NO BENEFIT OF ADDING TARCEVA IN AVASTIN MAINTENANCE IN NSCLC

In the phase IIIB ATLAS trial reported in the Journal of Clinical Oncology, Bruce E. Johnson, MD, of Dana-Farber Cancer Institute, and colleagues assessed the addition of maintenance erlotinib (Tarceva) to bevacizumab (Avastin) following chemotherapy plus bevacizumab in first-line treatment of advanced non–small cell lung cancer (NSCLC). The addition of erlotinib improved progression-free survival but not overall survival and was associated with additional toxicity.

Study Details

In the double-blind trial, 1,145 patients with histologically or cytologically confirmed NSCLC (stage IIIB with malignant pleural effusion, stage IV, or recurrent) received four cycles of chemotherapy plus bevacizumab. A total of 743 patients without disease progression or significant toxicity were then randomly assigned to bevacizumab 15 mg/kg on day 1 of 21-day cycles plus either placebo (n = 373) or erlotinib 150 mg/d (n = 370). The primary endpoint was progression-free survival. Patients were stratified by sex, smoking history (never vs former/current), Eastern Cooperative Oncology Group (ECOG) performance status (0 vs ≥ 1), and initial chemotherapy regimen.

The bevacizumab and bevacizumab/erlotinib groups were generally well balanced for age (median, 64 years in both), sex (53% and 52%), ECOG performance status (0 in 47% and 49%, 1 in 53% and 51%), clinical stage (IIIB in 10% and 9%, stage IV in 83% and 86%), histology (adenocarcinoma in 83% and 81%), smoking status (former or current in 83% and 84%), and chemotherapy (carboplatin/paclitaxel in 47% and 48%, carboplatin/gemcitabine in 28% in both).

Survival Outcomes

Median progression-free survival from time of random assignment was 3.7 months in the bevacizumab group vs 4.8 months in the bevacizumab/erlotinib group (hazard ratio [HR] = 0.71, P <.001 on stratified analysis; HR = 0.683, P < .001 on unstratified analysis). Median overall survival from random assignment was 13.3 months in the bevacizumab group vs 14.4 months in the bevacizumab/erlotinib group (HR = 0.92, P = .5341 on stratified analysis; HR = 0.941, P = .6473 on unstratified analysis) at the primary data cutoff. The 1-year survival rates were 58.6% vs 60.1%. On an updated analysis, median overall survival was 13.6 vs 14.4 months (HR = 0.904, P = .3534)

Effect of EGFR Mutation

Patients with an activating EGFR mutation (n = 52) had a greater improvement in progression-free survival with bevacizumab/erlotinib (HR = 0.44, 95% confidence interval [CI] = 0.22–0.86) compared with those (n = 295) with wild-type EGFR (HR = 0.85, 95% CI = 0.64–1.13). Updated overall survival results showed a similar difference in outcome by EGFR mutation status (HR = 0.46, 95% CI = 0.21–1.02 among EGFR mutation–positive patients; HR = 0.86, 95% CI = 0.65–1.15 among EGFR wild-type patients).

Toxicity

During the postchemotherapy phase, there were more adverse events of any grade (96% vs 87%), more grade 3 or 4 adverse events (46% vs 33%; mainly rash, 6.8% vs 0.5%, and diarrhea, 9.8% vs 1.9%), more serious adverse events, and more adverse events of special interest leading to erlotinib/placebo discontinuation (9.0% vs 5.7%) in the bevacizumab/erlotinib group.

Adverse events of special interest led to bevacizumab discontinuation in 7.6% of patients in both groups.  Among the prespecified adverse events of special interest (hemorrhage, proteinuria, hypertension, cardiovascular events, rash, diarrhea, and infection), the incidences of any-grade rash (63% vs 22%), diarrhea (52% vs 20%), and infection (30% vs 25%) were greater in the bevacizumab/erlotinib group.

No grade 3 or 4 interstitial lung disease–like events were reported in the bevacizumab group, and three patients (0.8%) in the bevacizumab/erlotinib group experienced a grade 3 interstitial lung disease-like event. Six grade 5 adverse events of special interest were reported, consisting of two in the bevacizumab group (congestive heart failure and lobar pneumonia) and four in the bevacizumab/erlotinib group (cardiac arrest in two, cerebellar infarction in one, and deep-vein thrombosis in one). An additional grade 5 event (gastrointestinal perforation) occurred in a patient in the bevacizumab/erlotinib group after the primary data cutoff.

The investigators concluded, “The addition of erlotinib to bevacizumab significantly improved [progression-free survival] but not [overall survival]. Although generally well tolerated, the modest impact on survival and increased toxicity associated with the addition of erlotinib to bevacizumab maintenance mean that this two-drug maintenance regimen will not lead to a new postchemotherapy standard of care.”

Dr. Johnson and Fairooz Kabbinavar, MD, of University of California Los Angeles, are both primary authors, and Dr. Johnson is the corresponding author for the Journal of  Clinical Oncology article.

ADJUVANT CHEMOTHERAPY IMPROVES SURVIVAL IN PANCREATIC CANCER

JAMA. 2013 Oct 9;310(14):1473-81. doi: 10.1001/jama.2013.279201.

