- Email: [email protected]
CHOP intensification: not yet state of the art
Comment
questions (the role of induction cisplatin and fluorouracil, and total radiation dose) but not the individual results of the four treatment groups. The data in these three trials can be summarised by the endpoints of colostomy-free survival, overall survival, and grade 3 or 4 acute and late toxic effects.4–9 First, the results of these three studies show that additional chemotherapy provides no benefit to colostomy-free survival or overall survival (as induction or maintenance). Second, the results of ACT II show that cisplatin compared with mitomycin does not improve of complete response rates or overall toxic effects with radiation therapy and fluorouracil. Likewise, 3-year colostomy-free survival and overall survival did not differ significantly between cisplatin and mitomycin groups. The long-term results9 of RTOG 98-11 show that disease-free and overall survival was significantly lower for patients receiving induction and concurrent cisplatin compared with concurrent mitomycin. Third, acute toxic effects are common in treatment of anal cancer, with haematological grade 3 or 4 toxic effects in up to 61% of patients and non-haematological grade 3 or 4 toxic effects in up to 74% of patients, irrespective of treatment approach. Finally, little progress has been made in improving the outcomes of patients with advanced primary tumours.4,5,7 In the ACT II trial,4 patients with tumours larger than 5 cm had unacceptably high failure rates, with 3 year progression-free survival of 62–67% versus 80–84% for patients with tumours 5 cm or smaller. Ultimately, the results of these trials do not suggest a groundbreaking improvement in outcome for these patients, especially those with very advanced local disease. At present, radiation therapy with fluorouracil and mitomycin remains the standard of care. Acute toxic effects can be mitigated by innovations in radiation
delivery—eg, intensity-modulated radiation therapy techniques—which are being rapidly adopted into clinical practice.10 Clinical trials are underway to assess EGFR inhibitors with radiation therapy and chemotherapy. Further understanding of the biology of human papillomavirus in anal cancer and translation of this knowledge to screening, prevention, and treatment resistance are also needed to advance the care of these patients. *Christopher G Willett, Brian G Czito, Manisha Palta Department of Radiation Oncology, Duke University, Durham, NC 27710, USA [email protected] We declare that we have no conflicts of interest. 1 2
3 4
5
6
7 8
9
10
Nigro ND, Vaitkevicius VK, Considine B Jr. Combined therapy for cancer of the anal canal: a preliminary report. Dis Colon Rectum 1974; 17: 354–56. Flam M, John M, Pajak T, et al. Role of mitomycin in combination with fluorouracil and radiotherapy, and of salvage chemoradiation in the definitive nonsurgical treatment of epidermoid carcinoma of the anal canal: results of a phase III randomized Intergroup study. J Clin Oncol 1996; 14: 2527–39. Palefsky JM, Giuliano AR, Goldstone S, et al. HPV vaccine against anal HPV infection and anal intraepithelial neoplasia. N Engl J Med 2011; 365: 1576–85. James RD, Glynne-Jones R, Meadows HM, et al. Mitomycin or cisplatin chemoradiation with or without maintenance chemotherapy for treatment of squamous-cell carcinoma of the anus (ACT II): a randomised, phase 3, open-label, 2×2 factorial trial. Lancet Oncol 2013; published online April 9. http://dx.doi.org/10.1016/S1470-2045(13)70086-X. Peiffert D, Tournier-Rangeard L, Gerard JP, et al. Induction chemotherapy and dose intensification of the radiation boost in locally advanced anal canal carcinoma: final analysis of the randomized UNICANCER ACCORD 03 trial. J Clin Oncol 2012; 30: 1941–48. Ajani JA, Winter KA, Gunderson LL, et al. Fluorouracil, mitomycin, and radiotherapy vs. fluorouracil, cisplatin, and radiotherapy for carcinoma of the anal canal: a randomized trial. JAMA 2008; 299: 1914–21. Ajani JA, Winter KA, Gunderson LL, et al. US Intergroup anal carcinoma trial: tumor diameter predicts for colostomy. J Clin Oncol 2009; 27: 1116–21. Ajani JA, Winter KA, Gunderson LL, et al. Prognostic factors derived from a prospective database dictate clinical biology of anal cancer: the Intergroup trial (RTOG 98-11). Cancer 2010; 116: 4007–13. Gunderson LL, Winter KA, Ajani JA, et al. Long-term update of US GI Intergroup RTOG 98-11 phase III trial for anal carcinoma: survival, relapse, and colostomy failure with concurrent chemoradiation involving fluorouracil/ mitomycin versus fluorouracil/cisplatin. J Clin Oncol 2012; 30: 4344–51. Kachnic LA, Winter K, Myerson RJ, et al. RTOG 0529: A phase 2 evaluation of dose-painted intensity modulated radiation therapy in combination with 5-fluorouracil and mitomycin-C for reduction of acute morbidity in carcinoma of the anal canal. Int J Radiat Oncol Biol Phys 2012; published online Nov 12. DOI:10.1016/j.ijrobp.2012.09.023.
