- Email: [email protected]
Adverse prognosis of bulky disease in good-risk DLBCL
Reflection and Reaction
8 9
Koutsky LA, Harper DM. Chapter 13: Current findings from prophylactic HPV vaccine trials. Vaccine 2006; 24 (suppl 3): S114–21. Wright TC Jr, Massad LS, Dunton CJ, et al. American Society for Colposcopy and Cervical Pathology-sponsored Consensus Conference. 2006 consensus guidelines for the management of women with cervical intraepithelial neoplasia or adenocarcinoma in situ. Am J Obstet Gynecol 2007; 197: 340–45.
10
Kyrgiou M, Koliopoulos G, Martin-Hirsch P, Arbyn M, Prendiville W, Paraskevaidis E. Obstetric outcomes after conservative treatment for intraepithelial or early invasive cervical lesions: systematic review and meta-analysis. Lancet 2006; 367: 489–98.
Adverse prognosis of bulky disease in good-risk DLBCL The prognosis of patients with diffuse large B-cell lymphoma (DLBCL) depends on many variables, derived from the patients, the lymphoma, or the treatment. Since CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisolone)-like chemotherapy in association with rituximab (R-CHOP) has been established as the standard treatment for these patients, the search for prognostic factors is mainly focused on the lymphoma itself and patient characteristics. Of these factors, the International Prognostic Index (IPI),1 which was developed in the prerituximab era, but is also useful for patients who receive immunochemotherapy, is a simple and widely used index for prognostication in patients with DLBCL at diagnosis. This index has also proven to be useful in other situations such as in the histological transformation of lowgrade non-Hodgkin lymphomas or in DLBCL in second complete or partial remission submitted to autologous stem-cell transplantation.2 Bulky disease is not identified as an independent risk factor in the IPI, but its negative prognostic effect was noted in some studies in the pre-
Colin Cuthbert/Science Photo Library
See Articles page 435
Patients could benefit from better prognostic information
406
rituximab era. The prognostic role of this parameter in the rituximab era has not been analysed up to now. In this issue of The Lancet Oncology, Pfreundschuh and colleagues3 have shown, for the first time to our knowledge, the adverse prognostic significance of bulky disease in young good-prognosis patients with DLBCL included in the MabThera International Trial (MInT),4 the largest prospective trial published so far in this subset of patients. Since the MInT trial included patients from cooperative groups from 18 countries, the definition of bulky disease was not uniform, ranging from more than 5·0 cm, more than 7·5 cm, or more than 10·0 cm. However, this limitation was overcome by the Martingale residual analysis, that showed linearity throughout maximum tumour diameter (MTD) ranges from more than 5·0 cm and under 10·0 cm, implying that there is no cut-off point with a marked increase of risk for shorter event-free survival (EFS) or overall survival (OS). This observation allowed the introduction of MTD irrespective of the cut-off value in the Cox regression model that showed an independent prognostic significance for EFS in patients who received CHOP-like and for OS in those treated with R-CHOP-like chemotherapies. However, in the patients assigned to R-CHOP-like chemotherapy, hazard ratios (HRs) were lower than those in patients who were not assigned to rituximab, implying that rituximab diminishes (but does not eliminate) the adverse effect of tumour size. Additionally, in the R-CHOP-like group, only the cut-off point at 10·0 cm distinguished between two populations with significantly different EFS, making this value adequate to delineate young patients with goodprognosis DLBCL and bulky disease in the rituximab era. Two additional points emerge from this study. First, the independent effect of MTD on prognosis of patients with DLBCL, other than young patients with good prognoses. Although, theoretically, the contribution of bulky disease might be smaller in advanced poor-prognosis disease (with high tumour burden) than in limited disease, this http://oncology.thelancet.com Vol 9 May 2008
Reflection and Reaction
should and is being studied in other ongoing studies.5 The second point is the role, if any, of radiotherapy in patients with bulky disease. In the MInT trial more than 90% of patients with MTD more than 7·5 cm received additional radiotherapy, by contrast with only 9% of patients with MTD ranging from 5·0 cm to 7·4 cm. Given the absence of a cut-off point for MTD in that trial, a small or null effect of radiotherapy on areas of bulky disease could be suggested. In fact, the value of involved-field radiotherapy in the rituximab era has not been definitively established in lymphomas.6 Again, randomised studies that are currently underway are specifically addressed to this question and will definitively identify the role of radiotherapy in the era of immunochemotherapy. The clinical and biological prognostic factors for DLBCL have been revalidated in the era of immunochemotherapy. Many biological parameters seem to have lost their prognostic significance (ie, the immunohistochemically defined patterns of germinal centre-like and activated B-cell-like),7 whereas new ones (ie, early assessment with PET scanning)8 might play a role in the prognostication of lymphomas. The commonly used indices, such as the IPI, either the original index or after modifications,9 seem to retain their prognostic usefulness. Furthermore, immunochemotherapy itself is also evolving. Therefore, a future issue is to show whether bulky disease retains its unfavourable prognostic significance in the setting of dose-densification strategies or in dose-intensification approaches.10 Dose-dense strategies have improved the outcome of elderly patients5 and they will probably also be useful for young patients with high-risk (IPI greater than or equal to 2) DLBCL. In these subgroups of patients, the role of bulky disease is uncertain and merits study in the setting of clinical trials.
