- 1 What are the measures to assess treatment response in BSSTs?
- 1.1 Introduction
- 1.2 Pathologic assessment of post therapy tumour necrosis
- 1.3 Pre-operative therapy and prediction of response
- 1.4 What approaches are used to monitor response to pre-operative therapy?
- 1.5 How predictive are the various response monitoring systems of histopathological tumour necrosis?
- 1.6 Other
- 2 Evidence summary and recommendations
- 3 Issues requiring further clinical study
- 4 References
- 5 Appendices
- 6 Further resources
What are the measures to assess treatment response in BSSTs?
For some sarcomas of the bone, particularly osteosarcoma and the primitive neuroectodermal tumours (PNET)/Ewing’s family of tumours, histologic evidence of a substantial level of treatment induced tumour necrosis has been found to be predictive of improved long term survival and conversely patients with a poor response are at an increased risk for local recurrence. Patients in whom treatment induces necrosis in at least 90% of their tumour have superior survival compared to those with lesser levels of response. Data are more conflicting regarding the prognostic significance of necrosis in other soft tissue sarcomas. This is related in part to the greater heterogeneity of soft tissue subtypes and to the inherent necrosis associated with high grade sarcomas unrelated to therapy effect.
Pathologic assessment of post therapy tumour necrosis
Post chemotherapy tumour necrosis is a powerful predictor of survival in patients with skeletal osteosarcoma and Ewing’s tumour. To assess pathologic response, one complete thin slice of tumour is taken through its largest axis. This is decalcified promptly. The entire specimen is sequentially embedded into blocks and the location of the blocks is mapped. Tumour necrosis is evidenced by sclerosis of bone and cell drop out, granulation tissue or coagulative tumour necrosis. The percentage of tumour necrosis is estimated in a semi-quantitative mmanner.
The response is graded based on percentage of necrosis as follows:
|% Necrosis||Grade of Pathologic Response|
Tumours with at 95% or more necrosis have a superior prognosis.
Pre-operative therapy and prediction of response
Given the large size of many bone and soft tissue sarcoma (STS), the possibility of achieving tumour shrinkage prior to surgical resection has appeal. If effective, this intervention may make more patients eligible for limb sparing surgery and indeed may make surgery a possibility, particularly for surgically challenging sites. Both combination chemotherapy and radiation therapy have been used in the pre-operative setting. Courses of such pre-operative therapy are administered over a number of weeks to months in the lead up to the planned resection. In this context, there is a risk that the tumour will not respond to the pre-operative therapy and may even grow or spread in the interim, the delay potentially rendering the tumour unresectable. Monitoring of the patient and tumour during the pre-operative phase is required to assess the response to pre-operative therapy and to tailor the approach, in case of a suboptimal response.
What approaches are used to monitor response to pre-operative therapy?
Two principal approaches have been used to monitor pre-operative response. One involves gauging significant changes in tumour size, through static imaging techniques, such as plain X-rays, computed tomography (CT) scans and Magnetic Resonance Imaging (MRI).
The other approach focuses on functional changes in the neoplasm induced by treatment. Monitoring changes in blood flow by angiography and colour Doppler sonography or recording the alterations in glucose metabolism by positron emission technology are examples of this approach.
In both settings, changes in specific parameters of interest are recorded by comparing pre-treatment data to repeat measurement carried out at predefined intervals during the treatment phase. After resection, these pre-operative changes are correlated with the degree of tumour necrosis as assessed by histopathological examination.
How predictive are the various response monitoring systems of histopathological tumour necrosis?
CT scans and MRI have been used for evaluating changes in size. Conventional radiography cannot adequately depict the soft tissue component of sarcomas and is not reliable for assessment of response. Techniques that assess changes in size are of most value in the setting of tumour progression. Even in the setting of substantial tumour necrosis, sarcomas may not shrink significantly, at least in the short term. Furthermore, cystic change and oedema induced by the therapy may even cause enlargement. In STS, while tumour growth was highly predictive of a poor response, stability or reduction in size predicts had only a 50% chance of being associated with a good response. Similarly, in osteosarcomas increased signal intensity on MRI predicted poor response but the reverse did not hold for good response. In the setting of pre-operative radiation therapy for STS radiologic size increase was not predictive of poor response.
