- Email: [email protected]
Is CA 19-9 useful in the management of pancreatic cancer?
Reflection and Reaction
morphology of benign masses is not listed. Despite this issue, the data do suggest that knowledge of the underlying pathology and the expertise of the level III gynaecologists were the main determinants of their high diagnostic accuracy. The difference in the number of minimally invasive procedures in the two groups has been ascribed to the greater diagnostic accuracy of level III ultrasonography. Various factors other than scan findings can affect the surgeon’s decision on the extent of the surgical procedure. There were no differences between the two groups in terms of age, proportion of malignant masses, serum CA-125 concentrations, preoperative CT or MRI, or surgical expertise. However, in such situations, factors such as obesity or other comorbidity and patient choice should also be assessed, because these can affect the choice of surgery for suspected benign masses. In the current climate, where there is an increasing effort to rationalise procedures done by medical staff, this study is extremely important. Its findings suggest that a greater number of minimally invasive procedures and shorter hospital stays can be achieved in women with adnexal lesions suspicious of ovarian malignancy if they are scanned by experienced gynaecologists rather than ultrasonographers. There is an urgent need for a detailed cost–benefit analysis and qualityof-life assessment of this management strategy and for its assessment in the primary-care setting. Independent validation should lead to the provision
of expert ultrasonography, at least in tertiary cancer centres. Additionally, in countries like the UK, where few gynaecologists specialise in ultrasonography and most scans are done by ultrasonographers, there are important implications for training and workforce planning. Usha Menon Gynaecological Oncology, University College London Elizabeth Garrett Institute for Women’s Health, London W1T 7DN [email protected] The author declared no conflicts of interest. 1 2 3
4
5
6 7
8
9
Pados G, Tsolakidis D, Bontis J. Laparoscopic management of the adnexal mass. Ann N Y Acad Sci 2006; 1092: 211–28. Valentin L. Ameye L, Testa A, et al. Ultrasound characteristics of different types of adnexal malignancies. Gynecol Oncol 2006; 102: 41–48. Timmerman D. The use of mathematical models to evaluate pelvic masses; can they beat an expert operator? Best Pract Res Clin Obstet Gynaecol 2004; 18: 91–104. Valentin L. Prospective cross-validation of Doppler ultrasound examination and gray-scale ultrasound imaging for discrimination of benign and malignant pelvic masses. Ultrasound Obstet Gynecol 1999; 14: 273–83. Van Calster B, Timmerman D, Bourne T, et al. Discrimination between benign and malignant adnexal masses by specialist ultrasound examination versus serum CA-125. J Natl Cancer Inst 2007; 99: 1706–14. Valentin L. Use of morphology to characterize and manage common adnexal masses. Best Pract Res Clin Obstet Gynecol 2004; 18: 71–89. Timmerman D, Schwarzler P, Collins WP, et al. Subjective assessment of adnexal masses with the use of ultrasonography: an analysis of interobserver variability and experience. Ultrasound Obstet Gynecol 1999; 13: 11–16. Yazbek J, Raju SK, Ben-Nagi J, Holland TK, Hillaby K, Jurkovic D. Effect of quality of gynaecological ultrasonography on management of patients with suspected ovarian cancer: a randomised controlled trial. Lancet Oncol 2008; 9: 124–31. Valentin L, Ameye L, Jurkovic D, et al. Which extrauterine pelvic masses are difficult to correctly classify as benign or malignant on the basis of ultrasound findings and is there a way of making a correct diagnosis? Ultrasound Obstet Gynecol 2006; 27: 438–44.
Is CA 19-9 useful in the management of pancreatic cancer? Pancreatic cancer is still an incurable disease for most patients.1 Despite advances in diagnostic and therapeutic methods, and the improvements in survival seen in recent years,2 survival in this patient group remains poor, typically 6 months in patients with advanced disease. However, the absence of a cure does not mean an absence of treatment options, but most treatments aim to improve quality of life rather than survival. Selection of the most appropriate treatment is, therefore, crucial when the patient’s lifeexpectancy is short. Serum carbohydrate antigen (CA) 19-9 has been suggested as a potential marker for selecting the http://oncology.thelancet.com Vol 9 February 2008
most appropriate treatment for patients with pancreatic cancer. CA 19-9 is a tumour-associated antigen that provides useful diagnostic information in suspected pancreatic cancer, with a sensitivity and specificity of around 70% and 80%, respectively.3 In addition to its diagnostic value, a prognostic role for CA 19-9 concentration has also been suggested. Use of CA 19-9 concentration could be applied in three main areas of pancreatic-cancer management. First, CA 19-9 concentration might have a role in the selection of patients for resection. High preoperative CA 19-9 concentrations have been reported to inversely correlate with postoperative survival.4 If this
See Articles page 132
89
Steve Gschmeissner/Science Photo Library
Reflection and Reaction
Can serum CA 19-9 concentration be used as a marker for selecting treatment in pancreatic cancer?