Adjuvant chemotherapy with gemcitabine and long-term outcomes among patients with resected pancreatic cancer: the CONKO-001 randomized trial.

Oettle H, Neuhaus P, Hochhaus A, Hartmann JT, Gellert K, Ridwelski K, Niedergethmann M, Zülke C, Fahlke J, Arning MB, Sinn M, Hinke A, Riess H.

Source

Medizinische Klinik mit Schwerpunkt Hämatologie, Onkologie und Tumorimmunologie, Charité-Universitätsmedizin Berlin, Berlin, Germany. helmut.oettle@charite.de

Abstract

IMPORTANCE:

The prognosis for patients with pancreatic cancer is poor, even after resection with curative intent. Gemcitabine-based chemotherapy is standard treatment for advanced pancreatic cancer, but its effect on survival in the adjuvant setting has not been demonstrated.

OBJECTIVE:

To analyze whether previously reported improvement in disease-free survival with adjuvant gemcitabine therapy translates into improved overall survival.

DESIGN, SETTING, AND PATIENTS:

CONKO-001 (Charité Onkologie 001), a multicenter, open-label, phase 3 randomized trial to evaluate the efficacy and toxicity of gemcitabine in patients with pancreatic cancer after complete tumor resection. Patients with macroscopically completely removed pancreatic cancer entered the study between July 1998 and December 2004 in 88 hospitals in Germany and Austria. Follow-up ended in September 2012.

INTERVENTIONS:

After stratification for tumor stage, nodal status, and resection status, patients were randomly assigned to either adjuvant gemcitabine treatment (1g/m2 d 1, 8, 15, q 4 weeks) for 6 months or to observation alone.

MAIN OUTCOMES AND MEASURES:

The primary end point was disease-free survival. Secondary end points included treatment safety and overall survival, with overall survival defined as the time from date of randomization to death. Patients lost to follow-up were censored on the date of their last follow-up.

RESULTS:

A total of 368 patients were randomized, and 354 were eligible for intention-to-treat-analysis. By September 2012, 308 patients (87.0% [95% CI, 83.1%-90.1%]) had relapsed and 316 patients (89.3% [95% CI, 85.6%-92.1%]) had died. The median follow-up time was 136 months. The median disease-free survival was 13.4 (95% CI, 11.6-15.3) months in the treatment group compared with 6.7 (95% CI, 6.0-7.5) months in the observation group (hazard ratio, 0.55 [95% CI, 0.44-0.69]; P < .001). Patients randomized to adjuvant gemcitabine treatment had prolonged overall survival compared with those randomized to observation alone (hazard ratio, 0.76 [95% CI, 0.61-0.95]; P = .01), with 5-year overall survival of 20.7% (95% CI, 14.7%-26.6%) vs 10.4% (95% CI, 5.9%-15.0%), respectively, and 10-year overall survival of 12.2% (95% CI, 7.3%-17.2%) vs 7.7% (95% CI, 3.6%-11.8%).

CONCLUSIONS AND RELEVANCE:

Among patients with macroscopic complete removal of pancreatic cancer, the use of adjuvant gemcitabine for 6 months compared with observation alone resulted in increased overall survival as well as disease-free survival. These findings provide strong support for the use of gemcitabine in this setting.

GI CARCINOID INCIDENCE INCREASES

NEW YORK (Reuters Health) Oct 16 - Women with platinum-resistant ovarian cancer may benefit from vintafolide (EC145) plus pegylated liposomal doxorubicin (PLD), a new paper reports.

An imaging agent, 99mTc-etarfolatide, can identify those most likely to benefit from the added vintafolide, the authors say.

"Vintafolide plus PLD is the first combination to demonstrate an improvement over standard therapy in a randomized trial of patients with platinum-resistant ovarian cancer," the authors wrote in their article online in the Journal of Clinical Oncology.

"It's like using smart bombs: we're not targeting every cell for treatment -- only the cancer cells. We're taking advantage of the difference between normal cells and cancer cells," said principal investigator Dr. R. Wendel Naumann, from the Levine Cancer Institute of Carolinas Medical Center in Charlotte, North Carolina, in a phone interview with Reuters Health.

"Vintafolide binds to the folate receptor (FR), which is on the majority of epithelial ovarian cancers," Dr. Naumann added.

He continued, "This could easily become the standard care for platinum-resistant ovarian cancer patients, and vintafolide could also potentially be used with lung, endometrial and many other cancers that carry folate receptors. Because of its limited toxicity, we can add vintafolide to pretty much any combination."

The randomized phase II PRECEDENT trial compared vintafolide plus PLD to PLD alone. It also assessed the usefulness of the FR-targeted imaging agent, 99mTc-etarfolatide (EC20), in selecting patients likely to benefit from vintafolide.

To compare progression-free survival (PFS) between the two groups, they looked at 195 ovarian cancer patients at 61 clinical centers in the United States, Canada, and Poland who were at least 18 years old and had received prior platinum-based chemotherapy.

The 162 women in the study had all undergone one or two prior cytotoxic regimens. They were randomly assigned in a 2:1 ratio to receive IV vintafolide (2.5 mg three times per week during weeks 1 and 3, every 28 days) plus IV PLD (50 mg/m2 on day 1, every 28 days) or PLD alone. Scanning with etarfolatide was optional.