For the purposes of documenting changes in size, the Response Evaluation Criteria In Solid Tumors (RECIST) criteria are preferred over the more complex World Health Organisation (WHO) criteria. There is some evidence that the adapted Choi criteria, using a combination of reduced tumour size and decreased density on contrast-enhanced CT, are more predictive of response in soft tissue sarcomas, particularly for Gastrointestinal Stromal Tumours (GISTS).
Functional imaging has focused on fluorodeoxyglucose positron emission tomography (FDG PET) imaging, often in combination with volumetric approaches (CT or MRI). Positron emission tomography (PET) standard uptake value (SUV) has been suggested to be proportional to the proliferative rate of the neoplastic cells. Changes in the SUV have been found to correlate with percentage necrosis both in osteosarcoma and the Ewing family of tumours. However the specific SUV indices used and the timing of the PET scan after the start of therapy are widely variable.
For osteosarcomas of the extremities, the Metabolic Tumor Volume (MTV), defined as the volume of tumor tissue with an SUV above a minimum threshold of 2.0 by 18F-FDG PET/CT was found recently to correlate with both pathologic response and survival. There was also some evidence of gradation of outcome by pathology response and MTV. PET has the added advantage that a metabolic response precedes volumetric response by several weeks, such that in osteosarcomas useful changes were documented even after the first cycle of chemotherapy. Furthermore, PET provides whole body imaging, useful for detecting occult metastases in the lungs, bones and viscera.
Scintigraphy using 99mTc-MIBI, or 201Tl imaging has also been used to predict response to chemotherapy in bone and soft tissue sarcomas. Changes in specific indices of these radioisotopes have been found to correlate with percentage necrosis. Doppler ultrasound has been used to gauge changes in blood flow through the sarcomas as a result of therapy and an increase in arterial resistance was found to correlate with histologic response in osteosarcomas.
In a small series genomic alterations in tumour samples pre- and post-chemotherapy, have been correlated with likelihood of response to chemotherapy. Patients with high scores for loss of heterozygosity more often had a poor response to chemotherapy than had patients with a low LOH-score. Similarly in a small study of twenty patients, global gene expression patterns or expression of a set of twenty-four genes were predictive of tumours likely to respond to Bevacizumab alone and with radiotherapy. But the role of gene changes as predictors of response while undergoing treatment was not addressed.
P-glycoprotein (Pgp) is the protein product of the multidrug resistance gene MDR1. Expression of Pgp can be assessed in tumours using immunohistochemistry. While some evidence is presented that Pgp expression is associated with a worse prognosis in OS, it has not been found to be predictive of response to pre-operative chemotherapy.
Evidence summary and recommendations
|Functional imaging such as FDG PET imaging, often in combination with volumetric approaches (CT or MRI) can be used in assessing response to pre-operative therapy in bone and soft tissue sarcomas.||IV||, , , , , , , , , , , , |
|Functional imaging may assist standard methods of evaluating response to pre-operative chemotherapy or radiation therapy.||D|
Issues requiring further clinical study
A gap in the evidence has been identified:
• Assessment of other in vivo methods of response monitoring is an area of clinical need. In particular, in acknowledgement of the limitations of the methods used to assess pathologic response, studies that use survival as the endpoint, rather than using the surrogate marker of pathologic response are highly desirable.
- Bacci G, Ferrari S, Bertoni F, Rimondini S, Longhi A, Bacchini P, et al. Prognostic factors in nonmetastatic Ewing's sarcoma of bone treated with adjuvant chemotherapy: analysis of 359 patients at the Istituto Ortopedico Rizzoli. J Clin Oncol 2000 Jan;18(1):4-11 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/10623687.
- Bacci G, Mercuri M, Longhi A, Ferrari S, Bertoni F, Versari M, et al. Grade of chemotherapy-induced necrosis as a predictor of local and systemic control in 881 patients with non-metastatic osteosarcoma of the extremities treated with neoadjuvant chemotherapy in a single institution. Eur J Cancer 2005 Sep;41(14):2079-85 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/16115755.
- Raymond AK, Chawla SP, Carrasco CH, Ayala AG, Fanning CV, Grice B, et al. Osteosarcoma chemotherapy effect: a prognostic factor. Semin Diagn Pathol 1987 Aug;4(3):212-36 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/3313606.