finding is confirmed, patients with resectable cancer on imaging, but high CA 19-9 concentrations, could be spared the complications of unnecessary surgery and avoid any delay in the start of chemotherapy. In this context, however, clinicians should note that biliary obstruction might be partially responsible for the increase in CA 19-9 concentration. Second, in patients with advanced cancer, baseline CA 19-9 concentrations have been noted to independently correlate with survival.5 Therefore, researchers have suggested that the value of CA 19-9 should be considered in the design of phase III trials, with CA 19-9 concentrations being used to balance prognostic factors in different treatment groups.6 Third, CA 19-9 concentration could potentially be used as a marker of treatment response. Standard assessment of response is made by CT scan, but imaging is expensive and might sometimes be inappropriate because of interference with the imaging findings by a desmoplastic reaction involving surrounding tissues. Several clinical studies have shown a relation between the kinetics of CA 19-9 and the outcome of patients undergoing either chemotherapy or radiotherapy; therefore, a decrease in CA 19-9 concentration has been proposed as a cheaper and 90
easier parameter for measuring clinical outcome than CT scans.7 In this issue of The Lancet Oncology, Hess and coworkers8 revisit the use of CA 19-9 as a marker of response and survival in pancreatic cancer. They retrospectively analysed prospectively collected data on CA 19-9 kinetics in a large cohort of patients with advanced pancreatic cancer, who had been enrolled in a randomised trial. Their aim was to verify whether a decrease in CA 19-9 concentration could be used as a surrogate endpoint for survival and, importantly, whether an early decrease in CA 19-9 concentration (ie, after two cycles of treatment) could serve as an early marker of response, to discriminate between patients who will benefit from continued treatment and patients who will not. Unfortunately, in disagreement with findings from previous smaller studies, their data did not support this hypothesis: neither CA 19-9 nadir concentration nor an early decrease in CA 19-9 concentration correlated significantly with survival, even when different levels of decreased CA 19-9 concentration were considered (ie, ≥25%, ≥50%, and ≥75%). Additionally, 11 of 23 patients who had progressive disease on CT showed a decrease of at least 50% in CA 19-9 concentration. Nevertheless, when looking at their findings in more detail, some correlations between a decrease in CA 19-9 concentration and clinical outcome can be noted: for example, an early decrease was significantly related to time to progression, and in the Cox regression model, patient response for those with a change in CA 19-9 concentration of at least 50% was statistically significant. A drawback of their analysis was that the trial was not designed to test the prognostic value of CA 19-9 concentration, which is highlighted by the percentage of missing values (72 of 247 patients)—a limitation that is acknowledged by the authors. However, the key message of the study is clear: the correlation between CA 19-9 response and survival is not robust enough to be used as a surrogate endpoint for survival in clinical trials. Finally, we propose two recommendations for the future study of the prognostic role of serum CA 19-9 concentration. First, the kinetics of CA 19-9 concentration should be considered as a secondary endpoint during the planning of future phase III trials, to ensure measurements at specific times. Such protocols should http://oncology.thelancet.com Vol 9 February 2008
Reflection and Reaction
help to decrease the high percentage of missing values. Second, studies should ensure that standard methods and antibodies to assess CA 19-9 concentration are used and should report survival according to different baseline CA 19-9 concentrations. These measures will allow appropriate comparisons of different studies and practical conclusions to be drawn to enable appropriate patient stratification in future phase III trials.
