Comment
value of 5 CTCs per 7·5 mL or higher have intrinsically resistant disease and will derive little benefit from standard treatments. Longitudinal monitoring enabled early identification of patients with refractory disease10 (no decrease below 5 CTCs per 7·5 mL or unchanged ≥5 CTCs per 7·5 mL) for whom alternative and more effective therapies, including CTC-directed therapies, must be developed. CTCs are an invaluable instrument for treating physicians who can now use a more rational approach to management of patients with metastatic breast cancer. Should CTCs be incorporated into stratification in prospective clinical trials? If existing randomisation procedures are unable to account for the difference in baseline phenotypic and clinical characteristics by CTC count then no matter how large the population, these randomised studies might include an intrinsic bias, which could affect results and interpretation. The FDA and pharmaceutical industry should carefully consider the incorporation of enumeration of CTCs and possibly molecular analysis in future clinical trials, particularly when testing molecularly targeted agents. This approach should allow detection of any preferential therapeutic benefit in specific CTC-subsets.
Massimo Cristofanilli Thomas Jefferson University, Philadelphia, PA 19107, USA massimo.cristofanilli@jefferson.edu I am a consultant for Cynvenio. 1
2
3 4
5
6
7
8
9
10
Cardoso F, Harbeck N, Fallowfield L, et al. Locally recurrent or metastatic breast cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2012; 23 (suppl 7): vii11–19. Yu KD, Zhu R, Zhan M, et al. Identification of prognosis-relevant subgroups in patients with chemoresistant triple-negative breast cancer. Clin Cancer Res 2013; 19: 2723–33. Kim MY, Oskarsson T, Acharyya S, et al. Tumor self-seeding by circulating cancer cells. Cell 2009; 139: 1315–26. Allard WJ, Matera J, Miller MC, et al. Tumor cells circulate in the peripheral blood of all major carcinomas but not in healthy subjects or patients with nonmalignant diseases. Clin Cancer Res 2004; 10: 6897–904. Powell AA, Talasaz AH, Zhang H, et al. Single cell profiling of circulating tumor cells: transcriptional heterogeneity and diversity from breast cancer cell lines. PLoS One 2012; 7: e33788. Singh JK, Farnie G, Bundred NJ, et al. Targeting CXCR1/2 significantly reduces breast cancer stem cell activity and increases the efficiency of inhibiting HER2 via HER2-dependent and -independent mechanisms. Clin Cancer Res 2013; 19: 643–56. Cristofanilli M, Budd GT, Ellis MJ, et al. Circulating tumor cells, disease progression, and survival in metastatic breast cancer. N Engl J Med 2004; 351: 781–91. Budd GT, Cristofanilli M, Ellis MJ, et al. Circulating tumor cells versus imaging: predicting overall survival in metastatic breast cancer. Clin Cancer Res 2006; 12: 6403–09. Harris L, Fritsche H, Mennel R, et al. American Society of Clinical Oncology 2007 update of recommendations for the use of tumor markers in breast cancer. J Clin Oncol 2007; 25: 5287–5312. Bidard F-C, Peeters DJ, Fehm T, et al. Clinical validity of circulating tumour cells in patients with metastatic breast cancer: a pooled analysis of individual patient data. Lancet Oncol 2014; published online March 11. http://dx.doi.org/10.1016/S1470-2045(14)70069-5.
