PROPRANOLOL USE FOR ANGIOSARCOMA

Early clinical trial results using the β-blocker propranolol for the treatment of advanced angiosarcoma are so positive that an international group of researchers is urging clinicians worldwide to "embrace this new therapeutic option."

In early January — after an international clinical trial reported results showing that propranolol and vinblastine-based metronomic chemotherapy led to a 100% response in 7 patients with inoperable angiosarcoma — propranolol was assigned orphan drug status in Europe.

"This is a major step forward towards the clinical development of propranolol in oncology in Europe and worldwide," study lead Eddy Pasquier, PhD, from the Centre de Recherche en Cancerologie de Marseille, France, said of the drug's new status in an email.

"Unless patients present with known contraindications to β-blockers, this nontoxic drug could benefit the majority of advanced angiosarcoma patients. Our take-home message to medical oncologists would be to embrace this new therapeutic option," he told Medscape Medical News.

The study was a collaborative effort between Dr Pasquier and Shripad D. Banavali, MD, professor and head of the Department of Medical and Pediatric Oncology at Tata Memorial Hospital in Mumbai, India. It followed on the heels of their earlier case report of a 69-year-old woman with metastatic angiosarcoma who was treated with a combination of metronomic chemotherapy and propranolol.

"The beta blockers were added since the tumour was positive for beta adrenergic receptor," they said in a report published on January 8, 2015, in ecancermedicalscience. "A complete response was quickly obtained and lasted for 20 months."

What surprised them most, said Dr Pasquier, was the 100% clinical response, which they defined as tumor regression or stabilization of the disease.

Reports suggest that propranolol may be effective when combined with chemotherapy agents commonly used in the treatment of angiosarcoma, including paclitaxel (Taxol, Bristol-Myers Squibb), doxorubicin (Adriamycin, Pfizer), and gemcitabine (Gemzar, Eli Lily).

However, the β-blocker appears to have a stronger synergistic effect when paired with chemotherapeutic drugs that are microtubule-targeting agents, especially vinca alkaloids, such as vinblastine (Alkaban-AQ, Velban), vincristine (Vincasar PFS), or vinorelbine (Navelbine), Dr Pasquier noted.

"Propranolol could be used alone shortly after diagnosis while treatment options are being decided and/or afterwards in combination with their chemotherapy of choice," he said.

While the regimen is not a cure, it may be enough to "tip the balance in terms of patient survival," says Brad A. Bryan, PhD, MBA, assistant professor of biomedical sciences, Paul L. Foster School of Medicine, Texas Tech University Health Sciences Center in Lubbock.

In one of the earliest studies, Dr Bryan used tumor cell lines and animal models to show that propranolol could significantly slow the rate of angiosarcoma tumor growth. The results were published on March 28, 2013, in PLoS One.

Dr Bryan's lab partnered with Erin B. Dickerson, PhD, a cancer researcher at the University of Minnesota Twin Cities in Minneapolis, and William Chow, DO, a dermatologist at the University of California San Francisco. Both are experts in soft tissue sarcomas and dermatologic cancers

In 2015, the trio published a single case report of a male patient in his 60s who presented with a β-adrenergic–positive multifocal stage T2 cutaneous angiosarcoma (≥20 cm) involving 80% of the scalp, left forehead, and left cheek, with no evidence of metastasis.

Results showed that propranolol-mediated β-blockade alone substantially reduced angiosarcoma proliferation and, in combination with standard chemotherapy, was effective for reducing the size of the tumor and preventing metastases.

"If successful, beta-blockade could be the first major advancement in the treatment of angiosarcoma in decades," the researchers said in a report published in November 2015 in JAMA Dermatology.

After partnering with Zeina Nahleh, MD, a medical oncologist at Texas Tech, Dr Bryan collaborated on a retrospective cross-sectional study looking at the use of nonselective β-blockers on tumor proliferation in 404 patients with early-stage breast cancer.

Their analysis revealed that nonselective β-blockers, but not selective β-blockers, reduced tumor proliferation by 66% (P < 0.0001) in early-stage breast cancer compared with nonusers.

Following this, they tested the efficacy of propranolol on a patient with early-stage breast cancer by quantifying the tumor proliferative index before and after treatment. After a 3-week period, there was a propranolol-mediated 23% reduction (P = .02) in Ki67-positive tumor cells, they said in a report publishedon December 23, 2016, in Oncotarget.

