- Email: [email protected]
PET-adapted salvage therapy for Hodgkin's lymphoma
Correspondence
therapy by receiving a short course of radiotherapy would be a preferable option.8 Patients with worse prognoses will be entitled to receive endocrine therapy as standard of care anyway, and for these patients, the value added by radiotherapy might be questionable. Unfortunately, because few such patients were entered into PRIME II, direct guidance as to how such patients should be managed remains to be established. DM has received consultancy fees from Ariane Medical Systems. All other authors declare no competing interests.
*Orit Kaidar-Person, Philip Poortmans, Abraham Kuten, David A L Morgan [email protected] Division of Oncology, Rambam Health Care Campus, Haifa 31096, Israel (OK-P); Department of Radiation Oncology, Radboud University Medical Center, Nijmegen, Netherlands (PP); Oncology Service, Italian Hospital of Haifa, Haifa, Israel (AK); and Breast Services, Sherwood Forest Hospitals NHS Foundation Trust, Nottinghamshire, England (DALM) 1
2
3
4
5
6
7
8
Kunkler IH, Williams LJ, Jack WJ, et al. Breastconserving surgery with or without irradiation in women aged 65 years or older with early breast cancer (PRIME II): a randomised controlled trial. Lancet Oncol 2015; 16: 266–73. Hughes KS, Schnaper LA, Bellon JR, et al. Lumpectomy plus tamoxifen with or without irradiation in women age 70 years or older with early breast cancer: long-term follow-up of CALGB 9343. J Clin Oncol 2013; 31: 2382–87. Fyles AW, McCready DR, Manchul LA, et al. Tamoxifen with or without breast irradiation in women 50 years of age or older with early breast cancer. N Engl J Med 2004; 351: 963–70. Blamey RW, Bates T, Chetty U, et al. Radiotherapy or tamoxifen after conserving surgery for breast cancers of excellent prognosis: British Association of Surgical Oncology (BASO) II trial. Eur J Cancer 2013; 49: 2294–302. Early Breast Cancer Trialists’ Collaborative Group (EBCTCG). Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomised trials. Lancet 2005; 365: 1687–717. Murphy CC, Bartholomew LK, Carpentier MY, et al. Adherence to adjuvant hormonal therapy among breast cancer survivors in clinical practice: a systematic review. Breast Cancer Res Treat 2012; 134: 459–78. Davies C, Pan H, Godwin J, et al. Long-term effects of continuing adjuvant tamoxifen to 10 years versus stopping at 5 years after diagnosis of oestrogen receptor-positive breast cancer: ATLAS, a randomised trial. Lancet 2013; 381: 805–16. Walker GA, Kaider-Person O, Kuten A, Morgan DAL. Radiotherapy as sole adjuvant treatment for older patients with low-risk breast cancer. Breast 2012; 21: 629–34.
