Two New Agents Show Promise in Glioblastoma and Metastatic Melanoma
What's Hot in July/August 2011
by David W. Sharp
Even in mid-summer in the Northern Hemisphere, the novel swine-origin influenza A (H1N1 ) virus still attracts headlines. The U.K.’s Health Protection Agency has published the death toll for last winter. It was 602, and that is just cases where influenza was given as a major cause on the death certificate.
Importantly, 70% of those dying were in the age group 15 to 64, a change from the usual pattern where older people are more vulnerable. No surprise then that this virus retains a dominant presence in citation listings: eight of the top 25 medicine reports in the current Hot Papers extraction examine this subject, with four of those in the Top Ten (#1, #2, #3, #9).
In 2005, a European and Canadian collaboration that has been looking at the effect of adding the drug temozolomide to postoperative radiotherapy in patients with high-grade brain tumors recorded improved two-year survival for patients on the combined regimen (R. Stupp, et al., New Engl. J. Med.,352[10]: 987-96, 2005).
In May, 2009, the group provided the results at five years, in The Lancet Oncology, which began life as a review journal but which now publishes original research (R. Stupp, et al., Lancet Oncol.,10[5]: 459-66, 2009; currently at #12, with 37 citations this period and 161 overall). Ninety-three percent of the 573 patients in this randomized trial had died at the median follow-up of five years, but overall survival was significantly better for those given temozolomide rather than radiotherapy alone. This drug is cytotoxic by virtue of methylation of guanine, and the resulting damage to DNA can be repaired by O-6-methylguanine-DNA transferase, or MGMT.
H1N1 test tubes.
The methylated status of a patient’s MGMT promoter (if methylated, MGMT repair of DNA is inactivated) proved to be a useful prognostic indicator in an analysis of survival in a subgroup of patients for whom MGMT status was known. In an ongoing controlled trial called CENTRIC, in which the drug cilengitide is added to combined temozolomide and radiotherapy, only patients with methylated MGMT promoter are being randomized (R. Stupp, et al., J Clin. Oncol.,28[15s]: abstr TPS152, 2010). This targeted approach—using molecular genetics to identify cancer patients who are most likely to benefit from the latest drugs—has become a recurrent theme in clinical trials.
An Italian group’s findings hint—and it is only a hint because the comparison is a historical one—at the impact this drug may already be making in non-trial settings. Among more than 1,000 patients treated at 18 centers in 2002-07, five-year survival was 3.9%, but this was better than that recorded in 1997-2001. In the later period, 71% of patients had had temozolomide as well as radiotherapy (S. Scoccianti, et al., Neurosurgery,67[2]: 446-58, 2010). According to one recent review, temozolomide should now be included in the "standard of care for newly diagnosed glioblastoma" (B.J. Theeler, M.D. Groves, Curr. Treat. Options Neurol.,Apr 16, 2011; Epub).
Even, so trial data and survival figures show how far off talk of a cure we are, and the same is true for a novel agent attracting attention in the management of another cancer with a very poor prognosis, metastatic melanoma. Ipilimumab is a monoclonal antibody that potentiates an anti-tumor T-cell response. In March of this year it was approved by the U.S. Food and Drug Administration, and strongly influential in that approval will have been a randomized trial publisheda year ago and already at #15 with 67 citations so far and 33 in the latest bimonthly count (F.S. Hodi, et al., New Engl. J. Med.,363[8]: 711-23, 2010).
The mode of attack this time is not via cytotoxicity but by promoting antitumor immunity. The control was a cancer vaccine derived from the melanosomal protein (gp100). Median overall survival was 10.0 months for those given both antibody and vaccine, 10.1 months for ipilimumab alone, and 6.4 months for gp100 alone. This drug attracted attention at the June, 2011, American Society for Clinical Oncology meeting in Chicago. So did vemurafenib, which targets a gene mutation present in roughly 50% of melanoma patients; six-month survival was 84% compared with 64% for patients on the control drug dacarbazine (New Engl. J. Med., Epub, 5 June 2011; 10.1056/NEJMoa1103782).
A former deputy editor of The Lancet, David W. Sharp, M.A. (Cambridge), is a freelance writer living in Minchinhampton, Gloucestershire, U.K.
What's Hot in Medicine | |||
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Rank | Paper |
Cites This Period Jan-Feb 11 |
Rank Last Period Nov-Dec 10 |
1 |
Novel Swine-Origin Influenza A (H1N1) Virus Investigation Team (F.S. Dawood, et al.), "Emergence of a novel swine-origin influenza A (H1N1) virus in humans," New Engl. J. Med., 360(25): 2605-15, 18 June 2009. [Writing group: Ctrs. for Disease Control & Prevent., Atlanta, GA] *458WR |
72 | 1 |
2 |
S. Jain, et al., "Hospitalized patients with 2009 H1N1 influenza in the United States, April-June 2009," New Engl. J. Med.", 361(20): 1935-44, 12 November 2009. [Ctrs. for Disease Control & Prevent., Atlanta, GA] *518AI |
55 | † |
3 |
R.J. Garten, et al., "Antigenic and genetic characteristics of swine-origin 2009 A(H1N1) influenza viruses circulating in humans," Science, 325(5937): 197-201, 10 July 2009. [26 institutions worldwide] *468FK |
54 | 5 |
4 |
S.J. Connolly, et al., "Dabigatran versus warfarin in patients with atrial fibrillation," New Engl. J. Med., 361(2): 1139-51, 17 September 2009. [12 institutions worldwide] *494QA |
48 | 10 |
5 |
T.S. Mok, et al., "Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma," New Engl. J. Med., 361(10): 947-57, 3 September 2009. [14 institutions worldwide] *490EI |
47 | 7 |
6 |
K.M. Flegal, et al., "Prevalence and trends in obesity among US adults,1999-2008," JAMA, 303(3): 235-41, 20 January 2010. [Ctrs. Disease Control & Prevent., Hyattsville, MD] *544VM |
47 | 9 |
7 |
E. Van Cutsem, et al., "Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer," New Engl. J. Med., 360(14): 1408-17, 2 April 2009. [15 institutions worldwide] *427AL |
45 | † |
8 |
A.S. Levey, et al., "A new equation to estimate glomerular filtration rate," Ann. Internal Med., 150(9): 604-12, 5 May 2009. [6 U.S. institutions] *443IQ |
41 | † |
9 |
K. Hancock, et al., "Cross-reactive antibody responses to the 2009 pandemic H1N1 influenza virus," New Engl. J. Med., 361(20): 1945-52, 12 November 2009. [Ctrs. for Disease Control & Prevent., Atlanta, GA] *518AI |
40 | † |
10 |
F.H. Schröder, et al., "Screening and prostate-cancer mortality in a randomized European study," New Engl. J. Med., 360(13): 1320-8, 26 March 2009. [15 institutions worldwide] *423VP |
37 | 2 |
SOURCE: Thomson Reuters Hot Papers Database. Read the Legend. |