CHOP intensification: not yet state of the art Addition of the anti-CD20 agent rituximab to CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) chemotherapy represents the most important progress in the treatment of diffuse large B-cell lymphoma in the past 30 years. Rituximab in combination with CHOP-like chemotherapy (R-CHOP) is now the worldwide accepted standard for all patients with diffuse large B-cell lymphoma.1–3 Interval reduction between CHOP www.thelancet.com/oncology Vol 14 May 2013
cycles from 3 weeks (CHOP21) to 2 weeks (CHOP14) improved outcomes significantly for elderly patients with diffuse large B-cell lymphoma;4 however, these elderly patients did not receive rituximab. In The Lancet Oncology, Richard Delarue and colleagues report the LNH03-6B study,5 a randomised comparison of eight cycles of R-CHOP every 3 weeks (R-CHOP21) or 2 weeks (R-CHOP14) in 602 elderly patients with diffuse large B-cell lymphoma.
Published Online April 9, 2013 http://dx.doi.org/10.1016/ S1470-2045(13)70156-6 See Articles page 525
445
Comment
Sam Ogden/Science Photo Library
3-year event-free survival did not differ between the two regimens (hazard ratio 1·04, 95% CI 0·82–1·31; p=0·7614). No differences in toxic effects were noted between R-CHOP14 and R-CHOP21, with the exception that patients assigned R-CHOP14 received more red-blood-cell transfusions (143 [47%] vs 93 [31%]; p=0·0001). Delarue and colleagues’ findings accord with those from the MabThera International Trial (MInT), which enrolled young people with diffuse large B-cell lymphoma of good prognosis.6 Superiority of the CHOEP (CHOP plus etoposide) regimen over CHOP disappeared when these regimens were combined with rituximab, establishing the antibody as a so-called chemotherapy equaliser. In view of their equal efficacy and toxicity, the key message from Delarue and colleagues’ study is the choice between R-CHOP14 and R-CHOP21 for elderly patients is left to the individual patient or their treating doctor, the advantage of R-CHOP14 being the shorter time under chemotherapy (98 days vs 148 days). Accordingly, the latest guidelines from the European Society for Medical Oncology7 recommend either eight cycles of R-CHOP21 or six cycles of R-CHOP14 (plus two additional cycles of rituximab) for the treatment of elderly patients with diffuse large B-cell lymphoma. Findings of a trial from the UK,8 in which eight cycles of R-CHOP21 were compared with six cycles of R-CHOP14 in patients aged 18–80 years with diffuse large B-cell lymphoma, showed no differences in efficacy and toxic effects between the two regimens. Discussion about R-CHOP14 versus R-CHOP21 could have been concluded if implementation of the LNH03-6B trial had not contained so many limitations. First, by contrast with the original R-CHOP14 regimen,3 use of granulocyte colonystimulating factor was not mandatory, and only 73% of patients in the R-CHOP14 arm received granulocyte colony-stimulating factor after the first cycle, when the leucocyte nadir was most pronounced. Second, it is unclear whether subgroups exist that might benefit most from R-CHOP14 or from R-CHOP21. Third, the authors do not present plots of cumulative dose to show data from all cycles and from all patients who started treatment. With this information to hand, the median dose intensity would be expected to be much lower than the reported 88% for R-CHOP14, making the difference between the 96% achieved in the German Ricover-60 trial3 accordingly bigger. Fourth, a major limitation of the LNH03-6B study is the learning curve the participants made with 446
