- Email: [email protected]
Blood-pressure drugs and cancer: much ado about nothing?
Comment
Deletions of the 3´ end of EPCAM lead to transcriptional read-through hypermethylation of the MSH2 promoter and subsequent epigenetic silencing of its neighbouring MSH2 gene, thus giving rise to Lynch syndrome. In addition to the diagnostic implications, the newly identified mutation in EPCAM predisposes a possible paradigm shift for screening and management of Lynch syndrome. Kempers and colleagues show that colorectal cancer is, as expected, the predominant malignant neoplastic lesion in the EPCAM variant of Lynch syndrome, but that the occurrence of endometrial cancer (which is the second most common cancer in Lynch syndrome caused by mutations in mismatch repair genes) is substantially reduced.2 Furthermore, other extracolonic cancers, which generally characterise Lynch syndrome, are rarely noted in association with the EPCAM mutation.2 Other genotype–phenotype correlations have been identified in Lynch syndrome. MSH2 mutations are associated with high rates of extracolonic cancers (especially endometrial); MLH1 mutations are associated with higher rates of colorectal cancer; and MSH6 mutations with increased risk of endometrial cancer but decreased colorectal cancer risk. However, these associations have resulted in few changes to patient management by most practitioners. Clearly, more research is needed to fully understand the clinical significance of EPCAM in relation to risk of colorectal cancer and the deficit of extracolonic cancers relative to that normally seen with MSH2 deficiency. However, if EPCAM deletions are indeed associated with lower risk of extracolonic cancers, in particular endometrial cancer, doctors, genetic counsellors, and patients could be advised about this paradigm change in screening and management strategy and to focus almost exclusively on colorectal cancer in patients with such deletions. This transition will save time and money because the array of costly diagnostic studies
will not be needed. For example, a young female EPCAM-mutation carrier might have her anxiety about gynaecological cancer alleviated if she had an EPCAM mutation that was only associated with colorectal cancer. If it is conclusively shown that Lynch syndrome due to EPCAM mutations were to harbour little risk for endometrial or ovarian cancer, some carriers could be spared the option of prophylactic hysterectomy and bilateral salpingo-oophorectomy after child-bearing is complete. A key point made by Kempers and colleagues2 was that carriers of EPCAM deletions in Lynch syndrome families harbour a distinct cancer risk that is dependent on the size and location of the deleted EPCAM region. The investigators conclude that omission of surveillance and prophylactic surgery for endometrial cancer would be reasonable for women who carry a small deletion that extends further away from the MSH2 promoter. The creation of a large international collaboration with access to an adequate number of patients to confirm this conclusion should be encouraged. Henry T Lynch*, Jane F Lynch, Carrie L Snyder, Douglas Riegert-Johnson Department of Preventive Medicine and Public Health, Creighton University, 2500 California Plaza, Omaha, NE, USA (HTL, JFL, CLS); Medical Genetics and Medicine, Mayo Clinic, Jacksonville, FL, USA (DR-J) [email protected] The authors declared no conflicts of interest. 1
2
3
4
Lindor NM, Rabe K, Petersen GM, et al. Lower cancer incidence in Amsterdam-I criteria families without mismatch repair deficiency: familial colorectal cancer type X. JAMA 2005; 293: 1979–85. Kempers MJE, Kuiper RP, Ockeloen CW, et al. Risk of colorectal and endometrial cancers in EPCAM deletion-positive Lynch syndrome: a cohort study. Lancet Oncol 2011; 12: 49–55. Ligtenberg MJL, Kuiper RP, Chan TL, et al. Heritable somatic methylation and inactivation of MSH2 in families with Lynch syndrome due to deletion of the 3´ exons of TACSTD1. Nat Genet 2009; 41: 112–17. Kovacs ME, Papp J, Szentirmay Z, Otto S, Olah E. Deletions removing the last exon of TACSTD1 constitute a distinct class of mutations predisposing to Lynch syndrome. Hum Mutat 2009; 30: 197–203.