Now, Drs Pasquier, Banavali, Bryan, and Dickerson and others are members of a collaborative international research effort called the Propranolol for Angiosarcoma Task Force. It was set up in 2016 by the Anticancer Fund, the nonprofit that successfully lobbied to have propranolol's status changed.

It is hoped that with sufficient evidence for the efficacy of propranolol in treating soft tissue sarcoma, the β-blocker can eventually be relicensed and that international health guidelines will be updated to list it as cancer drug.

"Our ultimate objective is to have propranolol, if proven effective, fully licensed as a new standard of care treatment for angiosarcoma," said Pan Pantziarka, PhD, an oncology researcher at the Anticancer Fund, in a statement from Texas Tech.

In Mumbai, Dr Banavali's group now has data from 14 patients with angiosarcoma, most of them with recurrent/metatastic disease. These patients are the "toughest to cure," he said.

While results from the expanded cohort "continue to hold," other, more effective combinations are also being explored, he noted in an email. A better immune-modulating agent to the regimen "may be the missing part of this jigsaw puzzle," he told Medscape Medical News.

Currently, Dr Pasquier's clinical experience involves about six patients with angiosarcoma, and results have been "extremely positive," he said. "Propranolol appears to be effective in combination with metronomic chemotherapy with very few side effects."

Although there are some long-term survivors in Dr Pasquier's cohort, most have eventually progressed after an initial response. Others have relapsed shortly after treatment cessation.

However, the therapy's impact on progression-free survival (PFS) has been "significant," he pointed out, noting that recent studies have reported a 4- to 6-month median PFS for advanced angiosarcoma in patients treated experimentally. His group has reported a median PFS of "11 plus" months.

The impact on the quality of life was also extremely positive, Dr Pasquier added, noting that one patient in their cohort was able to attend engineering school during treatment.

Finding cost-effective treatments remains one of the biggest challenges in cancer research, Dr Banavali said, noting that by 2030, 70% of patients with cancer will be in low- and middle-income countries, where resources are limited.

Because propranolol is off-label, it's an inexpensive drug, making it an attractive option for developing countries. 

With the cost of new anticancer drugs rising above $10,000 per month, "the arrival of a promising drug that costs roughly $4 a month is nothing short of a revolution," Dr Pasquier said. "It brings hope of affordable cancer treatments for all."

"We are making a small contribution for this cause," said Dr Banavali.

It's more than a small contribution, responded Dr Pasquier, pointing out that Dr Banavali "sees something like 200 new patients per week at Tata Memorial Hospital, both adults and children, with any form of cancer — both solid and hematological malignancies."

Once a month, Dr Banavali travels to a rural dispensary 500 km from Mumbai to treat cancer patients who can't afford to come to the hospital. "He's the most incredible oncologist I've ever met, " Dr Pasquier added.

A multicenter phase 1/2 trial in France is now enrolling patients with advanced angiosarcoma who will be treated with a combination of propranolol and metronomic cyclophosphamide (Cytoxan).

In addition, Dr Pasquier's group is about to launch a second trial for children with refractory and/or relapsing solid tumors who will be treated with propranolol in combination with the oral metronomic vinorelbine.

Ongoing clinical trials are also looking at the use of the drug in combination with various chemotherapies for treatment of many other cancers.

Dr Bryan's group will be testing propranolol, and possibly other β-blockers, in breast, ovarian, and pancreatic cancer.  Early results are promising in breast and ovarian cancer, as well as in multiple myeloma, he said.

"We are hoping these trials will yield positive results and will lead to larger trials and, more importantly, to the implementation of this therapeutic strategy in clinical practice worldwide," Dr Pasquier said.

Meanwhile, laboratory research continues to parallel clinical trials. Efforts are focused on deciphering the mechanisms involved in the antitumor and chemotherapy-boosting properties of propranolol in the hopes of identifying markers for selecting patients most likely to benefit from treatment.

"Wouldn't it be amazing if a drug that unsuspectedly sits in so many people's medicine cabinets can help treat cancer?" Dr Bryan commented. "This is our direction — to discover just how many various types of cancer respond to propranolol."

Dr Pasquier declares that he is a casual consultant for Pierre Fabre Oncology, which owns the patent for a new formulation of propranolol called Hemangiol. Drs Banavali and Bryan have disclosed no relevant financial relationships.