R-CHOP14. In the analysis of the first 200 patients,9 eventfree and overall survival were worse with R-CHOP14 than with R-CHOP21; these differences have since disappeared with completion of the trial (600 patients). The curves of the last 200 patients to receive R-CHOP14 would be interesting to see, because these individuals must have had much better outcomes than the first 100 who received R-CHOP14. This improvement is most obvious for treatment-associated deaths, which were unacceptably high in the first 100 patients (9%) assigned R-CHOP14, but were much lower in the last group of 200 assigned R-CHOP14 (only 2·5%). Finally, it is possible that R-CHOP14 efficacy was compromised by too short an exposure time to rituximab (last application day 98 vs day 148 with R-CHOP21). Findings of the SMARTE-R-CHOP-14 trial10 showed that administration of eight doses of rituximab over an extended period (last application on day 239) increased 3-year survival of patients with poor prognosis by 13% compared with eight cycles of rituximab every 2 weeks in the Ricover-60 trial. What does the future hold for rituximab and CHOP regimens? Besides new doses or schedules for rituximab, Delarue and colleagues suggest use of additional agents in combination with R-CHOP, such as lenalidomide, bortezomib, or other anti-CD20 agents, and I would add the Bruton tyrosine kinase inhibitor ibrutinib to this list. Whether R-CHOP14 or R-CHOP21 will prevail will depend on their feasibility in combination with these other drugs and on their differential efficacy in distinct biological subtypes of diffuse large B-cell lymphoma, which will go beyond the distinction between germinalcentre and non-germinal-centre subtypes, to provide personalised approaches for individuals with diffuse large B-cell lymphoma in the future. Michael Pfreundschuh Saarland University Medical School, Homburg, Saarland, Germany [email protected] MP is on advisory boards for Roche, Pfizer, and Celgene, and has received research support from Amgen and Roche. 1
2
3
Coiffier B, Lepage E, Briere J, et al. CHOP chemotherapy plus rituximab compared with CHOP alone in elderly patients with diffuse large-B-cell lymphoma. N Engl J Med 2002; 346: 235–42. Habermann TM, Weller EA, Morrison VA, et al. Rituximab-CHOP versus CHOP alone or with maintenance rituximab in older patients with diffuse large B-cell lymphoma. J Clin Oncol 2006; 24: 3121–27. Pfreundschuh M, Schubert J, Ziepert M, et al, for the German High-Grade Non-Hodgkin Lymphoma Study Group (DSHNHL). 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.
www.thelancet.com/oncology Vol 14 May 2013
Comment
4
5
6
7
Pfreundschuh M, Trumper L, Kloess M, et al. Two-weekly or 3-weekly CHOP chemotherapy with or without etoposide for the treatment of elderly patients with aggressive lymphomas: results of the NHL-B2 trial of the DSHNHL. Blood 2004; 104: 634–41. Delarue R, Tilly H, Mounier N et al. Dose-dense rituximab-CHOP compared with standard rituximab-CHOP in elderly patients with diffuse large B-cell lymphoma (the LNH03-6B study): a randomised phase 3 trial. Lancet Oncol 2013; published online April 9. http://dx.doi.org/10.1016/S14702045(13)70122-0. Pfreundschuh M, Kuhnt E, Trümper L, et al, for the MabThera International Trial (MInT) Group. CHOP-like chemotherapy with or without rituximab in young patients with good-prognosis diffuse large-B-cell lymphoma: 6-year results of an open-label randomised study of the MabThera International Trial (MInT) Group. Lancet Oncol 2011; 12: 1013–22. Ghielmini M, Vitolo U, Kimby E, et al. ESMO guidelines consensus conference on malignant lymphoma 2011, part 1: diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL) and chronic lymphocytic leukemia (CLL). Ann Oncol 2013; 24: 561–76.
