Urgent need for a validated tumor response evaluation system for use in immunotherapy

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Hentschke et al recently reported a detailed case series on reduced-intensity stem-cell transplantation (RIST) for the treatment of renal cell and colon cancers.1 While they provided important information on the feasibility of RIST and its possible antitumor effect, we would like to comment on their study design, especially focusing on the feasibility of response evaluation criteria. Although the Response Evaluation Criteria in Solid Tumors (RECIST) system has been used as a gold standard to evaluate the response of solid tumors to treatment,2 mainly in the field of cancer chemotherapy, it has not been fully validated in the area of allogeneic transplantation for solid tumors, where the immune-mediated destruction of tumor cells is the principle mechanism of tumor destruction (graft-versus-tumor effect, GVT). Compared to hematological malignancies, solid tumors are generally more resistant to the cytotoxic agents used in conditioning regimens administered before transplantation. Consequently, we considered that there may be some important differences in evaluating the response of solid tumors between RIST and conventional chemotherapy.

First, the feasibility of directly applying RECIST, including the optimal timing of response evaluation, should be critically validated before its extensive application in transplantation. Currently available reports on RIST for solid tumors commonly note that tumor regression occurs several months after transplantation.3 Some responses and GVHD effects, in general, occur during the late period of RIST. Thus, most tumors continue their natural growth until the manifestation of effective alloimmunity to restrain tumor growth. If the original RECIST criteria2 are applied to patients undergoing RIST for solid tumors, most of the GVT effects would be evaluated as progressive disease (PD), which would preclude subsequent evaluation (Figure 1a). Therefore, RECIST may underestimate the efficacy of RIST. Furthermore, while there is no concept of spontaneous regression in the field of chemotherapy, this is quite common in RIST.

Figure 1
figure1

Course of tumor size after transplantation. Primary solid tumors are progressive, despite chemoradiotherapy prior to transplantation. (a) Most tumors continue their natural growth until the development of a GVT effect, which usually occurs several months after transplantation. (b) If the tumor has increased in size compared to that at the time of transplant, regression from the largest size may overestimate the treatment effect. (c) If the tumor size at transplant is defined as a baseline, some treatment effects, observed in patients whose lesions show initial progression followed by regression with the development of GVHD, will be underestimated.

Second, the proper time to measure the tumor size as a baseline for evaluating a subsequent tumor response has not been clearly defined. In contrast to the results with chemotherapy, the tumor often temporarily increases in size following RIST. Some metastases initially progress slowly, while others progress rapidly. Accordingly, when the size at transplantation is used as a baseline, as in chemotherapy, a therapeutic effect following the initial progression could be overlooked or underestimated (Figure 1c). On the other hand, evaluating regression from the largest size after transplant certainly overestimates the effect of treatment (Figure 1b), and gives an unacceptable bias.

Third, the tumor size after RIST often fluctuates in response to a de novo GVT effect, post transplant immunotherapy including donor lymphocyte infusion, and adjustment of immunosuppressive agents (Figure 2). In this situation, it is clear that any evaluation of the response duration, such as progression-free survival and the overall response duration, is essentially impossible using the current RECIST criteria.

Figure 2
figure2

Fluctuation of tumor size after donor lymphocyte infusion or adjustment of immunosuppressive agents. It is difficult to handle patients in whom the tumor size fluctuates in response to post transplant immunotherapy, such as donor lymphocyte infusion and adjustment of immunosuppressive agents. Neither an appropriate timing of response evaluation nor an appropriate time to measure a baseline tumor size has been established in these cases.

These limitations in tumor response evaluation are also expected to be present in other areas including tumor vaccination and dendritic cell therapy strategy. Improved overall survival will ultimately be evaluated in phase III trials. To reach this point, a global standard evaluation system that enables the effective screening of a therapeutic effect in an earlier phase II study will need to be established. We hope that this letter will inspire a productive discussion.

References

  1. 1

    Hentschke P, Barkholt L, Uzunel M et al. Low-intensity conditioning and hematopoietic stem cell transplantation in patients with renal and colon carcinoma. Bone Marrow Transplant 2003; 31: 253–261.

  2. 2

    Therasse P, Arbuck SG, Eisenhauer EA 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; 92: 205–216.

  3. 3

    Childs R, Chernoff A, Contentin N et al. Regression of metastatic renal-cell carcinoma after nonmyeloablative allogeneic peripheral-blood stem-cell transplantation. N Engl J Med 2000; 343: 750–758.

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Hori, A., Kami, M., Kim, S. et al. Urgent need for a validated tumor response evaluation system for use in immunotherapy. Bone Marrow Transplant 33, 255–256 (2004) doi:10.1038/sj.bmt.1704371

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