Anti-androgen therapy improves survival for men with cancer recurrence after prostatectomy

Men with prostate cancer who have prostate-specific antigen recurrence following radical prostatectomy have improved survival with radiotherapy and a long-term course of anti androgen therapy.

It is well established that a rising serum prostate-specific antigen (PSA) level is an indication of cancer progression in men diagnosed with prostate cancer and treated with radical prostatectomy (RP). For these patients, adding 24 months of anti-androgen therapy (AAT) during and after salvage radiotherapy (RT) improves overall survival statistically compared with salvage RT alone, according to the long-term results of a clinical trial conducted by the Radiation Therapy Oncology Group (RTOG), now conducting research as NRG Oncology. The RTOG 9601 study results presented today at the plenary session of the 57th Annual Meeting of the American Society for Radiation Oncology (ASTRO) also reveal that the addition of ATT to salvage RT reduces prostate cancer death and the development of metastatic prostate cancer without increasing radiation toxicity.

Over the last 25 years, many men with intermediate-risk prostate cancer have undergone RP, yet many will face recurrence subsequently with a rising PSA,” says lead study author William U. Shipley, M.D., FACR, FASTRO, who is the Andres Soriano Distinguished Professor of Radiation Oncology at the Massachusetts General Hospital and the Harvard Medical School, both in Boston. “Our results show that salvage RT plus peripheral androgen blockade (AAT with bicalutamide), when compared with RT plus a placebo, improved long-term overall survival and reduced death from prostate cancer without adding significantly to radiation toxicity. Because prostate cancer progresses slowly, follow-up of over 12 years was necessary to demonstrate a statistically better patient survival with combined AAT and RT.

With a median follow-up now of 12.6 years, the study results showed the actuarial overall survival at 10 years was 82 percent for the RT plus AAT arm and 78 percent for the RT plus placebo arm (P = 0.036). The 12-year incidence of prostate cancer-related deaths was 2.3 percent for the RT plus AAT arm, compared with 7.5 percent for the RT plus placebo arm. At 12 years, the cancer had metastasized in 51 patients (14 percent) in the RT plus AAT arm, compared with in 83 patients (23 percent) in the RT plus placebo arm. Additionally, late bladder and bowel toxicity were low and similar in both groups, whereas 70 percent of men in the RT plus AAT arm reported swelling of the breasts, compared with 11 percent in the RT plus placebo arm.

Conducted at sites across the United States and Canada from 1998 to 2003, the RTOG 9601 trial enrolled 761 men with prostate cancer who had undergone RP and subsequently developed elevated PSA levels. The patients were randomized to receive either salvage RT plus placebo (377 patients) or salvage RT plus AAT (384 patients).

Further statistical analyses, which are underway, may identify subgroups of patients who may not benefit from hormone therapy added to salvage RT and other subgroups for whom it may be especially beneficial. Also, because anti-androgen therapy, which suppresses testosterone production, is now used more commonly than peripheral androgen blockade with AAT, its use should be evaluated,” says Shipley in regard to next research steps for the population of post-RP patients referred for salvage RT. Shipley also emphasizes the clinical researchers’ gratitude for the willingness of the patients to participate on this and other randomized trials and for the essential role they play in advancing cancer care.

The results of this trial are testament to the importance of phase III randomized controlled trials for determining significant benefits. Congratulations to the trial team for their commitment to obtaining the quality of research data necessary for impacting the clinical care of patients with prostate cancer,” says Walter J. Curran Jr., M.D., an NRG Oncology Group Chairman and Executive Director of the Winship Cancer Institute of Emory University in Atlanta.

57th Annual Meeting of the American Society for Radiation Oncology (ASTRO) 2015 San Antonio, Texas, USA

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Gene therapy doubles survival in recurrent glioblastoma

An experimental gene therapy essentially doubled the overall survival of patients with recurrent glioblastoma compared to the current standard of care. Glioblastoma is an aggressive brain cancer that kills two-thirds of patients within five years. A patient’s outlook with recurrence of the disease is considered to be weeks or months.