Patients had computed tomography (CT) imaging at baseline, every 1.5 months for the first six months, and then every two months. To identify patients with functionally active FR, patients had SPECT imaging with etarfolatide when available at least seven days before the start of therapy.

Patients were grouped as FR 100% (all lesions FR positive), FR 10% to 90% (one or more FR-positive lesion), and FR 0% (no FR-positive lesions).

Treatment continued until disease progression, intolerable toxicity, or maximum allowable cumulative dose of PLD (550 mg/m2 of doxorubicin hydrochloride). Some women treated with vintafolide plus PLD continued to receive vintafolide alone.

Patients who had 100% of lesions positive for FR had the greatest benefit, with median PFS of 5.5 months, compared with 1.5 months for PLD alone (HR, 0.38; p=0.013). Women with 10% to 90% FR-positive disease experienced some PFS improvement (HR, 0.87); and those with no FR expression had no PFS benefit (HR, 1.80).

"I was somewhat skeptical that we would see a benefit in this randomized phase II trial because there had been around 12 randomized trials of ovarian cancer and every single one has been negative, even some very large trials," Dr. Naumann said.

Dr. Tate Thigpen, director of the Division of Oncology-Hematology of the University of Mississippi Medical Center in Jackson, agreed with the potential clinical impact of this trial. "This is an excellent example of the sort of targeted therapy that everyone raves about. In ovarian cancer this is particularly significant because ovarian cancer is characterized by 'genomic instability,' which means essentially that specific targets like the folate receptor have been hard to come by," he said in an email.

"This is a potential breakthrough for patients who have the folate receptor on their tumor cells. Whether it will lead to an improved overall survival or cure rate is not clear yet, but the approach clearly improves progression-free survival, which is a very important and perhaps the best measure of patient benefit that we have in ovarian cancer," he added.

"If confirmed, this approach would allow us to provide far greater patient benefit to those positive for the folate receptor while avoiding the toxicities of the treatment for those without the receptor and thus unlikely to benefit from vintafolide," he said.

Dr. Naumann is looking forward to the confirmatory PROCEED randomized phase III trial, which is now recruiting patients and has conditional approval in Europe, he said. While he can't say how long it will take for approval in Europe, he estimated that in the US it will be a minimum of two to three years before the phase III trial is completed and vintafolide is approved for patient use outside of clinical trials.

Dr. Naumann's institution has received funding from Endocyte, the original developer of vintafolide, which was bought out by Merck. Dr. Thigpen has served on advisory boards for Endocyte and currently is a member of the Data and Safety Monitoring Board for an ongoing trial involving vintafolide.

SOURCE: http://bit.ly/H4HNM5

J Clin Oncol 2013.

ANTI-FGFR TREATMENT FOR RESISTANT OVARIAN CANCER

NEW YORK (Reuters Health) Oct 16 - Women with platinum-resistant ovarian cancer may benefit from vintafolide (EC145) plus pegylated liposomal doxorubicin (PLD), a new paper reports.

An imaging agent, 99mTc-etarfolatide, can identify those most likely to benefit from the added vintafolide, the authors say.

"Vintafolide plus PLD is the first combination to demonstrate an improvement over standard therapy in a randomized trial of patients with platinum-resistant ovarian cancer," the authors wrote in their article online in the Journal of Clinical Oncology.

"It's like using smart bombs: we're not targeting every cell for treatment -- only the cancer cells. We're taking advantage of the difference between normal cells and cancer cells," said principal investigator Dr. R. Wendel Naumann, from the Levine Cancer Institute of Carolinas Medical Center in Charlotte, North Carolina, in a phone interview with Reuters Health.

"Vintafolide binds to the folate receptor (FR), which is on the majority of epithelial ovarian cancers," Dr. Naumann added.

He continued, "This could easily become the standard care for platinum-resistant ovarian cancer patients, and vintafolide could also potentially be used with lung, endometrial and many other cancers that carry folate receptors. Because of its limited toxicity, we can add vintafolide to pretty much any combination."

The randomized phase II PRECEDENT trial compared vintafolide plus PLD to PLD alone. It also assessed the usefulness of the FR-targeted imaging agent, 99mTc-etarfolatide (EC20), in selecting patients likely to benefit from vintafolide.

To compare progression-free survival (PFS) between the two groups, they looked at 195 ovarian cancer patients at 61 clinical centers in the United States, Canada, and Poland who were at least 18 years old and had received prior platinum-based chemotherapy.

The 162 women in the study had all undergone one or two prior cytotoxic regimens. They were randomly assigned in a 2:1 ratio to receive IV vintafolide (2.5 mg three times per week during weeks 1 and 3, every 28 days) plus IV PLD (50 mg/m2 on day 1, every 28 days) or PLD alone. Scanning with etarfolatide was optional.

Patients had computed tomography (CT) imaging at baseline, every 1.5 months for the first six months, and then every two months. To identify patients with functionally active FR, patients had SPECT imaging with etarfolatide when available at least seven days before the start of therapy.

Patients were grouped as FR 100% (all lesions FR positive), FR 10% to 90% (one or more FR-positive lesion), and FR 0% (no FR-positive lesions).

