ASCO clinical guideline update: Use of chemotherapy sensitivity and resistance assays not supported

Technology assessment guidelines for clinical practice are published by the American Society for Clinical Oncology (ASCO) from reviews of the literature and are updated frequently to reflect new evidence. The guidelines for the use of chemotherapy sensitivity and resistance assays, or CSRAs, were last published in 2004 [1], and these have now been reviewed.

The overall recommendation is unchanged from that of the earlier guidelines, and does not support the use of these assays in standard clinical practice, although it strongly supports their continued evaluation in clinical trials [2].

Chemotherapy sensitivity and resistance assays are, as the name implies, in vitro tests of tumour cells from patients either before or after chemotherapy that are carried out to predict whether that tumour is likely to be sensitive or resistant to a particular drug.

This ASCO clinical update, by a team of oncologists chaired by Harold Burstein of the Dana-Farber Cancer Institute, Boston, MA, USA, focused on trials that compared the use of CSRAs performed on viable tumour tissue to select treatments with therapy chosen empirically based on expected clinical outcomes alone. Publications were selected for review if, besides fulfilling these conditions, they also had a study size of at least 20 patients per arm and primary end points concerned with cancer progression and/or survival.

Following a careful analysis of the literature, five papers were selected describing four different assays. Two papers covered an adenosine triphosphate bioluminescence assay (ATP), and one each covered extreme drug resistance (EDRA), methyl-thiazolyl-diphenyltetrazolium bromide (MTT) and the ChemoFX assay from Precision Therapeutics, Pittsburgh. The evidence for the efficacy of each assay was summarised in detail.

In one reported trial, 180 patients with recurrent ovarian cancer were assigned to receive either empirically selected chemotherapy or chemotherapy chosen based on the results of an ATP assay. Slightly more patients in the ATP arm than in the control arm had partial or complete responses (40.5% versus 31.5%), perhaps because more received combination therapy, but this difference was not significant enough to justify recommending the assay.

There was no difference in progression-free or overall survival. A second trial used this assay to divide patients with metastatic melanoma into predicted chemotherapy-sensitive and resistant groups, and found that those who were predicted to be chemotherapy-sensitive had a significantly better response. This trial, however, did not directly compare the assay with empirical treatment selection; a further Phase III trial has been proposed.

The single study involving the MTT assay was the largest in the set, and compared 157 patients with gastric cancer who received treatment directed by the assay with 196 similar patients who received empirically-selected treatment.

No significant difference in overall survival was observed. A much smaller study of 78 ovarian cancer patients observed a small improvement in overall response rate with the EDRA assay compared to empirical treatment selection, but this was again too small to be significant. The ChemoFX assay has been evaluated in retrospective studies with promising results, but methodological limitations of these studies and a lack of comparison with a clinical gold standard preclude its being recommended for standard clinical practice.

In summary, the guidance authors conclude that none of the chemotherapy sensitivity and resistance assays currently under evaluation have been proven to be effective enough for their routine use to be recommended. However, several of the results are promising, if inconclusive, and further trials of these and other similar assays should be prioritised.

References

1: Schrag, D., Garewal, H.S., Burstein, H.J. et al. (2004). American Society of Clinical Oncology Technology Assessment: Chemotherapy sensitivity and resistance assays. J Clin Oncol 22, 3631-3638

2: Burstein, H.J., Mangu, P.B., Somerfield, M.R., Schrag, D., Samson, D., Holt, L., Zelman, D. and Ajani, J.A. (2011). American Society of Clinical Oncology Clinical Practice Guideline Update on the Use of Chemotherapy Sensitivity and Resistance Assays. J. Clin. Oncol., published online ahead of print 25 July 2011. DOI: 10.1200/JCO.2011.36.0354