Share this article on:

Esophageal Cancer: Injectable TNF Synergizes with Chemotherapy & Radiotherapy

Carlson, Robert H.

doi: 10.1097/01.COT.0000373736.44725.06

ORLANDO, FL—The first clinical trial of the biologic agent TNFerade preoperatively in patients with locally advanced (Stage 2 or 3) esophageal cancer produced a pathological complete response (pCR) rate of 32% when administered concurrently with cisplatin and fluorouracil and 45 Gy external-beam radiation.

At the lower doses of four levels test, the pCR was 36%.

“TNF in combination with chemoradiation in a cohort of 24 patients resulted in a median survival of 47.7 months and a five-year survival of 56% in the three lowest dose levels,” said principal investigator Kenneth J. Chang, MD, Professor and Chief of Gastroenterology and Executive Director of the H.H. Chao Comprehensive Digestive Disease Center at the University of California Irvine Medical Center, in presenting the results here at the Gastrointestinal Cancers Symposium.

“This represents an encouraging increase in survival relative to historical controls of 9.7 to 34 months with adjuvant chemoradiation.” Despite neoadjuvant therapy and aggressive surgical resections, the prognosis for esophageal cancer remains poor, he said.

Back to Top | Article Outline

2nd-Gen Replication-Deficient Adenovector

TNFerade is a second-generation replication-deficient adenovector carrying the transgene encoding human TNF-alpha regulated by the radiation-inducible promoter Egr-1, Dr. Chang explained. The produce appears to work synergistically with both chemotherapy and radiation therapy.

“Ultimately the agent causes collapse of tumor vasculature and stimulates pro-inflammatory and apoptotic pathways within the tumor,” he said.

The 24 study patients were surgical candidates, and none had prior treatment for cancer. The majority of tumors were adenocarcinoma. The patients' median age was 61.

TNF was administered weekly for five weeks by intratumoral injections, either by endoscopic ultrasound-guided or conventional endoscopy during a five and a half week course of chemoradiation (45 Gy radiotherapy plus cisplatin at 75 mg/day on Days 1 and 29) and 5-FU at 1,000 mg/m2/day by continuous infusion for 96 hours starting on Days 1 and 29.

The 24 patients received four different doses: 4×108 particle units (PU) in seven patients); 4×109 PU in four patients; 4×1010 PU in four patients; and 4×1011 PU in eight patients.

The trial was sponsored by the drug's manufacturer, GenVec.

After Dr. Chang's presentation, he was asked by Jaffer Ajani, MD, of the University of Texas M. D. Anderson Cancer Center, about toxicity. There had been deaths in an earlier safety trial of TNFerade, but Dr. Chang said that none were attributable to the TNFerade injections, and that as an adjunct it appears to be safe.

Dr. Ajani, who said he has participated in TNFerade trials, also questioned how any survival benefit could be inferred from a trial with only 24 subjects. He also pointed out that the pCR rate was not much higher than in larger studies.

Dr. Chang agreed that it was a small study—“but all we're saying is that we have something interesting here and it's worth further study.”

Another member of the audience asked why injecting TNFerade into a tumor would make any difference if the tumor is to be resected later anyway.

Dr. Chang replied that, theoretically, there may be some systemic immune reaction occurring. “And we know that combination therapy in a neoadjuvant setting that produces a higher complete pathological response will, after surgery, do better than if the patient had gone straight to surgery,” he said. “Local therapies in conjunction with systemic therapies seem to be able to downstage and increase survival after surgery.”

Back to Top | Article Outline

Avoided Potential Toxicities of Systemic Administration

Speaking at a news briefing that featured the study, Leonard L. Gunderson, MD, Chair of the meeting's steering committee, said he thought TNFerade therapy by injection was an intriguing approach since it avoided the potential toxicities of systemic administration.

He also said he was impressed by the possibility that the agent is activated by both chemotherapy and radiotherapy. “This study ended up with an interesting five-year survival of 32%, which, compared with other studies, looks astoundingly good,” said Dr. Gunderson, of Mayo Clinic Cancer Center–Arizona.

“I think it's worth continuing to look at. What you'd like to do now is a randomized controlled trial of preop chemo-radiation plus or minus TNFerade.”

He noted that in a randomized trial in the United States in which patients received surgery alone, the five-year survival rate was 16%. And chemo-radiation without surgery in this same group of patients might produce five-year survival rates of 20% to 25%.

“So the results in this trial are very good,” he said.

© 2010 Lippincott Williams & Wilkins, Inc.
Home  Clinical Resource Center
Current Issue       Search OT
Archives Get OT Enews
Blogs Email us!