8
9
10
Cunningham D, Smith P, Mouncey P, et al. R-CHOP-14 versus R-CHOP-21: result of a randomized phase III trial for the treatment of patients with newly diagnosed diffuse large B-cell non-Hodgkin lymphoma. Proc Am Soc Clin Oncol 2011; 29: abstr 8000. Delarue R, Tilly H, Salles G, et al. R-CHOP14 compared to R-CHOP21 in elderly patients with diffuse large B-cell lymphoma: results of the interim analysis of the LNH03-6B GELA study. Blood 2009; 114: abstr 169a. Pfreundschuh M, Held G, Zeynalova S, et al. Improved outcome of elderly poor-prognosis DLBCL patients with 6xCHOP-14 and 8 applications of rituximab (R) given over an extended period: results of the SMARTE-R-CHOP-14 trial of the German High-Grade Non-Hodgkin Lymphoma Study Group (DSHNHL). Blood 2011; 118: abstr 272a–73a.
It is an exciting time to be an oncologist, especially because large amounts of data are being generated by genome-wide molecular studies of tumour samples. The integration of information from genomic, epigenomic, transcriptomic, proteomic, and metabolomic studies is giving researchers an unparalleled view of the inner workings of a cancer cell. Although it is a daunting task to attempt to make sense of this deluge of data, every cancer researcher and practising oncologist hopes that this effort will result in improved treatments for patients with cancer. One area of research that could potentially affect care in a fairly short timeframe is biomarker discovery. The qualitative or quantitative measurement of proteins, DNA, RNA, or lipids can serve as biomarkers to help with prevention, early detection, diagnosis, and treatment of disease. DNA methylation in the form of 5-methylcytosine has been particularly attractive as a biomarker, because several sensitive methods are available for measurement of this modification in patient samples ranging from frozen tissue to formalin-fixed paraffinembedded tissue sections.1 Aberrant DNA methylation— especially in the context of promoter CpG islands—has been well documented in many human malignancies. One mechanism by which this process is thought to actively contribute to the process of oncogenesis is through the epigenetic silencing of tumour suppressors.2 In The Lancet Oncology, Pedro Castelo-Branco and colleagues describe the discovery of a DNA methylation biomarker for malignancy and outcome in paediatric brain tumours.3 In a genome-wide assessment of CpG methylation in a discovery cohort of 280 patients, they identified one CpG site that was hypermethylated www.thelancet.com/oncology Vol 14 May 2013
(>15%) in 145 (72%) of 201 malignant tumours but not hypermethylated in 78 (99%) of 79 normal samples or low-grade tumours. In further analysis of a validation cohort of 190 patients, they established that a region upstream of the transcription start site (henceforth, UTSS) of the catalytic subunit of telomerase (TERT) was hypermethylated in all malignant paediatric brain tumours but not in various normal tissues and in lowgrade tumours (p<0·0001). This biomarker had a positive predictive value of 1·00 (95% CI 0·95–1·00) and a negative predictive value of 0·95 (0·87–0·99) to detect malignancy. Hypermethylation of UTSS was positively associated with cancer-specific expression of TERT. Although most malignant tumours displayed UTSS hypermethylation, four malignant gliomas did not. These tumours also did not express TERT. However, they did have long and heterogeneous telomeres, which is a hallmark of alternative lengthening of telomeres—a telomerase-independent, recombination-based mechanism of telomere maintenance that has been identified in about 10% of human malignancies.4 Castelo-Branco and colleagues3 also reported that methylation of UTSS increased in tumours as they progressed from low to high grade and from primary to metastatic. Lastly, UTSS hypermethylation was found to predict patient outcome in patients with posterior fossa ependymomas: 5-year overall survival was 51% (95% CI 31–71) in 25 patients with hypermethylated UTSS and 95% (86–100) in 20 with non-hypermethylated tumours (p=0·0008). These results are interesting from both clinical and basic science perspectives. For the practising paediatric neurooncologist, the potential of UTSS hypermethylation as a
Laguna Design/Science Photo Library
TERT hypermethylation: biomarker in paediatric brain tumours
Published Online April 16, 2013 http://dx.doi.org/10.1016/ S1470-2045(13)70124-4 See Articles page 534
447
