academic cooperatives in the US and abroad that catalogue cases, research advancements in treatment, and report outcomes.
Case Report:
A 15 year old male originally presented to his PCP with a 6 week history of enlarging perineal mass and a newly enlarging right inguinal mass. He did not disclose the presence of the mass until it became uncomfortable to sit down and alerted his parents at this time. After consultation with pediatric oncology, a CT chest, abdomen, and pelvis was performed which demonstrated a 10.3 cm solid perineal mass with bilateral inguinal lymphadenopathy, the largest on the right measuring 5.8 cm (Figure 1a). The chest CT was negative for distant metastasis. The radiographic findings were suspicious for rhabdomyosarcoma of genitourinary origin. He underwent whole body PET/CT , pelvic MRI (Figure 1b), bilateral bone marrow aspiration, needle core biopsy of right inguinal mass, and port placement. Biopsy results revealed rhabdomyosarcoma, alveolar subtype. Additional testing confirmed fusion-positive tumor with FOXO1 rearrangement, and CDK4 amplification. MRI suggested origin from the posterior aspect of the penile base/corpus spongiosum. He was classified as intermediate risk and enrolled in COG clinical trial ARST 1431; he was randomized to arm A. He received Vincristine, Dactinomycin, and Cyclophosphamide (VAC) alternating with Vincristine and Irinotecan (VI). After 9 weeks of chemotherapy (3 cycles) he then underwent repeat imaging. PET/CT and MRI showed no evidence of disease with complete tumor response (Figure 2). Pediatric Urology was then consulted regarding the role of surgical treatment. Due to the absence of any visible tumor on imaging, surgical intervention was not recommended. During this consultation, it was recommended the patient receive full dose radiation of 50.4 Gy to the primary and metastatic sites. This recommendation deviates from the COG ARST 1431 protocol that suggests reduced radiation dosage of 36 Gy to primary and metastatic sites, in the setting of complete response after chemotherapy. After the decision was made to proceed with this alternative radiation prescription, he was taken out of the clinical trial, and underwent full dose proton beam radiation. A total of 50.4 Gy was delivered to the perineum and bilateral inguinal node beds. He then resumed VAC/VI chemotherapy. His most recent imaging, performed 15-months after diagnosis, and 4 months after completing treatment shows no evidence of recurrence.
Discussion: The patient discussed in this case report presented with advanced RMS in an uncommon location. This patient has multiple high-risk features including: positive lymph node status, age >10 years, translocation
positive alveolar histology, and a large primary tumor at presentation. The data presented by Casey et al would estimate both event-free survival and overall survival at 13% at 5 years when considering this particular clinical scenario (5). When considering a treatment course for this individual patient, an established clinical trial that accounted for the numerous poor prognostic features in this rare location did not exist. Multiple chemotherapy regimens have been shown to be effective in the initial treatment of RMS. There is, however, controversy in the literature regarding recommendations for local control. Many protocols aim to limit radiation because of its long term morbidity. In our patient, where surgical resection was not feasible, high dose RT played a crucial role in treatment because of the anticipated poor outcome associated with his disease and location. Wharam et al demonstrated that the presence of positive lymph nodes at the time of diagnosis confers a higher risk of local and distant failure after radiotherapy in patients with group III RMS, compared with lymph node negative patients (7). With unfavorable histology, advanced age, and bilateral pathologic regional lymph nodes, higher dose RT to the affected areas appeared indicated. The patient population included in the study by Casey et al correlated most closely with our patient. Within this cohort, only one patient that had received full dose (50.4 Gy) nodal irradiation experienced regional failure in an area within the irradiated field (5). Fuchs et al published results from the German Cooperative (CWS) trials showing a clinically significant 19% improvement in 5-year event free survival (EFS) in patients receiving more than 36 Gy compared to those receiving less than 36 Gy (8). The COG ARST1431 algorithm prescribes RT with a dose of 36 Gy to regional nodes with NED following chemotherapy induction. Review of pertinent literature closely correlated to the clinical scenario of interest led to the recommendation to deviate from this protocol and proceed with 50.4 Gy to all sites. Perineal RMS is a difficult malignancy to successfully manage, and continued discussion regarding the best approach to each individual case is warranted.
