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Top oncology stories of 2008
This year, Harry Jacob, MD, and I, with the assistance of our other Section Editors, again chose to emphasize some of HemOnc Today’s recently-published articles. This column presents some comments about several oncology contributions.
Cancer screening
Two stories dealing with early diagnosis of cancer made the top articles of 2008 selected by the HemOnc Today Editorial Board. The first story attempted to answer how often the physician should follow-up an initial negative colonoscopy and the second story asked if CT colonography could replace colonoscopy for colorectal polyp and cancer detection. Screening for colorectal cancer is clearly important for patients aged 50 and older. Colonoscopy is the gold standard and can save lives through polyp removal and early cancer detection, especially in patients at increased risk, due to a family history of colorectal cancer. In these patients, repeat colonoscopy is indicated at shorter intervals (two to three years) in contrast to individuals who have a negative exam. Current guidelines from a U.S. Multisociety Task Force and the American Cancer Society for individuals aged 50 or older who have a negative exam recommended colonoscopy every 10 years. Evidence to support this recommendation came from a study that enrolled 2,536 patients aged 50 years and older who had baseline screening. When 51.6% were rescreened after five years, no cancers were found and 16% had adenomas. Only 19 advanced adenomas were found, leading investigators to conclude that the risk of colorectal cancer is “extremely low” in patients previously shown to have a negative previous exam and that a 10-year interval for rescreening is reasonable.
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Although colonoscopy is the gold standard for detection of colorectal cancers and precancerous polyps, it is labor-intensive, invasive and expensive. These factors prevent many individuals from undergoing this screening procedure. The use of noninvasive CT colonography was compared to colonoscopy in 2,531 symptomatic patients at 15 sites. Lesions of 10 mm or more could be detected with CT colonography. However, false positives are a problem as pointed out in an accompanying editorial to the paper by Robert Fletcher, MD. Of the 17% of patients that had one or more polyps of 1 cm or more, only one in four actually had a polyp. The other drawbacks to this procedure are radiation exposure and the need for follow-up colonoscopy in patients with suspected lesions.
Screening for prostate cancer
Should patients older than 75 be screened for prostate cancer? The U.S. Preventative Services Task Force reviewed evidence-based literature and concluded that the risks of screening outweighed the benefits, and therefore it does not recommend screening of this age group. The argument is that the therapy for prostate cancer in this age group is morbid (urinary incontinence, bowel dysfunction) and these patients with prostate cancer may not develop cancer-related symptoms in their lifetime. I disagree. Some patients without comorbid conditions and with clear evidence of Gleason 8-10 prostate cancer need treatment, and radiation therapy and anti-androgen therapy can save lives. Improved radiation therapy focused on the tumor (IMRT) has resulted in less urinary incontinence and bowel dysfunction. Physiologic age and the presence or absence of comorbid conditions should be the determining factors for screening, as well as discussions with the patients as to the pros and cons of screening.
New therapies for cancer patients
The only new “old” drug approved by the FDA in 2008, initially for treatment of patients with chronic lymphocytic leukemia and more recently for indolent non-Hodgkin’s lymphoma, was bendamustine (Treanda, Cephalon). The pivotal trial leading to approval of this drug for CLL was a randomized multicenter study of 301 treatment-naive patients that compared bendamustine with chlorambucil. Patients receiving bendamustine had a better overall response (59% vs. 26%; P=.0001) and a longer PFS (18 months vs. 6 months). Although considered an alkylating agent, the drug may have additional mechanism(s) of action, as it has activity even in previously treated patients refractory to other alkylating agents. Adverse effects of the drug are myelosuppression, nausea and vomiting. The drug was approved in a relatively short period, and experts in the treatment of CLL and lymphoma like Kanti Rai, MD, believe that this drug will provide additional treatment options for patients with these diseases, alone and in combination with rituximab (Rituxan, Genentech) and other agents.
Three other studies using approved drugs for new indications also were reported in 2008. Pemetrexed (Alimta, Eli Lily), a second generation antifolate that primarily targets thymidylate synthase, was approved in combination with cisplatin for the first-line treatment of non-squamous cell carcinoma. This combination was compared to cisplatin plus gemcitabine in a phase-3, open-labeled randomized study. There was no difference in median survival (10.3 months), median PFS (4.8 months for cisplatin and pemetrexed and 5.1 months for cisplatin plus gemcitabine), or response rates (27.1% vs. 24.7%). When the effect of histology was examined, the median survival for patients with non-squamous histology was 11.0 months for pemetrexed plus cisplatin vs. 10.1 months for patients treated with cisplatin and gemcitabine (unadjusted HR= 0.84). Median survival for patients with squamous cell histology was 9.4 months for pemetrexed plus cisplatin vs. 10.8 months for gemcitabine plus cisplatin (unadjusted HR=1.22).
Less hematologic toxicity occurred in the pemetrexed-cisplatin group, and growth factors were used less for this group of patients. Clearly the pemetrexed combination is not a great therapeutic advance, but the convenience of use (every three weeks) and the decreased toxicity gives clinicians an option for the treatment of patients with non-squamous cell lung.
The FDA granted accelerated approval for bevacizumab (Avastin, Genetech) in combination with paclitaxel for the first-line treatment of metastatic HER-2–negative breast cancer. Of interest, the recommendation of the Oncologic Drugs Advisory Committee was against approval. The basis for the approval by the FDA were the findings from the E2100 study that showed improvement in PFS when bevacizumab was combined with paclitaxel vs. paclitaxel alone, but not overall survival. Bevacizumab in combination with paclitaxel resulted in a 5.5-month increase in median PFS compared to paclitaxel, at the cost of an increase in grade-3 to -5 events. Before full approval is given, the FDA will review the results of phase-3 AVADO and RIBBON-1 trials, which will be available soon. I agree with Nancy Davidson, MD, who commented in HemOnc Today that the FDA made the right decision granting accelerated approval, “showing their commitment to the well being of patients,” she said.
Another report that made the top stories was the CONKO-001 trial, which showed that adjuvant treatment of patients following resection of pancreatic cancer more than doubled overall survival when compared to surgery alone. This was a randomized, multicenter phase-3 trial of 368 patients. At three years, 36.5% of patients treated with gemcitabine (days one, 8 and 15 per four-week cycle for six months) were alive compared with 19.5% of the patients assigned to observation. At five years, 21% of patients treated with adjuvant gemcitabine were alive compared with a 9% survival of patients not receiving gemcitabine. Clearly this is a major advance in the treatment of these patients. The role of radiation therapy, possibly together with or after treatment with gemcitabine would be worthy of study.
An important biomarker study
We all would like to be able to distinguish, a priori, those patients who will respond to a drug or drug combination and those who will not. For colorectal cancer, there has been an important breakthrough in this regard for the use of cetuximab (Erbitux, ImClone). Eric Van Cutsem, MD, PhD, from Belgium, analyzed patients who benefited from the combination of FOLFIRI and cetuximab and those who did not. Of 1,198 patients in the CRYSTAL trial, 540 were evaluable for KRAS mutation status: 65% were KRAS wild type and 35% were mutant. In contrast to the patients with wild type KRAS in which the one-year PFS for patients who received cetuximab and FOLFIRI benefited as compared to FOLFIRI alone (43% vs. 25%), there was no difference in the PFS in the KRAS mutant population. This and a confirmatory study has led to a change in practice in that cetuximab should not be used in colorectal patient with mutant KRAS — an impotent step forward in finding tumor markers that lead to more individualized treatment.