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Tumor Histopathological Response to Neoadjuvant Chemotherapy In Review J Investig Med: first published as 10.1136/jim-2017-000531 on 27 September 2017. Downloaded from Tumor histopathological response to neoadjuvant chemotherapy in childhood solid malignancies: is it still impressive? Ehab Hanafy, Abdullah Al Jabri, Gelan Gadelkarim, Abdulaziz Dasaq, Faisal Nazim, Mohammed Al Pakrah Prince Sultan Oncology ABSTRACT responders as no benefits are seen with regard Center, King Salman Armed The management of oncological malignancies has to disease outcome when compared with histor- Forces Hospital, Tabuk, Saudi Arabia significantly improved over the last decades. In ical counterparts. These can be seen clearly from modern medicine, new concepts and trends have results like in large osteosarcoma trials where Correspondence to emerged paving the way for the era of personalized ifosfamide and etoposide (IE) did not show a Dr Ehab Hanafy, King and evidence-based strategies adapted to the valid benefit when added adjuvantly to high- Salman Armed Forces patients’ prognostic variables and requirements. risk patients and in Wilms' tumor (WT) where Hospital, Tabuk, 71411, Several challenges do exist that are encountered doxorubicin can be safely removed from post- Saudi Arabia; ehab. hmahmoud@ gmail. during the management, including the difficulty to operative chemotherapy in intermediate-risk com assess chemotherapy response with certainty. Having patients; even the results have to be validated known that neoadjuvant chemotherapy might in Ewing’s sarcoma (ES) despite the promising Accepted 28 August 2017 be the only solution for a proportion of patients results in the busulfan/melphalan arm in poor with tumors that are unresectable at diagnosis, responders. emergence of strategies that use risk group-directed A widely used method for histological assess- therapy became an integral part in the management ment was described by Huvos and was based of oncological malignancies. Tumor histopathological on evaluation of osteosarcoma samples.1 The change post neoadjuvant chemotherapy is one Huvos system includes grades I–IV according to of the most important predictors of management the degree of necrosis (table 1).2 outcome and is being used in many chemotherapy This method showed effectiveness in the protocols as an essential determinant of the most management of ES as the degree of necrosis suitable postoperative chemotherapy regimen. Bone has been directly correlated with the improve- tumors are the classic models of this approach; ment of overall survival (OS).2 There is a however, other childhood solid tumors show difference between ES and osteosarcoma as http://jim.bmj.com/ significant variations in outcome as a result of ES does not produce any major extracellular tumor histopathological response to neoadjuvant matrix component, so there is no evidence left chemotherapy. The aim of this review is therefore by the tumor cells. Furthermore, ES cells may to summarize the significance of histopathological disappear completely in response to chemo- responses seen after neoadjuvant chemotherapy therapy. Due to this fact, there might be a in childhood solid tumors. Moreover, it suggests decrease in tumor volume after neoadjuvant that the effect on tumor histopathology through chemotherapy without histological delineation on September 29, 2021 by guest. Protected copyright. modifying neoadjuvant chemotherapy and, on the of where the tumor was located originally.3 other hand, toxicities from intensifying adjuvant Dramatic changes in tumor volume following chemotherapy might either necessitate the change neoadjuvant chemotherapy make it difficult of a number of arm groups in different protocol to calculate tumor necrosis based only on the regimens or include newer chemotherapeutic agents viable cells per unit area of residual tumor. So, adjuvantly for better outcome and lesser toxicities in a quantitative way to calculate tumor necrosis poor tumor histopathological responders. is not optimal in ES.4 Picci et al proposed evaluation of the amount of remaining viable tumor rather than INTRODUCTION the amount of non-viable tumor. The scoring Tumor necrosis and histopathological changes system proposed by Picci et al includes three 4 in childhood solid tumors following neoadju- grades. Grade 1 represents a tumor with at vant chemotherapy are important predictors least one macroscopic residual nodule of viable To cite: Hanafy E, Al of disease outcome. Survival rates are better tumor. Grade 2 represents a tumor with only Jabri A, Gadelkarim G, in good responders to neoadjuvant chemo- isolated microscopic foci of viable tumor. Grade et al. J Investig Med 3 Published Online First: therapy with high tumor necrosis than those 3 indicates no evidence of viable tumor cells. [please include Day Month with poor response. Despite these facts, there is This method is easy to interpret; however, it Year]. doi:10.1136/jim- little evidence to recommend for more intensi- fails to determine the original size of the tumor 2017-000531 fied adjuvant chemotherapy regimens for poor as seen when the persistence