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Are We Ready for the 10% Solution?

Are We Ready for the 10% Solution? Downloaded from https://academic.oup.com/oncolo/article/19/5/439/6399311 by DeepDyve user on 01 February 2022 Commentary a b c a HELEN X. CHEN, LARRY V. RUBINSTEIN, LALITHA K. SHANKAR, JEFFREY S. ABRAMS a b c Cancer Therapy Evaluation Program, Biometric Research Branch, and Cancer Imaging Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute, Bethesda, Maryland, USA Disclosures of potential conflicts of interest may be found at the end of this article. The Response Evaluation Criteria in Solid Tumors (RECIST) significantly better outcomes, compared with that of non- criteria, which categorize quantitative tumor size changes into responders (those who did not achieve 10% SLD reduction). complete response, partial response (PR), stable disease (SD), Time to treatment failure was 8.4 months versus 4.1 months, orprogressive disease (PD) [1], provide standardized, objective and overall survival was 35 months versus 15 months, both measurements of tumor response to therapy and have been with p values, .01. In contrast, the RECIST threshold of230% used extensively over the last decade for early to late drug DSLDs at the first scan failed to predict patient outcome (TTF development and regulatory approvals, as well as for treat- of 6.9 months versus 5.5 months). It further suggested that ment decisions in individual patient care. The RECIST criteria 210%DSLDs atfirstscan couldbeused fortreatmentdecisions were generated based on data from cytotoxic chemotherapy as to whether the anti-VEGF therapies should be continued, trials; their limitations for the assessment of molecularly although the negative predictive value of “nonresponse,” by targeted agents have been increasingly recognized with the either the 210% or 230% cutoffs, was not discussed. advance of new therapies. In particular, the cutoff of 30% As already recognized by the authors, there are multiple change in the sum of longest diameters (DSLD) as the criterion limitations of this series, including limited sample size and of response has been criticized for not adequately capturing small numbers in each marker subgroup, heterogeneity of the potentially effective therapies. As exemplified by antiangio- VEGF-targeting therapies ranging from tyrosine-kinase inhib- genic therapies, such as sorafenib in renal cell carcinoma (RCC) itors (TKIs) to monoclonal antibodies, and inconsistency in and hepatocellular carcinoma, drugs with very low rates of the timing of first scans (20–170 days from start of therapy) RECIST-defined responses (10% or less) can still succeed and on which the cutoff optimization was based. Despite the confer significant clinical benefit. For that reason, manyclinical limitations, this study joined a large body of independent trials also use SD as an additional indicator of therapeutic retrospective studies that collectively demonstrated a signifi- effect. However, inclusion of SD and progression-free survival cant correlation between tumor size changes at the first scan (PFS)intheefficacyreadoutoftenrequiresrandomizedtrialsto and the clinical outcome [3–5]. One of the largest series was distinguish the drug effect from the natural course of the reported by Thiam et al. [5] based on 334 patients with tumor. For patients receiving therapy, the implication of SD is advanced RCC treated on the sunitinib arm in a phase III trial often uncertain, because the criterion encompasses a wide for sunitinib versus interferon-a. It tested a series of DSLD range of tumor size changes, from 29% reduction to 19% in- thresholds at the first scan at 6 weeks (245%, 230%, 220%, crease. Exploration and validation of optimal criteria of tumor 210%, 0%, 110%) for their correlations with PFS and found burden changes or functional imaging parameters as markers that DSLDs of 210% provided the optimal cutoff that of drug effect and/or clinical benefit have the promise to distinguished the PFS outcomes (median PFS of 5.6 months improve the efficiency of both development of new thera- versus 11 months). The 210% cutoff was also examined in peutics and therapeutic management of individual patients. a number of other retrospective studies in independent A study published in this issue of The Oncologist [2] patient cohorts and was consistently found to be significantly represents one of the many retrospective analyses of the associated with outcomes ([5–7] and this study). relation between tumor size changes and clinical