www.thelancet.com/oncology Vol 16 May 2015
PET-adapted salvage therapy for Hodgkin’s lymphoma In patients with relapsed or refractory Hodgkin’s lymphoma, Alison Moskowitz and colleagues1 assessed the activity and safety of PET-adapted salvage therapy with brentuximab vedotin, which, for patients who were positive for PET after the first salvage treatment with brentuximab vedotin, was followed by augmented ifosfamide, carboplatin, and etoposide (augICE). The aim of the salvage therapy was to attain PET negativity in patients before high-dose therapy and autologous stem-cell transplant, because patients who are PETnegative have excellent outcomes. 18F-fluorodeoxyglucose PET imaging was done after completion of brentuximab vedotin and interpreted by use of the five-point Deauville scale. Patients with a Deauville score of 1 (no uptake) or 2 (uptake less than or equal to the mediastinum) were deemed PET-negative.2 Patients who scored 3 (mediastinum less than uptake, but uptake less than or equal to liver) or more received augICE and were re-examined with PET. Moskowitz and colleagues discussed the fact that the five-point Deauville scale is crucial for assessment of response to treatment, because it differentiates between positive and negative PET scans. Moreover, the scale enables physicians to adjust their decision according to the clinical trial design. Specifically, the researchers commented: “If a negative interim PET scan leads to de-escalation of therapy, stringent criteria should be applied to determine PET-negativity (we used a score of 2 on the five-point scale) to reduce the number of false-negative scans and avoid the undertreatment of patients.”1 With respect to this statement, we would like to point out that the standardised uptake value (SUV) measurement error, which occurs even with strict standardisation
of PET methods, should be considered when defining such stringent criteria. We recently addressed this issue with respect to both liver and mediastinum SUV measurement errors.3,4 Here, we would like to show the potential consequences for clinical decision making with an example with a borderline (cutoff) SUV score between 2 and 3 on the five-point Deauville scale. This example patient has a maximum mediastinum SUV (SUVmax) of 2·0 g/mL with a relative measurement error of 25% (with 95% reliability).4,5 The true mediastinum SUVmax might therefore range between 1·5 and 2·5 g/mL (ie, lower and upper 95% CI limits). Consequently, to avoid a false-negative PET scan leading to undertreatment of this patient, the 2–3 cutoff should be set at 1·5 g/mL, instead of 2·0 g/mL. Conversely, to avoid a false-positive PET scan leading to unwanted escalation of therapy,1 this cutoff should be increased to 2·5 g/mL. For the sake of clarity, this example uses a relative measurement error for mediastinum SUVmax outcome of 25%, which is likely to be an underestimation.4 Furthermore, the 95% CI could be increased to a 99% CI. In conclusion, Moskowitz and colleagues reported proportions of patients with PET negativity after each round of treatment completion, including 95% CIs. To be consistent, we suggest that the five-point Deauville scale should also take account of the SUV measurement error, with appropriate CIs, to adjust clinical decisions. We believe that our example provides evidence that implementation of measurement error, is easy to integrate into assessment of PET, and could be efficient in clinical practice. Furthermore, we suggest that similar reasoning should be used for any cutoff value for SUV, regardless of the disease setting. We declare no competing interests.
*Eric Laffon, Roger Marthan elaff[email protected]
e197
Correspondence
Centre Hospitalier Universitaire de Bordeaux, Universitaire de Bordeaux, Centre de Recherche Cardio-Thoracique de Bordeaux, INSERM U-1045, Bordeaux, France (EL, RM); Service de Médecine Nucléaire, Hôpital du Haut-Lévèque, Pessac 33604, France (EL) 1
2
3
4
5
Moskowitz AJ, Schöder H, Yahalom J, et al. PET-adapted sequential salvage therapy with brentuximab vedotin followed by augmented ifosamide, carboplatin, and etoposide for patients with relapsed and refractory Hodgkin’s lymphoma: a non-randomised, open-label, single-centre, phase 2 study. Lancet Oncol 2015; 16: 284–92. Barrington SL, Mikhaeel NG, Kostakoglu L, et al. Role of imaging in the staging and response assessment of lymphoma: consensus of the International Conference on Malignant Lymphomas Imaging Working Group. J Clin Oncol 2014; 32: 3048–58. Laffon E, Marthan R. Interim FDG PET scans in lymphoma: SUV measurement error may impair qPET methodology. Eur J Nucl Med Mol Imaging 2014; 41: 2154. Laffon E, Marthan R. Quantitative PET imaging for response assessment of FDG-avid lymphomas: should we report SUV confidence limits? J Clin Oncol 2015; published online Feb 17. DOI:10.1200/JCO.2014.59.6833. de Langen AJ, Vincent A, Velasquez LM, et al. Repeatability of 18F-FDG uptake measurements in tumors: a meta-analysis. J Nucl Med 2012; 53: 701–8.