2
3
4
5
6
Gianpaolo Balzano,*Valerio Di Carlo Pancreas Unit, Department of Surgery, San Raffaele Scientific Institute, Milan, Italy [email protected] The authors declared no conflicts of interest 1
Berrino F, De Angelis R, Sant M, et al. Survival for eight major cancers and all cancers combined for European adults diagnosed in 1995-99: results of the EUROCARE-4 study. Lancet Oncol 2007; 8: 773–83.
7
8
Brenner H, Gondos A, Arndt V. Recent major progress in long-term cancer patient survival disclosed by modelled period analysis. J Clin Oncol 2007; 25: 3274–80. Boeck S, Stieber P, Holdenrieder S, Wilkowski R, Heinemann V. Prognostic and therapeutic significance of carbohydrate antigen 19-9 as tumor marker in patients with pancreatic cancer. Oncology 2006; 70: 255–64. Lundin J, Roberts PJ, Kuusela P, Haglund C. The prognostic value of preoperative serum levels of CA 19-9 and CEA in patients with pancreatic cancer. Br J Cancer 1994; 69: 515–19. Louvet C, Labianca R, Hammel P, et al. Gemcitabine in combination with oxaliplatin compared with gemcitabine alone in locally advanced or metastatic pancreatic cancer: results of a GERCOR and GISCAD phase III trial. J Clin Oncol 2005; 23: 3509–16. Maisey NR, Norman AR, Hill A, Massey A, Oates J, Cunningham D. CA19-9 as a prognostic factor in inoperable pancreatic cancer: the implication for clinical trials. Br J Cancer 2005; 93: 740–43. Ko AH, Hwang J, Venook AP, Abbruzzese JL, Bergsland EK, Tempero MA. Serum CA19-9 response as a surrogate for clinical outcome in patients receiving fixed-dose rate gemcitabine for advanced pancreatic cancer. Br J Cancer 2005; 93: 195–99. Hess V, Glimelius B, Grawe P, et al. CA 19-9 tumour marker response to chemotherapy in patients with advanced pancreatic cancer treated in a randomized controlled trial. Lancet Oncol 2008; 9: 132–38.
Overexpression of HDACs: a prognostic marker for gastric cancer identified by tissue microarray Acetylation and deacetylation of histones have important roles in transcriptional regulation in eukaryotic cells.1 The acetylation status of histones is decided by the activity of histone acetyltransferases (HATs) and histone deacetylases (HDACs). HATs acetylate the ε-amino group of lysine residues on histones, thereby neutralising their positive charge and diminishing their ability to bind negatively charged DNA. An open chromatin configuration provides accessibility for transcription factors. Cross-talk between histone acetylation or methylation and DNA methylation has profound implications for gene expression. HDACs remove the acetyl groups, thereby allowing compacted chromatin to reform. So far, 18 HDAC isoforms have been identified and classified based on homology with yeast HDACs. HDACs also have many non-histone protein substrates, such as transcription factors and signal transduction mediators. Histone acetylation is, along with DNA methylation, one of the most consistent epigenetic mechanisms of multistage human carcinogenesis.2 Histone hypoacetylation affects the expression of genes involved in uncontrolled cell growth, differentiation, and apoptosis. The p21 gene is one of the best-studied targets of histone hypoacetylation in human cancers. In gastric http://oncology.thelancet.com Vol 9 February 2008
cancer, overexpression at the mRNA and protein levels of HDAC isoform 13 has been reported in 25 samples of gastric-cancer tissue and in 71 samples of gastric-cancer tissue for HDAC isoform 2.4 However, to my knowledge, there have been no published systematic reports about the expression levels of HDACs in large series of patients with gastric cancer. In this issue of The Lancet Oncology, Weichert and colleagues5 report an immunohistochemical study of the expression levels of HDAC isoforms 1, 2, and 3 in two cohorts of patients with gastric cancer (143 patients in a training group and 150 patients in a validation group). Initially, nuclear staining of HDACs in cancer cells was scored according to staining intensity and percentage of immunoreactive cells. After several grouping algorithms were tested, the simplest cut-off values were chosen for reproducibility, since clinicopathological and survival correlations were fairly robust. This system showed that concurrent overexpression of HDACs and overexpression of HDAC2 were significantly correlated with lymph-node metastasis and shorter survival. Immunohistochemical assessment of HDACs might therefore be of substantial prognostic value for gastric cancer, although the present system should be validated in appropriate prospective studies.
