CHICAGO, May 31 — Flexible sigmoidoscopy screening failed to significantly reduce colorectal cancer incidence or mortality a large randomized trial showed.

• Explain to interested patients that colorectal cancer screening is recommended for most individuals at age 50 and every 10 years after, or more frequently if polyps are detected.
• Explain that sigmoidoscopy is easier, faster, and cheaper than full colonoscopy, but it visualizes only part of the colon and therefore may miss some cancerous or precancerous lesions.
• Explain that this study was a randomized trial, the strongest form of medical evidence. But the seven years of follow-up in the study may not have been long enough to fully evaluate the effectiveness of sigmoidoscopy.

With seven years of follow-up, colorectal cancer was diagnosed at a rate of 134.5 cases per 100,000 person-years in people who underwent one-time flexible sigmoidoscopy, compared with 131.9 per 100,000 person-years in an unscreened control group, reported Geir Hoff, M.D., Ph.D., of the Norway Cancer Registry, and colleagues online in BMJ.

But additional follow up may yet reveal a benefit, the researchers said in the paper released early in advance of an oral presentation of the data scheduled here for Monday at Digestive Disease Week.

The researchers found that colorectal cancer mortality was reduced 27% on an intent-to-treat basis — 0.176% in the screening group versus 0.241% with usual care — but the difference failed to reach statistical significance (P=0.16).

The total number of deaths, however, was relatively small, 123 in the entire sample.

But one-third of the 13,653 people assigned to the screening group skipped the appointment and were not actually screened, although they were included in the intent-to-treat results.

When the analysis was restricted to those individuals undergoing the screening, a significant reduction in mortality was seen (HR 0.41, 95% CI 0.21 to 0.82).

The benefit was even more pronounced for mortality from rectosigmoidal cancer (HR 0.24, 95% CI 0.08 to 0.76) in patients who underwent the screening.

Nevertheless, Dr. Hoff and colleagues said the effectiveness of sigmoidoscopy screening and polypectomy within the seven-year time frame was lower than expected.

They said additional follow-up — participants in the study are to be tracked for 15 years — would determine whether the benefits of screening become more evident in later years.

The trial, called NORCCAP (NORwegian Colorectal CAncer Prevention), is the first large randomized study to report on the efficacy of sigmoidoscopy-based screening, Dr. Hoff and colleagues said.

NORCCAP randomized nearly 55,000 apparently healthy individuals, 50 to 64 years old, to screening with flexible sigmoidoscopy, accompanied in some patients by fecal occult blood testing, or to usual care. Assignments were made at a 1:3 ratio to screening versus control.

The control participants were not offered screening and did not otherwise interact with study personnel. Follow-up data on subsequent colorectal cancer diagnosis or death were obtained from their records in Norway’s national health registry.

Residents of Oslo, the country’s largest city, and the mixed urban-rural county of Telemark were included in the study.

Participants in the screening group with positive findings then underwent full colonoscopy and polypectomy. They received additional care as clinically warranted according to Norway’s general standards.

In an accompanying editorial, Thomas F. Imperiale, M.D., of Indiana University in Indianapolis, interpreted the findings as suggesting that sigmoidoscopy is effective in reducing colorectal cancer mortality.

He pointed out that, initially, more cancer diagnoses would be expected in the screening group relative to the unscreened control participants because the screening would detect prevalent cancers.

“We should be encouraged by NORCCAP’s interim findings,” he wrote, though he added that the magnitude and duration of benefit remain uncertain.

But he also noted that the data from this and other studies of sigmoidoscopy suggest the longer-term benefit is mainly in preventing cancers occurring within range of the sigmoidoscope, which only visualizes the final one-third of the colon.

In the United States, the use of sigmoidoscopy in place of full colonoscopy is controversial for this reason. (See: Sigmoidoscopy for Women Has Biological Deficiencies and Mortality from Right-Side Colon Cancer Not Lowered by Colonoscopy)

The study was funded by the Norwegian Cancer Society and the Norwegian Ministry of Health. No potential conflicts of interest were reported.

Primary source: BMJ

Source reference:
Hoff G, et al., “Risk of colorectal cancer seven years after flexible sigmoidoscopy screening: randomised controlled trial” BMJ 2009; DOI: 10.1136/bmj.b1846.