- Wunder JS, Paulian G, Huvos AG, Heller G, Meyers PA, Healey JH. The histological response to chemotherapy as a predictor of the oncological outcome of operative treatment of Ewing sarcoma. J Bone Joint Surg Am 1998 Jul;80(7):1020-33 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/9698007.
- Zunino JH, Johnston JO. Prognostic value of histologic tumor necrosis assessment in osteogenic sarcoma of bone. Am J Orthop (Belle Mead NJ) 2000 May;29(5):369-72 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/10868437.
- Huvos AG, Rosen G, Marcove RC. Primary osteogenic sarcoma: pathologic aspects in 20 patients after treatment with chemotherapy en bloc resection, and prosthetic bone replacement. Arch Pathol Lab Med 1977 Jan;101(1):14-8 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/299812.
- Alvegård TA, Berg NO, Ranstam J, Rydholm A, Rööser B. Prognosis in high-grade soft tissue sarcomas. The Scandinavian Sarcoma Group experience in a randomized adjuvant chemotherapy trial. Acta Orthopaedica 1989 Oct;60(5):517-21 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/2690557.
- Eilber FC, Eilber FR, Eckardt J, Rosen G, Riedel E, Maki RG, et al. The impact of chemotherapy on the survival of patients with high-grade primary extremity liposarcoma. Ann Surg 2004 Oct;240(4):686-95; discussion 695-7 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/15383796.
- Grobmyer SR, Maki RG, Demetri GD, Mazumdar M, Riedel E, Brennan MF, et al. Neo-adjuvant chemotherapy for primary high-grade extremity soft tissue sarcoma. Ann Oncol 2004 Nov;15(11):1667-72 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/15520069.
- Menendez LR, Ahlmann ER, Savage K, Cluck M, Fedenko AN. Tumor necrosis has no prognostic value in neoadjuvant chemotherapy for soft tissue sarcoma. Clin Orthop Relat Res 2007 Feb;455:219-24 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/17016226.
- Van Glabbeke M, van Oosterom AT, Oosterhuis JW, Mouridsen H, Crowther D, Somers R, et al. Prognostic factors for the outcome of chemotherapy in advanced soft tissue sarcoma: an analysis of 2,185 patients treated with anthracycline-containing first-line regimens--a European Organization for Research and Treatment of Cancer Soft Tissue and Bone Sarcoma Group Study. J Clin Oncol 1999 Jan;17(1):150-7 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/10458228.
- Huvos A G. Osteosarcoma: Pathologic assessment of preoperative (adjuvant) chemotherapy. in boone tumors: diagnosis, treatment and prognosis. Philadelphia, PA: W.B. Saunders; 1991.
- Rosen G, Caparros B, Huvos AG, Kosloff C, Nirenberg A, Cacavio A, et al. Preoperative chemotherapy for osteogenic sarcoma: selection of postoperative adjuvant chemotherapy based on the response of the primary tumor to preoperative chemotherapy. Cancer 1982 Mar 15;49(6):1221-30 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/6174200.
- Holscher HC, Hermans J, Nooy MA, Taminiau AH, Hogendoorn PC, Bloem JL. Can conventional radiographs be used to monitor the effect of neoadjuvant chemotherapy in patients with osteogenic sarcoma? Skeletal Radiol 1996 Jan;25(1):19-24 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/8717114.
- Holscher HC, Bloem JL, van der Woude HJ, Hermans J, Nooy MA, Taminiau AH, et al. Can MRI predict the histopathological response in patients with osteosarcoma after the first cycle of chemotherapy? Clin Radiol 1995 Jun;50(6):384-90 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/7789022.
- Kim MS, Lee SY, Cho WH, Song WS, Koh JS, Lee JA, et al. Effect of increases in tumor volume after neoadjuvant chemotherapy on the outcome of stage II osteosarcoma regardless of histological response. J Orthop Sci 2009 May;14(3):292-7 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/19499296.
- Roberge D, Skamene T, Nahal A, Turcotte RE, Powell T, Freeman C. Radiological and pathological response following pre-operative radiotherapy for soft-tissue sarcoma. Radiother Oncol 2010 Dec;97(3):404-7 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/21040989.
