Correspondence
with 7% in MITO-7, and grade 3–4 anaemia occurred in 44% of patients in NOVEL versus 3% in MITO-7. Pignata and colleagues1 speculate that such large differences indicate possible genetic causes, especially genetic polymorphisms in paclitaxel metabolism that differ between European and Asian patients. However, differences in the methods used to measure creatinine might also have a role. The dose of carboplatin is traditionally calculated using the Calvert formula, which includes glomerular filtration rate (GFR) as a parameter. However, creatinine clearance is usually used instead of GFR. Various methods can be used to measure serum creatinine concentration (and thus to calculate creatinine clearance), such as the Jaffe kinetic method, the enzymatic method, and the isotope dilution mass spectrometry traceable method. We have previously reported that serum creatinine concentrations measured by the Jaffe kinetic method are consistently higher than the true concentrations by 0·1–0·3 mg/dL, because of interference by non-specific substrates in the serum.4 Thus the creatinine clearance rate based on results from the Jaffe kinetic method is an underestimation of the GFR, but remains close to the GFR. By contrast, measurement of the creatinine clearance rate using the serum creatinine concentrations measured with specific assays overestimates the GFR in some patients with normal renal function. Thus, measurement with specific assays can potentially lead to overdosing with carboplatin.4,5 Even a small overdose with carboplatin can cause unexpected severe toxicity because of its narrow therapeutic index,4 particularly in women who have lower creatinine concentrations than men. The MITO-7 investigators1 used the Cockcroft-Gault formula to calculate creatinine clearance rate, but the method used to measure serum e250
creatinine concentrations was not reported. The NOVEL investigators2,3 used the Calvert formula. In the MITO-7 trial,1 neither the means used to determine creatinine clearance rate nor the method used to determine serum creatinine concentrations were reported. By contrast, the NOVEL investigators2,3 used the Jelliffe method to estimate the creatinine clearance rate, although they do not state explicitly what method was used to estimate serum creatinine concentrations. In Japan, enzymatic methods have been commonly used in clinical laboratories since the mid-1990s, whereas it seems that methods might be less standardised in Italy.6 Thus, it is possible that the higher rate of toxicity in the Japanese NOVEL trial than in the European MITO-7 trial might be due to overdosing of carboplatin as a result of using standardised methods to assess serum creatinine concentration. Of note, standardised serum creatinine measurements became widely used in the USA by the end of 2010, which could lead to an increased incidence of carboplatin-related toxicity.7 We declare no competing interests.
*Tomoya Shimokata, Yuichi Ando [email protected] Department of Clinical Oncology and Chemotherapy, Nagoya University Hospital, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan (TS, YA) 1
2
3
Pignata S, Scambia G, Katsaros D, et al. Carboplatin plus paclitaxel once a week versus every 3 weeks in patients with advanced ovarian cancer (MITO-7): a randomised, multicentre, open-label, phase 3 trial. Lancet Oncol 2014; 15: 396–405. Katsumata N, Yasuda M, Takahashi F, et al. Dose-dense paclitaxel once a week in combination with carboplatin every 3 weeks for advanced ovarian cancer: a phase 3, open-label, randomised controlled trial. Lancet 2009; 374: 1331–38. Katsumata N, Yasuda M, Isonishi S, et al, for the Japanese Gynecologic Oncology Group. Long-term results of dose-dense paclitaxel and carboplatin versus conventional paclitaxel and carboplatin for treatment of advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer (JGOG 3016): a randomised, controlled, open-label trial. Lancet Oncol 2013; 14: 1020–26.
4
5
6
7
Ando Y, Shimokata T, Yasuda Y, Hasegawa Y. Carboplatin dosing for adult Japanese patients. Nagoya J Med Sci 2014; 76: 1–9. Shimokata T, Ando Y, Yasuda Y, et al. Prospective evaluation of pharmacokinetically guided dosing of carboplatin in Japanese patients with cancer. Cancer Sci 2010; 101: 2601–05. Carobene A, Ceriotti F, Infusino I, et al. Evaluation of the impact of standardization process on the quality of serum creatinine determination in Italian laboratories. Clin Chim Acta 2014; 427: 100–06. US Department of Health and Human Services. Follow-up for information letter regarding AUC-based dosing of Carboplatin. Oct 22, 2010. http://ctep.cancer.gov/content/docs/ Carboplatin_Information_Letter.pdf (accessed May 7, 2014).