Additional source: BMJ

Source reference:
Imperiale T, “Sigmoidoscopy screening for colorectal cancer” BMJ 2009; DOI: 10.1136/bmj.b2084.

Related Article(s):

• Sigmoidoscopy for Women Has Biological Deficiencies
• Mortality from Right-Side Colon Cancer Not Lowered by Colonoscopy

ORLANDO, May 31 — A vaccine approach that trains immune cells and sends them marching into battle has shown promise in advanced melanoma, a researcher said here.

• Explain to interested patients that metastatic melanoma is a difficult disease to treat.
• Note that this study is the first late-stage clinical trial to show a benefit for a therapeutic vaccine approach to the disease.
• Note that this study was published as an abstract and presented at a conference. These data and conclusions should be considered to be preliminary until published in a peer-reviewed journal.

The vaccine, used along with a powerful stimulant of the immune system, shrank melanoma metastases and prolonged the time before the disease resumed progression, according to Patrick Hwu, M.D., of M.D. Anderson Cancer Center in Houston.

In the phase III controlled trial, there was also a trend to longer overall survival that did not reach statistical significance, Dr. Hwu said at the annual meeting of the American Society of Clinical Oncology.

The vaccine consists of part of a molecule — dubbed gp100 — that is on the surface of melanoma cells. It’s delivered along with interleukin-2, a powerful immune system stimulant.

The vaccine, Dr. Hwu said, “takes T cells to boot camp” and trains them to attack the tumor. The interleukin-2 multiplies the killer cells into a “large army that can then attack the tumors to kill them.”

The approach is not new — a 1998 early stage trial in 31 patients showed good response — but this is the first phase III trial to show positive results, Dr. Hwu said.

The researchers randomized 185 patients with metastatic melanoma in 21 centers to get either interleukin-2 alone or interleukin-2 with the gp100 vaccine.

The primary endpoint was clinical response, but the researchers also measured time to relapse.

The overall response rate was 22.1% in the vaccine arm, compared with 9.7% in the patients who got interleukin-2 alone, Dr. Hwu said.

Progression-free survival also favored the vaccine, at 2.9 months compared with 1.6 months for interleukin-2 alone — a difference that was significant at P=0.0101.

The median overall survival favored the vaccine — at 17.6 months compared with 12.8 — but the difference did not reach statistical significance, Dr. Hwu said.

The finding is very preliminary, according to Len Lichtenfeld, M.D., of the American Cancer Society, who was not part of the study.

“There’s a long way to go before it can be generally applied,” he said.

But he said much of the progress in cancer care has been composed of small steps and this study is part of the pattern.

“A lot of our advances in cancer treatment take years if not decades,” he said, “and those years and decades are made up of small changes over a very long time.”

The findings are “definitely very promising for a very poor-prognosis group of patients,” said Sonali Smith, M.D., of the University of Chicago Medical Center, who moderated a press conference at which the research was presented.

She said the approach might act as a “platform” for more refined and potent vaccines.

Indeed, Dr. Hwu noted, the results mean that about 80% of patients did not respond. “We have to do better and I think we can” by employing different immune stimulants, he said.

The study was sponsored by the NIH. Some of the researchers reported financial links with Novartis. Dr. Lichtenfeld is an employee of the American Cancer Society. Dr. Smith said she had no disclosures to report.

Primary source: Journal of Clinical Oncology

Source reference:

Schwartzentrube SJ et al. “A phase III multi-institutional randomized study of immunization with the gp100: 209-217(210M) peptide followed by high dose IL-2 compared with high dose IL-2 alone in patients with metastatic melanoma” J Clin Oncol 2009; 27(15S): Abstract CRA9011.

ORLANDO, May 31 — Patients with triple-negative breast cancer had significant improvement survival with a new class of therapy that targets an enzyme crucial to a cancer’s DNA repair mechanisms, a randomized trial showed.

• Explain to patients that a new type of drug demonstrated activity in advanced breast cancer when used alone or combined with conventional chemotherapy.
• The results came from studies involving relatively few patients.
• Note that this study was published as an abstract and presented at a conference. These data and conclusions should be considered to be preliminary until published in a peer-reviewed journal.