Josep-Maria Ribera Clinical Haematology Department, Institut Català d’OncologiaHospital Universitari Germans Trias i Pujol, Badalona, Universitat Autònoma de Barcelona, Spain [email protected] Supported in part by grant RD06/0020/1056 from RETICS (Redes Temáticas de Investigación Cooperativa en Salud. Ministerio de Sanidad y Consumo). The author declared no other conflicts of interest. 1
2
3
4
5
6
7
8
9
10
The International Non-Hodgkin’s Lymphoma Prognostic Factors Project. A predictive model for aggressive non-Hodgkin’s lymphoma. N Engl J Med 1993; 329: 379–91. Lerner RE, Thomas W, Defor TE, Weisdorf DJ, Burns LJ. The International Prognostic Index assessed at relapse predicts outcomes of autologous transplantation for diffuse large-cell non-Hodgkin’s lymphoma in second complete or partial remission. Biol Bone Marrow Transplant 2007; 13: 486–92. Pfreundschuh M, Ho AD, Cavallin-Stahl E, et al. Prognostic significance of maximum tumour (bulk) diameter in young patients with good-prognosis diffuse large-B-cell lymphoma treated with CHOP-like chemotherapy with or without rituximab: an exploratory analysis of the MabThera International Trial Group (MInT) Study. Lancet Oncol 2008; 9: 435–44. Pfreundschuh M, Truemper L, Osterborg A, et al. CHOP-like chemotherapy plus rituximab compared with CHOP-like chemotherapy alone in young patients with good-prognosis diffuse large B-cell lymphoma: a randomised controlled trial by the MabThera International Trial (MInT) Group. Lancet Oncol 2006; 7: 379–91. Pfreundschuh M, Schubert J, Ziepert M, et al. Six versus eight cycles of bi-weekly CHOP-14 with or without rituximab in elderly patients with aggressive CD20+ B-cell lymphomas: a randomised controlled trial (RICOVER-60). Lancet Oncol 2008; 9: 105–16. Horning SJ, Weller E, Kim K, et al. Chemotherapy with or without radiotherapy in limited-stage diffuse aggressive non-Hodgkin’s lymphoma: Eastern Cooperative Oncology Group study 1484. J Clin Oncol 2004; 22: 3032–38. Nyman H, Adde M, Karjalinen-Lindsbverg ML, et al. Prognostic impact of immunohistochemically defined germinal center phenotype in diffuse large B-cell lymphoma patients treated with immunochemotherapy. Blood 2007; 109: 4930–35. Dupuis J, Gaulard P, Hemary F, et al. Respective prognostic value of germinal center phenotype and early (18)fluorodeoxyglucose-positron emission tomography scanning in previously untreated patients with diffuse large B-cell lymphoma. Haematologica 2007; 92: 778–83. Sehn LH, Berry B, Chhanabhai M, et al. The revised International Prognostic Index (R-IPI) is a better predictor of outcome than the standard IPI for patients with diffuse large B-cell lymphoma treated with R-CHOP. Blood 2007; 109: 1857–61. Tarella C, Zanni M, Di Incola M, et al. Prolonged survival in poor-risk diffuse large B-cell lymphoma following front-line treatment with rituximab-supplemented, early-intensified chemotherapy with multiple autologous haematopoietic stem cell support: a multicenter study by GITIL (Gruppo Italiano Terapie Innovative nei Limfomi). Leukemia 2007; 21: 1802–11.
Studies of prostate-cancer mortality: caution advised For years, the similarity in rates of prostate-cancer deaths between the UK and in the USA1–3 has been used to highlight the probable futility of prostate-specific antigen (PSA) screening. Now that rates of prostate-cancer deaths in the USA and the UK are diverging, might we finally be privy to some convincing evidence in favour of screening efficacy?
Apparently not, according to Collin and colleagues1 who, in this issue of The Lancet Oncology, provide the most comprehensive comparison so far to our knowledge http://oncology.thelancet.com Vol 9 May 2008
of trends in prostate cancer in the USA, known for high PSA use, with those in the UK, known for much lower PSA use. Although previous UK–US comparisons provided data solely on mortality trends, Collin and co-workers present new information on UK practice patterns that greatly assists inquiry into why death rates in the two countries are diverging (since the mid 1990s, prostatecancer mortality in the USA has declined at an annual rate almost four-times that in the UK).