Treatment continued until disease progression, intolerable toxicity, or maximum allowable cumulative dose of PLD (550 mg/m2 of doxorubicin hydrochloride). Some women treated with vintafolide plus PLD continued to receive vintafolide alone.

Patients who had 100% of lesions positive for FR had the greatest benefit, with median PFS of 5.5 months, compared with 1.5 months for PLD alone (HR, 0.38; p=0.013). Women with 10% to 90% FR-positive disease experienced some PFS improvement (HR, 0.87); and those with no FR expression had no PFS benefit (HR, 1.80).

"I was somewhat skeptical that we would see a benefit in this randomized phase II trial because there had been around 12 randomized trials of ovarian cancer and every single one has been negative, even some very large trials," Dr. Naumann said.

Dr. Tate Thigpen, director of the Division of Oncology-Hematology of the University of Mississippi Medical Center in Jackson, agreed with the potential clinical impact of this trial. "This is an excellent example of the sort of targeted therapy that everyone raves about. In ovarian cancer this is particularly significant because ovarian cancer is characterized by 'genomic instability,' which means essentially that specific targets like the folate receptor have been hard to come by," he said in an email.

"This is a potential breakthrough for patients who have the folate receptor on their tumor cells. Whether it will lead to an improved overall survival or cure rate is not clear yet, but the approach clearly improves progression-free survival, which is a very important and perhaps the best measure of patient benefit that we have in ovarian cancer," he added.

"If confirmed, this approach would allow us to provide far greater patient benefit to those positive for the folate receptor while avoiding the toxicities of the treatment for those without the receptor and thus unlikely to benefit from vintafolide," he said.

Dr. Naumann is looking forward to the confirmatory PROCEED randomized phase III trial, which is now recruiting patients and has conditional approval in Europe, he said. While he can't say how long it will take for approval in Europe, he estimated that in the US it will be a minimum of two to three years before the phase III trial is completed and vintafolide is approved for patient use outside of clinical trials.

Dr. Naumann's institution has received funding from Endocyte, the original developer of vintafolide, which was bought out by Merck. Dr. Thigpen has served on advisory boards for Endocyte and currently is a member of the Data and Safety Monitoring Board for an ongoing trial involving vintafolide.

SOURCE: http://bit.ly/H4HNM5

J Clin Oncol 2013.

PONATINIB INCREASE THROMBOEMBOLISM RISK

The US Food and Drug Administration (FDA) is investigating a rise in reports of life-threatening blood clots and blood-vessel narrowing in patients taking ponatinib (Iclusig, ARIAD Pharmaceuticals, Inc.) to treat leukemia, the agency announced today.

Ponatinib is indicated for adults with chronic phase, accelerated phase, or blast phase chronic myeloid leukemia (CML) or Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL) who do not tolerate or no longer benefit from other therapies such as imatinib (Gleevec, Novartis Pharmaceuticals Corporation).

When the FDA approved ponatinib just 10 months ago, it required the label to feature a boxed warning about the risk for blood clots. Clinical trials prior to approval reported serious arterial blood clots in 8% of patients treated with the drug, and venous blood clots in 3%. Since then, the manufacturer has submitted additional clinical trial data to the FDA showing that at least 20% of patients given ponatinib have experienced blood clots or narrowed blood vessels.

According to these data as well as postmarket adverse event reports submitted to the FDA, patients receiving the drug have had fatal heart attacks, worsening coronary artery disease, stroke, narrowing of large brain arteries, severe narrowing of blood vessels in the arms and legs, and "the need for urgent surgical procedures to restore blood flow."

The agency is advising clinicians to consider for each patient whether the risks of ponatinib will likely outweigh the benefits. Patients should be instructed to seek immediate medical care if they experience any symptoms suggesting a heart attack or stroke.

"FDA is actively working to further evaluate these adverse events and will notify the public when more information is available," the agency stated in a news release.

More information about today's announcement is available on the FDA Web site.

ABRAXANE IMPROVES SURVIVAL IN PANCREATIC CANCER

In September, the US Food and Drug (FDA) approved, for the first time in nearly 8 years, a new treatment for metastatic pancreatic cancer.

Clinicians can now review the details of the clinical trial that was the basis for the FDA approval of nanoparticle albumin-bound (nab)-paclitaxel (Abraxane, Celgene). The study waspublished online October 17 in the New England Journal of Medicine.

The drug was specifically approved for adenocarcinoma of the pancreas, a subtype that accounts for about 95% of cancers of the pancreas.

In the pivotal clinical trial, known as the Metastatic Pancreatic Adenocarcinoma Clinical Trial (MPACT), median overall survival was about 2 months better with nab-paclitaxel plus gemcitabine than with gemcitabine alone (8.5 vs 6.7 months; hazard ratio [HR], 0.72; P < .0001).

"The past few decades have brought us very few treatment advances for patients with advanced pancreatic cancer, which is both deadly and incredibly difficult to treat," said lead author Daniel Von Hoff, MD, in a press statement when the study was first presented at the 2013 Gastrointestinal Cancers Symposium. He is from the University of Arizona College of Medicine in Tucson.

"While a 2-month improvement may seem modest, in the pancreatic cancer space, this is a major improvement," said Kenneth Yu, MD, at that time. He is from the Memorial Sloan-Kettering Cancer Center in New York City, and was not involved in the study.