Photostock-Israel/Science Photo Library
One step forward, two steps back
See Articles page 415
366
Doxorubicin was shown to have activity against softtissue sarcomas in 1969.1 Combination treatment with dacarbazine2 and ifosfamide3 improves responses but not progression-free survival or overall survival.4 Single-agent doxorubicin is still standard treatment in much of Europe. Dose-intensive doxorubicin and ifosfamide, taking advantage of the steep dose– response curves for both drugs, results in high responses and improved progression-free survival and possibly overall survival.5,6 In The Lancet Oncology, Ian Judson and colleagues7 report results of a randomised phase 3 study of 455 patients with metastatic soft-tissue sarcoma. Patients entering the study had to have disease progression within 6 weeks of study entry. Doxorubicin alone failed to prevent further progression in 32% of patients, while the combination failed in only 13%. The combination group had a higher overall response than the doxrubicin only group (26% vs
14%) and longer median progression-free survival (7·4 months vs 4·6 months). Judson and colleagues interpreted their data negatively, concluding that that the difference for the primary endpoint—overall survival—was not statistically significant. We believe that their findings provide convincing evidence that dose-intensive doxorubicin and ifosfamide is superior to doxorubicin alone. Readers should draw their own conclusions. Our research group was approached, but declined, to participate in this study, primarily because we felt that overall survival is the wrong primary endpoint for phase 3 studies of initial treatment. Survival is a perfect endpoint for a laboratory study. In a clinical trial it is a composite endpoint, affected not only by the treatment under study, but also by everything that happens subsequently until the patient dies. Survival is an appropriate endpoint only for patients near death or those who are probably curable. Physicians try to www.thelancet.com/oncology Vol 15 April 2014
Comment
keep their patients alive. In this study 64% of patients had subsequent chemotherapy and 20% had surgery, which might have affected overall survival. The only realistic expectation of initial treatment is to add the time that it controls the disease to the time the patient has to live as a result of the disease’s natural history and subsequent treatment. If a treatment associated with lower disease progression decreased survival because of late toxic effects or increased secondary resistance, survival should be the critical controlling factor for interpretation of benefit. Otherwise, progression-free survival is a better endpoint. Patients in this trial were highly selected: those who might benefit substantially from tumour regression were less likely to be enrolled and those not expected to tolerate the combination regimen were excluded. What proportion of patients who were eligible for the study was offered participation is unclear. The sample size and power calculation for the study were based on the assumptions that the overall survival follows the exponential distribution and that survival improvement would be considered as clinically significant if 1-year survival was at least a 10% higher in the combination group (60% vs 50%, hazard ratio [HR] 0·737). 60% of patients in the combination group were still alive after 1 year, but 51% treated with doxorubicin alone were alive at 1 year, so the HR under the exponential model should be 0·76. However, the actual HR was 0·83 (95·5% CI 0·67–1·03) by stratified logrank test (p=0·076). The survival curves for the two groups separate early on, but approach each other after 2 years. Thus, the proportional hazards assumption is violated. In this case, the original statistical power could not be attained without a larger study. The increased late mortality was predictable in patients eligible for this study. The choice of the 5% significance level—albeit conventional—is arbitrary.8 Had the investigators chosen a 10% type 1 error or targeted an 8% improvement in 1-year survival, they would have concluded that survival was improved. Few patients would prefer a 51% chance of being alive at 1 year over a 60% chance, despite increased toxic effects. An alternative method to evaluate the evidence against the null hypothesis is the Bayes factor approach. With an approximately 20% or lower previous probability that the null hypothesis is true, a p value of 0·07 provides moderate evidence against the null hypothesis.9 www.thelancet.com/oncology Vol 15 April 2014