- Therasse P, Arbuck SG, Eisenhauer EA, Wanders J, Kaplan RS, Rubinstein L, et al. New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst 2000 Feb 2;92(3):205-16 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/10655437.
- Stacchiotti S, Collini P, Messina A, Morosi C, Barisella M, Bertulli R, et al. High-grade soft-tissue sarcomas: tumor response assessment--pilot study to assess the correlation between radiologic and pathologic response by using RECIST and Choi criteria. Radiology 2009 May;251(2):447-56 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/19261927.
- Schuetze SM, Rubin BP, Vernon C, Hawkins DS, Bruckner JD, Conrad EU 3rd, et al. Use of positron emission tomography in localized extremity soft tissue sarcoma treated with neoadjuvant chemotherapy. Cancer 2005 Jan 15;103(2):339-48 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/15578712.
- Hawkins DS, Rajendran JG, Conrad EU 3rd, Bruckner JD, Eary JF. Evaluation of chemotherapy response in pediatric bone sarcomas by [F-18]-fluorodeoxy-D-glucose positron emission tomography. Cancer 2002 Jun 15;94(12):3277-84 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/12115361.
- Byun BH, Kong CB, Park J, Seo Y, Lim I, Choi CW, et al. Initial metabolic tumor volume measured by 18F-FDG PET/CT can predict the outcome of osteosarcoma of the extremities. J Nucl Med 2013 Oct;54(10):1725-32 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/23949909.
- Im HJ, Kim TS, Park SY, Min HS, Kim JH, Kang HG, et al. Prediction of tumour necrosis fractions using metabolic and volumetric 18F-FDG PET/CT indices, after one course and at the completion of neoadjuvant chemotherapy, in children and young adults with osteosarcoma. Eur J Nucl Med Mol Imaging 2012 Jan;39(1):39-49 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/21953008.
- Moustafa H, Riad R, Omar W, Zaher A, Ebied E. 99mTc-MIBI in the assessment of response to chemotherapy and detection of recurrences in bone and soft tissue tumours of the extremities. Q J Nucl Med 2003 Mar;47(1):51-7 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/12714955.
- Taki J, Higuchi T, Sumiya H, Tsuchiya H, Minato H, Tomita K, et al. Prediction of final tumor response to preoperative chemotherapy by Tc-99m MIBI imaging at the middle of chemotherapy in malignant bone and soft tissue tumors: comparison with Tl-201 imaging. J Orthop Res 2008 Mar;26(3):411-8 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/17960652.
- van der Woude HJ, Bloem JL, van Oostayen JA, Nooy MA, Taminiau AH, Hermans J, et al. Treatment of high-grade bone sarcomas with neoadjuvant chemotherapy: the utility of sequential color Doppler sonography in predicting histopathologic response. AJR Am J Roentgenol 1995 Jul;165(1):125-33 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/7785571.
- Bramer JA, Gubler FM, Maas M, Bras H, de Kraker J, van der Eijken JW, et al. Colour Doppler ultrasound predicts chemotherapy response, but not survival in paediatric osteosarcoma. Pediatr Radiol 2004 Aug;34(8):614-9 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/15148555.
- Smida J, Baumhoer D, Rosemann M, Walch A, Bielack S, Poremba C, et al. Genomic alterations and allelic imbalances are strong prognostic predictors in osteosarcoma. Clin Cancer Res 2010 Aug 15;16(16):4256-67 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/20610556.
- Yoon SS, Duda DG, Karl DL, Kim TM, Kambadakone AR, Chen YL, et al. Phase II study of neoadjuvant bevacizumab and radiotherapy for resectable soft tissue sarcomas. Int J Radiat Oncol Biol Phys 2011 Nov 15;81(4):1081-90 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/20932656.
- Pakos EE, Ioannidis JP. The association of P-glycoprotein with response to chemotherapy and clinical outcome in patients with osteosarcoma. A meta-analysis. Cancer 2003 Aug 1;98(3):581-9 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/12879476.
- Kim MS, Lee SY, Cho WH, Song WS, Koh JS, Lee JA, et al. Prognostic effects of doctor-associated diagnostic delays in osteosarcoma. Arch Orthop Trauma Surg 2009 Oct;129(10):1421-5 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/19280203.