- Email: [email protected]
How does TPF improve survival over PF?
Correspondence
Median follow-up
PF vs TPF Total failures
LF, RF, or LRF
Distant failure
Second malignancy
Lorch (TAX 324)1
72·2 months
NR
No difference in LRF; no p value
No difference; no p value
NR
Hitt2
23 months
49% vs 43%; no p value
Total 34% LRF; no p value
Total 7%; no p value
5% vs 8%; no p value
Vermorken (TAX 323)3
32·5 months
65% vs 57%;* no p value 52% vs 49% LRF;* no p value
7% vs 7%;* no p value
NR
Pointreau (GORTEC 2000–01)4
36 months
NR
16% vs 11%; p=0·38
10% vs 4%; p=0·12
24% vs 19% LF and 20% vs 15% RF; no p values
PF=cisplatin and fluorouracil. TPF=taxane, cisplatin, and fluorouracil. LF=local failure. RF=regional failure. LRF=locoregional failure. NR=not reported. *Patterns of first failure (ie, not total failures).
Table: Randomised studies comparing PF with TPF
If the benefit was not caused by reductions in recurrence or metastasis, then a comparison of response to comorbidities, second malignancies, or deaths caused by late toxicity could provide important information regarding the effects of docetaxel. The question of whether there is a reduction in either locoregional or distant failure is a theme that also resonates through the other randomised studies (table). Hitt and colleagues2 reported the total number of failures in their study and stated the type of relapse was similar between groups, but did not provide a statistical comparison. In TAX 323,3 patterns of first failure were reported, but also without a statistical comparison. In GORTEC 2000–01,4 no statistical difference in distant failure was reported and, although TPF seemed to confer a small reduction in locoregional failure, again no statistical comparison was reported. As discussed elsewhere,6 eventfree survival endpoints (eg, overall survival and progression-free survival) are useful for assessment of the net benefit of a treatment but do not provide sufficient evidence as to its specific effects. A comparison of disease-specific endpoints is essential for appropriate inferences to be made regarding the effects of docetaxel in the study by Lorch and colleagues1 and its source of therapeutic benefit. As stated eloquently by Schulz and colleagues:7 420
“to assess a trial accurately, readers of a published report need complete, clear, and transparent information on its methodology and findings.” More complete reporting of diseasespecific outcomes in randomised trials should be standard to provide a better understanding of the effects and benefits of treatment. This in turn would assist the development of future strategies to address the areas that need improvement. The authors declared no conflicts of interest.
Kiran Devisetty*, Stuart J Wong, Loren K Mell [email protected] Department of Radiation Oncology (KD) and Department of Hematology and Oncology (SJW), Medical College of Wisconsin, Milwaukee, WI, USA; and Department of Radiation Oncology, University of California San Diego, La Jolla, CA, USA (LKM) 1
2
3
4
5
Lorch JH, Goloubeva O, Haddad RI, et al. Induction chemotherapy with cisplatin and fluorouracil alone or in combination with docetaxel in locally advanced squamous-cell cancer of the head and neck: long-term results of the TAX 324 randomised phase 3 trial. Lancet Oncol 2011; 12: 153–59. Hitt R, Lopez-Pousa A, Martinez-Trufero J, et al. Phase III study comparing cisplatin plus fluorouracil to paclitaxel, cisplatin, and fluorouracil induction chemotherapy followed by chemoradiotherapy in locally advanced head and neck cancer. J Clin Oncol 2005; 23: 8636–45. Vermorken JB, Remenar E, van Herpen C, et al. Cisplatin, fluorouracil, and docetaxel in unresectable head and neck cancer. N Engl J Med 2007; 357: 1695–704. Pointreau Y, Garaud P, Chapet S, et al. Randomized trial of induction chemotherapy with cisplatin and 5-fluorouracil with or without docetaxel for larynx preservation. J Natl Cancer Inst 2009; 101: 498–506. Posner MR, Hershock DM, Blajman CR, et al. Cisplatin and fluorouracil alone or with docetaxel in head and neck cancer. N Engl J Med 2007; 357: 1705–15.