Blood-pressure drugs and cancer: much ado about nothing? Published Online November 30, 2010 DOI:10.1016/S14702045(10)70271-0 See Articles page 65
6
For more than 35 years, the risk of cancer has been discussed in relation to high blood pressure. Some case–control studies and post-hoc analyses from prospective intervention trials have suggested that several classes of blood-pressure-lowering drugs were
associated with an increased cancer risk. A difficulty with interpretation of these results, however, is that followup is only around 2–5 years, which is too short to show an increase in cancer detection. Moreover, an increased risk of cancer death has been reported in treated and www.thelancet.com/oncology Vol 12 January 2011
Comment
www.thelancet.com/oncology Vol 12 January 2011
risk of cancer when an ACEi was given together with an ARB. This outcome was, however, not significant when heterogeneity between trials was corrected for, with the random-effects model. Moreover, these results are mainly driven by the results of one trial only.5 In fact, in most of the trials in Bangalore and colleagues’ study, randomised treatment was given in addition to several other blood-pressure-lowering drugs, which makes interpretation of the results difficult. In the ONTARGET trial,6 for example, more than half of the patients also received a β blocker, a third a calcium antagonist, and more than a quarter a diuretic in addition to an ARB (telmisartan), an ACEi (ramipril), or both. Bangalore and colleagues’ comprehensive analyses do not lend support to the hypothesis that any of the blood-pressure-lowering drug classes promotes cancer, nor to the hypothesis that any of these strategies protect against cancer. This finding is hardly surprising since it seems far-fetched that a cancer would develop in such a short time of exposure in human beings. Further, there is no really plausible mechanism by which patients with high blood pressure would develop cancer in several sites, with the exception that some underlying factors—eg, old age, obesity, high salt and alcohol consumption—are common in these patients and are known to increase the risk of both cancer and cardiovascular disease.1,7 Increased angiogenesis from high concentrations of vascular endothelial growth factor (VEGF) has also been suggested as a mechanism,7 since a high activity in the renin-angiotensin system activates VEGF, and some drugs (eg, ACEi) lower it. The clinical significance of this hypothesis, however, is unknown. Finally, a few rare malignant diseases such as malignant phaeochromocytoma might cause very high blood pressure. The investigators cautiously conclude that an increased cancer risk cannot be completely ruled out for ARB combined with ACEi—the only combination that they investigated, and which nowadays is not a preferred combination for long-term treatment of high blood pressure. Although this combination is frequently prescribed for patients with severe heart failure, the expected survival time of such patients is short. Ruling out cancer risk is a difficult task to undertake since elderly patients (from developed countries) are likely to die either of cancer or of cardiovascular disease.
Cristina Pedrazzini/Science Photo Library