In MPACT, the rate of 1-year survival was also better with the combination than with monotherapy (35% vs 22%; P = .0002), as was the rate of 2-year survival (9% vs 4%; P = .02).

In the 861 chemotherapy-naïve patients with metastatic pancreatic cancer, median progression-free survival was better with the combination than with monotherapy (5.5 vs 3.7 months; HR, 0.69; P < .001). The overall response rate was also better with the combination (23% vs 7%; P < .001).

The level of adverse events in the study was acceptable.

Table. Common Adverse Events

Adverse Event	Nab-Paclitaxel Plus Gemcitabine Combination, %	Gemcitabine Monotherapy, %
Febrile neutropenia	3	1
Grade 3 or higher
Neutropenia	38	27
Fatigue	17	7
Neuropathy	17	1

In the combination group, neuropathy of grade 3 or higher improved to grade 1 or lower in a median of 29 days.

Dr. Von Hoff and his coauthors conclude that "in patients with metastatic pancreatic adenocarcinoma, nab-paclitaxel plus gemcitabine significantly improved overall survival, progression-free survival, and response rate, but rates of peripheral neuropathy and myelosuppression were increased."

The addition of nab-paclitaxel to the treatment options in this setting has been welcomed by clinicians. As a combination therapy with gemcitabine, it now rivals 5-fluorouracil, leucovorin, irinotecan, and oxaliplatin (FOLFIRINOX).

An earlier study comparing FOLFIRINOX with gemcitabine (N Engl J Med. 2011;364:1817-1825) showed that the 4-drug combination provided the best survival time ever reported in metastatic pancreatic cancer. Overall survival was significantly better with FOLFIRINOX than with gemcitabine (11.1 vs 6.8 months; P < .0001).

A number of factors will influence which drug combination clinicians will chose in the future.

The New York Times reported that nab-paclitaxel therapy costs around $6000 to $8000 a month, which will likely be more expensive than FOLFIRINOX.

However, toxicity has been a concern with the 4-drug combination, and experts have expressed doubtthat FOLFIRINOX will become the international standard of care for metastatic pancreatic cancer because of its adverse effects. Researchers have stated that FOLFIRINOX might be best used in patients younger than 76 years who have advanced disease and a good performance status.

In less-robust patients, the combination of gemcitabine plus nab-paclitaxel "is a new and effective treatment that we can offer," Dr. Yu said earlier this year.

The study was funded by Celgene. Some of the study authors have financial ties to Celgene, as detailed in the paper.

N Engl J Med. Published online October 16, 2013. Abstract

DOXIL-CAELYX MAY DISAPPEAR FROM THE MARKET?

The only company in the world that manufactures Doxil, the branded version of doxorubicin hydrochloride liposome injection, will close its production facility in Bedford, Ohio, before the end of this year, according to news reports.

Ben Venue Laboratories announced the closure earlier this month, citing manufacturing problems, as reported by Crain's Cleveland Business.

Doxil is administered intravenously and is most commonly used in patients with ovarian cancer whose disease has progressed or recurred after platinum-based chemotherapy.

The drug is also indicated, in combination with bortezomib, for the treatment of patients with multiple myeloma.

Doxil is a liposomal injection form of doxorubicin, but the workhorse cancer drug is also available as a lyophilized powder (Adriamycin). Both forms have been in short supply in the United States for an extended period of time.

Ben Venue Laboratories, which specializes in making injectable drugs, currently manufactures Doxil for Johnson & Johnson, which owns the product.

Johnson & Johnson is reportedly suing Ben Venue for breach of contract. "We have taken action to ensure Ben Venue meets its contractual obligations to manufacture Doxil," said Lisa Vaga, a spokesperson for Johnson & Johnson, in an email to Medscape Medical News.

The possible disappearance of Doxil from the market will be eased by the availability of a generic version of doxorubicin hydrochloride liposomal injection, which was approved by US Food and Drug Administration (FDA) earlier this year. The generic product, which is available in 20 mg and 450 mg vials, is manufactured by Sun Pharma Global FZE in India, and was approved in a priority review aimed at helping to alleviate drug shortages.

Nevertheless, with the possibility that there will be 1 less source of doxorubicin, some healthcare professionals are worrying about a subsequent shortage of the generic version. "Once the supply of one goes down, it greatly impacts the amount available of the next agent," Jan Kover, RPh, a pharmacy specialist for oncology at MetroHealth System in Cleveland, told Crain's.

Johnson & Johnson is seeking a new manufacturer for Doxil. "We continue our discussions with Ben Venue about various alternatives to ensure continued supplies of Doxil into 2014," said Vaga, on behalf of Johnson & Johnson.

The closure of the Ben Venue factory will have a widespread impact on the generic injectables market, according to another report.

"If you had asked me 2 months ago how long we thought it would be before we would see real improvement in the number of ongoing and active drug shortages, I would have told you it was going to be about 2 years," said Erin Fox, PharmD, director of the drug information service at the University of Utah Pharmacy Services in Salt Lake City, in a report published October 11 in the Cancer Letter, an industry newsletter.

That time period now doubles or triples, she said.

