What are the measures to assess treatment response in BSSTs?

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What are the measures to assess treatment response in BSSTs?

Introduction

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.[1][2][3][4][5] Patients in whom treatment induces necrosis in at least 90% of their tumour have superior survival compared to those with lesser levels of response.[6] Data are more conflicting regarding the prognostic significance of necrosis in other soft tissue sarcomas.[7][8][9][10][11] 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.[12][3][13]

The response is graded based on percentage of necrosis as follows:

% Necrosis Grade of Pathologic Response
≤50% I
50-≤90% II
90-99% III
100% IV

Tumours with at 95% or more necrosis have a superior prognosis.

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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.

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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.

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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.[14] 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.[15][16] 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.[17]

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.[18] 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).[19]

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.[20][21] 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.[22] 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.[23] Furthermore, PET provides whole body imaging, useful for detecting occult metastases in the lungs, bones and viscera.

Scintigraphy using 99mTc-MIBI,[24] or 201Tl[25] 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.[26][27]

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Other

In a small series genomic alterations in tumour samples pre- and post-chemotherapy, have been correlated with likelihood of response to chemotherapy.[28] 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.[29]

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.[30]

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Evidence summary and recommendations

Evidence summary Level References
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 [14], [15], [31], [17], [18], [19], [20], [21], [23], [24], [25], [26], [27]
Evidence-based recommendationQuestion mark transparent.png Grade
Functional imaging may assist standard methods of evaluating response to pre-operative chemotherapy or radiation therapy.
D


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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.

References

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Appendices

Further resources