Sources: 1. Howlader N, Noone AM, Krapcho M, Miller D, Bishop K, Altekruse SF, Kosary CL, Yu M, Ruhl J, Tatalovich Z, Mariotto A, Lewis DR, Chen HS, Feuer EJ, Cronin KA (eds). SEER Cancer Statistics Review, 1975-2013, National Cancer Institute. Bethesda, MD, https://seer.cancer.gov/archive/csr/1975_2013/, based on November 2015 SEER data submission, posted to the SEER web site, April 2016. 2. Pappo, A. S., Shapiro, D. N., Crist, W. M., & Maurer, H. M. (1995). Biology and therapy of pediatric rhabdomyosarcoma. Journal of clinical oncology, 13(8), 2123-2139. 3. Blakely, M. L., Andrassy, R. J., Raney, R. B., Anderson, J. R., Wiener, E. S., Rodeberg, D. A., ... & Crist, W. M. (2003). Prognostic factors and surgical treatment guidelines for children with rhabdomyosarcoma of the perineum or anus: a report of Intergroup Rhabdomyosarcoma Studies I through IV, 1972 through 1997. Journal of pediatric surgery, 38(3), 347-353. 4. Meza, J. L., Anderson, J., Pappo, A. S., & Meyer, W. H. (2006). Analysis of prognostic factors in patients with nonmetastatic rhabdomyosarcoma treated on intergroup rhabdomyosarcoma studies III and IV: the Children's Oncology Group. J Clin Oncol, 24(24), 3844-51. 5. Casey, D. L., Wexler, L. H., LaQuaglia, M. P., Meyers, P. A., & Wolden, S. L. (2014). Patterns of failure for rhabdomyosarcoma of the perineal and perianal region. International Journal of Radiation Oncology* Biology* Physics, 89(1), 82-87. 6. Okamura, K., Yamamoto, H., Ishimaru, Y., Takayasu, H., Otani, Y., Yamagishi, J., ... & Ikeda, H. (2006). Clinical characteristics and surgical treatment of perianal and perineal rhabdomyosarcoma:
analysis of Japanese patients and comparison with IRSG reports. Pediatric surgery international, 22(2), 129-134. 7. Wharam, M. D., Meza, J., Anderson, J., Breneman, J. C., Donaldson, S. S., Fitzgerald, T. J., ... & Meyer, W. H. (2004). Failure pattern and factors predictive of local failure in rhabdomyosarcoma: a report of group III patients on the third Intergroup Rhabdomyosarcoma Study. Journal of clinical oncology, 22(10), 1902-1908. 8.
Fuchs, Joerg; Dantonello, Tobias M; Blumenstock, Gunnar; Kosztyla, Daniel; Klingebiel, Thomas;
Leuschner, Ivo; Schuck, Andreas; Niggli, Felix K; Koscielniak, Ewa; Seitz, Guido (2014). Treatment and outcome of patients suffering from perineal/perianal rhabdomyosarcoma: results from the cws trialsretrospective clinical study. Annals of Surgery, 259(6):1166-1172.
Figure 1 Pre-treatment CT saggital (A) and pre-treatment MRI coronal (B)
A
B
Figure 2 Post-treatment CT Axial (A) and post-treatment MRI coronal (B)
A
B
Local Control of Perineal Rhabdomyosarcoma: Are Current Recommendations Adequate? Jerrod T. Heermans MD , John H. Makari MD,FAAP, FACS , Fernando A. Ferrer Jr. MD, FAAP, FACS PII: DOI: Reference:
S0090-4295(19)31013-1 https://doi.org/10.1016/j.urology.2019.11.011 URL 21855
To appear in:
Urology
Received date: Revised date: Accepted date:
2 August 2019 10 November 2019 12 November 2019
Please cite this article as: Jerrod T. Heermans MD , John H. Makari MD,FAAP, FACS , Fernando A. Ferrer Jr. MD, FAAP, FACS , Local Control of Perineal Rhabdomyosarcoma: Are Current Recommendations Adequate?, Urology (2019), doi: https://doi.org/10.1016/j.urology.2019.11.011
This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2019 Published by Elsevier Inc.
Local Control of Perineal Rhabdomyosarcoma: Are Current Recommendations Adequate? Authors: 1.
Jerrod T. Heermans,MD – Corresponding author Division of Urologic Surgery, University of Nebraska Medical Center, Omaha, NE [email protected] ; [email protected] Home Address: 1816 N 49th Ave Omaha, NE 68104 Cell: (972) 207-0889 Work Address: 4400 Emile St. Omaha, NE 68104 (402) 559-4292
2. John H. Makari, MD,FAAP, FACS Section of Pediatric Urology, University of Nebraska Medical Center and Children’s Hospital & Medical Center, Omaha, NE 3. Fernando A. Ferrer, Jr. MD, FAAP, FACS Section of Pediatric Urology, University of Nebraska Medical Center and Children’s Hospital & Medical Center, Omaha, NE
Key Words: Perineal rhabdomyosarcoma; pediatric rhabdomyosarcoma; local control rhabdomyosarocma; soft tissue sarcoma
To whom it may concern: This case report is part of a multiple case report group invited by Dr. Stock and Dr. Nicholas Cost (Pediatric Urologic Oncology Working Group)
Abstract: Rhabdomyosarcoma (RMS) is a rare malignancy that can develop in nearly any soft-tissue of the body. Location of the primary tumor affects treatment strategy and prognosis, and RMS of the perineal areas can be especially difficult to treat successfully. RMS is treated systemically with chemotherapy. Local control options include surgical excision, radiation treatment (RT), or a combination of the two. Treating RMS with RT can be challenging due to the absence of standardized dosage protocols, along with the presence of conflicting recommendations in the literature. Each case of perineal RMS may benefit from a more individualized treatment plan.