6
7
Mell LK, Jeong JH. Pitfalls of using composite primary end points in the presence of competing risks. J Clin Oncol 2010; 28: 4297–99. Schulz KF, Altman DG, Moher D. CONSORT 2010 statement: updated guidelines for reporting parallel group randomized trials. Ann Intern Med 2010; 152: 726–32.
The long-term analysis of the TAX 324 trial1 was important because it established the consequences of treatment with docetaxel, cisplatin, and fluorouracil (TPF) or cisplatin and fluorouracil (PF) and the durability of the findings, especially in terms of functional results. Although the long-term results of this very promising trial are exciting, there are some limitations. Lorch and colleagues concluded that induction chemotherapy with TPF provides a long-term survival benefit compared with PF in patients with locally advanced head and neck cancer; however, these results might be biased and thus conclusions need to be revised. First, 61 (12%) of 501 patients were lost to followup and, surprisingly, were deemed to be alive, and data from the initial analysis in 2005 were used. The authors claimed that they did not find sufficient evidence to believe that characteristics of patients lost to follow-up was significantly different to the other 440 patients. We think this is an optimistic hypothesis and we are therefore unsure of the reliability of the data. We believe that for such a trial the worst case should be considered. www.thelancet.com/oncology Vol 12 May 2011
Correspondence
These 61 patients should be excluded from the analyses and all analyses recalculated. The inclusion of these patients is not only a trial limitation but might also have affected the results and conclusions. Another limitation that was mentioned by the authors was long-term toxicity, which was only assessed by the presence of a tracheostomy or feeding tube. These outcomes are not always a result of late toxicity and their presence could be because of salvage surgery as a result of disease recurrence. Therefore, there are no reliable data on the quality of life of the patients in this study. Moreover, no details are included about the questionnaire that was used to gather clinical information. Despite these comments, we still believe that induction chemotherapy is a good treatment option for locally advanced head and neck cancer. The superiority of TPF protocol over PF has been reported in several studies, such as TAX 323,2 TAX 324,3 Hitt and colleagues’ paper,4 and the GORTEC 2000-01 trial.5 The authors declared no conflicts of interest.
Yoann Pointreau*, Ibrahim Atean, Gilles Calais [email protected] CHRU Bretonneau, Tours, 37044, France 1
2
Lorch JH, Goloubeva O, Haddad RI, et al. Induction chemotherapy with cisplatin and fluorouracil alone or in combination with docetaxel in locally advanced squamous-cell cancer of the head and neck: long-term results of the TAX 324 randomised phase 3 trial. Lancet Oncol 2011; 12: 153–59. Vermorken JB, Remenar E, Van Herpen C, et al. Cisplatin, fluorouracil and docetaxel in unresectable head and neck cancer. N Engl J Med 2007; 357: 1695–704.
TPF (n=255)
3
4
5
Posner MR, Hershock D, Blajman CR, et al. Cisplatin and fluorouracil alone or with docetaxel in head and neck cancer. N Engl J Med 2007; 357: 1705–15. Hitt R, Lopez-Pousa A, Martinez-Trufero J, et al. Phase III study comparing cisplatin plus fluorouracil to paclitaxel, cisplatin, and fluorouracil induction chemotherapy followed by chemoradiotherapy in locally advanced head and neck cancer. J Clin Oncol 2005; 23: 8636–45. Pointreau Y, Garaud P, Chapet S, et al. Randomized trial of induction chemotherapy with cisplatin and 5-fluorouracil with or without docetaxel for larynx preservation. J Natl Cancer Inst 2009; 101: 498–506.