Authors’ reply Baratti and colleagues claim that the quality of surgical procedures in MITO-71 could substantially affect the generalisability of the results. We agree that the best quality surgical procedures should always be used. Of the 690 patients in MITO-7 with stage III–IV disease, including 201 patients with stage IV disease, 312 (45%) were optimally debulked at baseline, and a further 143 (21%) achieved optimum debulking after three (n=104) or six (n=39) cycles of chemotherapy. Therefore, optimum debulking was reported in two-thirds of these patients. Additionally, our baseline optimum debulking rate was consistent with large multicentre trials that tackled non-surgical questions, which ranged from 39% to 59%.2, 3 We do not agree with Baratti and colleagues’ statement that an absence of standardised surgical techniques might limit the translation of our results to routine practice. First, there is no evidence from the MITO-7 results that treatment comparison is affected by the extent of surgery at baseline (pinteraction=0·41) or by the size of the centre (pinteraction=0·91). Second, as for any pragmatic trial, the participation of many centres is a strength and enhances the generalisability of results. However, because the quality of the centres might affect the prognosis of a patient, this was taken into account in the minimisation procedure and www.thelancet.com/oncology Vol 15 June 2014
Correspondence
the size of the centre, indirectly calculated with accrual, was entered as a covariate in the multivariable analysis. In particular, the Cox model reported in our Article1 clearly shows that the prognostic effect of the size of the centre is negligible and not statistically significant; indeed, the estimated hazard ratio of progressionfree survival is better for small centres (0·85). Shimokata and Ando suggest that differences in toxic effects in the standard arms between MITO-71 and the Japanese NOVEL trial4 might be due to the different techniques used for measuring serum creatinine, which might have led to an underestimation of creatinine concentrations in NOVEL and consequent overdosing of carboplatin. We did not collect information on whether creatinine clearance was directly measured or estimated, or which analytical method was used to measure serum creatinine concentrations. We acknowledge the potential implications of the proposed hypothesis. However, this hypothesis does not bias the internal validity of either trial. We declare no competing interests.
*Sandro Pignata, Massimo Di Maio, Ciro Gallo, Francesco Perrone [email protected] Dipartimento di Oncologia Uroginecologia, Istituto Nazionale per lo Studio e la Cura dei Tumori, Fondazione G Pascale IRCCS, 80131 Napoli, Italy (SP); Unità Sperimentazioni Cliniche, Istituto Nazionale per lo Studio e la Cura dei Tumori, Fondazione G Pascale, IRCCS, Napoli, Italy (MDM, FP); Statistica Medica, Seconda Università di Napoli, Napoli, Italy (CG) 1
2
3
Pignata S, Scambia G, Katsaros D, et al. Carboplatin plus paclitaxel once a week versus every 3 weeks in patients with advanced ovarian cancer (MITO-7): a randomised, multicentre, open-label, phase 3 trial. Lancet Oncol 2014; 15: 396–405. Piccart MJ, Bertelsen K, James K, et al. Randomized intergroup trial of cisplatinpaclitaxel versus cisplatin-cyclophosphamide in women with advanced epithelial ovarian cancer: three-year results. J Natl Cancer Inst 2000; 92: 699–708. du Bois A, Luck HJ, Meier W, et al. A randomized clinical trial of cisplatin/paclitaxel versus carboplatin/paclitaxel as first-line treatment of ovarian cancer. J Natl Cancer Inst 2003; 95: 1320–29.
www.thelancet.com/oncology Vol 15 June 2014
4
Katsumata N, Yasuda M, Takahashi F, et al. Dose-dense paclitaxel once a week in combination with carboplatin every 3 weeks for advanced ovarian cancer: a phase 3, open-label, randomised controlled trial. Lancet 2009; 374: 1331–38.