outcomes What is the clinical utility of this finding? Although $10% in patients treated with vascular endothelial growth factor shrinkage is clearly associated with significantly better out- (VEGF) pathway-targeting agents, focusing on a specific come, the practical concern for a given patient is the likelihood patient care question: what degree of tumor size change early of benefiting from therapy if that threshold is not reached. As in the course of therapy may predict the clinical outcome in the an inherent limitation of post-treatment biomarkers, it is not patient and therefore provide guidance for decisions on possible to distinguish between predictive and prognostic further treatment? The analysis was based on 66 patients markers because all marker subgroups would have received treated with 1 of the 6 different VEGF-pathway inhibitors, the same therapy. PFS of 5 months was often selected as an and thresholds of 230% (as in RECIST) or 210% DSLDs were arbitrary landmark to estimate presence or lack of therapeutic tested for their ability to classify patients with good or poor benefit from VEGF-pathway inhibitors in first-line metastatic outcomes. This analysis concluded that $10% reduction in RCC. In several studies, including Thiam et al. [5] and the SLD (responders) at the first scan was associated with current study, median PFS values in nonresponders by the Correspondence: Jeffrey S. Abrams, M.D., National Cancer Institute, Cancer Therapy Evaluation Program, 9609 Medical Center Drive, Rockville, Maryland 20850, USA.Telephone: 240-276-6515; E-Mail: [email protected] Received March 27, 2014; accepted for publication April 8, 2014; first published online in The Oncologist Express on April 22, 2014. ©AlphaMed Press 1083-7159/2014/$20.00/0 http://dx.doi.org/10.1634/ theoncologist.2014-0126 The Oncologist 2014;19:439–440 www.TheOncologist.com ©AlphaMed Press 2014 Downloaded from https://academic.oup.com/oncolo/article/19/5/439/6399311 by DeepDyve user on 01 February 2022 440 Are We Ready for the 10% Solution? 210% criterion were 5–6 months, indicating that although and potentially improve the accuracy of early drug evaluation. these patients did not do well on average, 50% of the On the other hand, finding the optimal cutoff can be chal- patients were progression-free for longer than 5–6months. lenging, because the threshold may differ for the same agents Furthermore, in tumors in which the target pathways in different indications or for different agents in the same remain relevant through progression, continuation of indication. For example, although studies on VEGFR TKIs in therapy may be beneficial whichever PD criteria are used. metastatic RRC identified 10% as the optimal cutoff, similar Given that the treatment benefit in an individual patient tests for everolimus in second-line metastatic RCC failed to cannot be ruled out with high certainty, the value of this identify anycutoffs(from245% to120%) that separatebetter early post-treatment marker would depend on the avail- and poorer outcomes [8]. Technical limitations, such as mea- ability of better, less toxic treatment options. surement variability, may also limit the choice of thresholds Is this new criterion of response ($10% SLD reduction) that can be adopted. Efforts are under way by the RECIST better than RECIST in guiding treatment decisions? The answer committee to expand the database to include large random- depends on how RECIST is used. It is clear that objective ized clinical trials of targeted agents, as well as studies using response ($30% SLD reduction) is not a good predictor of molecular imaging with fluorodeoxyglucose-positron emis- outcomes. However, treatment decisions in general practice sion tomography (FDG-PET), with the plan to evaluate and are not based on response, but rather on progression. Patients update the guidelines and criteria to meet the needs of drug not achieving PR, but in SD, by RECIST definition (DSLDs in the development and patient care in the era of novel therapies. range of 229% to 119%) would continue therapy until PD. In summary, the current study and others focusing on To demonstrate the potential advantage of the 210% cutoff VEGF-pathway inhibitors in advanced RCC highlight the over the current practice, outcome differences using the observation that tumor shrinkage below the threshold of cutoffs of RECIST PR/SD versus 210% should be compared. RECIST can be associated with significant clinical benefit, and However, such comparisons are not always feasible because that flexibility