So, despite the fact that it was the wrong endpoint, overall survival was improved. We believe that clinical investigators and regulators should reject the complex, partly indirect, and easily confounded endpoint of overall survival as the primary measure of therapeutic efficacy in favour of endpoints that measure the direct effects of the treatments studied: progression-free survival, response rate, and failure rate. We do need treatment that improves survival of patients with advanced soft-tissue sarcoma, but if we refuse to build on the small steps that have been made in sarcoma treatment, we will not improve overall survival without major breakthroughs. Clinicians who have patients with soft-tissue sarcoma should choose dose-intense doxorubicin and ifosfamide if they want the treatment that is most likely to benefit their patients. Investigators should design studies that build on the findings— admittedly inadequate—about dose-intense doxorubicin and ifosfamide and use it as their comparator while searching for more effective approaches. We need to move forward, but just because we have not progressed far enough, we should not move back. *Robert S Benjamin, J Jack Lee Department of Sarcoma Medical Oncology, Unit 450, PO Box 301439 (RSB), and Department of Biostatistics (JJL), University of Texas MD Anderson Cancer Center, Houston, TX 77230-1439, USA [email protected] We declare that we have no competing interests. 1
2
3
4
5
6 7
8
9
Bonadonna G, Monfardini S, de Lena M, Fossati-Bellani F. Clinical evaluation of adriamycin, a new antitumor antibiotic. Br Med J 1969; 3: 503–06. Gottlieb JA, Baker LH, Quagliana JM, et al. Chemotherapy of sarcomas with a combination of adriamycin and dimethyl triazeno imidazole carboxamide. Cancer 1972; 30: 1632–38. Wiltshaw E, Westbury G, Harmer C, McKinna A, Fisher C. Ifosfamide plus mesna with and without adriamycin in soft tissue sarcoma. Cancer Treat Rev 1983; 10 (suppl A): 163–64. Santoro A, Tursz T, Mouridsen H, et al. Doxorubicin versus doxorubicin plus ifosfamide versus CYVADIC in first-line treatment of advanced soft tissue sarcomas: a randomized study of the European Organization for Research and Treatment of Cancer Soft Tissue and Bone Sarcoma Group. J Clin Oncol 1995; 13: 1537–45. Patel SR, Vadhan-Raj S, Burgess MA, et al. Results of two consecutive trials of dose-intensive chemotherapy with doxorubicin and ifosfamide in patients with sarcomas. Am J Clin Oncol 1998; 21: 317–21. Patel SR. Dose-intensive chemotherapy for soft-tissue sarcomas. Am Soc Clin Oncol Educ Book 2000; 453–57. Judson I, Verweij J, Gelderblom H, et al. Doxorubicin alone versus intensified doxorubicin plus ifosfamide for first-line treatment of advanced or metastatic soft-tissue sarcoma: a randomised controlled phase 3 trial. Lancet Oncol 2014; 15: 415–23. Freireich EJ. Who took the clinical out of clinical research? – Mouse versus man: seventh David A Karnofsky Memorial Lecture – 1976. Clin Cancer Res 1997; 3: 2711–22. Goodman SN. Toward evidence-based medical statistics 2: The Bayes factor. Ann Intern Med 1999; 130: 1005–13.
367
value of 5 CTCs per 7·5 mL or higher have intrinsically resistant disease and will derive little benefit from standard treatments. Longitudinal monitoring enabled early identification of patients with refractory disease10 (no decrease below 5 CTCs per 7·5 mL or unchanged ≥5 CTCs per 7·5 mL) for whom alternative and more effective therapies, including CTC-directed therapies, must be developed. CTCs are an invaluable instrument for treating physicians who can now use a more rational approach to management of patients with metastatic breast cancer. Should CTCs be incorporated into stratification in prospective clinical trials? If existing randomisation procedures are unable to account for the difference in baseline phenotypic and clinical characteristics by CTC count then no matter how large the population, these randomised studies might include an intrinsic bias, which could affect results and interpretation. The FDA and pharmaceutical industry should carefully consider the incorporation of enumeration of CTCs and possibly molecular analysis in future clinical trials, particularly when testing molecularly targeted agents. This approach should allow detection of any preferential therapeutic benefit in specific CTC-subsets.