of one nodule is Hanafy E, et al. J Investig Med 2017;0:1–8. doi:10.1136/jim-2017-000531 1 Copyright 2017 by American Federation for Medical Research (AFMR). Review J Investig Med: first published as 10.1136/jim-2017-000531 on 27 September 2017. Downloaded from Table 1 Schemes for assessment of tumor responsiveness in Table 2 Grading of histological response to neoadjuvant osteosarcoma and Ewing's sarcoma2 chemotherapy in osteosarcoma9 10 Salzer- Grading of histological response to neoadjuvant chemotherapy in Description Huvos Kuntschik WHO 2013 osteosarcoma No vital tumor cells IV I Responder Response Grade Histology Single vital tumor cells or one vital – II Poor I Necrosis minimal or absent tumor nest smaller than 0.5 cm II Necrosis is <90% of the tumor but greater than Less than 10% vital tumor tissue III III minimal 10–50% vital tumor tissue II IV Non- Good III Scattered areas of viable tumor but >90% of tumor More than 50% vital tumor tissue – V responder necrotic No effect of chemotherapy I VI IV No viable tumor graded the same, regardless of whether the tumor volume 11 12 3 3 5 of cisplatin (CP) and doxorubicin. Neoadjuvant treat- was 10 cm or 200 cm . ment consisted of HDMTX, BCD, and doxorubicin in the MSKCC T10 protocol and CP was the drug used to REVIEW OF MOST COMMON SOLID TUMORS intensify the adjuvant phase. Patients in the poor responder OSTEOSARCOMA group had a similar outcome to those who did not receive The extent of tumor necrosis after neoadjuvant chemo- augmented chemotherapy, in spite of chemotherapy inten- therapy is the most important predictor of outcome in sification except in T10 protocol. patients with osteosarcoma. Different degrees of necrosis Similarly, HDMTX, doxorubicin, and CP were given in on histological examination of tumor specimens were first the neoadjuvant phase in the Scandinavian Sarcoma Group noted by investigators from Memorial Sloan-Kettering 13 14 (SSG) protocol SSGVIII and recent Rizzoli trial, so new Cancer Center (MSKCC) and it was observed that signif- drugs like IE were offered as adjuvant chemotherapy to icant necrosis is associated with better event-free survival poor responders. In the Rizzoli trial, patients did not have (EFS) and OS.6–8 a better outcome than those who did not receive IE inten- Good responders are those who have tumor necrosis of sification, whereas in the SSGVIII trial, the outcome was more than 90% corresponding to grades III and IV, whereas better, with an OS of 70% in patients with a poor histolog- poor responders are those who have tumor necrosis of less 8 than 90% corresponding to grades I and II.9 10 The disease- ical response. free survival rates are 50% and 80%, respectively (figure 1), Using another approach, COSS stratified patients into (table 2). high-risk and low-risk groups based on pathology, tumor Different osteosarcoma protocols have used the poor size, and clinical response to neoadjuvant therapy. Patients response to neoadjuvant chemotherapy as a determinant in the high-risk group were treated with HDMTX, doxoru- of more intensified adjuvant chemotherapy. Protocols used bicin, and CP in addition to ifosfamide. The stratification http://jim.bmj.com/ by Children’s Cancer Group (COG), Rizzoli Institute, has not succeeded as the outcome of the high-risk group 8 and German-Austrian-Swiss Cooperative Osteosarcoma was the same as the low-risk one. On the other hand, there Study Group (COSS) include neoadjuvant chemotherapy is a good evidence that attempting to reduce toxicity for consisting of high-dose methotrexate (HDMTX) and bleo- low-risk patients who have a good chemotherapy response mycin + cyclophosphamide + dactinomycin (BCD) and by minimizing chemotherapy results in a worse prog- adjuvant chemotherapy was intensified with the addition nosis.11 12 on September 29, 2021 by guest. Protected copyright. A large European and American Osteosarcoma Study Group-1 (EURAMOS-1) trial that represents a collabora- tion between four research groups in osteosarcoma, the COG, COSS, European Osteosarcoma Intergroup (EOI) and the SSG investigated whether more intensive adjuvant chemotherapy to poor responders with high grade osteo- sarcoma (more than 10% viable tumor) improved EFS. Patients were randomised to receive postoperative meth- otrexate, cisplatin, and doxorubicin (MAP) or MAP plus ifosfamide and etoposide (MAPIE). Because of increased toxicity, secondary leukemias and no improvement in EFS, EURAMOS-1 results recommended against any adjustment to the standard of care and against the addition of IE to adjuvant chemotherapy in poorly responding osteosarcoma (figure 2, figure 3, figure 4).15 All data considered, there seems to be no solid evidence Figure 1 Event-free survival of patients with localized that intensifying adjuvant chemotherapy for patients with osteosarcoma who had ≥90% or <90% tumor necrosis after osteosarcoma with poor histological response led to an neoadjuvant chemotherapy.8 9 improved outcome. 2 Hanafy E, et al. J Investig Med 2017;0:1–8. doi:10.1136/jim-2017-000531 Review J Investig Med: first published as 10.1136/jim-2017-000531 on 27 September 2017.
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