in the size change categorization should be the numbers of patients with PD on first scans are usually very considered in future modification of the response criteria. small, at least for anti-VEGF therapies in RCC. On the other However, whether 210% or other cutoffs would be optimal hand, the use of the SD category as a basis for continuing for treatment decisions in individual patients is uncertain therapy is conceivably problematic, because the tumor size and would require further, sufficiently powered, prospective could have increased by up to 19%. Indeed, lack of tumor studies. It should be noted that criteria for one agent or one shrinkage (0% SLD reduction) or 110% SLD at the first scan disease setting may not be generalizable to others. As newer was associated with an extremely poor outcome in patients therapeutic agents become available in various clinical treated with sunitinib, with a median PFS of 1.5 months [5]. settings, it may be necessary to further modify existing tumor Further studies with sufficient power would be required to size-based response criteria, verify promising molecular and confirm this finding. functional imaging methods, and investigate new technologies. What isthe general implication of the findings on the use of Finally, before optimal criteria are defined for dichotomous tumor imaging in drug development? This study, among many characterization of tumor responses, it would be desirable to others, reinforced the notion that clinically viable targeted collect tumor size measurements as a continuous variable and agents may have low response rates as defined by RECIST, but evaluate the reporting of antitumor activity based on several tumor shrinkage with smaller magnitudes is common. These cutoffs, rather than just one, for responses or progression. studies further suggest that modification of the response criteria to capture and categorize minor responses may DISCLOSURES provide a more sensitive readout of the therapeutic effect The authors indicated no financial relationships. REFERENCES 1. Therasse P, Arbuck SG, Eisenhauer EA et al. Current perspectives. Discov Med 2010;10: 6. Abel EJ, Culp SH, Tannir NM et al. Early primary New guidelines to evaluate the response to 394–405. tumor size reduction is an independent predictor of treatment in solid tumors. European Organization improved overall survival in metastatic renal cell 4. Krajewski KM, Guo M, Van den Abbeele AD for Research and Treatment of Cancer, National carcinoma patients treated with sunitinib. Eur Urol et al. Comparison of four early posttherapy Cancer Institute of the United States, National 2011;60:1273–1279. imaging changes (EPTIC; RECIST 1.0, tumor shrink- Cancer Institute of Canada. J Natl Cancer Inst 2000; age, computed tomography tumor density, Choi 7. Smith AD, Lieber ML, Shah SN. Assessing tumor 92:205–216. criteria) in assessing outcome to vascular endo- response and detecting recurrence in metastatic 2. Krajewski KM, Franchetti Y, Nishino M et al. 10% thelial growth factor-targeted therapy in patients renal cell carcinoma on targeted therapy: Impor- tumor diameter shrinkage on the first follow-up with advanced renal cell carcinoma. Eur Urol 2011; tance of size and attenuation on contrast-enhanced computed tomography predicts clinical outcome in 59:856–862. CT. AJR Am J Roentgenol 2010;194:157–165. patients with advanced renal cell carcinoma treated 5. Thiam R, Fournier LS, Trinquart L et al. Opti- 8. Oudard S,Thiam R, Fournier LS et al. Optimisation with angiogenesis inhibitors: A follow-up validation mizing the size variation threshold for the CT of the tumour response threshold in patients treated study. The Oncologist 2014;19:507–514. evaluation of response in metastatic renal cell with everolimus for metastatic renal cell carcinoma: 3. van der Veldt AA, Haanen JB, van den Eertwegh carcinoma treated with sunitinib. Ann Oncol 2010; Analysis of response and progression-free survival in AJ et al. Targeted therapy for renal cell cancer: 21:936–941. theRECORD-1study.EurJCancer2012;48:1512–1518. EDITOR’S NOTE: See the related article, “10% Tumor Diameter Shrinkage on the First Follow-Up Computed Tomography Predicts Clinical Outcome in Patients With Advanced Renal Cell Carcinoma Treated With Angiogenesis Inhibitors: A Follow-Up Validation Study,” by Katherine M. Krajewski et al., on page 507 of this issue. The ©AlphaMed Press 2014 Oncologist http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png The Oncologist Oxford University Press

Are We Ready for the 10% Solution?