See Articles page 139
91
morphology of benign masses is not listed. Despite this issue, the data do suggest that knowledge of the underlying pathology and the expertise of the level III gynaecologists were the main determinants of their high diagnostic accuracy. The difference in the number of minimally invasive procedures in the two groups has been ascribed to the greater diagnostic accuracy of level III ultrasonography. Various factors other than scan findings can affect the surgeon’s decision on the extent of the surgical procedure. There were no differences between the two groups in terms of age, proportion of malignant masses, serum CA-125 concentrations, preoperative CT or MRI, or surgical expertise. However, in such situations, factors such as obesity or other comorbidity and patient choice should also be assessed, because these can affect the choice of surgery for suspected benign masses. In the current climate, where there is an increasing effort to rationalise procedures done by medical staff, this study is extremely important. Its findings suggest that a greater number of minimally invasive procedures and shorter hospital stays can be achieved in women with adnexal lesions suspicious of ovarian malignancy if they are scanned by experienced gynaecologists rather than ultrasonographers. There is an urgent need for a detailed cost–benefit analysis and qualityof-life assessment of this management strategy and for its assessment in the primary-care setting. Independent validation should lead to the provision
of expert ultrasonography, at least in tertiary cancer centres. Additionally, in countries like the UK, where few gynaecologists specialise in ultrasonography and most scans are done by ultrasonographers, there are important implications for training and workforce planning. Usha Menon Gynaecological Oncology, University College London Elizabeth Garrett Institute for Women’s Health, London W1T 7DN [email protected] The author declared no conflicts of interest. 1 2 3
4
5
6 7
8
9
Pados G, Tsolakidis D, Bontis J. Laparoscopic management of the adnexal mass. Ann N Y Acad Sci 2006; 1092: 211–28. Valentin L. Ameye L, Testa A, et al. Ultrasound characteristics of different types of adnexal malignancies. Gynecol Oncol 2006; 102: 41–48. Timmerman D. The use of mathematical models to evaluate pelvic masses; can they beat an expert operator? Best Pract Res Clin Obstet Gynaecol 2004; 18: 91–104. Valentin L. Prospective cross-validation of Doppler ultrasound examination and gray-scale ultrasound imaging for discrimination of benign and malignant pelvic masses. Ultrasound Obstet Gynecol 1999; 14: 273–83. Van Calster B, Timmerman D, Bourne T, et al. Discrimination between benign and malignant adnexal masses by specialist ultrasound examination versus serum CA-125. J Natl Cancer Inst 2007; 99: 1706–14. Valentin L. Use of morphology to characterize and manage common adnexal masses. Best Pract Res Clin Obstet Gynecol 2004; 18: 71–89. Timmerman D, Schwarzler P, Collins WP, et al. Subjective assessment of adnexal masses with the use of ultrasonography: an analysis of interobserver variability and experience. Ultrasound Obstet Gynecol 1999; 13: 11–16. Yazbek J, Raju SK, Ben-Nagi J, Holland TK, Hillaby K, Jurkovic D. Effect of quality of gynaecological ultrasonography on management of patients with suspected ovarian cancer: a randomised controlled trial. Lancet Oncol 2008; 9: 124–31. Valentin L, Ameye L, Jurkovic D, et al. Which extrauterine pelvic masses are difficult to correctly classify as benign or malignant on the basis of ultrasound findings and is there a way of making a correct diagnosis? Ultrasound Obstet Gynecol 2006; 27: 438–44.
Is CA 19-9 useful in the management of pancreatic cancer? Pancreatic cancer is still an incurable disease for most patients.1 Despite advances in diagnostic and therapeutic methods, and the improvements in survival seen in recent years,2 survival in this patient group remains poor, typically 6 months in patients with advanced disease. However, the absence of a cure does not mean an absence of treatment options, but most treatments aim to improve quality of life rather than survival. Selection of the most appropriate treatment is, therefore, crucial when the patient’s lifeexpectancy is short. Serum carbohydrate antigen (CA) 19-9 has been suggested as a potential marker for selecting the http://oncology.thelancet.com Vol 9 February 2008
most appropriate treatment for patients with pancreatic cancer. CA 19-9 is a tumour-associated antigen that provides useful diagnostic information in suspected pancreatic cancer, with a sensitivity and specificity of around 70% and 80%, respectively.3 In addition to its diagnostic value, a prognostic role for CA 19-9 concentration has also been suggested. Use of CA 19-9 concentration could be applied in three main areas of pancreatic-cancer management. First, CA 19-9 concentration might have a role in the selection of patients for resection. High preoperative CA 19-9 concentrations have been reported to inversely correlate with postoperative survival.4 If this
See Articles page 132
89
Steve Gschmeissner/Science Photo Library
Reflection and Reaction
Can serum CA 19-9 concentration be used as a marker for selecting treatment in pancreatic cancer?
