National Cancer Institute NCI Cancer Bulletin: A Trusted Source for Cancer Research News
June 12, 2012 • Volume 9 / Number 12

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Cancer Research Highlights

For Some Breast Cancers, New Drug May Be Treatment Option

Results from an international clinical trial suggest that women with metastatic, HER2-positive breast cancer that is no longer responding to the targeted therapy trastuzumab (Herceptin) may soon have a new treatment option.
                
Women who received the investigational drug trastuzumab emtansine (T-DM1) lived more than 3 months longer without their tumors progressing than women who received the chemotherapy drug capecitabine (Xeloda) and the targeted drug lapatinib (Tykerb). With one exception, T-DM1 also had far fewer serious side effects than the capecitabine-lapatinib combination, the trial’s leaders reported last week at the American Society of Clinical Oncology annual meeting.

 “T-DM1 should offer an important therapeutic option in the treatment of HER2-positive breast cancer,” said the study’s lead investigator, Dr. Kimberly Blackwell of the Duke Cancer Institute at Duke University.

The drug’s manufacturer, Genentech, stated it will seek approval from the Food and Drug Administration this year for use of T-DM1 in women with metastatic breast cancer.

T-DM1 is an antibody-drug conjugate composed of the monoclonal antibody trastuzumab, which targets the HER2 receptor on breast cancer cells, chemically linked to the chemotherapy drug DM1.

The median progression-free survival in women treated with T-DM1 was 9.6 months, compared with 6.4 months in women treated with capecitabine and lapatinib, Dr. Blackwell reported. The results were based on an interim analysis of the trial’s data. Overall survival was similar in the two treatment groups, but at the time of the analysis there was a statistical trend toward improved overall survival, with more than 65 percent of patients in the T-DM1 treatment group still alive after 2 years compared with more than 47 percent of patients in the capecitabine-lapatinib control group.

Although more women taking T-DM1 had a potentially dangerous drop in platelet levels (thrombocytopenia), other side effects such as vomiting, diarrhea, and hand-foot syndrome were much more likely in women in the control group. The thrombocytopenia was effectively managed with dose reductions, Dr. Blackwell noted, and more women in the control group had to have their dose reduced because of side effects.

“T-DM1 really works in this population,” said Dr. Louis Weiner of the Georgetown Lombardi Comprehensive Cancer Center during the plenary session. Additional research is needed to better understand how best to use it in combination with other available treatments, Dr. Weiner continued.

Preoperative Chemotherapy, Radiation Improve Survival in Esophageal Cancer

Patients with esophageal cancer who received chemotherapy and radiation before surgery survived, on average, nearly twice as long as patients treated with surgery alone. The findings, from a large randomized trial of neoadjuvant chemoradiotherapy for the disease, were published May 31 in the New England Journal of Medicine.

Patients treated with carboplatin and paclitaxel chemotherapy plus radiation prior to surgery had a median overall survival of nearly 50 months, compared with 24 months for patients treated with surgery alone.

Dr. Pieter van Hagen of Erasmus University Medical Center and his colleagues enrolled 368 patients who had cancer of the esophagus or of the junction between the stomach and the esophagus that had not spread to other organs. Trial participants were mostly men, and the median age was 60. Patients benefited from preoperative therapy regardless of whether they had adenocarcinoma, the most prevalent form of esophageal cancer in the United States, or squamous cell carcinoma, the most prevalent form of the disease worldwide.

Previous trials to test the superiority of preoperative chemotherapy and radiation in esophageal cancer failed to enroll enough patients to reach definitive conclusions. “The successful completion of this trial is an impressive effort, and the results should be considered high-level evidence in favor of this preoperative regimen,” commented Dr. Jack Welch, head of gastrointestinal therapeutics for NCI’s Cancer Therapy Evaluation Program, who was not involved in the study.

Patients randomly assigned to the chemoradiotherapy arm of the study received five courses of chemotherapy with carboplatin and paclitaxel plus concurrent external-beam radiation therapy, followed by surgery, usually within 4 to 6 weeks of completing preoperative treatment. This preoperative regimen has been widely adopted in the United States within the past year and has also been adopted as a standard therapy in some trials being conducted by NCI-supported cooperative groups, Dr. Welch said. For example, a phase III trial is testing a combination of neoadjuvant chemoradiotherapy with the targeted agent trastuzumab in patients whose tumors express the HER2 biomarker, explained Dr. Welch.