untreated patients with high blood pressure, raising the possibility that high blood pressure in itself is a risk factor for cancer at some sites.1 By contrast, in a 5-year trial from Sweden, elderly patients (mean age 76 years) with high blood pressure were matched to the comprehensive Swedish cancer registry, and their cancer incidence compared with expected values based on age, sex, and calendar-yearspecific reference frequencies for the general Swedish population.2 There was no deviation from the expected number of cancers for any type; the standardised incidence rate was 0·96 (95% CI 0·88–1·04), and was similar for men and women. Moreover, the incidence of new cancers (all tumours and those at individual sites) did not differ significantly between patients randomly assigned to diuretic drugs and β blockers, calcium antagonists, or angiotensin-converting-enzyme inhibitors (ACEi). However, the standardised mortality rate (death of all causes) was only 0·63, showing how selective trials in elderly patients are. Finally, in a followup of patients at the Glasgow blood pressure clinic,3 use of long-term renin-angiotensin blockade might, in fact, protect against cancer. Treatment with a newer class of blood-pressurelowering drugs, angiotensin-receptor blockers (ARBs), was suggested to be associated with a modestly (1·2%) increased risk of new cancer.4 The follow-up in this study was only around 4 years, and new cancer data were available for 61 590 patients from five trials. Obvious limitations, acknowledged by the investigators, were that few trials were included, the analyses were made post hoc, and importantly, the trials were not designed to study new cancers. There might also be a competing death risk (cardiovascular vs cancer) if one regimen leads to longer survival and thus a longer time to be diagnosed with a cancer. Furthermore, many patients were treated with several blood-pressure-lowering drugs at the same time and we do not have information about which drugs the patients had received before the start of the trial. In The Lancet Oncology, Bangalore and co-workers5 present an elegant series of analyses of the risk of cancer comprising 70 randomised controlled trials and 324 168 patients. In their meta-analyses they do not record any different risk of cancer between the treatment groups (including ARBs) and no difference in cancer mortality, confirming data from the Swedish cancer registry.2 The investigators report a slightly increased
7
Comment
Lars H Lindholm, Bo Carlberg Department of Public Health and Clinical Medicine, Umeå University, SE 90185 Umeå, Sweden [email protected] LHL is a past President of the International Society of Hypertension. BC declares no conflicts of interest. 1 2
Dyer AR, Stamler J, Berkson DM, Lindberg HA, Stevens E. High blood pressure: a risk for cancer mortality. Lancet 1975; 305: 1051–56. Lindholm LH, Anderson H, Ekbom T, et al. Relation between drug treatment and cancer in hypertensives in Swedish Trial in Old Patients with Hypertension 2: a 5-year prospective randomised controlled trial. Lancet 2001; 358: 539–44.
3 4
5
6 7
Lever AF, Hole DJ, Gillis CR, et al. Do inhibitors of angiotensin-1-converting enzyme protect against risk of cancer? Lancet 1998; 352: 179–84. Sipahi I, Debanne SM, Rowland DY, Simon DI, Fang JC. Angiotensin-receptor blockade and risk of cancer: meta-analysis of randomised controlled trials. Lancet Oncol 2010; 11: 627–36. Bangalore S, Kumar S, Kjeldsen SE, et al. Antihypertensive drugs and risk of cancer: network meta-analyses and trial sequential analyses of 324 168 participants from randomised trials. Lancet Oncol 2010; published online Nov 30. DOI:10.1016/S1470-2045(10)70260-6. Yusuf S, Teo KK, Pogue J, et al. Telmisartan, ramipril, or both in patients with high risk of vascular events. N Engl J Med 2008; 358: 1547–59. Khakoo AY, Sidman RL, Pasqualini R, Arap W. Does the renin-angiotensin system participate in regulation of human vasculogenesis and angiogenesis? Cancer Res 2008; 68: 9112–15.
Steve Gschmeissner/Science Photo Library
FOLFIRINOX: a new standard treatment for advanced pancreatic cancer?