See Articles page 445
407
8 9
Koutsky LA, Harper DM. Chapter 13: Current findings from prophylactic HPV vaccine trials. Vaccine 2006; 24 (suppl 3): S114–21. Wright TC Jr, Massad LS, Dunton CJ, et al. American Society for Colposcopy and Cervical Pathology-sponsored Consensus Conference. 2006 consensus guidelines for the management of women with cervical intraepithelial neoplasia or adenocarcinoma in situ. Am J Obstet Gynecol 2007; 197: 340–45.
10
Kyrgiou M, Koliopoulos G, Martin-Hirsch P, Arbyn M, Prendiville W, Paraskevaidis E. Obstetric outcomes after conservative treatment for intraepithelial or early invasive cervical lesions: systematic review and meta-analysis. Lancet 2006; 367: 489–98.
Adverse prognosis of bulky disease in good-risk DLBCL The prognosis of patients with diffuse large B-cell lymphoma (DLBCL) depends on many variables, derived from the patients, the lymphoma, or the treatment. Since CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisolone)-like chemotherapy in association with rituximab (R-CHOP) has been established as the standard treatment for these patients, the search for prognostic factors is mainly focused on the lymphoma itself and patient characteristics. Of these factors, the International Prognostic Index (IPI),1 which was developed in the prerituximab era, but is also useful for patients who receive immunochemotherapy, is a simple and widely used index for prognostication in patients with DLBCL at diagnosis. This index has also proven to be useful in other situations such as in the histological transformation of lowgrade non-Hodgkin lymphomas or in DLBCL in second complete or partial remission submitted to autologous stem-cell transplantation.2 Bulky disease is not identified as an independent risk factor in the IPI, but its negative prognostic effect was noted in some studies in the pre-
Colin Cuthbert/Science Photo Library
See Articles page 435
Patients could benefit from better prognostic information
406
rituximab era. The prognostic role of this parameter in the rituximab era has not been analysed up to now. In this issue of The Lancet Oncology, Pfreundschuh and colleagues3 have shown, for the first time to our knowledge, the adverse prognostic significance of bulky disease in young good-prognosis patients with DLBCL included in the MabThera International Trial (MInT),4 the largest prospective trial published so far in this subset of patients. Since the MInT trial included patients from cooperative groups from 18 countries, the definition of bulky disease was not uniform, ranging from more than 5·0 cm, more than 7·5 cm, or more than 10·0 cm. However, this limitation was overcome by the Martingale residual analysis, that showed linearity throughout maximum tumour diameter (MTD) ranges from more than 5·0 cm and under 10·0 cm, implying that there is no cut-off point with a marked increase of risk for shorter event-free survival (EFS) or overall survival (OS). This observation allowed the introduction of MTD irrespective of the cut-off value in the Cox regression model that showed an independent prognostic significance for EFS in patients who received CHOP-like and for OS in those treated with R-CHOP-like chemotherapies. However, in the patients assigned to R-CHOP-like chemotherapy, hazard ratios (HRs) were lower than those in patients who were not assigned to rituximab, implying that rituximab diminishes (but does not eliminate) the adverse effect of tumour size. Additionally, in the R-CHOP-like group, only the cut-off point at 10·0 cm distinguished between two populations with significantly different EFS, making this value adequate to delineate young patients with goodprognosis DLBCL and bulky disease in the rituximab era. Two additional points emerge from this study. First, the independent effect of MTD on prognosis of patients with DLBCL, other than young patients with good prognoses. Although, theoretically, the contribution of bulky disease might be smaller in advanced poor-prognosis disease (with high tumour burden) than in limited disease, this http://oncology.thelancet.com Vol 9 May 2008
Reflection and Reaction
should and is being studied in other ongoing studies.5 The second point is the role, if any, of radiotherapy in patients with bulky disease. In the MInT trial more than 90% of patients with MTD more than 7·5 cm received additional radiotherapy, by contrast with only 9% of patients with MTD ranging from 5·0 cm to 7·4 cm. Given the absence of a cut-off point for MTD in that trial, a small or null effect of radiotherapy on areas of bulky disease could be suggested. In fact, the value of involved-field radiotherapy in the rituximab era has not been definitively established in lymphomas.6 Again, randomised studies that are currently underway are specifically addressed to this question and will definitively identify the role of radiotherapy in the era of immunochemotherapy. The clinical and biological prognostic factors for DLBCL have been revalidated in the era of immunochemotherapy. Many biological parameters seem to have lost their prognostic significance (ie, the immunohistochemically defined patterns of germinal centre-like and activated B-cell-like),7 whereas new ones (ie, early assessment with PET scanning)8 might play a role in the prognostication of lymphomas. The commonly used indices, such as the IPI, either the original index or after modifications,9 seem to retain their prognostic usefulness. Furthermore, immunochemotherapy itself is also evolving. Therefore, a future issue is to show whether bulky disease retains its unfavourable prognostic significance in the setting of dose-densification strategies or in dose-intensification approaches.10 Dose-dense strategies have improved the outcome of elderly patients5 and they will probably also be useful for young patients with high-risk (IPI greater than or equal to 2) DLBCL. In these subgroups of patients, the role of bulky disease is uncertain and merits study in the setting of clinical trials.