Authors’ reply We appreciate the comments by Eric Laffon and Roger Marthan about our study.1 They are concerned that repeat measurements of standardised
e198
uptake values (SUVs) are subject to statistical and technical error and cite their previous work showing that reproducibility is reasonably high in the liver, but less so for mediastinal blood pool. They also encourage reporting of 95% CI for SUV measurements and measurement errors. We are also interested in the issue of SUV measurement reproducibility and are currently investigating this in our own patient population. Although we recognise these concerns, we would like to point out that interpretation with the five-point scale is essentially based on visual assessment of 18F-fluorodeoxyglucose (FDG) uptake in sites of suspected residual disease compared with reference regions. In this respect, each patient is their own control. Other researchers2,3 have addressed the potential utility of SUV measurements, percentage change in SUV, and cutoffs, but these were not the focus of our study. Some of these metrics might improve the predictive value of FDG PET in response assessment in lymphoma. Once more such data become available, addressing the issue of quantitative
measurement reproducibility and error more thoroughly will become important. Nevertheless, we believe that our results, which are based on the visual five-point scale, are accurate and clinically meaningful, and can provide guidance for future clinical studies to improve the outcome of patients with Hodgkin’s lymphoma. AJM served on an advisory board for Seattle Genetics and received an honorarium. HS and CHM declare no competing interests.
Heiko Schöder, Craig H Moskowitz, *Alison J Moskowitz [email protected] Sloan Kettering Cancer Center, New York, NY, 10065, USA 1
2
3
Moskowitz AJ, Schoder H, Yahalom J, et al. PET-adapted sequential salvage therapy with brentuximab vedotin followed by augmented ifosamide, carboplatin, and etoposide for patients with relapsed and refractory Hodgkin’s lymphoma: a non-randomised, open-label, single-centre, phase 2 study. Lancet Oncology 2015; 16: 284–92. Rossi C, Kanoun S, Berriolo-Riedinger A, et al. Interim 18F-FDG PET SUVmax reduction is superior to visual analysis in predicting outcome early in Hodgkin lymphoma patients. J Nucl Med 2014; 55: 569–73. Kanoun S, Rossi C, Berriolo-Riedinger A, et al. Baseline metabolic tumour volume is an independent prognostic factor in Hodgkin lymphoma. Eur J Nucl Med Mol Imaging 2014; 41: 1735–43.
www.thelancet.com/oncology Vol 16 May 2015
therapy by receiving a short course of radiotherapy would be a preferable option.8 Patients with worse prognoses will be entitled to receive endocrine therapy as standard of care anyway, and for these patients, the value added by radiotherapy might be questionable. Unfortunately, because few such patients were entered into PRIME II, direct guidance as to how such patients should be managed remains to be established. DM has received consultancy fees from Ariane Medical Systems. All other authors declare no competing interests.
*Orit Kaidar-Person, Philip Poortmans, Abraham Kuten, David A L Morgan [email protected] Division of Oncology, Rambam Health Care Campus, Haifa 31096, Israel (OK-P); Department of Radiation Oncology, Radboud University Medical Center, Nijmegen, Netherlands (PP); Oncology Service, Italian Hospital of Haifa, Haifa, Israel (AK); and Breast Services, Sherwood Forest Hospitals NHS Foundation Trust, Nottinghamshire, England (DALM) 1
2
3
4
5
6
7
8
Kunkler IH, Williams LJ, Jack WJ, et al. Breastconserving surgery with or without irradiation in women aged 65 years or older with early breast cancer (PRIME II): a randomised controlled trial. Lancet Oncol 2015; 16: 266–73. Hughes KS, Schnaper LA, Bellon JR, et al. Lumpectomy plus tamoxifen with or without irradiation in women age 70 years or older with early breast cancer: long-term follow-up of CALGB 9343. J Clin Oncol 2013; 31: 2382–87. Fyles AW, McCready DR, Manchul LA, et al. Tamoxifen with or without breast irradiation in women 50 years of age or older with early breast cancer. N Engl J Med 2004; 351: 963–70. Blamey RW, Bates T, Chetty U, et al. Radiotherapy or tamoxifen after conserving surgery for breast cancers of excellent prognosis: British Association of Surgical Oncology (BASO) II trial. Eur J Cancer 2013; 49: 2294–302. Early Breast Cancer Trialists’ Collaborative Group (EBCTCG). Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomised trials. Lancet 2005; 365: 1687–717. Murphy CC, Bartholomew LK, Carpentier MY, et al. Adherence to adjuvant hormonal therapy among breast cancer survivors in clinical practice: a systematic review. Breast Cancer Res Treat 2012; 134: 459–78. Davies C, Pan H, Godwin J, et al. Long-term effects of continuing adjuvant tamoxifen to 10 years versus stopping at 5 years after diagnosis of oestrogen receptor-positive breast cancer: ATLAS, a randomised trial. Lancet 2013; 381: 805–16. Walker GA, Kaider-Person O, Kuten A, Morgan DAL. Radiotherapy as sole adjuvant treatment for older patients with low-risk breast cancer. Breast 2012; 21: 629–34.