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Downloaded from https://academic.oup.com/oncolo/article/19/5/439/6399311 by DeepDyve user on 01 February 2022 Commentary a b c a HELEN X. CHEN, LARRY V. RUBINSTEIN, LALITHA K. SHANKAR, JEFFREY S. ABRAMS a b c Cancer Therapy Evaluation Program, Biometric Research Branch, and Cancer Imaging Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute, Bethesda, Maryland, USA Disclosures of potential conflicts of interest may be found at the end of this article. The Response Evaluation Criteria in Solid Tumors (RECIST) significantly better outcomes, compared with that of non- criteria, which categorize quantitative tumor size changes into responders (those who did not achieve 10% SLD reduction). complete response, partial response (PR), stable disease (SD), Time to treatment failure was 8.4 months versus 4.1 months, orprogressive disease (PD) [1], provide standardized, objective and overall survival was 35 months versus 15 months, both measurements of tumor response to therapy and have been with p values, .01. In contrast, the RECIST threshold of230% used extensively over the last decade for early to late drug DSLDs at the first scan failed to predict patient outcome (TTF development and regulatory approvals, as well as for treat- of 6.9 months versus 5.5 months). It further suggested that ment decisions in individual patient care. The RECIST criteria 210%DSLDs atfirstscan couldbeused fortreatmentdecisions were generated based on data from cytotoxic chemotherapy as to whether the anti-VEGF therapies should be continued, trials; their limitations for the assessment of molecularly although the negative predictive value of “nonresponse,” by targeted agents have been increasingly recognized with the either the 210% or 230% cutoffs, was not discussed. advance of new therapies. In particular, the cutoff of 30% As already recognized by the authors, there are multiple change in the sum of longest diameters (DSLD) as the criterion limitations of this series, including limited sample size and of response has been criticized for not adequately capturing small numbers in each marker subgroup, heterogeneity of the potentially effective therapies. As exemplified by antiangio- VEGF-targeting therapies ranging from tyrosine-kinase inhib- genic therapies, such as sorafenib in renal cell carcinoma (RCC) itors (TKIs) to monoclonal antibodies, and inconsistency in and hepatocellular carcinoma, drugs with very low rates of the timing of first scans (20–170 days from start of therapy) RECIST-defined responses (10% or less) can still succeed and on which the cutoff optimization was based. Despite the confer significant clinical benefit. For that reason, manyclinical limitations, this study joined a large body of independent trials also use SD as an additional indicator of therapeutic retrospective studies that collectively demonstrated a signifi- effect. However, inclusion of SD and progression-free survival cant correlation between tumor size changes at the first scan (PFS)intheefficacyreadoutoftenrequiresrandomizedtrialsto and the clinical outcome [3–5]. One of the largest series was distinguish the drug effect from the natural course of the reported by Thiam et al. [5] based on 334 patients with tumor. For patients receiving therapy, the implication of SD is advanced RCC treated on the sunitinib arm in a phase III trial often uncertain, because the criterion encompasses a wide for sunitinib versus interferon-a. It tested a series of DSLD range of tumor size changes, from 29% reduction to 19% in- thresholds at the first scan at 6 weeks (245%, 230%, 220%, crease. Exploration and validation of optimal criteria of tumor 210%, 0%, 110%) for their correlations with PFS and found burden changes or functional imaging parameters as markers that DSLDs of 210% provided the optimal cutoff that of drug effect and/or clinical benefit have the promise to distinguished the PFS outcomes (median PFS of 5.6 months improve the efficiency of both development of new thera- versus 11 months). The 210% cutoff was also examined in peutics and therapeutic management of individual patients. a number of other retrospective studies in independent A study published in this issue of The Oncologist [2] patient cohorts and was consistently found to be significantly represents one of the many retrospective analyses of the associated with outcomes ([5–7] and this study). relation between tumor size changes and clinical outcomes What is the clinical utility of this