questions (the role of induction cisplatin and fluorouracil, and total radiation dose) but not the individual results of the four treatment groups. The data in these three trials can be summarised by the endpoints of colostomy-free survival, overall survival, and grade 3 or 4 acute and late toxic effects.4–9 First, the results of these three studies show that additional chemotherapy provides no benefit to colostomy-free survival or overall survival (as induction or maintenance). Second, the results of ACT II show that cisplatin compared with mitomycin does not improve of complete response rates or overall toxic effects with radiation therapy and fluorouracil. Likewise, 3-year colostomy-free survival and overall survival did not differ significantly between cisplatin and mitomycin groups. The long-term results9 of RTOG 98-11 show that disease-free and overall survival was significantly lower for patients receiving induction and concurrent cisplatin compared with concurrent mitomycin. Third, acute toxic effects are common in treatment of anal cancer, with haematological grade 3 or 4 toxic effects in up to 61% of patients and non-haematological grade 3 or 4 toxic effects in up to 74% of patients, irrespective of treatment approach. Finally, little progress has been made in improving the outcomes of patients with advanced primary tumours.4,5,7 In the ACT II trial,4 patients with tumours larger than 5 cm had unacceptably high failure rates, with 3 year progression-free survival of 62–67% versus 80–84% for patients with tumours 5 cm or smaller. Ultimately, the results of these trials do not suggest a groundbreaking improvement in outcome for these patients, especially those with very advanced local disease. At present, radiation therapy with fluorouracil and mitomycin remains the standard of care. Acute toxic effects can be mitigated by innovations in radiation
delivery—eg, intensity-modulated radiation therapy techniques—which are being rapidly adopted into clinical practice.10 Clinical trials are underway to assess EGFR inhibitors with radiation therapy and chemotherapy. Further understanding of the biology of human papillomavirus in anal cancer and translation of this knowledge to screening, prevention, and treatment resistance are also needed to advance the care of these patients. *Christopher G Willett, Brian G Czito, Manisha Palta Department of Radiation Oncology, Duke University, Durham, NC 27710, USA [email protected] We declare that we have no conflicts of interest. 1 2
3 4
5
6
7 8
9
10
Nigro ND, Vaitkevicius VK, Considine B Jr. Combined therapy for cancer of the anal canal: a preliminary report. Dis Colon Rectum 1974; 17: 354–56. Flam M, John M, Pajak T, et al. Role of mitomycin in combination with fluorouracil and radiotherapy, and of salvage chemoradiation in the definitive nonsurgical treatment of epidermoid carcinoma of the anal canal: results of a phase III randomized Intergroup study. J Clin Oncol 1996; 14: 2527–39. Palefsky JM, Giuliano AR, Goldstone S, et al. HPV vaccine against anal HPV infection and anal intraepithelial neoplasia. N Engl J Med 2011; 365: 1576–85. James RD, Glynne-Jones R, Meadows HM, et al. Mitomycin or cisplatin chemoradiation with or without maintenance chemotherapy for treatment of squamous-cell carcinoma of the anus (ACT II): a randomised, phase 3, open-label, 2×2 factorial trial. Lancet Oncol 2013; published online April 9. http://dx.doi.org/10.1016/S1470-2045(13)70086-X. Peiffert D, Tournier-Rangeard L, Gerard JP, et al. Induction chemotherapy and dose intensification of the radiation boost in locally advanced anal canal carcinoma: final analysis of the randomized UNICANCER ACCORD 03 trial. J Clin Oncol 2012; 30: 1941–48. Ajani JA, Winter KA, Gunderson LL, et al. Fluorouracil, mitomycin, and radiotherapy vs. fluorouracil, cisplatin, and radiotherapy for carcinoma of the anal canal: a randomized trial. JAMA 2008; 299: 1914–21. Ajani JA, Winter KA, Gunderson LL, et al. US Intergroup anal carcinoma trial: tumor diameter predicts for colostomy. J Clin Oncol 2009; 27: 1116–21. Ajani JA, Winter KA, Gunderson LL, et al. Prognostic factors derived from a prospective database dictate clinical biology of anal cancer: the Intergroup trial (RTOG 98-11). Cancer 2010; 116: 4007–13. Gunderson LL, Winter KA, Ajani JA, et al. Long-term update of US GI Intergroup RTOG 98-11 phase III trial for anal carcinoma: survival, relapse, and colostomy failure with concurrent chemoradiation involving fluorouracil/ mitomycin versus fluorouracil/cisplatin. J Clin Oncol 2012; 30: 4344–51. Kachnic LA, Winter K, Myerson RJ, et al. RTOG 0529: A phase 2 evaluation of dose-painted intensity modulated radiation therapy in combination with 5-fluorouracil and mitomycin-C for reduction of acute morbidity in carcinoma of the anal canal. Int J Radiat Oncol Biol Phys 2012; published online Nov 12. DOI:10.1016/j.ijrobp.2012.09.023.