Published Online November 1, 2010 DOI:10.1016/S14702045(10)70237-0 For more on future trial design see Leading Edge Lancet Oncol 2010; 11: 1009
8
Pancreatic cancer is still a lethal disease because of its tendency to undergo early subclinical metastasis to the regional lymph nodes and liver. Gemcitabine has been the standard chemotherapy for metastatic pancreatic cancer for many years on the basis of a phase 3 trial showing its clinical benefit over fluorouracil;1 however, the median survival was only 5·6 months and response rate only 5%. Since then, many trials have been done with gemcitabine being the backbone of the doublet or triplet regimens to improve overall outcome in patients. Results were mostly disappointing except for one trial using a combination of erlotinib and gemcitabine. In this randomised phase 3 trial, gemcitabine plus erlotinib led to a median survival of 6·2 months compared with 5·9 months in the gemcitabine-only group.2 Although this 2-week survival difference was statistically significant, it might not be clinically significant because of increased toxic effects. Therefore most oncologists still consider single-agent gemcitabine as the standard chemotherapy for first-line therapy. A randomised phase 3 trial comparing the FOLFIRINOX regimen (oxaliplatin and irinotecan plus fluorouracil and leucovorin) to gemcitabine in advanced pancreatic cancer was presented at the 2010 American Society of Clinical Oncology (ASCO) meeting.3 Results were impressive because median overall survival increased from 6·8 months to 11·1 months (p<0·0001). More interestingly, almost half the patients in the FOLFIRINOX group were alive after 1 year, and response rate was 31·6%—the highest rate seen in phase 3 pancreatic cancer trials. On the basis of this new phase 3 trial,
should FOLFIRINOX be considered standard therapy for advanced pancreatic cancer instead of gemcitabine? Does this trial represent the start of a change for the management of advanced pancreatic cancer? The results of the FOLFIRINOX trial are more impressive than those of the gemcitabine plus erlotinib trial, but in a palliative setting, are the toxic effects worth the outcome? The FOLFIRINOX regimen was quite toxic because 46% of the patients had grade 3 or 4 neutropenia and 5·4% had grade 3 and 4 febrile neutropenia, despite 42% of patients receiving support with granulocyte-colony stimulating factor. This trial was highly selective—only 39% of patients had a primary tumour in the head of the pancreas; while in clinical practice, about two-thirds of patients will present with a primary tumour in the pancreas, possibly requiring biliary stents. Chemotherapy regimens that cause severe neutropenia are a major concern in this setting because of the risk of cholangitis development. Specific analysis on toxic effects, with and without stents, is ongoing; however, the benefit in highly selective patients with pancreatic cancer is groundbreaking and should not be ignored. Therefore, for patients with a good performance status, normal bilirubin, and a good supportive care system, FOLFIRINOX could be a viable option. This trial provides many valuable insights, which can be incorporated in future trials of advanced pancreatic cancer. The FOLFIRINOX regimen should be studied further in borderline or unresectable pancreatic tumour together with radiation for a possible downstaging effect. Chemotherapy has generally been ineffective in www.thelancet.com/oncology Vol 12 January 2011
Deletions of the 3´ end of EPCAM lead to transcriptional read-through hypermethylation of the MSH2 promoter and subsequent epigenetic silencing of its neighbouring MSH2 gene, thus giving rise to Lynch syndrome. In addition to the diagnostic implications, the newly identified mutation in EPCAM predisposes a possible paradigm shift for screening and management of Lynch syndrome. Kempers and colleagues show that colorectal cancer is, as expected, the predominant malignant neoplastic lesion in the EPCAM variant of Lynch syndrome, but that the occurrence of endometrial cancer (which is the second most common cancer in Lynch syndrome caused by mutations in mismatch repair genes) is substantially reduced.2 Furthermore, other extracolonic cancers, which generally characterise Lynch syndrome, are rarely noted in association with the EPCAM mutation.2 Other genotype–phenotype correlations have been identified in Lynch syndrome. MSH2 mutations are associated with high rates of extracolonic cancers (especially endometrial); MLH1 mutations are associated with higher rates of colorectal cancer; and MSH6 mutations with increased risk of endometrial cancer but decreased colorectal cancer risk. However, these associations have resulted in few changes to patient management by most practitioners. Clearly, more research is needed to fully understand the clinical significance of EPCAM in relation to risk of colorectal cancer and the deficit of extracolonic cancers relative to that normally seen with MSH2 deficiency. However, if EPCAM deletions are indeed associated with lower risk of extracolonic cancers, in particular endometrial cancer, doctors, genetic counsellors, and patients could be advised about this paradigm change in screening and management strategy and to focus almost exclusively on colorectal cancer in patients with such deletions. This transition will save time and money because the array of costly diagnostic studies