Rituximab for follicular lymphoma: watch and wait, watch and worry, or watch and live? We read with interest the Article by Kirit Ardeshna1 that compared a watch-and-wait approach versus rituximab in patients with advanced, asymptomatic, follicular lymphoma. This study addresses an important clinical question for patients with an incurable yet often indolent disease—should cancer-directed treatment begin sooner or later if the cancer cannot be cured? Although we applaud the inclusion of patient-reported outcome measures in the study,2 we are concerned about an implicit assertion in the authors’ conclusions, and in the accompanying Comment, namely, that chemotherapy is the solution to psychosocial problems in the cancer clinic. The only differences in patientreported outcomes between the watch-and-wait approach and rituximab treatment in Ardeshna and colleagues’ study1 were for measures of psychological wellbeing, which were higher in the rituximab group. There were otherwise no significant differences in symptom burden, physical functioning, or other key domains of quality of life, nor in survival or rate of disease transformation, and no other key outcome measure were meaningfully different between the groups. With these data, the authors felt that “this finding might be because these patients felt that something active was being done
to combat their lymphoma”. Are they therefore suggesting that cancer-directed therapy should be the primary way to improve patients’ coping and emotional well-being? Is chemotherapy just a more convenient (and often more reimbursable) way of attending to psychosocial needs? We contend that the data from Ardeshna and colleagues’ Article1 tell a very different story: that patients living with an incurable cancer worry about the future and that physicians should be more attuned to this issue as an essential part of providing patientcentred, high-quality, comprehensive cancer care. Instead, little attention is given to how patients and their caregivers can be helped to cope with the uncertainty of an incurable illness. Consequently, lymphoma survivors are known to be at high risk for posttraumatic stress disorder.3 Similar issues are described in patients with chronic lymphocytic leukaemia, who are often told they have so-called good leukaemia, yet they have worse emotional well-being scores compared with patients with other cancers.4 Perhaps if oncologists valued the power of psychosocial care above that of resource-intensive therapies that do not improve outcomes, patients’ experiences of living with cancer could be improved. Rather than to espouse a watch-and-wait strategy, or even—watch-andworry—we should help patients to watch and live. Patients’ difficulties in coping with a chronic cancer diagnosis could be improved by more proven alternatives, such as concurrent palliative and supportive care, psychotherapy, resilience training, physiotherapy, yoga, or other complementary therapies that are provided in many support programmes for cancer patients. In fact, better support with coping skills as delivered by palliative care professionals has been identified as a key factor for how cancer patients might live longer with the e251
with 7% in MITO-7, and grade 3–4 anaemia occurred in 44% of patients in NOVEL versus 3% in MITO-7. Pignata and colleagues1 speculate that such large differences indicate possible genetic causes, especially genetic polymorphisms in paclitaxel metabolism that differ between European and Asian patients. However, differences in the methods used to measure creatinine might also have a role. The dose of carboplatin is traditionally calculated using the Calvert formula, which includes glomerular filtration rate (GFR) as a parameter. However, creatinine clearance is usually used instead of GFR. Various methods can be used to measure serum creatinine concentration (and thus to calculate creatinine clearance), such as the Jaffe kinetic method, the enzymatic method, and the isotope dilution mass spectrometry traceable method. We have previously reported that serum creatinine concentrations measured by the Jaffe kinetic method are consistently higher than the true concentrations by 0·1–0·3 mg/dL, because of interference by non-specific substrates in the serum.4 Thus the creatinine clearance rate based on results from the Jaffe kinetic method is an underestimation of the GFR, but remains close to the GFR. By contrast, measurement of the creatinine clearance rate using the serum creatinine concentrations measured with specific assays overestimates the GFR in some patients with normal renal function. Thus, measurement with specific assays can potentially lead to overdosing with carboplatin.4,5 Even a small overdose with carboplatin can cause unexpected severe toxicity because of its narrow therapeutic index,4 particularly in women who have lower creatinine concentrations than men. The MITO-7 investigators1 used the Cockcroft-Gault formula to calculate creatinine clearance rate, but the method used to measure serum e250
creatinine concentrations was not reported. The NOVEL investigators2,3 used the Calvert formula. In the MITO-7 trial,1 neither the means used to determine creatinine clearance rate nor the method used to determine serum creatinine concentrations were reported. By contrast, the NOVEL investigators2,3 used the Jelliffe method to estimate the creatinine clearance rate, although they do not state explicitly what method was used to estimate serum creatinine concentrations. In Japan, enzymatic methods have been commonly used in clinical laboratories since the mid-1990s, whereas it seems that methods might be less standardised in Italy.6 Thus, it is possible that the higher rate of toxicity in the Japanese NOVEL trial than in the European MITO-7 trial might be due to overdosing of carboplatin as a result of using standardised methods to assess serum creatinine concentration. Of note, standardised serum creatinine measurements became widely used in the USA by the end of 2010, which could lead to an increased incidence of carboplatin-related toxicity.7 We declare no competing interests.