Authors’ reply We thank Devisetty and colleagues for their thoughtful comments. Although the proportion of patients with locoregional failure in the docetaxel, cisplatin, and fluorouracil (TPF) group was significantly lower than in the cisplatin and fluorouracil (PF) group in the original TAX 324 article,1 in the 5-year follow-up study,2 there was no statistically significant difference. More detailed 5-year data are summarised in the table and below. With longer follow-up, differences between treatment groups tend to diminish as patients die from late toxicity or unrelated causes and are lost to follow-up, making detection of statistically meaningful differences less likely over long periods of time. This might be the reason for the absence of a statistically meaningful difference between local and regional failure versus distant failure in our follow-up study, whereas the overall survival difference was maintained for over 5 years. We analysed further information as suggested by Devisetty and
HR for death (95% CI)
p value
Local or regional failure
81 (32%)
97 (39%)
0·90 (0·65–1·24)
0·52
Distant failure
16 (6%)
23 (9%)
0·71 (0·36–1·40)
0·32
5 (2%)
4 (2%)
Total failures
92 (36%)
116 (47%)
0·89 (0·66–1·20)
0·43
Total failures with second primary tumours
96 (38%)
118 (48%)
0·87 (0·65–1·17)
0·37
Both
PF (n=246)
colleagues and undertook separate subgroup analyses. For example, patients with laryngeal cancer who have an effective surgical salvage option were examined. We did not identify a significant difference in locoregional versus distant disease between treatment groups—probably also a result of small patient numbers in this subgroup. Although more detail would have been desirable and perhaps interesting, we doubt that this would have provided any further statistically meaningful insight because of the small numbers of patients in each group. With this in mind, we agree with Devisetty and colleagues that more research is needed to identify the individual risk for disease recurrence further and to offer guidance for therapeutic decisions. A meta-analysis of TPF and PF studies may provide more robust data on the effect of TPF on site of failure. In response to the points raised by Pointreau and colleagues, analysis of the baseline characteristics of patients with missing data versus those who had follow-up data available showed that there were no significant differences (webappendix). There is no reason to believe that loss to follow-up was related to factors associated with overall survival, the primary endpoint of our study. Modelling the censoring process with a multivariable logistic regression approach with the risk factors used for modelling overall survival—as described in the manuscript—to assess whether there
See Online for webappendix
··
Data are number (%). HR=hazard ratio.
Table: Patterns of disease recurrence
www.thelancet.com/oncology Vol 12 May 2011
421
Median follow-up
PF vs TPF Total failures
LF, RF, or LRF
Distant failure
Second malignancy
Lorch (TAX 324)1
72·2 months
NR
No difference in LRF; no p value
No difference; no p value
NR
Hitt2
23 months
49% vs 43%; no p value
Total 34% LRF; no p value
Total 7%; no p value
5% vs 8%; no p value
Vermorken (TAX 323)3
32·5 months
65% vs 57%;* no p value 52% vs 49% LRF;* no p value
7% vs 7%;* no p value
NR
Pointreau (GORTEC 2000–01)4
36 months
NR
16% vs 11%; p=0·38
10% vs 4%; p=0·12
24% vs 19% LF and 20% vs 15% RF; no p values
PF=cisplatin and fluorouracil. TPF=taxane, cisplatin, and fluorouracil. LF=local failure. RF=regional failure. LRF=locoregional failure. NR=not reported. *Patterns of first failure (ie, not total failures).
Table: Randomised studies comparing PF with TPF
If the benefit was not caused by reductions in recurrence or metastasis, then a comparison of response to comorbidities, second malignancies, or deaths caused by late toxicity could provide important information regarding the effects of docetaxel. The question of whether there is a reduction in either locoregional or distant failure is a theme that also resonates through the other randomised studies (table). Hitt and colleagues2 reported the total number of failures in their study and stated the type of relapse was similar between groups, but did not provide a statistical comparison. In TAX 323,3 patterns of first failure were reported, but also without a statistical comparison. In GORTEC 2000–01,4 no statistical difference in distant failure was reported and, although TPF seemed to confer a small reduction in locoregional failure, again no statistical comparison was reported. As discussed elsewhere,6 eventfree survival endpoints (eg, overall survival and progression-free survival) are useful for assessment of the net benefit of a treatment but do not provide sufficient evidence as to its specific effects. A comparison of disease-specific endpoints is essential for appropriate inferences to be made regarding the effects of docetaxel in the study by Lorch and colleagues1 and its source of therapeutic benefit. As stated eloquently by Schulz and colleagues:7 420
“to assess a trial accurately, readers of a published report need complete, clear, and transparent information on its methodology and findings.” More complete reporting of diseasespecific outcomes in randomised trials should be standard to provide a better understanding of the effects and benefits of treatment. This in turn would assist the development of future strategies to address the areas that need improvement. The authors declared no conflicts of interest.