finding is confirmed, patients with resectable cancer on imaging, but high CA 19-9 concentrations, could be spared the complications of unnecessary surgery and avoid any delay in the start of chemotherapy. In this context, however, clinicians should note that biliary obstruction might be partially responsible for the increase in CA 19-9 concentration. Second, in patients with advanced cancer, baseline CA 19-9 concentrations have been noted to independently correlate with survival.5 Therefore, researchers have suggested that the value of CA 19-9 should be considered in the design of phase III trials, with CA 19-9 concentrations being used to balance prognostic factors in different treatment groups.6 Third, CA 19-9 concentration could potentially be used as a marker of treatment response. Standard assessment of response is made by CT scan, but imaging is expensive and might sometimes be inappropriate because of interference with the imaging findings by a desmoplastic reaction involving surrounding tissues. Several clinical studies have shown a relation between the kinetics of CA 19-9 and the outcome of patients undergoing either chemotherapy or radiotherapy; therefore, a decrease in CA 19-9 concentration has been proposed as a cheaper and 90
easier parameter for measuring clinical outcome than CT scans.7 In this issue of The Lancet Oncology, Hess and coworkers8 revisit the use of CA 19-9 as a marker of response and survival in pancreatic cancer. They retrospectively analysed prospectively collected data on CA 19-9 kinetics in a large cohort of patients with advanced pancreatic cancer, who had been enrolled in a randomised trial. Their aim was to verify whether a decrease in CA 19-9 concentration could be used as a surrogate endpoint for survival and, importantly, whether an early decrease in CA 19-9 concentration (ie, after two cycles of treatment) could serve as an early marker of response, to discriminate between patients who will benefit from continued treatment and patients who will not. Unfortunately, in disagreement with findings from previous smaller studies, their data did not support this hypothesis: neither CA 19-9 nadir concentration nor an early decrease in CA 19-9 concentration correlated significantly with survival, even when different levels of decreased CA 19-9 concentration were considered (ie, ≥25%, ≥50%, and ≥75%). Additionally, 11 of 23 patients who had progressive disease on CT showed a decrease of at least 50% in CA 19-9 concentration. Nevertheless, when looking at their findings in more detail, some correlations between a decrease in CA 19-9 concentration and clinical outcome can be noted: for example, an early decrease was significantly related to time to progression, and in the Cox regression model, patient response for those with a change in CA 19-9 concentration of at least 50% was statistically significant. A drawback of their analysis was that the trial was not designed to test the prognostic value of CA 19-9 concentration, which is highlighted by the percentage of missing values (72 of 247 patients)—a limitation that is acknowledged by the authors. However, the key message of the study is clear: the correlation between CA 19-9 response and survival is not robust enough to be used as a surrogate endpoint for survival in clinical trials. Finally, we propose two recommendations for the future study of the prognostic role of serum CA 19-9 concentration. First, the kinetics of CA 19-9 concentration should be considered as a secondary endpoint during the planning of future phase III trials, to ensure measurements at specific times. Such protocols should http://oncology.thelancet.com Vol 9 February 2008
Reflection and Reaction
help to decrease the high percentage of missing values. Second, studies should ensure that standard methods and antibodies to assess CA 19-9 concentration are used and should report survival according to different baseline CA 19-9 concentrations. These measures will allow appropriate comparisons of different studies and practical conclusions to be drawn to enable appropriate patient stratification in future phase III trials.