*Tomoya Shimokata, Yuichi Ando [email protected] Department of Clinical Oncology and Chemotherapy, Nagoya University Hospital, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan (TS, YA) 1
2
3
Pignata S, Scambia G, Katsaros D, et al. Carboplatin plus paclitaxel once a week versus every 3 weeks in patients with advanced ovarian cancer (MITO-7): a randomised, multicentre, open-label, phase 3 trial. Lancet Oncol 2014; 15: 396–405. Katsumata N, Yasuda M, Takahashi F, et al. Dose-dense paclitaxel once a week in combination with carboplatin every 3 weeks for advanced ovarian cancer: a phase 3, open-label, randomised controlled trial. Lancet 2009; 374: 1331–38. Katsumata N, Yasuda M, Isonishi S, et al, for the Japanese Gynecologic Oncology Group. Long-term results of dose-dense paclitaxel and carboplatin versus conventional paclitaxel and carboplatin for treatment of advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer (JGOG 3016): a randomised, controlled, open-label trial. Lancet Oncol 2013; 14: 1020–26.
4
5
6
7
Ando Y, Shimokata T, Yasuda Y, Hasegawa Y. Carboplatin dosing for adult Japanese patients. Nagoya J Med Sci 2014; 76: 1–9. Shimokata T, Ando Y, Yasuda Y, et al. Prospective evaluation of pharmacokinetically guided dosing of carboplatin in Japanese patients with cancer. Cancer Sci 2010; 101: 2601–05. Carobene A, Ceriotti F, Infusino I, et al. Evaluation of the impact of standardization process on the quality of serum creatinine determination in Italian laboratories. Clin Chim Acta 2014; 427: 100–06. US Department of Health and Human Services. Follow-up for information letter regarding AUC-based dosing of Carboplatin. Oct 22, 2010. http://ctep.cancer.gov/content/docs/ Carboplatin_Information_Letter.pdf (accessed May 7, 2014).
Authors’ reply Baratti and colleagues claim that the quality of surgical procedures in MITO-71 could substantially affect the generalisability of the results. We agree that the best quality surgical procedures should always be used. Of the 690 patients in MITO-7 with stage III–IV disease, including 201 patients with stage IV disease, 312 (45%) were optimally debulked at baseline, and a further 143 (21%) achieved optimum debulking after three (n=104) or six (n=39) cycles of chemotherapy. Therefore, optimum debulking was reported in two-thirds of these patients. Additionally, our baseline optimum debulking rate was consistent with large multicentre trials that tackled non-surgical questions, which ranged from 39% to 59%.2, 3 We do not agree with Baratti and colleagues’ statement that an absence of standardised surgical techniques might limit the translation of our results to routine practice. First, there is no evidence from the MITO-7 results that treatment comparison is affected by the extent of surgery at baseline (pinteraction=0·41) or by the size of the centre (pinteraction=0·91). Second, as for any pragmatic trial, the participation of many centres is a strength and enhances the generalisability of results. However, because the quality of the centres might affect the prognosis of a patient, this was taken into account in the minimisation procedure and www.thelancet.com/oncology Vol 15 June 2014
Correspondence
the size of the centre, indirectly calculated with accrual, was entered as a covariate in the multivariable analysis. In particular, the Cox model reported in our Article1 clearly shows that the prognostic effect of the size of the centre is negligible and not statistically significant; indeed, the estimated hazard ratio of progressionfree survival is better for small centres (0·85). Shimokata and Ando suggest that differences in toxic effects in the standard arms between MITO-71 and the Japanese NOVEL trial4 might be due to the different techniques used for measuring serum creatinine, which might have led to an underestimation of creatinine concentrations in NOVEL and consequent overdosing of carboplatin. We did not collect information on whether creatinine clearance was directly measured or estimated, or which analytical method was used to measure serum creatinine concentrations. We acknowledge the potential implications of the proposed hypothesis. However, this hypothesis does not bias the internal validity of either trial. We declare no competing interests.