www.thelancet.com/oncology Vol 16 May 2015
PET-adapted salvage therapy for Hodgkin’s lymphoma In patients with relapsed or refractory Hodgkin’s lymphoma, Alison Moskowitz and colleagues1 assessed the activity and safety of PET-adapted salvage therapy with brentuximab vedotin, which, for patients who were positive for PET after the first salvage treatment with brentuximab vedotin, was followed by augmented ifosfamide, carboplatin, and etoposide (augICE). The aim of the salvage therapy was to attain PET negativity in patients before high-dose therapy and autologous stem-cell transplant, because patients who are PETnegative have excellent outcomes. 18F-fluorodeoxyglucose PET imaging was done after completion of brentuximab vedotin and interpreted by use of the five-point Deauville scale. Patients with a Deauville score of 1 (no uptake) or 2 (uptake less than or equal to the mediastinum) were deemed PET-negative.2 Patients who scored 3 (mediastinum less than uptake, but uptake less than or equal to liver) or more received augICE and were re-examined with PET. Moskowitz and colleagues discussed the fact that the five-point Deauville scale is crucial for assessment of response to treatment, because it differentiates between positive and negative PET scans. Moreover, the scale enables physicians to adjust their decision according to the clinical trial design. Specifically, the researchers commented: “If a negative interim PET scan leads to de-escalation of therapy, stringent criteria should be applied to determine PET-negativity (we used a score of 2 on the five-point scale) to reduce the number of false-negative scans and avoid the undertreatment of patients.”1 With respect to this statement, we would like to point out that the standardised uptake value (SUV) measurement error, which occurs even with strict standardisation
of PET methods, should be considered when defining such stringent criteria. We recently addressed this issue with respect to both liver and mediastinum SUV measurement errors.3,4 Here, we would like to show the potential consequences for clinical decision making with an example with a borderline (cutoff) SUV score between 2 and 3 on the five-point Deauville scale. This example patient has a maximum mediastinum SUV (SUVmax) of 2·0 g/mL with a relative measurement error of 25% (with 95% reliability).4,5 The true mediastinum SUVmax might therefore range between 1·5 and 2·5 g/mL (ie, lower and upper 95% CI limits). Consequently, to avoid a false-negative PET scan leading to undertreatment of this patient, the 2–3 cutoff should be set at 1·5 g/mL, instead of 2·0 g/mL. Conversely, to avoid a false-positive PET scan leading to unwanted escalation of therapy,1 this cutoff should be increased to 2·5 g/mL. For the sake of clarity, this example uses a relative measurement error for mediastinum SUVmax outcome of 25%, which is likely to be an underestimation.4 Furthermore, the 95% CI could be increased to a 99% CI. In conclusion, Moskowitz and colleagues reported proportions of patients with PET negativity after each round of treatment completion, including 95% CIs. To be consistent, we suggest that the five-point Deauville scale should also take account of the SUV measurement error, with appropriate CIs, to adjust clinical decisions. We believe that our example provides evidence that implementation of measurement error, is easy to integrate into assessment of PET, and could be efficient in clinical practice. Furthermore, we suggest that similar reasoning should be used for any cutoff value for SUV, regardless of the disease setting. We declare no competing interests.
