- Early clinical trials of propranolol combined with chemotherapy for advanced angiosarcoma showed a 100% response rate, leading researchers to urge its adoption. - Further trials combining propranolol and vinblastine in 7 patients with inoperable angiosarcoma resulted in a 100% response rate, earning propranolol orphan drug status in Europe. - Researchers are conducting additional clinical trials of propranolol in combination with various chemotherapy agents for several cancer types, hoping to establish it as a new standard affordable treatment given its low $4 per month cost.

1. Propranolol in Angiosarcoma:
First Major Advance in Decades
January 31, 201

2. Early clinical trial results
• 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."

3. propranolol and vinblastine-based
metronomic chemotherapy
• 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.

4. take-home message
• "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.

5. Tata Memorial Hospital in
Mumbai,
• 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.

6. 100% clinical response,
• "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.

7. propranolol
• 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).

8. microtubule-targeting agents
• 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.

9. not a cure
• "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.

10. University of Minnesota
• 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.

11. cutaneous angiosarcoma
• 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.

12. JAMA Dermatology
• "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.

13. nonselective β-blockers
• 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.

14. early-stage breast cancer
• 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 published on December 23, 2016,
in Oncotarget.

15. Propranolol for Angiosarcoma Task Force.
• 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.

16. license
• 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.

17. A better immune-modulating agent
• 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.

18. Dr Pasquier's clinical experience
• 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.

19. median PFS
• 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.

20. propranolol is off-label
• 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.

21. $4 a month
• 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."

22. Dr Pasquier
• "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."

23. propranolol and metronomic
cyclophosphamide
• 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).

24. children with refractory and/or
relapsing solid tumors
• 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.

25. Solid tumors
• 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.

26. the mechanisms
• 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.

27. our direction — to discover
• "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."

28. Pierre Fabre Oncology
• 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.