"I think we are closer to maybe 4 to 6 years out, because Ben Venue was such a significant manufacturer and such a large provider of these injectable products," said Dr. Fox. "I think we'll see some improvements, but unless we see a very large company commit to making a large number of these drugs that are in short supply, we aren't going to see real improvement any time soon."

A Lot of Other Cancer Drugs Out of Stock

Ben Venue will cease operations because of "systemic manufacturing challenges," according to acompany statement issued on October 3. It notes that the company, which is owned by Boehringer Ingelheim, has invested more than $350 million in their plant, but that more changes are needed. An estimated $700 million in operating losses are expected over the next 5 years.

The company suspended production in 2011 because of manufacturing issues, and has worked with the FDA and other global regulatory agencies to remediate problems. Production at the factory has been off and on since that time.

TYPE OF ANESTHESIA MAY HAS AN EFEFCT ON CANCER SURVIVAL?

SAN FRANCISCO — Women with breast cancer appear to live longer and have less chance of a cancer recurrence if they receive a paravertebral nerve block combined with general anesthesia during their cancer surgery, a study from Denmark has found.

This double-blind study of 77 patients is the first randomized prospective clinical trial to compare the effect paravertebral block plus general anesthesia has on breast cancer recurrence with general anesthesia alone, the researchers say.

They report that women treated with the combined anesthetic technique were approximately 3 times less likely to have had a cancer recurrence and to have died of breast cancer at least 6 years after mastectomy or lumpectomy than women treated with general anesthesia.

"Anesthesiologists should use regional anesthesia as much as possible during cancer surgery, because it seems to improve survival and cancer recurrence and is without the potential side effects of morphine," senior researcher Palle Carlsson, MD, DMSc, associate professor in the Department of Anesthesiology at Aarhus University Hospital in Denmark.

However, breast cancer experts approached by Medscape Medical News said it is too early to incorporate these findings into clinical practice.

The role of regional anesthesia in cancer recurrence remains intriguing but speculative," said Daniel Sessler, MD, anesthesiologist, professor, and chair of the Department of Outcomes Research at The Cleveland Clinic, who is heading an ongoing phase 3 trial addressing this issue.

It is possible that paravertebral block improves outcomes by reducing surgical stress and increasing the number of natural killer cells, which are vital to the immune system and the body's defense against cancer, Dr. Carlsson explained. However, the women with better outcomes also had less postoperative use of opioids, and opioids are known to decrease natural killer cells, he added.

Results Presented at ASA Meeting

Asser Oppfeldt, MD, an anesthesiology resident at Aarhus University Hospital, presented the findings here at American Society of Anesthesiologists 2013 Annual Meeting.

In the study group, approximately two thirds of breast cancer patients underwent mastectomy and one third underwent lumpectomy and sentinel node biopsy.

All patients received 4 to 6 paravertebral injections from level C7 to T5 on the surgical side and standardized anesthesia with propofol and doses of fentanyl or alfentanil as needed.

In addition, 39 patients were randomly assigned to receive nerve block with 0.5% ropivacaine 30 mL, and 38 patients received a placebo of an equivalent volume of isotonic saline.

There were no statistically significant differences between the treatment and placebo groups in mean age (57.6 vs 57.2 years), body mass index (23.8 vs 24.4 kg/m²), or preoperative chemotherapy (5% vs 11%). Cancer characteristics, including tumor size, histological grade, lymph node status, and estrogen-receptor status, were also similar in the 2 groups.

The researchers searched the patients' medical records at least 6 years after the procedure to determine the number of deaths and breast cancer recurrences. One patient in each group died of causes other than breast cancer.

They found significant between-group differences in both recurrence and mortality.

Table. Recurrence and Mortality Outcomes of Patients With Breast Cancer

Outcome	Ropivacaine, % (n = 39)	Placebo, % (n = 38)	P Value
Local or metastatic recurrence	13.0	37.0	.02
Overall mortality	10.0	32.0	.03
Breast cancer mortality	7.7	29.0	.03

 In addition, there was significantly less postoperative opioid use in patients whose cancer did not recur (45.0 vs 58.8 mg morphine-equivalent; P = .02).

There are no plans for a larger study, Dr. Carlsson said.

Too Small to Change Practice

The study did not have enough patients for the results to alter clinical practice. "It's too small to change our routine," said Kevin Bethke, MD, a breast cancer surgeon at Northwestern University Hospital in Chicago, who was not involved in the study. "But it's a great start."

A strength of the study is that it used only 1 regional anesthetic technique, Dr. Bethke told Medscape Medical News.

However, Dr. Carlsson said anesthesiologists at his hospital now use a different postoperative pain relief system for cancer surgery. The ON-Q PainBuster (I-Flow Corp) system allows them to infuse local anesthetic into the surgical wound through a catheter with a balloon, which is left in place for 1 to 2 days. They switched techniques, he said, because "it is easier and safer than paravertebral block and achieves the same amount of pain relief."

They are not yet investigating this technique for any effect on cancer recurrence, he said.

Dr. Carlsson acknowledged that the adjunctive use of regional anesthesia in cancer surgery might not gain acceptance until researchers find the mechanism of action or until results are obtained from a much larger prospective study.