*Eric Laffon, Roger Marthan elaff[email protected]
e197
Correspondence
Centre Hospitalier Universitaire de Bordeaux, Universitaire de Bordeaux, Centre de Recherche Cardio-Thoracique de Bordeaux, INSERM U-1045, Bordeaux, France (EL, RM); Service de Médecine Nucléaire, Hôpital du Haut-Lévèque, Pessac 33604, France (EL) 1
2
3
4
5
Moskowitz AJ, Schöder H, Yahalom J, et al. PET-adapted sequential salvage therapy with brentuximab vedotin followed by augmented ifosamide, carboplatin, and etoposide for patients with relapsed and refractory Hodgkin’s lymphoma: a non-randomised, open-label, single-centre, phase 2 study. Lancet Oncol 2015; 16: 284–92. Barrington SL, Mikhaeel NG, Kostakoglu L, et al. Role of imaging in the staging and response assessment of lymphoma: consensus of the International Conference on Malignant Lymphomas Imaging Working Group. J Clin Oncol 2014; 32: 3048–58. Laffon E, Marthan R. Interim FDG PET scans in lymphoma: SUV measurement error may impair qPET methodology. Eur J Nucl Med Mol Imaging 2014; 41: 2154. Laffon E, Marthan R. Quantitative PET imaging for response assessment of FDG-avid lymphomas: should we report SUV confidence limits? J Clin Oncol 2015; published online Feb 17. DOI:10.1200/JCO.2014.59.6833. de Langen AJ, Vincent A, Velasquez LM, et al. Repeatability of 18F-FDG uptake measurements in tumors: a meta-analysis. J Nucl Med 2012; 53: 701–8.
Authors’ reply We appreciate the comments by Eric Laffon and Roger Marthan about our study.1 They are concerned that repeat measurements of standardised
e198
uptake values (SUVs) are subject to statistical and technical error and cite their previous work showing that reproducibility is reasonably high in the liver, but less so for mediastinal blood pool. They also encourage reporting of 95% CI for SUV measurements and measurement errors. We are also interested in the issue of SUV measurement reproducibility and are currently investigating this in our own patient population. Although we recognise these concerns, we would like to point out that interpretation with the five-point scale is essentially based on visual assessment of 18F-fluorodeoxyglucose (FDG) uptake in sites of suspected residual disease compared with reference regions. In this respect, each patient is their own control. Other researchers2,3 have addressed the potential utility of SUV measurements, percentage change in SUV, and cutoffs, but these were not the focus of our study. Some of these metrics might improve the predictive value of FDG PET in response assessment in lymphoma. Once more such data become available, addressing the issue of quantitative
measurement reproducibility and error more thoroughly will become important. Nevertheless, we believe that our results, which are based on the visual five-point scale, are accurate and clinically meaningful, and can provide guidance for future clinical studies to improve the outcome of patients with Hodgkin’s lymphoma. AJM served on an advisory board for Seattle Genetics and received an honorarium. HS and CHM declare no competing interests.
Heiko Schöder, Craig H Moskowitz, *Alison J Moskowitz [email protected] Sloan Kettering Cancer Center, New York, NY, 10065, USA 1
2
3
Moskowitz AJ, Schoder H, Yahalom J, et al. PET-adapted sequential salvage therapy with brentuximab vedotin followed by augmented ifosamide, carboplatin, and etoposide for patients with relapsed and refractory Hodgkin’s lymphoma: a non-randomised, open-label, single-centre, phase 2 study. Lancet Oncology 2015; 16: 284–92. Rossi C, Kanoun S, Berriolo-Riedinger A, et al. Interim 18F-FDG PET SUVmax reduction is superior to visual analysis in predicting outcome early in Hodgkin lymphoma patients. J Nucl Med 2014; 55: 569–73. Kanoun S, Rossi C, Berriolo-Riedinger A, et al. Baseline metabolic tumour volume is an independent prognostic factor in Hodgkin lymphoma. Eur J Nucl Med Mol Imaging 2014; 41: 1735–43.
www.thelancet.com/oncology Vol 16 May 2015