Local Control of Perineal Rhabdomyosarcoma: Are Current Recommendations Adequate?
Background: Rhabdomyosarcoma (RMS) in the pediatric population is a rare soft-tissue malignancy that occurs at an incidence rate of 4.7 cases per million in children 0-19 (1). RMS can have a variable prognosis, although the past several decades of research has led to a significant increase in 5-year and overall cure rates. The cure rate for localized RMS was previously 25% or lower in 1970, but has improved to 70% or better with the use of multimodal treatment regimens including surgery, multiagent chemotherapy, and radiation therapy (2). Advances in treatment options and specific protocols have improved outcomes significantly over time, but there remains specific subsets of patients with poorer prognoses due to anatomic and histologic considerations. Genetic anomalies including chromosomal translocations have also been found to have prognostic value, and may predict the efficacy of specific systemic therapies (2). Additionally, the issue of the best way to attain local control remains controversial. Rhabdomyosarcoma of the perineal or perianal area is an uncommon diagnosis, and has been shown to have a much more discouraging prognosis (3). Additional factors that carry a poor prognosis for even-free and overall survival include alveolar histology, age greater than 10 years, tumor greater 5 cm at the time of diagnosis, and presence of pathologic lymph regional or distant lymph nodes at time of diagnosis (4,5,6,7). Because of the rarity and variability of each individual case of RMS, there are multiple academic cooperatives in the US and abroad that catalogue cases, research advancements in treatment, and report outcomes.
Case Report:
A 15 year old male originally presented to his PCP with a 6 week history of enlarging perineal mass and a newly enlarging right inguinal mass. He did not disclose the presence of the mass until it became uncomfortable to sit down and alerted his parents at this time. After consultation with pediatric oncology, a CT chest, abdomen, and pelvis was performed which demonstrated a 10.3 cm solid perineal mass with bilateral inguinal lymphadenopathy, the largest on the right measuring 5.8 cm (Figure 1a). The chest CT was negative for distant metastasis. The radiographic findings were suspicious for rhabdomyosarcoma of genitourinary origin. He underwent whole body PET/CT , pelvic MRI (Figure 1b), bilateral bone marrow aspiration, needle core biopsy of right inguinal mass, and port placement. Biopsy results revealed rhabdomyosarcoma, alveolar subtype. Additional testing confirmed fusion-positive tumor with FOXO1 rearrangement, and CDK4 amplification. MRI suggested origin from the posterior aspect of the penile base/corpus spongiosum. He was classified as intermediate risk and enrolled in COG clinical trial ARST 1431; he was randomized to arm A. He received Vincristine, Dactinomycin, and Cyclophosphamide (VAC) alternating with Vincristine and Irinotecan (VI). After 9 weeks of chemotherapy (3 cycles) he then underwent repeat imaging. PET/CT and MRI showed no evidence of disease with complete tumor response (Figure 2). Pediatric Urology was then consulted regarding the role of surgical treatment. Due to the absence of any visible tumor on imaging, surgical intervention was not recommended. During this consultation, it was recommended the patient receive full dose radiation of 50.4 Gy to the primary and metastatic sites. This recommendation deviates from the COG ARST 1431 protocol that suggests reduced radiation dosage of 36 Gy to primary and metastatic sites, in the setting of complete response after chemotherapy. After the decision was made to proceed with this alternative radiation prescription, he was taken out of the clinical trial, and underwent full dose proton beam radiation. A total of 50.4 Gy was delivered to the perineum and bilateral inguinal node beds. He then resumed VAC/VI chemotherapy. His most recent imaging, performed 15-months after diagnosis, and 4 months after completing treatment shows no evidence of recurrence.