*Sandro Pignata, Massimo Di Maio, Ciro Gallo, Francesco Perrone [email protected] Dipartimento di Oncologia Uroginecologia, Istituto Nazionale per lo Studio e la Cura dei Tumori, Fondazione G Pascale IRCCS, 80131 Napoli, Italy (SP); Unità Sperimentazioni Cliniche, Istituto Nazionale per lo Studio e la Cura dei Tumori, Fondazione G Pascale, IRCCS, Napoli, Italy (MDM, FP); Statistica Medica, Seconda Università di Napoli, Napoli, Italy (CG) 1
2
3
Pignata S, Scambia G, Katsaros D, et al. Carboplatin plus paclitaxel once a week versus every 3 weeks in patients with advanced ovarian cancer (MITO-7): a randomised, multicentre, open-label, phase 3 trial. Lancet Oncol 2014; 15: 396–405. Piccart MJ, Bertelsen K, James K, et al. Randomized intergroup trial of cisplatinpaclitaxel versus cisplatin-cyclophosphamide in women with advanced epithelial ovarian cancer: three-year results. J Natl Cancer Inst 2000; 92: 699–708. du Bois A, Luck HJ, Meier W, et al. A randomized clinical trial of cisplatin/paclitaxel versus carboplatin/paclitaxel as first-line treatment of ovarian cancer. J Natl Cancer Inst 2003; 95: 1320–29.
www.thelancet.com/oncology Vol 15 June 2014
4
Katsumata N, Yasuda M, Takahashi F, et al. Dose-dense paclitaxel once a week in combination with carboplatin every 3 weeks for advanced ovarian cancer: a phase 3, open-label, randomised controlled trial. Lancet 2009; 374: 1331–38.
Rituximab for follicular lymphoma: watch and wait, watch and worry, or watch and live? We read with interest the Article by Kirit Ardeshna1 that compared a watch-and-wait approach versus rituximab in patients with advanced, asymptomatic, follicular lymphoma. This study addresses an important clinical question for patients with an incurable yet often indolent disease—should cancer-directed treatment begin sooner or later if the cancer cannot be cured? Although we applaud the inclusion of patient-reported outcome measures in the study,2 we are concerned about an implicit assertion in the authors’ conclusions, and in the accompanying Comment, namely, that chemotherapy is the solution to psychosocial problems in the cancer clinic. The only differences in patientreported outcomes between the watch-and-wait approach and rituximab treatment in Ardeshna and colleagues’ study1 were for measures of psychological wellbeing, which were higher in the rituximab group. There were otherwise no significant differences in symptom burden, physical functioning, or other key domains of quality of life, nor in survival or rate of disease transformation, and no other key outcome measure were meaningfully different between the groups. With these data, the authors felt that “this finding might be because these patients felt that something active was being done
to combat their lymphoma”. Are they therefore suggesting that cancer-directed therapy should be the primary way to improve patients’ coping and emotional well-being? Is chemotherapy just a more convenient (and often more reimbursable) way of attending to psychosocial needs? We contend that the data from Ardeshna and colleagues’ Article1 tell a very different story: that patients living with an incurable cancer worry about the future and that physicians should be more attuned to this issue as an essential part of providing patientcentred, high-quality, comprehensive cancer care. Instead, little attention is given to how patients and their caregivers can be helped to cope with the uncertainty of an incurable illness. Consequently, lymphoma survivors are known to be at high risk for posttraumatic stress disorder.3 Similar issues are described in patients with chronic lymphocytic leukaemia, who are often told they have so-called good leukaemia, yet they have worse emotional well-being scores compared with patients with other cancers.4 Perhaps if oncologists valued the power of psychosocial care above that of resource-intensive therapies that do not improve outcomes, patients’ experiences of living with cancer could be improved. Rather than to espouse a watch-and-wait strategy, or even—watch-andworry—we should help patients to watch and live. Patients’ difficulties in coping with a chronic cancer diagnosis could be improved by more proven alternatives, such as concurrent palliative and supportive care, psychotherapy, resilience training, physiotherapy, yoga, or other complementary therapies that are provided in many support programmes for cancer patients. In fact, better support with coping skills as delivered by palliative care professionals has been identified as a key factor for how cancer patients might live longer with the e251