Kiran Devisetty*, Stuart J Wong, Loren K Mell [email protected] Department of Radiation Oncology (KD) and Department of Hematology and Oncology (SJW), Medical College of Wisconsin, Milwaukee, WI, USA; and Department of Radiation Oncology, University of California San Diego, La Jolla, CA, USA (LKM) 1
2
3
4
5
Lorch JH, Goloubeva O, Haddad RI, et al. Induction chemotherapy with cisplatin and fluorouracil alone or in combination with docetaxel in locally advanced squamous-cell cancer of the head and neck: long-term results of the TAX 324 randomised phase 3 trial. Lancet Oncol 2011; 12: 153–59. Hitt R, Lopez-Pousa A, Martinez-Trufero J, et al. Phase III study comparing cisplatin plus fluorouracil to paclitaxel, cisplatin, and fluorouracil induction chemotherapy followed by chemoradiotherapy in locally advanced head and neck cancer. J Clin Oncol 2005; 23: 8636–45. Vermorken JB, Remenar E, van Herpen C, et al. Cisplatin, fluorouracil, and docetaxel in unresectable head and neck cancer. N Engl J Med 2007; 357: 1695–704. Pointreau Y, Garaud P, Chapet S, et al. Randomized trial of induction chemotherapy with cisplatin and 5-fluorouracil with or without docetaxel for larynx preservation. J Natl Cancer Inst 2009; 101: 498–506. Posner MR, Hershock DM, Blajman CR, et al. Cisplatin and fluorouracil alone or with docetaxel in head and neck cancer. N Engl J Med 2007; 357: 1705–15.
6
7
Mell LK, Jeong JH. Pitfalls of using composite primary end points in the presence of competing risks. J Clin Oncol 2010; 28: 4297–99. Schulz KF, Altman DG, Moher D. CONSORT 2010 statement: updated guidelines for reporting parallel group randomized trials. Ann Intern Med 2010; 152: 726–32.
The long-term analysis of the TAX 324 trial1 was important because it established the consequences of treatment with docetaxel, cisplatin, and fluorouracil (TPF) or cisplatin and fluorouracil (PF) and the durability of the findings, especially in terms of functional results. Although the long-term results of this very promising trial are exciting, there are some limitations. Lorch and colleagues concluded that induction chemotherapy with TPF provides a long-term survival benefit compared with PF in patients with locally advanced head and neck cancer; however, these results might be biased and thus conclusions need to be revised. First, 61 (12%) of 501 patients were lost to followup and, surprisingly, were deemed to be alive, and data from the initial analysis in 2005 were used. The authors claimed that they did not find sufficient evidence to believe that characteristics of patients lost to follow-up was significantly different to the other 440 patients. We think this is an optimistic hypothesis and we are therefore unsure of the reliability of the data. We believe that for such a trial the worst case should be considered. www.thelancet.com/oncology Vol 12 May 2011
Correspondence
These 61 patients should be excluded from the analyses and all analyses recalculated. The inclusion of these patients is not only a trial limitation but might also have affected the results and conclusions. Another limitation that was mentioned by the authors was long-term toxicity, which was only assessed by the presence of a tracheostomy or feeding tube. These outcomes are not always a result of late toxicity and their presence could be because of salvage surgery as a result of disease recurrence. Therefore, there are no reliable data on the quality of life of the patients in this study. Moreover, no details are included about the questionnaire that was used to gather clinical information. Despite these comments, we still believe that induction chemotherapy is a good treatment option for locally advanced head and neck cancer. The superiority of TPF protocol over PF has been reported in several studies, such as TAX 323,2 TAX 324,3 Hitt and colleagues’ paper,4 and the GORTEC 2000-01 trial.5 The authors declared no conflicts of interest.