Such a study is underway. The Regional Anesthesia and Breast Cancer Recurrence trial (NCT00418457), headed by Dr. Sessler, is a phase 3 multicenter trial sponsored by the Outcomes Research Consortium. Patients with stage I, II, or III breast cancer undergoing mastectomy are being randomly assigned to thoracic epidural or paravertebral anesthesia/analgesia, or to sevoflurane anesthesia and morphine analgesia.

Approximately 600 patients have been enrolled so far, Dr. Sessler reported.

That study was designed 7 years ago for 1500 patients with a 10-year follow-up. It will need many more patients than that to be adequately powered, given the decreasing incidence of breast cancer recurrence, Dr. Sessler told Medscape Medical News.

The authors have disclosed no relevant financial relationships.

American Society of Anesthesiologists (ASA) 2013 Annual Meeting: Abstract 4253. Presented October 15, 2013.

AVSTIN-XELODA: AN EFFECTIVE AND SAFE REGIMEN FOR ELDERLY PATIENTS WITH METASTATIC COLORECTAL CANCER

Adding bevacizumab (Avastin, Roche) to capecitabine (Xeloda, Roche) significantly improves progression-free survival in elderly patients with metastatic colorectal cancer, with no unexpected safety concerns, according to results from the first phase 3 study of bevacizumab in an exclusively elderly population.

The findings, from the AVEX (Avastin in the Elderly With Xeloda) study, were published in the October issue of theLancet Oncology.

"Our data suggest that bevacizumab plus capecitabine is an effective and tolerable treatment regimen for patients with metastatic colorectal cancer aged 70 years and older who are deemed unsuitable for irinotecan-based or oxaliplatin-based treatments," say the researchers, headed by David Cunningham, MD, from the Royal Marsden Hospital, London, United Kingdom.

In an accompanying comment, Stefan Kubicka, MD, from the Cancer Center Reutlingen in Germany, wonders if this trial establishes the combination as a new standard of care in elderly patients with metastatic colorectal cancer. "Most oncologists would agree that it does," he writes.

"The AVEX study has shown a clinically meaningful benefit," he notes. For most elderly patients with advanced colorectal cancer, "the combination of bevacizumab with capecitabine seems to be a good option for the initiation of systemic treatment."

Dr. Kubicka emphasizes that this study is an "essential" addition to the evidence base because patients with colorectal cancer older than 70 years have been highly underrepresented in clinical trials, despite the fact that this age group accounts for about half of all patients with metastatic colorectal cancer.

Survival Advantage With Combination

The study was conducted in 280 patients 70 to 87 years of age. About two thirds of the patients were older than 75 years, and the majority had comorbidities and received concomitant medications.

These patients had previously untreated and unresectable metastatic colorectal cancer, and were not deemed to be candidates for oxaliplatin-based or irinotecan-based chemotherapy regimens.

They were randomized to 1 of 2 treatments: twice-daily oral capecitabine 1000 mg/m² on days 1 to 14, or the same regimen of capecitabine plus intravenous bevacizumab 7.5 mg/kg on day 1 every 3 weeks until disease progression, unacceptable toxic effects, or withdrawal of consent.

The daily dose of capecitabine used in the study is slightly lower than the standard dose used in clinical practice, which is 2500 mg/m².

The results show a significant improvement in median progression-free survival with the combination, compared with monotherapy (9.1 vs 5.1 months; hazard ratio [HR], 0.53; P < .0001).

Median overall survival did not differ significantly in the combination and monotherapy groups (20.7 vs 16.8 months; HR, 0.79; P = .18), but the study was not sufficiently powered to detect an overall survival difference, the researchers note. The proportion of patients who used any subsequent treatment was the same in the 2 groups.

The results were consistent across all age subgroups assessed, and the HR for progression-free survival benefit was the same in patients younger than 75 years and those 75 years and older, the researchers report.

Toxicity in Elderly With Comorbidities

Many oncologists are reluctant to treat elderly patients with combination chemotherapy or molecular drugs because they are concerned about the possibility of severe toxic effects, especially in patients with comorbidities, the researchers write. This is a common perception that contributed to the rationale underpinning the AVEX trial. All patients enrolled in the trial were older than 70 years so that the use of bevacizumab plus capecitabine in this specific population could be assessed.

Despite concerns about the safety of bevacizumab in elderly patient populations, the researchers identified no new safety signals. "The safety profile was consistent with that reported by other studies of bevacizumab plus capecitabine in metastatic colorectal cancer," Dr. Cunningham and his colleagues write.

The most common any-grade adverse event of special interest for bevacizumab was hemorrhage. It affected 25% of patients in the combination group and 7% in the monotherapy group.

Table. Treatment-related Outcomes

Treatment-related Outcomes	Capecitabine Plus Bevacizumab, n (%), n = 140	Capecitabine Monotherapy, n (%), n = 140
Deaths	5	4
Serious adverse events	19 (14)	11 (8)
Grade 3 or higher adverse events
Total	53 (40)	30 (20)
Hand–foot syndrome	21 (16)	9 (7)
Venous thromboembolic events	11 (8)	6 (4)

Overall rates of thromboembolic events were consistent with findings from previous trials of bevacizumab in patients with metastatic colorectal cancer. The researchers suggest that this provides "further evidence that bevacizumab is safe to give to elderly patients."