will not be needed. For example, a young female EPCAM-mutation carrier might have her anxiety about gynaecological cancer alleviated if she had an EPCAM mutation that was only associated with colorectal cancer. If it is conclusively shown that Lynch syndrome due to EPCAM mutations were to harbour little risk for endometrial or ovarian cancer, some carriers could be spared the option of prophylactic hysterectomy and bilateral salpingo-oophorectomy after child-bearing is complete. A key point made by Kempers and colleagues2 was that carriers of EPCAM deletions in Lynch syndrome families harbour a distinct cancer risk that is dependent on the size and location of the deleted EPCAM region. The investigators conclude that omission of surveillance and prophylactic surgery for endometrial cancer would be reasonable for women who carry a small deletion that extends further away from the MSH2 promoter. The creation of a large international collaboration with access to an adequate number of patients to confirm this conclusion should be encouraged. Henry T Lynch*, Jane F Lynch, Carrie L Snyder, Douglas Riegert-Johnson Department of Preventive Medicine and Public Health, Creighton University, 2500 California Plaza, Omaha, NE, USA (HTL, JFL, CLS); Medical Genetics and Medicine, Mayo Clinic, Jacksonville, FL, USA (DR-J) [email protected] The authors declared no conflicts of interest. 1
2
3
4
Lindor NM, Rabe K, Petersen GM, et al. Lower cancer incidence in Amsterdam-I criteria families without mismatch repair deficiency: familial colorectal cancer type X. JAMA 2005; 293: 1979–85. Kempers MJE, Kuiper RP, Ockeloen CW, et al. Risk of colorectal and endometrial cancers in EPCAM deletion-positive Lynch syndrome: a cohort study. Lancet Oncol 2011; 12: 49–55. Ligtenberg MJL, Kuiper RP, Chan TL, et al. Heritable somatic methylation and inactivation of MSH2 in families with Lynch syndrome due to deletion of the 3´ exons of TACSTD1. Nat Genet 2009; 41: 112–17. Kovacs ME, Papp J, Szentirmay Z, Otto S, Olah E. Deletions removing the last exon of TACSTD1 constitute a distinct class of mutations predisposing to Lynch syndrome. Hum Mutat 2009; 30: 197–203.
Blood-pressure drugs and cancer: much ado about nothing? Published Online November 30, 2010 DOI:10.1016/S14702045(10)70271-0 See Articles page 65
6
For more than 35 years, the risk of cancer has been discussed in relation to high blood pressure. Some case–control studies and post-hoc analyses from prospective intervention trials have suggested that several classes of blood-pressure-lowering drugs were
associated with an increased cancer risk. A difficulty with interpretation of these results, however, is that followup is only around 2–5 years, which is too short to show an increase in cancer detection. Moreover, an increased risk of cancer death has been reported in treated and www.thelancet.com/oncology Vol 12 January 2011
Comment
www.thelancet.com/oncology Vol 12 January 2011
risk of cancer when an ACEi was given together with an ARB. This outcome was, however, not significant when heterogeneity between trials was corrected for, with the random-effects model. Moreover, these results are mainly driven by the results of one trial only.5 In fact, in most of the trials in Bangalore and colleagues’ study, randomised treatment was given in addition to several other blood-pressure-lowering drugs, which makes interpretation of the results difficult. In the ONTARGET trial,6 for example, more than half of the patients also received a β blocker, a third a calcium antagonist, and more than a quarter a diuretic in addition to an ARB (telmisartan), an ACEi (ramipril), or both. Bangalore and colleagues’ comprehensive analyses do not lend support to the hypothesis that any of the blood-pressure-lowering drug classes promotes cancer, nor to the hypothesis that any of these strategies protect against cancer. This finding is hardly surprising since it seems far-fetched that a cancer would develop in such a short time of exposure in human beings. Further, there is no really plausible mechanism by which patients with high blood pressure would develop cancer in several sites, with the exception that some underlying factors—eg, old age, obesity, high salt and alcohol consumption—are common in these patients and are known to increase the risk of both cancer and cardiovascular disease.1,7 Increased angiogenesis from high concentrations of vascular endothelial growth factor (VEGF) has also been suggested as a mechanism,7 since a high activity in the renin-angiotensin system activates VEGF, and some drugs (eg, ACEi) lower it. The clinical significance of this hypothesis, however, is unknown. Finally, a few rare malignant diseases such as malignant phaeochromocytoma might cause very high blood pressure. The investigators cautiously conclude that an increased cancer risk cannot be completely ruled out for ARB combined with ACEi—the only combination that they investigated, and which nowadays is not a preferred combination for long-term treatment of high blood pressure. Although this combination is frequently prescribed for patients with severe heart failure, the expected survival time of such patients is short. Ruling out cancer risk is a difficult task to undertake since elderly patients (from developed countries) are likely to die either of cancer or of cardiovascular disease.