CTRC medical oncologist Andrew J. Brenner, M.D., Ph.D., associate professor in medicine, neurology and neurosurgery at the UT Health Science Center School of Medicine, presented final results of a Phase 2 clinical research study that evaluated the gene therapy, called VB-111, in continuous and intermittent doses and in comparison to the treatment standard, the chemotherapy Avastin™. Patients receiving VB-111 survived 15 months on average, compared to 8 months on average for patients receiving Avastin alone. The CTRC and three other centers enrolled 62 patients with recurrent glioblastoma for the studies.

These are the patients with the most serious cases, whose glioblastoma has recurred after surgery and who, as a result, have a very short life expectancy,” Dr. Brenner said.

Dr. Brenner, principal investigator for the studies, presented the results this week at the European Cancer Congress meeting in Vienna, Austria. “In addition to the benefit in overall survival, VB-111 was safe and well-tolerated in the patients, and proved to be effective both as a single therapy for recurrent glioblastoma and in combination with Avastin,” he said.

VB-111 effectively starves the tumor by blocking its ability to grow new blood vessels, Dr. Brenner said. Tumors themselves begin the process by secreting a factor that activates the VB-111 drug. “This drug outsmarts the cancer,” Dr. Brenner said. 
“VB-111 is administered by intravenous infusion once every two months, which is convenient for patients and families,” he said. VB-111 has orphan drug status in the U.S. and Europe.

“The most frequent side effect in the study was fever, lasting one to two days following the infusion. This suggests an immune system response to the drug, which may play a role in its effectiveness,” Dr. Brenner said.

The improvement in overall survival is clinically significant. “These numbers compare favorably to any current benchmark in recurrent glioblastoma and may change the treatment paradigm for these patients,” Dr. Brenner said.

I am very proud of the work of Dr. Brenner and his team who are setting the stage for breakthrough advances in the treatment of brain cancer here at the CTRC,” said Ian Thompson Jr., M.D., CTRC director. “We are also especially thankful that Dr. Brenner is helping lead the large team of scientists and physicians who are developing next-generation cancer treatments at our cancer center.”

Phase 2 studies, conducted after first-in-human studies, add detail about the effectiveness and safety of experimental treatments for disease. VBL Therapeutics of Tel Aviv, Israel, maker of VB-111, recently launched a Phase 3 clinical research study of the drug to provide more detail.

The CTRC is currently the only site open for the Phase 3 trial, with the first patients enrolled here in San Antonio. Approximately 50 more sites in North America, Israel and Canada will be added in November 2015.

18th ECCO – 40th ESMO European Cancer Congress Vienna, Austria.

Genes of colon cancer recurrence differs among blacks, whites and Asians

The genetic makeup of colon cancer tumors and survival rates for patients with the disease differ by race, according to a study from researchers at the Mayo Clinic Cancer Center, published in the Journal of the National Cancer Institute.

These findings put the issue of race more prominently on the radar of investigators that cancer biology may contribute to race-based disparities,” says the study’s co-lead author, Harry Yoon, M.D., an oncologist at Mayo Clinic. “While it is too early to change the way we treat these patients, our results indicate that future studies are needed to examine potential biological drivers of these differences more closely.

According to the American Cancer Society, colon cancer is the third most common cancer in both men and women with more than 93,000 cases estimated to be diagnosed in 2015. Researchers have long known that blacks develop colon cancer at an earlier age and blacks with colon cancer are at higher risk of dying than whites. However, it has been difficult to identify why the differences in survival exist.

Researchers analyzed data from a large clinical trial of more than 3,000 patients with stage III colon cancer. The analysis revealed that tumors from whites, blacks, and Asians had different frequencies of mutations in two key cancer-related genes, BRAF and KRAS, which have been associated with worse outcomes. It also found that colon cancers were twice as likely to recur in black patients as in whites; however, the discrepancy was only evident in those under age 50.

Some of the potential reasons for this disparity include socio-economic factors, such as diagnosis at a later stage, decreased access to health care and suboptimal treatment.

The role of the biology of colon tumors according to race has not been examined as extensively,” says Dr. Yoon. “This biology can be reflected in the genetic makeup of tumors, as well as by whether and how quickly cancer returns after the patient has been treated.”

Dr. Yoon and his colleagues focused their efforts on finding out if colon cancers are genetically different based on race, as well as if race-based differences exist in recurrence rates. To do this, they examined data from a large clinical trial – Alliance N0147 – which included patients with stage III colon cancer from many centers in North America who all underwent surgery to remove their cancer and chemotherapy after surgery.