The breast cancer subtype, which accounts for about 15% of all breast cancer, derives its name from a lack of receptors for estrogen, progesterone, and HER2, which are targeted by many currently available drugs.

Progression-free survival doubled and overall survival increased from less than six months to more than nine in patients with triple-negative disease who were treated with BSI-201 plus chemotherapy, Joyce O’Shaughnessy, M.D., of Baylor Sammons Cancer Center in Dallas, reported at the American Society of Clinical Oncology meeting.

Patients treated with the targeted agent had a total clinical benefit of 62%, compared with 21% in patients who received only chemotherapy (P=0.0002).

The addition of BSI-201 also tripled the overall response rate, while adding no new toxicities, Dr. O’Shaughnessy said during a press briefing.

“The key findings are the event-free and overall survival,” said Dr. O’Shaughnessy. “There was a 50% reduction in the risk of death with BSI-201 in this small randomized phase 2 clinical trial, and that was statistically significant.”

Also at the briefing, a British investigator reported an overall response rate of 41% in a small clinical study of women with BRCA-deficient (mutated) breast cancer treated with another member of the new drug class, known as PARP inhibitors.

Cancer cells make extensive use of the enzyme poly (ADP-ribose) polymerase, or PARP, to repair DNA damage, including damage caused by chemotherapeutic agents.

PARP inhibitors evolved from the rationale that inhibition of the enzyme would disrupt cancer cells’ self-repair mechanisms, thereby potentiating chemotherapy’s ability to inflict DNA damage.

Triple-negative breast cancer is associated with BRCA mutations and defects in DNA repair, which contribute to an aggressive natural history.

Dr. O’Shaughnessy presented data from a clinical trial involving 116 women with metastatic triple-negative breast cancer. The patients received conventional chemotherapy with gemcitabine (Gemzar) and carboplatin and were randomized to BSI-201 or no additional therapy.

The addition of the PARP inhibitor to chemotherapy resulted in an overall response rate of 48% compared with 16% in the chemotherapy-only group (P=0.002).

The median progression-free survival was 6.9 months with BSI-201 versus 3.3 months without (P<0.0001).

Median overall survival was 9.2 months with the targeted agent and 5.7 months with chemotherapy alone (P=0.0005).

British investigators evaluated the oral PARP inhibitor olaparib in patients with BRCA-deficient (mutated) advanced breast cancer, another therapeutically challenging population. All of the patients had chemotherapy-refractory tumors, said Andrew Tutt, M.B. Ch.B., Ph.D., of Kings College in London.

The study involved 54 patients, who received either olaparib 400 mg BID or 100 mg BID. The higher dose led to one complete response and 10 partial responses for an overall response rate of 41% (11 of 27) compared with an overall response rate of 22% (six partial responses) with the lower dose.

Olaparib was well tolerated, with the most common adverse effects being low-grade nausea and fatigue, said Dr. Tutt.

Oncologists have anticipated the development of an effective targeted agent for use in advanced breast cancer, said Eric Winer, M.D., of Dana Farber Cancer Institute in Boston, who moderated the press briefing.

“We have been left largely with chemotherapy alone and there haven’t been any targeted agents,” said Dr. Winer, who was not involved in either study. “This, while still very preliminary, is one of the most exciting things we’ve seen in a long time.”

Investigators in the BSI-201 study included employees of BiPar Sciences. One or more investigators in the olaparib study disclosed relationships with AstraZeneca, Myriad Genetics, Kudos, and the Institute of Cancer Research. Dr. Winer disclosed that he has received research funding from Genentech.

Primary source: Journal of Clinical Oncology

Source reference:

O’Shaughnessy J et al. “Efficacy of BSI-201, a poly (ADP-ribose) polymerase-1 (PARP1) inhibitor, in combination with gemcitabine/carboplatin in patients with metastatic triple-negative breast cancer: results of a randomized phase II trial” J Clin Oncol 2009; 27(15S): Abstract 3.

Additional source: Journal of Clinical Oncology

Source reference:

Tutt A et al. “Phase II trial of the oral PARP inhibitor olaparib in BRCA-deficient advanced breast cancer” J Clin Oncol 2009; 27(15S): Abstract CRA501.