Cristina Pedrazzini/Science Photo Library
untreated patients with high blood pressure, raising the possibility that high blood pressure in itself is a risk factor for cancer at some sites.1 By contrast, in a 5-year trial from Sweden, elderly patients (mean age 76 years) with high blood pressure were matched to the comprehensive Swedish cancer registry, and their cancer incidence compared with expected values based on age, sex, and calendar-yearspecific reference frequencies for the general Swedish population.2 There was no deviation from the expected number of cancers for any type; the standardised incidence rate was 0·96 (95% CI 0·88–1·04), and was similar for men and women. Moreover, the incidence of new cancers (all tumours and those at individual sites) did not differ significantly between patients randomly assigned to diuretic drugs and β blockers, calcium antagonists, or angiotensin-converting-enzyme inhibitors (ACEi). However, the standardised mortality rate (death of all causes) was only 0·63, showing how selective trials in elderly patients are. Finally, in a followup of patients at the Glasgow blood pressure clinic,3 use of long-term renin-angiotensin blockade might, in fact, protect against cancer. Treatment with a newer class of blood-pressurelowering drugs, angiotensin-receptor blockers (ARBs), was suggested to be associated with a modestly (1·2%) increased risk of new cancer.4 The follow-up in this study was only around 4 years, and new cancer data were available for 61 590 patients from five trials. Obvious limitations, acknowledged by the investigators, were that few trials were included, the analyses were made post hoc, and importantly, the trials were not designed to study new cancers. There might also be a competing death risk (cardiovascular vs cancer) if one regimen leads to longer survival and thus a longer time to be diagnosed with a cancer. Furthermore, many patients were treated with several blood-pressure-lowering drugs at the same time and we do not have information about which drugs the patients had received before the start of the trial. In The Lancet Oncology, Bangalore and co-workers5 present an elegant series of analyses of the risk of cancer comprising 70 randomised controlled trials and 324 168 patients. In their meta-analyses they do not record any different risk of cancer between the treatment groups (including ARBs) and no difference in cancer mortality, confirming data from the Swedish cancer registry.2 The investigators report a slightly increased
7
Comment
Lars H Lindholm, Bo Carlberg Department of Public Health and Clinical Medicine, Umeå University, SE 90185 Umeå, Sweden [email protected] LHL is a past President of the International Society of Hypertension. BC declares no conflicts of interest. 1 2
Dyer AR, Stamler J, Berkson DM, Lindberg HA, Stevens E. High blood pressure: a risk for cancer mortality. Lancet 1975; 305: 1051–56. Lindholm LH, Anderson H, Ekbom T, et al. Relation between drug treatment and cancer in hypertensives in Swedish Trial in Old Patients with Hypertension 2: a 5-year prospective randomised controlled trial. Lancet 2001; 358: 539–44.