CHOP intensification: not yet state of the art Addition of the anti-CD20 agent rituximab to CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) chemotherapy represents the most important progress in the treatment of diffuse large B-cell lymphoma in the past 30 years. Rituximab in combination with CHOP-like chemotherapy (R-CHOP) is now the worldwide accepted standard for all patients with diffuse large B-cell lymphoma.1–3 Interval reduction between CHOP www.thelancet.com/oncology Vol 14 May 2013
cycles from 3 weeks (CHOP21) to 2 weeks (CHOP14) improved outcomes significantly for elderly patients with diffuse large B-cell lymphoma;4 however, these elderly patients did not receive rituximab. In The Lancet Oncology, Richard Delarue and colleagues report the LNH03-6B study,5 a randomised comparison of eight cycles of R-CHOP every 3 weeks (R-CHOP21) or 2 weeks (R-CHOP14) in 602 elderly patients with diffuse large B-cell lymphoma.
Published Online April 9, 2013 http://dx.doi.org/10.1016/ S1470-2045(13)70156-6 See Articles page 525
445
Comment
Sam Ogden/Science Photo Library
3-year event-free survival did not differ between the two regimens (hazard ratio 1·04, 95% CI 0·82–1·31; p=0·7614). No differences in toxic effects were noted between R-CHOP14 and R-CHOP21, with the exception that patients assigned R-CHOP14 received more red-blood-cell transfusions (143 [47%] vs 93 [31%]; p=0·0001). Delarue and colleagues’ findings accord with those from the MabThera International Trial (MInT), which enrolled young people with diffuse large B-cell lymphoma of good prognosis.6 Superiority of the CHOEP (CHOP plus etoposide) regimen over CHOP disappeared when these regimens were combined with rituximab, establishing the antibody as a so-called chemotherapy equaliser. In view of their equal efficacy and toxicity, the key message from Delarue and colleagues’ study is the choice between R-CHOP14 and R-CHOP21 for elderly patients is left to the individual patient or their treating doctor, the advantage of R-CHOP14 being the shorter time under chemotherapy (98 days vs 148 days). Accordingly, the latest guidelines from the European Society for Medical Oncology7 recommend either eight cycles of R-CHOP21 or six cycles of R-CHOP14 (plus two additional cycles of rituximab) for the treatment of elderly patients with diffuse large B-cell lymphoma. Findings of a trial from the UK,8 in which eight cycles of R-CHOP21 were compared with six cycles of R-CHOP14 in patients aged 18–80 years with diffuse large B-cell lymphoma, showed no differences in efficacy and toxic effects between the two regimens. Discussion about R-CHOP14 versus R-CHOP21 could have been concluded if implementation of the LNH03-6B trial had not contained so many limitations. First, by contrast with the original R-CHOP14 regimen,3 use of granulocyte colonystimulating factor was not mandatory, and only 73% of patients in the R-CHOP14 arm received granulocyte colony-stimulating factor after the first cycle, when the leucocyte nadir was most pronounced. Second, it is unclear whether subgroups exist that might benefit most from R-CHOP14 or from R-CHOP21. Third, the authors do not present plots of cumulative dose to show data from all cycles and from all patients who started treatment. With this information to hand, the median dose intensity would be expected to be much lower than the reported 88% for R-CHOP14, making the difference between the 96% achieved in the German Ricover-60 trial3 accordingly bigger. Fourth, a major limitation of the LNH03-6B study is the learning curve the participants made with 446