As part of the trial, the patients provided a self-description of their race as either white, Asian, or black or African-American. The researchers then evaluated the tumors from these participants to see if a mutation was present in the cancer-related genes BRAF and KRAS. They also noted if the cancer had returned after treatment.

Analysis of the data showed that tumors from whites, blacks and Asians were different in terms of the frequency of mutations in the BRAF and KRAS genes. Tumors from whites were twice as likely to have BRAF mutations; whereas, tumors from blacks had the highest frequency of KRAS mutations. Tumors from Asians were the most likely to have normal copies of both genes.

The analysis also indicated that the colon cancers among blacks had more than double the risk of cancer recurrence, compared to whites. However, this discrepancy was only visible among young patients – those under age 50. Almost half of younger black patients experienced colon cancer recurrence within five years, compared to only 22 to 35 percent of whites or Asian patients of any age.

This difference could not be explained by the genetic mutations most frequently found in the tumors of the different races. The researchers adjusted for a number of other potential confounders, such as tumor grade, the degree of lymph node involvement, depth of tumor invasion, body mass index, location of the tumor within the colon, history of smoking, and anomalies in mismatch repair genes; however, none seemed to affect the outcome for young blacks.

Because all patients were treated and had their disease monitored in a clinical trial,” says Dr. Yoon, “suboptimal treatment, differences in cancer stage, or reduced access to care cannot adequately explain the disparity.”

“In addition to published data indicating that a limited number of genes are preferentially mutated in colon cancers from black versus white patients, our study revealed differences in the mutation frequencies of BRAF and KRAS oncogenes that provide prognostic information in colon cancer patients,” says Frank Sinicrope, M.D., an oncologist at Mayo Clinic and co-lead author. “Our data provide further evidence that colon cancers from blacks are intrinsically different and are associated with more aggressive clinical behavior in young black patients.

​Yoon et al. Racial Differences in BRAF/KRAS Mutation Rates and Survival in Stage III Colon Cancer Patients. J Natl Cancer Inst. 2015; 107 (10): djv186 doi:10.1093/jnci/djv186 [Abstract]

Late-stage lung cancer is often over-treated with radiation

Almost half of patients with advanced lung cancer receive more than the recommended number of radiation treatments to reduce their pain, according to a new study published in the Journal of the National Cancer Institute.

Radiation therapy that is palliative, or not intended to cure, can reduce the pain from lung tumors and improve quality of life. But unnecessary treatments add to costs and require needless trips to the hospital – and can lead to radiation toxicity and difficulty in swallowing.

Guidelines developed from clinical trials recommend no more than 15 radiation treatments be given for pain in stage 4 lung cancer. The guidelines recommend that patients not receive chemotherapy at the same time, to reduce the risk of toxicity.

The new analysis looked at 47,000 patients who received palliative radiation for stage 4 lung cancer in the U.S. between 2004 and 2012 and found that about one in five had received chemotherapy at the same time. Nearly a third of patients received more than 25 radiation treatments — 10 above the recommended maximum.

This study uncovered that there’s a lot of treatment of late-stage lung cancer with palliative radiation that goes beyond what is recommended by several national guidelines and multiple clinical trials,” said the study’s lead author, Dr. Matthew Koshy, a radiation oncologist at the University of Illinois Hospital & Health Sciences System.

More education is needed for radiation oncologists, to prevent over-treatment — which has not been proven to further improve symptoms or quality of life, and can have some significant side effects,” Koshy said.

The researchers also looked for any particular type of patient more likely to be overtreated.

Having private insurance was the number-one predictor of being overtreated,” Koshy said. Privately insured patients were 40 percent more likely than others to receive more than the recommended 15 treatments. Patients treated in community cancer centers – clinics without ties to an academic institution – were also more likely to be over-treated.

Koshy said physicians might tend to overtreat privately insured patients because services are billed per-treatment, creating a financial incentive. However, he said, “it could also be because these patients may be perceived to have better potential for a more positive outcome.”

Koshy et al. Prevalence and predictors of inappropriate delivery of palliative thoracic radiotherapy for metastatic lung cancer. J Natl Cancer Inst. 2015; 107 (12): djv278 doi: 10.1093/jnci/djv278 [Abstract]