Josep-Maria Ribera Clinical Haematology Department, Institut Català d’OncologiaHospital Universitari Germans Trias i Pujol, Badalona, Universitat Autònoma de Barcelona, Spain [email protected] Supported in part by grant RD06/0020/1056 from RETICS (Redes Temáticas de Investigación Cooperativa en Salud. Ministerio de Sanidad y Consumo). The author declared no other conflicts of interest. 1
2
3
4
5
6
7
8
9
10
The International Non-Hodgkin’s Lymphoma Prognostic Factors Project. A predictive model for aggressive non-Hodgkin’s lymphoma. N Engl J Med 1993; 329: 379–91. Lerner RE, Thomas W, Defor TE, Weisdorf DJ, Burns LJ. The International Prognostic Index assessed at relapse predicts outcomes of autologous transplantation for diffuse large-cell non-Hodgkin’s lymphoma in second complete or partial remission. Biol Bone Marrow Transplant 2007; 13: 486–92. Pfreundschuh M, Ho AD, Cavallin-Stahl E, et al. Prognostic significance of maximum tumour (bulk) diameter in young patients with good-prognosis diffuse large-B-cell lymphoma treated with CHOP-like chemotherapy with or without rituximab: an exploratory analysis of the MabThera International Trial Group (MInT) Study. Lancet Oncol 2008; 9: 435–44. Pfreundschuh M, Truemper L, Osterborg A, et al. CHOP-like chemotherapy plus rituximab compared with CHOP-like chemotherapy alone in young patients with good-prognosis diffuse large B-cell lymphoma: a randomised controlled trial by the MabThera International Trial (MInT) Group. Lancet Oncol 2006; 7: 379–91. Pfreundschuh M, Schubert J, Ziepert M, et al. Six versus eight cycles of bi-weekly CHOP-14 with or without rituximab in elderly patients with aggressive CD20+ B-cell lymphomas: a randomised controlled trial (RICOVER-60). Lancet Oncol 2008; 9: 105–16. Horning SJ, Weller E, Kim K, et al. Chemotherapy with or without radiotherapy in limited-stage diffuse aggressive non-Hodgkin’s lymphoma: Eastern Cooperative Oncology Group study 1484. J Clin Oncol 2004; 22: 3032–38. Nyman H, Adde M, Karjalinen-Lindsbverg ML, et al. Prognostic impact of immunohistochemically defined germinal center phenotype in diffuse large B-cell lymphoma patients treated with immunochemotherapy. Blood 2007; 109: 4930–35. Dupuis J, Gaulard P, Hemary F, et al. Respective prognostic value of germinal center phenotype and early (18)fluorodeoxyglucose-positron emission tomography scanning in previously untreated patients with diffuse large B-cell lymphoma. Haematologica 2007; 92: 778–83. Sehn LH, Berry B, Chhanabhai M, et al. The revised International Prognostic Index (R-IPI) is a better predictor of outcome than the standard IPI for patients with diffuse large B-cell lymphoma treated with R-CHOP. Blood 2007; 109: 1857–61. Tarella C, Zanni M, Di Incola M, et al. Prolonged survival in poor-risk diffuse large B-cell lymphoma following front-line treatment with rituximab-supplemented, early-intensified chemotherapy with multiple autologous haematopoietic stem cell support: a multicenter study by GITIL (Gruppo Italiano Terapie Innovative nei Limfomi). Leukemia 2007; 21: 1802–11.
Studies of prostate-cancer mortality: caution advised For years, the similarity in rates of prostate-cancer deaths between the UK and in the USA1–3 has been used to highlight the probable futility of prostate-specific antigen (PSA) screening. Now that rates of prostate-cancer deaths in the USA and the UK are diverging, might we finally be privy to some convincing evidence in favour of screening efficacy?
Apparently not, according to Collin and colleagues1 who, in this issue of The Lancet Oncology, provide the most comprehensive comparison so far to our knowledge http://oncology.thelancet.com Vol 9 May 2008
of trends in prostate cancer in the USA, known for high PSA use, with those in the UK, known for much lower PSA use. Although previous UK–US comparisons provided data solely on mortality trends, Collin and co-workers present new information on UK practice patterns that greatly assists inquiry into why death rates in the two countries are diverging (since the mid 1990s, prostatecancer mortality in the USA has declined at an annual rate almost four-times that in the UK).
See Articles page 445
407