finding? Although $10% in patients treated with vascular endothelial growth factor shrinkage is clearly associated with significantly better out- (VEGF) pathway-targeting agents, focusing on a specific come, the practical concern for a given patient is the likelihood patient care question: what degree of tumor size change early of benefiting from therapy if that threshold is not reached. As in the course of therapy may predict the clinical outcome in the an inherent limitation of post-treatment biomarkers, it is not patient and therefore provide guidance for decisions on possible to distinguish between predictive and prognostic further treatment? The analysis was based on 66 patients markers because all marker subgroups would have received treated with 1 of the 6 different VEGF-pathway inhibitors, the same therapy. PFS of 5 months was often selected as an and thresholds of 230% (as in RECIST) or 210% DSLDs were arbitrary landmark to estimate presence or lack of therapeutic tested for their ability to classify patients with good or poor benefit from VEGF-pathway inhibitors in first-line metastatic outcomes. This analysis concluded that $10% reduction in RCC. In several studies, including Thiam et al. [5] and the SLD (responders) at the first scan was associated with current study, median PFS values in nonresponders by the Correspondence: Jeffrey S. Abrams, M.D., National Cancer Institute, Cancer Therapy Evaluation Program, 9609 Medical Center Drive, Rockville, Maryland 20850, USA.Telephone: 240-276-6515; E-Mail: [email protected] Received March 27, 2014; accepted for publication April 8, 2014; first published online in The Oncologist Express on April 22, 2014. ©AlphaMed Press 1083-7159/2014/$20.00/0 http://dx.doi.org/10.1634/ theoncologist.2014-0126 The Oncologist 2014;19:439–440 www.TheOncologist.com ©AlphaMed Press 2014 Downloaded from https://academic.oup.com/oncolo/article/19/5/439/6399311 by DeepDyve user on 01 February 2022 440 Are We Ready for the 10% Solution? 210% criterion were 5–6 months, indicating that although and potentially improve the accuracy of early drug evaluation. these patients did not do well on average, 50% of the On the other hand, finding the optimal cutoff can be chal- patients were progression-free for longer than 5–6months. lenging, because the threshold may differ for the same agents Furthermore, in tumors in which the target pathways in different indications or for different agents in the same remain relevant through progression, continuation of indication. For example, although studies on VEGFR TKIs in therapy may be beneficial whichever PD criteria are used. metastatic RRC identified 10% as the optimal cutoff, similar Given that the treatment benefit in an individual patient tests for everolimus in second-line metastatic RCC failed to cannot be ruled out with high certainty, the value of this identify anycutoffs(from245% to120%) that separatebetter early post-treatment marker would depend on the avail- and poorer outcomes [8]. Technical limitations, such as mea- ability of better, less toxic treatment options. surement variability, may also limit the choice of thresholds Is this new criterion of response ($10% SLD reduction) that can be adopted. Efforts are under way by the RECIST better than RECIST in guiding treatment decisions? The answer committee to expand the database to include large random- depends on how RECIST is used. It is clear that objective ized clinical trials of targeted agents, as well as studies using response ($30% SLD reduction) is not a good predictor of molecular imaging with fluorodeoxyglucose-positron emis- outcomes. However, treatment decisions in general practice sion tomography (FDG-PET), with the plan to evaluate and are not based on response, but rather on progression. Patients update the guidelines and criteria to meet the needs of drug not achieving PR, but in SD, by RECIST definition (DSLDs in the development and patient care in the era of novel therapies. range of 229% to 119%) would continue therapy until PD. In summary, the current study and others focusing on To demonstrate the potential advantage of the 210% cutoff VEGF-pathway inhibitors in advanced RCC highlight the over the current practice, outcome differences using the observation that tumor shrinkage below the threshold of cutoffs of RECIST PR/SD versus 210% should be compared. RECIST can be associated with significant clinical benefit, and However, such comparisons are not always feasible because that flexibility in the size change