In another study, patients initially treated with chemotherapy based either on the Dutch study regimen or an alternative regimen are being assessed with PET scans; those who do not respond are switched to the other therapy, which is then combined with radiation. In both studies, researchers are trying to tailor the chemoradiation regimen used in Dr. van Hagen’s study to obtain the best possible result for individual patients, Dr. Welch said.

For Some Skin Cancers, Targeted Drug Hits the Mark

In January, the Food and Drug Administration approved a drug called vismodegib (Erivedge) for treating advanced cases of basal cell carcinoma (BCC). The vast majority of BCCs, the most common form of skin cancer, can be treated surgically, but patients with locally advanced or metastatic disease have had no effective treatments until this year.

Final results from the trial that led to the approval of vismodegib appeared in the New England Journal of Medicine on June 7. A companion report describes how vismodegib, which is taken as a pill, prevented and shrank tumors in people with basal cell nevus syndrome (BCNS), an inherited condition that can cause a person to develop hundreds to thousands of BCCs.

“It is a landmark day for patients with basal cell carcinoma and all those involved in their care—the greatest advance in therapy yet seen for this disease,” noted Dr. John T. Lear of University of Manchester in an accompanying editorial. But continuous administration of the drug can cause “considerable and frequent” side effects, including muscle cramps, hair loss, and loss of the sense of taste. 

These side effects led some patients to stop taking the drug, he noted. One-quarter of the patients experienced serious adverse events, and seven died. "The relationship between the study drug and the deaths is unknown," the researchers wrote.

Modified dosing schedules may limit the side effects and are being investigated, noted Dr. Aleksandar Sekulic of the Mayo Clinic, who led the BCC study. In the phase II trial, 30 percent of patients with metastatic disease had a partial response, and 43 percent of patients with locally advanced disease had a complete or partial response. The study included 104 patients.

The BCNS study was a randomized trial involving 41 patients. Patients who received vismodegib developed, on average, two new BCCs that warranted surgery per year, compared with 29 new BCCs among those who received a placebo. However, more than half of the patients taking vismodegib discontinued treatment because of side effects. Once patients stopped taking the drug, tumors began to slowly reappear.

“We still feel that this medicine is a life-changing therapy for these patients,” said Dr. Jean Tang of Stanford University, the first author of the study. “But patients cannot take the drug every day.” Her team has initiated a second trial to investigate the best way to give the drug.

The drug is designed to block signals that drive the growth of cancer cells though the Hedgehog signaling pathway. This pathway is silent in adult tissues, except in certain parts of the body, such as hair follicles. By shutting down the pathway in normal cells, the drug may cause hair loss and other side effects.

Although unpleasant, the side effects are an indication that the drug is hitting its target, noted Dr. Sekulic. These studies are “an important step forward,” he continued, adding that “the vast majority of BCCs can be prevented with good sun protection.”

Further reading: “For People with Rare Skin Cancer Syndrome, Drug Brings Relief and Hope” and “Drug to Treat Basal Cell Skin Cancer Approved after Priority Review

Study Suggests New Treatment Option for Some Lymphomas

Updated findings from a large European clinical trial indicate that patients with some types of lymphoma could initially be treated with the chemotherapy drug bendamustine (Treanda) and the targeted agent rituximab (Rituxan). The majority of patients in the trial had follicular lymphoma, and the remainder had either mantle cell or indolent (slow-growing) lymphoma.

Findings from the trial, which involved 514 newly diagnosed patients, were reported last week by lead investigator Dr. Mathias J. Rummel of the University Hospital Giessen in Germany at the American Society of Clinical Oncology annual meeting.

After a median follow-up of nearly 4 years, patients who received the two-drug combination lived more than twice as long without their disease progressing (69.5 months versus 31.2 months) as patients who received the standard first-line treatment, rituximab and a chemotherapy regimen called CHOP, or R-CHOP.

Despite the improvement in progression-free survival in patients treated with bendamustine and rituximab, overall survival did not differ between the two patient groups. As a result, some researchers may hesitate to promote the drug combination as the new standard of care for all patients with these lymphomas, according to Dr. Wyndham Wilson, head of the Lymphoma Therapeutics Section in NCI’s Center for Cancer Research, who was not involved in the study.

Although there was a higher incidence of mild skin reactions in patients who received bendamustine and rituximab, other major side effects were far less common, including neuropathy and the dangerous drops in white blood cell count known as neutropenia. Only 4 percent of patients who received bendamustine and rituximab required treatment with granulocyte colony-stimulating factor to counter neutropenia compared with 20 percent of patients who received R-CHOP.