Massimo Cristofanilli Thomas Jefferson University, Philadelphia, PA 19107, USA massimo.cristofanilli@jefferson.edu I am a consultant for Cynvenio. 1
2
3 4
5
6
7
8
9
10
Cardoso F, Harbeck N, Fallowfield L, et al. Locally recurrent or metastatic breast cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2012; 23 (suppl 7): vii11–19. Yu KD, Zhu R, Zhan M, et al. Identification of prognosis-relevant subgroups in patients with chemoresistant triple-negative breast cancer. Clin Cancer Res 2013; 19: 2723–33. Kim MY, Oskarsson T, Acharyya S, et al. Tumor self-seeding by circulating cancer cells. Cell 2009; 139: 1315–26. Allard WJ, Matera J, Miller MC, et al. Tumor cells circulate in the peripheral blood of all major carcinomas but not in healthy subjects or patients with nonmalignant diseases. Clin Cancer Res 2004; 10: 6897–904. Powell AA, Talasaz AH, Zhang H, et al. Single cell profiling of circulating tumor cells: transcriptional heterogeneity and diversity from breast cancer cell lines. PLoS One 2012; 7: e33788. Singh JK, Farnie G, Bundred NJ, et al. Targeting CXCR1/2 significantly reduces breast cancer stem cell activity and increases the efficiency of inhibiting HER2 via HER2-dependent and -independent mechanisms. Clin Cancer Res 2013; 19: 643–56. Cristofanilli M, Budd GT, Ellis MJ, et al. Circulating tumor cells, disease progression, and survival in metastatic breast cancer. N Engl J Med 2004; 351: 781–91. Budd GT, Cristofanilli M, Ellis MJ, et al. Circulating tumor cells versus imaging: predicting overall survival in metastatic breast cancer. Clin Cancer Res 2006; 12: 6403–09. Harris L, Fritsche H, Mennel R, et al. American Society of Clinical Oncology 2007 update of recommendations for the use of tumor markers in breast cancer. J Clin Oncol 2007; 25: 5287–5312. Bidard F-C, Peeters DJ, Fehm T, et al. Clinical validity of circulating tumour cells in patients with metastatic breast cancer: a pooled analysis of individual patient data. Lancet Oncol 2014; published online March 11. http://dx.doi.org/10.1016/S1470-2045(14)70069-5.
Photostock-Israel/Science Photo Library
One step forward, two steps back
See Articles page 415
366
Doxorubicin was shown to have activity against softtissue sarcomas in 1969.1 Combination treatment with dacarbazine2 and ifosfamide3 improves responses but not progression-free survival or overall survival.4 Single-agent doxorubicin is still standard treatment in much of Europe. Dose-intensive doxorubicin and ifosfamide, taking advantage of the steep dose– response curves for both drugs, results in high responses and improved progression-free survival and possibly overall survival.5,6 In The Lancet Oncology, Ian Judson and colleagues7 report results of a randomised phase 3 study of 455 patients with metastatic soft-tissue sarcoma. Patients entering the study had to have disease progression within 6 weeks of study entry. Doxorubicin alone failed to prevent further progression in 32% of patients, while the combination failed in only 13%. The combination group had a higher overall response than the doxrubicin only group (26% vs
14%) and longer median progression-free survival (7·4 months vs 4·6 months). Judson and colleagues interpreted their data negatively, concluding that that the difference for the primary endpoint—overall survival—was not statistically significant. We believe that their findings provide convincing evidence that dose-intensive doxorubicin and ifosfamide is superior to doxorubicin alone. Readers should draw their own conclusions. Our research group was approached, but declined, to participate in this study, primarily because we felt that overall survival is the wrong primary endpoint for phase 3 studies of initial treatment. Survival is a perfect endpoint for a laboratory study. In a clinical trial it is a composite endpoint, affected not only by the treatment under study, but also by everything that happens subsequently until the patient dies. Survival is an appropriate endpoint only for patients near death or those who are probably curable. Physicians try to www.thelancet.com/oncology Vol 15 April 2014
Comment
keep their patients alive. In this study 64% of patients had subsequent chemotherapy and 20% had surgery, which might have affected overall survival. The only realistic expectation of initial treatment is to add the time that it controls the disease to the time the patient has to live as a result of the disease’s natural history and subsequent treatment. If a treatment associated with lower disease progression decreased survival because of late toxic effects or increased secondary resistance, survival should be the critical controlling factor for interpretation of benefit. Otherwise, progression-free survival is a better endpoint. Patients in this trial were highly selected: those who might benefit substantially from tumour regression were less likely to be enrolled and those not expected to tolerate the combination regimen were excluded. What proportion of patients who were eligible for the study was offered participation is unclear. The sample size and power calculation for the study were based on the assumptions that the overall survival follows the exponential distribution and that survival improvement would be considered as clinically significant if 1-year survival was at least a 10% higher in the combination group (60% vs 50%, hazard ratio [HR] 0·737). 