R-CHOP14. In the analysis of the first 200 patients,9 eventfree and overall survival were worse with R-CHOP14 than with R-CHOP21; these differences have since disappeared with completion of the trial (600 patients). The curves of the last 200 patients to receive R-CHOP14 would be interesting to see, because these individuals must have had much better outcomes than the first 100 who received R-CHOP14. This improvement is most obvious for treatment-associated deaths, which were unacceptably high in the first 100 patients (9%) assigned R-CHOP14, but were much lower in the last group of 200 assigned R-CHOP14 (only 2·5%). Finally, it is possible that R-CHOP14 efficacy was compromised by too short an exposure time to rituximab (last application day 98 vs day 148 with R-CHOP21). Findings of the SMARTE-R-CHOP-14 trial10 showed that administration of eight doses of rituximab over an extended period (last application on day 239) increased 3-year survival of patients with poor prognosis by 13% compared with eight cycles of rituximab every 2 weeks in the Ricover-60 trial. What does the future hold for rituximab and CHOP regimens? Besides new doses or schedules for rituximab, Delarue and colleagues suggest use of additional agents in combination with R-CHOP, such as lenalidomide, bortezomib, or other anti-CD20 agents, and I would add the Bruton tyrosine kinase inhibitor ibrutinib to this list. Whether R-CHOP14 or R-CHOP21 will prevail will depend on their feasibility in combination with these other drugs and on their differential efficacy in distinct biological subtypes of diffuse large B-cell lymphoma, which will go beyond the distinction between germinalcentre and non-germinal-centre subtypes, to provide personalised approaches for individuals with diffuse large B-cell lymphoma in the future. Michael Pfreundschuh Saarland University Medical School, Homburg, Saarland, Germany [email protected] MP is on advisory boards for Roche, Pfizer, and Celgene, and has received research support from Amgen and Roche. 1
2
3
Coiffier B, Lepage E, Briere J, et al. CHOP chemotherapy plus rituximab compared with CHOP alone in elderly patients with diffuse large-B-cell lymphoma. N Engl J Med 2002; 346: 235–42. Habermann TM, Weller EA, Morrison VA, et al. Rituximab-CHOP versus CHOP alone or with maintenance rituximab in older patients with diffuse large B-cell lymphoma. J Clin Oncol 2006; 24: 3121–27. Pfreundschuh M, Schubert J, Ziepert M, et al, for the German High-Grade Non-Hodgkin Lymphoma Study Group (DSHNHL). 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.
www.thelancet.com/oncology Vol 14 May 2013
Comment
4
5
6
7
Pfreundschuh M, Trumper L, Kloess M, et al. Two-weekly or 3-weekly CHOP chemotherapy with or without etoposide for the treatment of elderly patients with aggressive lymphomas: results of the NHL-B2 trial of the DSHNHL. Blood 2004; 104: 634–41. Delarue R, Tilly H, Mounier N et al. Dose-dense rituximab-CHOP compared with standard rituximab-CHOP in elderly patients with diffuse large B-cell lymphoma (the LNH03-6B study): a randomised phase 3 trial. Lancet Oncol 2013; published online April 9. http://dx.doi.org/10.1016/S14702045(13)70122-0. Pfreundschuh M, Kuhnt E, Trümper L, et al, for the MabThera International Trial (MInT) Group. CHOP-like chemotherapy with or without rituximab in young patients with good-prognosis diffuse large-B-cell lymphoma: 6-year results of an open-label randomised study of the MabThera International Trial (MInT) Group. Lancet Oncol 2011; 12: 1013–22. Ghielmini M, Vitolo U, Kimby E, et al. ESMO guidelines consensus conference on malignant lymphoma 2011, part 1: diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL) and chronic lymphocytic leukemia (CLL). Ann Oncol 2013; 24: 561–76.