They add that although more patients experienced adverse events that led to death or discontinuation in this study than in other studies of bevacizumab plus fluoropyrimidine monotherapy, this was expected because the patients studied were elderly and many had comorbidities. "Importantly, the number of deaths from treatment-related adverse events was low in both groups, and much the same in each group," they note.

Dr. Cunningham and colleagues suggest that their findings might inform treatment options for younger patients who are not candidates for irinotecan-based or oxaliplatin-based chemotherapy. "Bevacizumab plus capecitabine might also be considered when patients choose to avoid the toxic effects of irinotecan and oxaliplatin," they write.

The study was sponsored by F. Hoffmann-La Roche. Dr. Cunningham reports receiving research funding from F. Hoffmann-La Roche, Merck KgaA, Novartis, Celgene, Amgen, and AstraZeneca. Dr. Kubicka reports being a scientific advisor to and receiving honoraria from Merck, Amgen, sanofi-aventis, and Roche.

Lancet Oncol. 2013;14:1031-1032, 1077-1085. Comment, Abstract

AGGRESSIVE MANAGEMENT OF METASTATIC COLORECTAL CANCER

Int J Colorectal Dis. 2013 Jul 31. [Epub ahead of print]

Survival after resection of liver and lung colorectal metastases in the era of modern multidisciplinary therapy.

Tsukamoto S, Kinugasa Y, Yamaguchi T, Shiomi A.

Source

Division of Colon and Rectal Surgery, Shizuoka Cancer Center, 1007 Shimonagakubo, Nagaizumi-cho, Sunto-gun, Shizuoka, 411-8777, Japan, shtsukam@ncc.go.jp.

Abstract

PURPOSE:

Despite recent improvement of the outcomes of colorectal cancer (CRC), the benefits of resection and appropriate selection criteria in patients with both liver and lung metastases remain controversial. The aim of this study was to analyze the outcomes and prognostic factors for survival in patients who underwent both hepatic and pulmonary resection for CRC metastases in the era of modern multidisciplinary therapy.

METHODS:

A retrospective analysis of 43 consecutive patients who underwent both liver and lung resections for metastatic CRC at our institute from 2003 to 2011 was performed. All patients in this study had achieved cancer-free status after resection of the second metastatic site.

RESULTS:

Of the patients, 24 (56 %) had synchronous metastatic disease with their primary tumor. Twenty-seven patients had developed recurrence after resection of the second metastatic site. In 14 cases, re-metastasectomy was performed for recurrence. Fourteen patients received palliative chemotherapy after recurrence, and all of these patients received oxaliplatin and/or irinotecan-based chemotherapy. After resection of the second metastatic organ, the 5-year relapse-free and overall survival rates were 29.6 and 70.0 %, respectively. Patients with multiple lung metastases had worse relapse-free survival than patients with solitary lung metastases at first lung resection (p = 0.046).

CONCLUSIONS:

Aggressive surgical resection and a combination of modern chemotherapeutic agents improve the survival of patients with lung and liver metastases from CRC. The presence of multiple lung metastases at resection suggests a poor prognosis.

DRIVER CANCER MUTATIONS NOT MORE THAN 200

Most common tumors are driven by just two to six DNA mutations, according to a genetic analysis of 3000 tumor samples that brings scientists closer to devising a comprehensive list of all the key mutations that cause cancer or contribute to its progression.

In the study, researchers from Washington University in St. Louis analyzed 3,281 tumors from 12 cancer types, including breast cancer, lung cancer and colon cancer. They found 127 mutated genes in those tumors that appeared to be involved in either in cancer initiation or progression. The results indicate that a relatively small number of genetic changes fuel tumor growth, said Li Ding, senior author on the study.

“This is a really small number. This suggests that only a few driver mutations are required for developing tumors,” said Ding, assistant director of the genome institute at the university, in a phone interview. In the long run, cataloging cancer’s genetic changes “will help develop personalized treatment strategies for each patient.”

The new work, published in the journal Nature, is part of the Cancer Genome Atlas project, a U.S. National Institutes of Health-funded effort to discover what changes make a normal cell cancerous and pinpoint more effective treatments. After performing several studies examining mutated genes found in specific tumor types, researchers in the project are now scanning multiple cancer types simultaneously to find patterns of genetic abnormalities common to different tumors. The ultimate goal is to treat patients with therapies tailored to the specific mutations involved in each individual’s cancer.

Moving Closer

The new study moves researchers closer towards devising a comprehensive list of the key genes involved in cancer, said Ding in a phone interview. Her study, though, is not the final word on this subject, because it only looked at certain types of common mutations and didn’t examine other genetic changes where large chunks of DNA are rearranged abnormally.

Still, given the rapid rate at which researchers are generating cancer genome data, “we have a reasonable chance of identifying most of the core cancer genes” in the next three to five years, Ding said.

One promising result of Ding’s study is that it identified several mutated genes that are bad prognostic factors across a number of cancers, said Thomas Hudson, a genome scientist at the Ontario Institute for Cancer Research, in a phone interview. If confirmed, the findings could help doctors develop new prognostic tests that indicate which patients need the most aggressive treatment, he said.

“Having markers of bad prognosis is really critical” as it may help doctors decide which patients may benefit from drug treatment after surgery to prevent cancer from recurring, said Hudson.