60% of patients in the combination group were still alive after 1 year, but 51% treated with doxorubicin alone were alive at 1 year, so the HR under the exponential model should be 0·76. However, the actual HR was 0·83 (95·5% CI 0·67–1·03) by stratified logrank test (p=0·076). The survival curves for the two groups separate early on, but approach each other after 2 years. Thus, the proportional hazards assumption is violated. In this case, the original statistical power could not be attained without a larger study. The increased late mortality was predictable in patients eligible for this study. The choice of the 5% significance level—albeit conventional—is arbitrary.8 Had the investigators chosen a 10% type 1 error or targeted an 8% improvement in 1-year survival, they would have concluded that survival was improved. Few patients would prefer a 51% chance of being alive at 1 year over a 60% chance, despite increased toxic effects. An alternative method to evaluate the evidence against the null hypothesis is the Bayes factor approach. With an approximately 20% or lower previous probability that the null hypothesis is true, a p value of 0·07 provides moderate evidence against the null hypothesis.9 www.thelancet.com/oncology Vol 15 April 2014
So, despite the fact that it was the wrong endpoint, overall survival was improved. We believe that clinical investigators and regulators should reject the complex, partly indirect, and easily confounded endpoint of overall survival as the primary measure of therapeutic efficacy in favour of endpoints that measure the direct effects of the treatments studied: progression-free survival, response rate, and failure rate. We do need treatment that improves survival of patients with advanced soft-tissue sarcoma, but if we refuse to build on the small steps that have been made in sarcoma treatment, we will not improve overall survival without major breakthroughs. Clinicians who have patients with soft-tissue sarcoma should choose dose-intense doxorubicin and ifosfamide if they want the treatment that is most likely to benefit their patients. Investigators should design studies that build on the findings— admittedly inadequate—about dose-intense doxorubicin and ifosfamide and use it as their comparator while searching for more effective approaches. We need to move forward, but just because we have not progressed far enough, we should not move back. *Robert S Benjamin, J Jack Lee Department of Sarcoma Medical Oncology, Unit 450, PO Box 301439 (RSB), and Department of Biostatistics (JJL), University of Texas MD Anderson Cancer Center, Houston, TX 77230-1439, USA [email protected] We declare that we have no competing interests. 1
2
3
4
5
6 7
8
9
Bonadonna G, Monfardini S, de Lena M, Fossati-Bellani F. Clinical evaluation of adriamycin, a new antitumor antibiotic. Br Med J 1969; 3: 503–06. Gottlieb JA, Baker LH, Quagliana JM, et al. Chemotherapy of sarcomas with a combination of adriamycin and dimethyl triazeno imidazole carboxamide. Cancer 1972; 30: 1632–38. Wiltshaw E, Westbury G, Harmer C, McKinna A, Fisher C. Ifosfamide plus mesna with and without adriamycin in soft tissue sarcoma. Cancer Treat Rev 1983; 10 (suppl A): 163–64. Santoro A, Tursz T, Mouridsen H, et al. Doxorubicin versus doxorubicin plus ifosfamide versus CYVADIC in first-line treatment of advanced soft tissue sarcomas: a randomized study of the European Organization for Research and Treatment of Cancer Soft Tissue and Bone Sarcoma Group. J Clin Oncol 1995; 13: 1537–45. Patel SR, Vadhan-Raj S, Burgess MA, et al. Results of two consecutive trials of dose-intensive chemotherapy with doxorubicin and ifosfamide in patients with sarcomas. Am J Clin Oncol 1998; 21: 317–21. Patel SR. Dose-intensive chemotherapy for soft-tissue sarcomas. Am Soc Clin Oncol Educ Book 2000; 453–57. Judson I, Verweij J, Gelderblom H, et al. Doxorubicin alone versus intensified doxorubicin plus ifosfamide for first-line treatment of advanced or metastatic soft-tissue sarcoma: a randomised controlled phase 3 trial. Lancet Oncol 2014; 15: 415–23. Freireich EJ. Who took the clinical out of clinical research? – Mouse versus man: seventh David A Karnofsky Memorial Lecture – 1976. Clin Cancer Res 1997; 3: 2711–22. Goodman SN. Toward evidence-based medical statistics 2: The Bayes factor. Ann Intern Med 1999; 130: 1005–13.
367
