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| Tumour treating fields: more than just fun with physics |
Glioblastoma (GBM), that most
aggressive of brain cancers, is notoriously resistant to treatment and a variety of leading edge approaches, including immunotherapy, virotherapy and gene therapy are under investigation as means of extending survival by a meaningful amount.
One of the few treatments to have gained regulatory approval in the last decade is a medical device, Optune™, a custom-made, shower cap-like array of electrodes worn constantly on a shaven scalp, which is claimed to disrupt and slow tumour growth through the application of low intensity, alternating electrical current- so-called “tumour treating fields (TTFs).
I’m probably not alone in being
reminded of 19th century quackery and the various galvanic
treatments advocated by the beauty industry, but Optunes’s developer, NovoCure,
a publicly traded US-based company, has managed to navigate the rocky path of
clinical development to satisfy both American and European regulators, although
approval was not without controversy.
Optune™ (then designated NovoTTF-100A) received FDA approval for the treatment of
recurrent GBM in April 2011, on the back of clinical data that hinted at,
rather than conclusively established, a degree of benefit comparable to
chemotherapy, a comparison in itself made complex by differences in
investigator choices of chemotherapy regimen. The FDA panel was accused of
being overly influenced by pleas from GBM patients and their families during an
open public hearing. Approval did come with the rider that NovoCure conduct a
post-approval study to establish non-inferiority of TTF treatment to chemotherapy.
FDA approval for the
treatment of newly-diagnosed GBM in conjunction with chemotherapy was granted in
2015 on the back of interim clinical data gathered from almost 700 GBM patients
receiving radiotherapy and chemotherapy following surgery. The addition of TTF
treatment increased the median time to progression, and overall survival, by
almost three months over chemotherapy alone.
Neuro-oncologists
remain divided on Optune™, being, with reason, critical of a pivotal clinical
study that did not include sham treatment as a control, and the vagueness of
the TTF mechanism of action, stated as involving “misalignment” of charged
proteins critical to cell division. On the other hand, TTF in combination with
chemotherapy is recommended in the authoritative National Comprehensive Cancer
Center treatment guidelines. Despite the requirement of near constant wear (a
minimum of 18 hours a day) and high treatment cost
(around $20,000 per month with as yet limited reimbursement, Optune™ is currently
in use by over 2,000 GBM patients in the US, Europe and Japan.
Recent data suggests
that TTF may be of benefit in other forms of solid tumour. Two completed pilot
studies of TTF in combination with standard chemotherapy in malignant mesothelioma
and pancreatic cancer patients indicated improvements over historical
progression-free survival and one year survival rates obtained with
chemotherapy alone.
An apparent improvement
in progression-free survival was observed in a small study conducted patients
with recurrent ovarian cancer is more difficult to interpret due to difference
in the treatment histories of individual patients and historical chemotherapy
comparators.
Nonetheless, NovoCure
is sponsoring three pivotal TTF studies in pancreatic cancer, non-small cell
lung cancer (NSCLC) and in brain metastases arising from NSCLC, with final data from the latter study anticipated in 2020. TTF faces tougher competition in these indications from advances
in precision chemotherapy and immuno-oncology, but should TTF even prove to be non-inferior to conventional therapies,
it could find use in individuals intolerant of, or unresponsive to, other forms
of cancer treatment. Success may also
serve to disarm TTF’s critics, as might elucidation of the putative
mechanism(s) of action, along with the acid test of undertaking a TTF study that includes a sham treatment control
arm.
Image credit: Wikipedia(creative commons licence)