Discussion: The patient discussed in this case report presented with advanced RMS in an uncommon location. This patient has multiple high-risk features including: positive lymph node status, age >10 years, translocation
positive alveolar histology, and a large primary tumor at presentation. The data presented by Casey et al would estimate both event-free survival and overall survival at 13% at 5 years when considering this particular clinical scenario (5). When considering a treatment course for this individual patient, an established clinical trial that accounted for the numerous poor prognostic features in this rare location did not exist. Multiple chemotherapy regimens have been shown to be effective in the initial treatment of RMS. There is, however, controversy in the literature regarding recommendations for local control. Many protocols aim to limit radiation because of its long term morbidity. In our patient, where surgical resection was not feasible, high dose RT played a crucial role in treatment because of the anticipated poor outcome associated with his disease and location. Wharam et al demonstrated that the presence of positive lymph nodes at the time of diagnosis confers a higher risk of local and distant failure after radiotherapy in patients with group III RMS, compared with lymph node negative patients (7). With unfavorable histology, advanced age, and bilateral pathologic regional lymph nodes, higher dose RT to the affected areas appeared indicated. The patient population included in the study by Casey et al correlated most closely with our patient. Within this cohort, only one patient that had received full dose (50.4 Gy) nodal irradiation experienced regional failure in an area within the irradiated field (5). Fuchs et al published results from the German Cooperative (CWS) trials showing a clinically significant 19% improvement in 5-year event free survival (EFS) in patients receiving more than 36 Gy compared to those receiving less than 36 Gy (8). The COG ARST1431 algorithm prescribes RT with a dose of 36 Gy to regional nodes with NED following chemotherapy induction. Review of pertinent literature closely correlated to the clinical scenario of interest led to the recommendation to deviate from this protocol and proceed with 50.4 Gy to all sites. Perineal RMS is a difficult malignancy to successfully manage, and continued discussion regarding the best approach to each individual case is warranted.
Sources: 1. Howlader N, Noone AM, Krapcho M, Miller D, Bishop K, Altekruse SF, Kosary CL, Yu M, Ruhl J, Tatalovich Z, Mariotto A, Lewis DR, Chen HS, Feuer EJ, Cronin KA (eds). SEER Cancer Statistics Review, 1975-2013, National Cancer Institute. Bethesda, MD, https://seer.cancer.gov/archive/csr/1975_2013/, based on November 2015 SEER data submission, posted to the SEER web site, April 2016. 2. Pappo, A. S., Shapiro, D. N., Crist, W. M., & Maurer, H. M. (1995). Biology and therapy of pediatric rhabdomyosarcoma. Journal of clinical oncology, 13(8), 2123-2139. 3. Blakely, M. L., Andrassy, R. J., Raney, R. B., Anderson, J. R., Wiener, E. S., Rodeberg, D. A., ... & Crist, W. M. (2003). Prognostic factors and surgical treatment guidelines for children with rhabdomyosarcoma of the perineum or anus: a report of Intergroup Rhabdomyosarcoma Studies I through IV, 1972 through 1997. Journal of pediatric surgery, 38(3), 347-353. 4. Meza, J. L., Anderson, J., Pappo, A. S., & Meyer, W. H. (2006). Analysis of prognostic factors in patients with nonmetastatic rhabdomyosarcoma treated on intergroup rhabdomyosarcoma studies III and IV: the Children's Oncology Group. J Clin Oncol, 24(24), 3844-51. 5. Casey, D. L., Wexler, L. H., LaQuaglia, M. P., Meyers, P. A., & Wolden, S. L. (2014). Patterns of failure for rhabdomyosarcoma of the perineal and perianal region. International Journal of Radiation Oncology* Biology* Physics, 89(1), 82-87. 6. Okamura, K., Yamamoto, H., Ishimaru, Y., Takayasu, H., Otani, Y., Yamagishi, J., ... & Ikeda, H. (2006). Clinical characteristics and surgical treatment of perianal and perineal rhabdomyosarcoma:
analysis of Japanese patients and comparison with IRSG reports. Pediatric surgery international, 22(2), 129-134. 7. Wharam, M. D., Meza, J., Anderson, J., Breneman, J. C., Donaldson, S. S., Fitzgerald, T. J., ... & Meyer, W. H. (2004). Failure pattern and factors predictive of local failure in rhabdomyosarcoma: a report of group III patients on the third Intergroup Rhabdomyosarcoma Study. Journal of clinical oncology, 22(10), 1902-1908. 8.
Fuchs, Joerg; Dantonello, Tobias M; Blumenstock, Gunnar; Kosztyla, Daniel; Klingebiel, Thomas;
Leuschner, Ivo; Schuck, Andreas; Niggli, Felix K; Koscielniak, Ewa; Seitz, Guido (2014). Treatment and outcome of patients suffering from perineal/perianal rhabdomyosarcoma: results from the cws trialsretrospective clinical study. Annals of Surgery, 259(6):1166-1172.
Figure 1 Pre-treatment CT saggital (A) and pre-treatment MRI coronal (B)
A
B
Figure 2 Post-treatment CT Axial (A) and post-treatment MRI coronal (B)
A
B