2
3
4
5
6
Gianpaolo Balzano,*Valerio Di Carlo Pancreas Unit, Department of Surgery, San Raffaele Scientific Institute, Milan, Italy [email protected] The authors declared no conflicts of interest 1
Berrino F, De Angelis R, Sant M, et al. Survival for eight major cancers and all cancers combined for European adults diagnosed in 1995-99: results of the EUROCARE-4 study. Lancet Oncol 2007; 8: 773–83.
7
8
Brenner H, Gondos A, Arndt V. Recent major progress in long-term cancer patient survival disclosed by modelled period analysis. J Clin Oncol 2007; 25: 3274–80. Boeck S, Stieber P, Holdenrieder S, Wilkowski R, Heinemann V. Prognostic and therapeutic significance of carbohydrate antigen 19-9 as tumor marker in patients with pancreatic cancer. Oncology 2006; 70: 255–64. Lundin J, Roberts PJ, Kuusela P, Haglund C. The prognostic value of preoperative serum levels of CA 19-9 and CEA in patients with pancreatic cancer. Br J Cancer 1994; 69: 515–19. Louvet C, Labianca R, Hammel P, et al. Gemcitabine in combination with oxaliplatin compared with gemcitabine alone in locally advanced or metastatic pancreatic cancer: results of a GERCOR and GISCAD phase III trial. J Clin Oncol 2005; 23: 3509–16. Maisey NR, Norman AR, Hill A, Massey A, Oates J, Cunningham D. CA19-9 as a prognostic factor in inoperable pancreatic cancer: the implication for clinical trials. Br J Cancer 2005; 93: 740–43. Ko AH, Hwang J, Venook AP, Abbruzzese JL, Bergsland EK, Tempero MA. Serum CA19-9 response as a surrogate for clinical outcome in patients receiving fixed-dose rate gemcitabine for advanced pancreatic cancer. Br J Cancer 2005; 93: 195–99. Hess V, Glimelius B, Grawe P, et al. CA 19-9 tumour marker response to chemotherapy in patients with advanced pancreatic cancer treated in a randomized controlled trial. Lancet Oncol 2008; 9: 132–38.
Overexpression of HDACs: a prognostic marker for gastric cancer identified by tissue microarray Acetylation and deacetylation of histones have important roles in transcriptional regulation in eukaryotic cells.1 The acetylation status of histones is decided by the activity of histone acetyltransferases (HATs) and histone deacetylases (HDACs). HATs acetylate the ε-amino group of lysine residues on histones, thereby neutralising their positive charge and diminishing their ability to bind negatively charged DNA. An open chromatin configuration provides accessibility for transcription factors. Cross-talk between histone acetylation or methylation and DNA methylation has profound implications for gene expression. HDACs remove the acetyl groups, thereby allowing compacted chromatin to reform. So far, 18 HDAC isoforms have been identified and classified based on homology with yeast HDACs. HDACs also have many non-histone protein substrates, such as transcription factors and signal transduction mediators. Histone acetylation is, along with DNA methylation, one of the most consistent epigenetic mechanisms of multistage human carcinogenesis.2 Histone hypoacetylation affects the expression of genes involved in uncontrolled cell growth, differentiation, and apoptosis. The p21 gene is one of the best-studied targets of histone hypoacetylation in human cancers. In gastric http://oncology.thelancet.com Vol 9 February 2008
cancer, overexpression at the mRNA and protein levels of HDAC isoform 13 has been reported in 25 samples of gastric-cancer tissue and in 71 samples of gastric-cancer tissue for HDAC isoform 2.4 However, to my knowledge, there have been no published systematic reports about the expression levels of HDACs in large series of patients with gastric cancer. In this issue of The Lancet Oncology, Weichert and colleagues5 report an immunohistochemical study of the expression levels of HDAC isoforms 1, 2, and 3 in two cohorts of patients with gastric cancer (143 patients in a training group and 150 patients in a validation group). Initially, nuclear staining of HDACs in cancer cells was scored according to staining intensity and percentage of immunoreactive cells. After several grouping algorithms were tested, the simplest cut-off values were chosen for reproducibility, since clinicopathological and survival correlations were fairly robust. This system showed that concurrent overexpression of HDACs and overexpression of HDAC2 were significantly correlated with lymph-node metastasis and shorter survival. Immunohistochemical assessment of HDACs might therefore be of substantial prognostic value for gastric cancer, although the present system should be validated in appropriate prospective studies.
See Articles page 139
91