8
9
10
Cunningham D, Smith P, Mouncey P, et al. R-CHOP-14 versus R-CHOP-21: result of a randomized phase III trial for the treatment of patients with newly diagnosed diffuse large B-cell non-Hodgkin lymphoma. Proc Am Soc Clin Oncol 2011; 29: abstr 8000. Delarue R, Tilly H, Salles G, et al. R-CHOP14 compared to R-CHOP21 in elderly patients with diffuse large B-cell lymphoma: results of the interim analysis of the LNH03-6B GELA study. Blood 2009; 114: abstr 169a. Pfreundschuh M, Held G, Zeynalova S, et al. Improved outcome of elderly poor-prognosis DLBCL patients with 6xCHOP-14 and 8 applications of rituximab (R) given over an extended period: results of the SMARTE-R-CHOP-14 trial of the German High-Grade Non-Hodgkin Lymphoma Study Group (DSHNHL). Blood 2011; 118: abstr 272a–73a.
It is an exciting time to be an oncologist, especially because large amounts of data are being generated by genome-wide molecular studies of tumour samples. The integration of information from genomic, epigenomic, transcriptomic, proteomic, and metabolomic studies is giving researchers an unparalleled view of the inner workings of a cancer cell. Although it is a daunting task to attempt to make sense of this deluge of data, every cancer researcher and practising oncologist hopes that this effort will result in improved treatments for patients with cancer. One area of research that could potentially affect care in a fairly short timeframe is biomarker discovery. The qualitative or quantitative measurement of proteins, DNA, RNA, or lipids can serve as biomarkers to help with prevention, early detection, diagnosis, and treatment of disease. DNA methylation in the form of 5-methylcytosine has been particularly attractive as a biomarker, because several sensitive methods are available for measurement of this modification in patient samples ranging from frozen tissue to formalin-fixed paraffinembedded tissue sections.1 Aberrant DNA methylation— especially in the context of promoter CpG islands—has been well documented in many human malignancies. One mechanism by which this process is thought to actively contribute to the process of oncogenesis is through the epigenetic silencing of tumour suppressors.2 In The Lancet Oncology, Pedro Castelo-Branco and colleagues describe the discovery of a DNA methylation biomarker for malignancy and outcome in paediatric brain tumours.3 In a genome-wide assessment of CpG methylation in a discovery cohort of 280 patients, they identified one CpG site that was hypermethylated www.thelancet.com/oncology Vol 14 May 2013
(>15%) in 145 (72%) of 201 malignant tumours but not hypermethylated in 78 (99%) of 79 normal samples or low-grade tumours. In further analysis of a validation cohort of 190 patients, they established that a region upstream of the transcription start site (henceforth, UTSS) of the catalytic subunit of telomerase (TERT) was hypermethylated in all malignant paediatric brain tumours but not in various normal tissues and in lowgrade tumours (p<0·0001). This biomarker had a positive predictive value of 1·00 (95% CI 0·95–1·00) and a negative predictive value of 0·95 (0·87–0·99) to detect malignancy. Hypermethylation of UTSS was positively associated with cancer-specific expression of TERT. Although most malignant tumours displayed UTSS hypermethylation, four malignant gliomas did not. These tumours also did not express TERT. However, they did have long and heterogeneous telomeres, which is a hallmark of alternative lengthening of telomeres—a telomerase-independent, recombination-based mechanism of telomere maintenance that has been identified in about 10% of human malignancies.4 Castelo-Branco and colleagues3 also reported that methylation of UTSS increased in tumours as they progressed from low to high grade and from primary to metastatic. Lastly, UTSS hypermethylation was found to predict patient outcome in patients with posterior fossa ependymomas: 5-year overall survival was 51% (95% CI 31–71) in 25 patients with hypermethylated UTSS and 95% (86–100) in 20 with non-hypermethylated tumours (p=0·0008). These results are interesting from both clinical and basic science perspectives. For the practising paediatric neurooncologist, the potential of UTSS hypermethylation as a
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TERT hypermethylation: biomarker in paediatric brain tumours
Published Online April 16, 2013 http://dx.doi.org/10.1016/ S1470-2045(13)70124-4 See Articles page 534
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