Dr. Rummel cited several reasons why the bendamustine-containing combination did not lead to improved overall survival: First, almost half of the patients whose cancer progressed after R-CHOP crossed over to treatment with bendamustine and rituximab. Second, these types of lymphoma grow slowly and tend to have better long-term survival, so patients would need to be followed for a longer time before a difference in overall survival might be seen.

Bendamustine, which was developed in Germany and has been used in Europe for decades to treat blood cancers, is approved in the United States for the treatment of indolent lymphoma, but only for cancers that have progressed following treatment with a regimen that includes rituximab. Bendamustine is also approved for the treatment of chronic lymphocytic leukemia.

Study Shows First Effective Drug for Cancer Patients with Peripheral Neuropathy

Results of a phase III trial (CALGB-170601) show that duloxetine (Cymbalta) effectively treats painful peripheral neuropathy caused by certain types of chemotherapy. The results, from the first randomized clinical trial to show an effective treatment for chemotherapy-induced peripheral neuropathy (CIPN), were presented last week at the American Society of Clinical Oncology annual meeting.

CIPN causes chronic pain, tingling, and numbness—mainly in the hands and feet—that can interfere with a patient’s ability to perform everyday activities and to receive needed doses of chemotherapy. CIPN affects 20 to 30 percent of cancer patients treated with taxane and platinum-based chemotherapy drugs, which can damage nerve cells. CIPN may continue for months or even years after treatment is stopped and may worsen over time.

Dr. Ellen Lavoie Smith of the University of Michigan and her colleagues studied 181 people 18 years old or older who had previously reported high levels of pain from peripheral neuropathy caused by prior treatment with paclitaxel or oxaliplatin. They found that almost 60 percent of patients taking daily duloxetine for 6 weeks reported a decrease in pain, compared with nearly 40 percent of patients taking a placebo. Pain levels increased in 11 percent of duloxetine-treated patients and in 28 percent of those who took the placebo.

The most commonly reported side effect was fatigue, which was significantly higher in patients taking duloxetine than in patients taking the placebo.

“This study is the first to demonstrate statistically significant improvements in established neuropathic pain compared to placebo,” said Dr. Joanna Brell of NCI’s Division of Cancer Prevention. “While duloxetine is approved by the Food and Drug Administration for painful neuropathy caused by diabetes, there are no such treatments for CIPN.” Duloxetine is also approved to treat depression.

Also in the News: Even Low Doses of Radiation in Childhood May Raise Breast Cancer Risk

More childhood cancer survivors who received radiation to the chest as part of cancer treatment may be at risk of breast cancer later in life than previously thought, according to data presented at the American Society of Clinical Oncology annual meeting.

Dr. Chaya Moskowitz of Memorial Sloan-Kettering Cancer Center presented data from more than 1,200 women participating in the Childhood Cancer Survivor Study who received radiation to the chest as children, adolescents, or young adults. She and her colleagues found that nearly one-quarter of the women who received 20 gray (Gy), a unit of absorbed dose, of radiation or more developed breast cancer by age 50, with about half of those developing the disease before age 40. In addition, 7 percent of women who received lower doses of radiation—10 to 19 Gy—developed breast cancer by the age of 40. In contrast, a 20-year-old woman in the general population has a less than 2 percent chance of developing breast cancer by age 50.

Current guidelines for childhood cancer survivors generally recommend early screening—with breast MRI— only for patients who received 20 Gy of radiation or more; the guidelines do not recommend earlier screening for women who received lower doses.



Also in the Journals: Global Cancer Burden Expected to Shift 

Researchers from the International Agency for Research on Cancer (IARC) estimate that 16 percent, or around 2 million, of the 12.7 million new cancer cases diagnosed in 2008 were caused by infectious agents (viruses, bacteria, and parasites). Existing public health efforts to prevent infection “could have a substantial effect on the future burden of cancer worldwide,” the authors concluded. Their analysis was published May 9 in Lancet Oncology.

A second study suggests that “any reductions in infection-related cancers will be offset by an increasing number of new cases that are more associated with reproductive, dietary, and hormonal factors,” including breast, colorectal, and prostate cancers. Using a variety of data on cancer patterns and health and economic measures, the researchers calculated that in 2030 there would be 22.2 million new cases of cancer, up 75 percent from 2008. Their findings were published June 1 in Lancet Oncology.

For more information about global cancer research, visit NCI’s Center for Global Health.

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