Yoann Pointreau*, Ibrahim Atean, Gilles Calais [email protected] CHRU Bretonneau, Tours, 37044, France 1
2
Lorch JH, Goloubeva O, Haddad RI, et al. Induction chemotherapy with cisplatin and fluorouracil alone or in combination with docetaxel in locally advanced squamous-cell cancer of the head and neck: long-term results of the TAX 324 randomised phase 3 trial. Lancet Oncol 2011; 12: 153–59. Vermorken JB, Remenar E, Van Herpen C, et al. Cisplatin, fluorouracil and docetaxel in unresectable head and neck cancer. N Engl J Med 2007; 357: 1695–704.
TPF (n=255)
3
4
5
Posner MR, Hershock D, Blajman CR, et al. Cisplatin and fluorouracil alone or with docetaxel in head and neck cancer. N Engl J Med 2007; 357: 1705–15. Hitt R, Lopez-Pousa A, Martinez-Trufero J, et al. Phase III study comparing cisplatin plus fluorouracil to paclitaxel, cisplatin, and fluorouracil induction chemotherapy followed by chemoradiotherapy in locally advanced head and neck cancer. J Clin Oncol 2005; 23: 8636–45. Pointreau Y, Garaud P, Chapet S, et al. Randomized trial of induction chemotherapy with cisplatin and 5-fluorouracil with or without docetaxel for larynx preservation. J Natl Cancer Inst 2009; 101: 498–506.
Authors’ reply We thank Devisetty and colleagues for their thoughtful comments. Although the proportion of patients with locoregional failure in the docetaxel, cisplatin, and fluorouracil (TPF) group was significantly lower than in the cisplatin and fluorouracil (PF) group in the original TAX 324 article,1 in the 5-year follow-up study,2 there was no statistically significant difference. More detailed 5-year data are summarised in the table and below. With longer follow-up, differences between treatment groups tend to diminish as patients die from late toxicity or unrelated causes and are lost to follow-up, making detection of statistically meaningful differences less likely over long periods of time. This might be the reason for the absence of a statistically meaningful difference between local and regional failure versus distant failure in our follow-up study, whereas the overall survival difference was maintained for over 5 years. We analysed further information as suggested by Devisetty and
HR for death (95% CI)
p value
Local or regional failure
81 (32%)
97 (39%)
0·90 (0·65–1·24)
0·52
Distant failure
16 (6%)
23 (9%)
0·71 (0·36–1·40)
0·32
5 (2%)
4 (2%)
Total failures
92 (36%)
116 (47%)
0·89 (0·66–1·20)
0·43
Total failures with second primary tumours
96 (38%)
118 (48%)
0·87 (0·65–1·17)
0·37
Both
PF (n=246)
colleagues and undertook separate subgroup analyses. For example, patients with laryngeal cancer who have an effective surgical salvage option were examined. We did not identify a significant difference in locoregional versus distant disease between treatment groups—probably also a result of small patient numbers in this subgroup. Although more detail would have been desirable and perhaps interesting, we doubt that this would have provided any further statistically meaningful insight because of the small numbers of patients in each group. With this in mind, we agree with Devisetty and colleagues that more research is needed to identify the individual risk for disease recurrence further and to offer guidance for therapeutic decisions. A meta-analysis of TPF and PF studies may provide more robust data on the effect of TPF on site of failure. In response to the points raised by Pointreau and colleagues, analysis of the baseline characteristics of patients with missing data versus those who had follow-up data available showed that there were no significant differences (webappendix). There is no reason to believe that loss to follow-up was related to factors associated with overall survival, the primary endpoint of our study. Modelling the censoring process with a multivariable logistic regression approach with the risk factors used for modelling overall survival—as described in the manuscript—to assess whether there
See Online for webappendix
··
Data are number (%). HR=hazard ratio.
Table: Patterns of disease recurrence
www.thelancet.com/oncology Vol 12 May 2011
421