3 4
5
6 7
Lever AF, Hole DJ, Gillis CR, et al. Do inhibitors of angiotensin-1-converting enzyme protect against risk of cancer? Lancet 1998; 352: 179–84. Sipahi I, Debanne SM, Rowland DY, Simon DI, Fang JC. Angiotensin-receptor blockade and risk of cancer: meta-analysis of randomised controlled trials. Lancet Oncol 2010; 11: 627–36. Bangalore S, Kumar S, Kjeldsen SE, et al. Antihypertensive drugs and risk of cancer: network meta-analyses and trial sequential analyses of 324 168 participants from randomised trials. Lancet Oncol 2010; published online Nov 30. DOI:10.1016/S1470-2045(10)70260-6. Yusuf S, Teo KK, Pogue J, et al. Telmisartan, ramipril, or both in patients with high risk of vascular events. N Engl J Med 2008; 358: 1547–59. Khakoo AY, Sidman RL, Pasqualini R, Arap W. Does the renin-angiotensin system participate in regulation of human vasculogenesis and angiogenesis? Cancer Res 2008; 68: 9112–15.
Steve Gschmeissner/Science Photo Library
FOLFIRINOX: a new standard treatment for advanced pancreatic cancer?
Published Online November 1, 2010 DOI:10.1016/S14702045(10)70237-0 For more on future trial design see Leading Edge Lancet Oncol 2010; 11: 1009
8
Pancreatic cancer is still a lethal disease because of its tendency to undergo early subclinical metastasis to the regional lymph nodes and liver. Gemcitabine has been the standard chemotherapy for metastatic pancreatic cancer for many years on the basis of a phase 3 trial showing its clinical benefit over fluorouracil;1 however, the median survival was only 5·6 months and response rate only 5%. Since then, many trials have been done with gemcitabine being the backbone of the doublet or triplet regimens to improve overall outcome in patients. Results were mostly disappointing except for one trial using a combination of erlotinib and gemcitabine. In this randomised phase 3 trial, gemcitabine plus erlotinib led to a median survival of 6·2 months compared with 5·9 months in the gemcitabine-only group.2 Although this 2-week survival difference was statistically significant, it might not be clinically significant because of increased toxic effects. Therefore most oncologists still consider single-agent gemcitabine as the standard chemotherapy for first-line therapy. A randomised phase 3 trial comparing the FOLFIRINOX regimen (oxaliplatin and irinotecan plus fluorouracil and leucovorin) to gemcitabine in advanced pancreatic cancer was presented at the 2010 American Society of Clinical Oncology (ASCO) meeting.3 Results were impressive because median overall survival increased from 6·8 months to 11·1 months (p<0·0001). More interestingly, almost half the patients in the FOLFIRINOX group were alive after 1 year, and response rate was 31·6%—the highest rate seen in phase 3 pancreatic cancer trials. On the basis of this new phase 3 trial,
should FOLFIRINOX be considered standard therapy for advanced pancreatic cancer instead of gemcitabine? Does this trial represent the start of a change for the management of advanced pancreatic cancer? The results of the FOLFIRINOX trial are more impressive than those of the gemcitabine plus erlotinib trial, but in a palliative setting, are the toxic effects worth the outcome? The FOLFIRINOX regimen was quite toxic because 46% of the patients had grade 3 or 4 neutropenia and 5·4% had grade 3 and 4 febrile neutropenia, despite 42% of patients receiving support with granulocyte-colony stimulating factor. This trial was highly selective—only 39% of patients had a primary tumour in the head of the pancreas; while in clinical practice, about two-thirds of patients will present with a primary tumour in the pancreas, possibly requiring biliary stents. Chemotherapy regimens that cause severe neutropenia are a major concern in this setting because of the risk of cholangitis development. Specific analysis on toxic effects, with and without stents, is ongoing; however, the benefit in highly selective patients with pancreatic cancer is groundbreaking and should not be ignored. Therefore, for patients with a good performance status, normal bilirubin, and a good supportive care system, FOLFIRINOX could be a viable option. This trial provides many valuable insights, which can be incorporated in future trials of advanced pancreatic cancer. The FOLFIRINOX regimen should be studied further in borderline or unresectable pancreatic tumour together with radiation for a possible downstaging effect. Chemotherapy has generally been ineffective in www.thelancet.com/oncology Vol 12 January 2011