categorization should be the numbers of patients with PD on first scans are usually very considered in future modification of the response criteria. small, at least for anti-VEGF therapies in RCC. On the other However, whether 210% or other cutoffs would be optimal hand, the use of the SD category as a basis for continuing for treatment decisions in individual patients is uncertain therapy is conceivably problematic, because the tumor size and would require further, sufficiently powered, prospective could have increased by up to 19%. Indeed, lack of tumor studies. It should be noted that criteria for one agent or one shrinkage (0% SLD reduction) or 110% SLD at the first scan disease setting may not be generalizable to others. As newer was associated with an extremely poor outcome in patients therapeutic agents become available in various clinical treated with sunitinib, with a median PFS of 1.5 months [5]. settings, it may be necessary to further modify existing tumor Further studies with sufficient power would be required to size-based response criteria, verify promising molecular and confirm this finding. functional imaging methods, and investigate new technologies. What isthe general implication of the findings on the use of Finally, before optimal criteria are defined for dichotomous tumor imaging in drug development? This study, among many characterization of tumor responses, it would be desirable to others, reinforced the notion that clinically viable targeted collect tumor size measurements as a continuous variable and agents may have low response rates as defined by RECIST, but evaluate the reporting of antitumor activity based on several tumor shrinkage with smaller magnitudes is common. These cutoffs, rather than just one, for responses or progression. studies further suggest that modification of the response criteria to capture and categorize minor responses may DISCLOSURES provide a more sensitive readout of the therapeutic effect The authors indicated no financial relationships. REFERENCES 1. Therasse P, Arbuck SG, Eisenhauer EA et al. Current perspectives. Discov Med 2010;10: 6. Abel EJ, Culp SH, Tannir NM et al. Early primary New guidelines to evaluate the response to 394–405. tumor size reduction is an independent predictor of treatment in solid tumors. European Organization improved overall survival in metastatic renal cell 4. Krajewski KM, Guo M, Van den Abbeele AD for Research and Treatment of Cancer, National carcinoma patients treated with sunitinib. Eur Urol et al. Comparison of four early posttherapy Cancer Institute of the United States, National 2011;60:1273–1279. imaging changes (EPTIC; RECIST 1.0, tumor shrink- Cancer Institute of Canada. J Natl Cancer Inst 2000; age, computed tomography tumor density, Choi 7. Smith AD, Lieber ML, Shah SN. Assessing tumor 92:205–216. criteria) in assessing outcome to vascular endo- response and detecting recurrence in metastatic 2. Krajewski KM, Franchetti Y, Nishino M et al. 10% thelial growth factor-targeted therapy in patients renal cell carcinoma on targeted therapy: Impor- tumor diameter shrinkage on the first follow-up with advanced renal cell carcinoma. Eur Urol 2011; tance of size and attenuation on contrast-enhanced computed tomography predicts clinical outcome in 59:856–862. CT. AJR Am J Roentgenol 2010;194:157–165. patients with advanced renal cell carcinoma treated 5. Thiam R, Fournier LS, Trinquart L et al. Opti- 8. Oudard S,Thiam R, Fournier LS et al. Optimisation with angiogenesis inhibitors: A follow-up validation mizing the size variation threshold for the CT of the tumour response threshold in patients treated study. The Oncologist 2014;19:507–514. evaluation of response in metastatic renal cell with everolimus for metastatic renal cell carcinoma: 3. van der Veldt AA, Haanen JB, van den Eertwegh carcinoma treated with sunitinib. Ann Oncol 2010; Analysis of response and progression-free survival in AJ et al. Targeted therapy for renal cell cancer: 21:936–941. theRECORD-1study.EurJCancer2012;48:1512–1518. EDITOR’S NOTE: See the related article, “10% Tumor Diameter Shrinkage on the First Follow-Up Computed Tomography Predicts Clinical Outcome in Patients With Advanced Renal Cell Carcinoma Treated With Angiogenesis Inhibitors: A Follow-Up Validation Study,” by Katherine M. Krajewski et al., on page 507 of this issue. The ©AlphaMed Press 2014 Oncologist

Journal

The Oncologist – Oxford University Press

Published: May 1, 2014

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