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Clinical study challenges off-label use of targeted cancer therapies

  • Oncologists increasingly use targeted agents directed at molecular features of cancer cells
  • There is increased off label use of these new targeted agents without evidence to support the practice
  • A landmark study concludes that off label use of targeted agents show no benefit and should be discouraged
  • Professor Gabra, head of cancer at Imperial College, says more research is needed
 

Despite significant progress in cancer care over the past decade, there remain substantial challenges in the treatment of advanced cancers. This has increased off-label use of newer drugs based on molecular studies of tumours, largely without much evidence to support the practice.

A landmark clinical study, known as SHIVA, led by Christophe le Tourneau, a senior medical oncologist at the Institut Curie in Paris, raised expectations among both doctors and patients, because it is one of the first randomized studies to explore molecularly targeted agents applied outside their indicated use (off-label) among those with advanced cancers for whom standard therapies had failed.
 
Findings, published in Lancet Oncology, September 2015, concluded that, “off-label use of molecularly targeted agents should be discouraged,” since the study detected no improvement in survival rates when compared to treatments selected by clinicians that were not based on such sophisticated DNA profiling. 

What are the implications of the study’s negative findings for personalised medicine?

Christophe le Tourneau

In the videos below Le Tourneau describes the SHIVA trail and some of the challenges it faced.

   

   
     (click to play the video) 

 

The context

Cancer is a heterogeneous, complex, and challenging disease to treat. Tumours formerly categorized as a single entity on the basis of microscopic appearance are now known to be diverse in their molecular characteristics. Cancer chemotherapy is on an evolutionary path from non-specific cytotoxic drugs that damage both tumour and normal cells to targeted agents that are directed at unique molecular features of cancer cells, and aims to produce greater effectiveness with less toxicity.
 
Over the past decade our understanding of cancer and the basis of its treatment has been significantly changed by the advent of rapid and cheap DNA sequencing technology. The application of these sophisticated analytic techniques to arrive at a therapy for a particular cancer has been called “personalized oncology.” The idea of personalized cancer care based on molecular characteristics of the tumour promises to expand the boundaries of precision medicine. Numerous case reports and other observations have suggested that therapy targeted at molecular characteristics of a tumour can have significant beneficial effects.
 
These personalized therapeutic strategies have rendered traditional classifications of many cancers redundant, because they have advanced our understanding of the underlying biology and molecular mechanisms of specific cancers. Cancer is no longer considered a single disease entity, and is now being subdivided into molecular subtypes with dedicated targeted and chemotherapeutic strategies. The concept of using information from a patient's tumour to make therapeutic and treatment decisions has changed the landscapes of both cancer care and cancer research.

 

The SHIVA study

The SHIVA study, carried out at eight academic centres in France and conducted in 195 patients with metastatic cancer resistant to standard care, was a proof-of-concept, open-label, randomized controlled study. The patients were randomly assigned to receive either molecularly targeted agents (used off-label) chosen on the basis of the molecular profile of the tumour; or therapy based on the clinician's choice. The median follow-up period was 11.3 months. Findings showed a median progression free survival (PFS) of 2.3 months for patients receiving targeted therapy, versus 2.0 months for patients receiving therapy based on the clinician's choice.

"So far, no evidence from our randomised clinical trial supports the use of molecularly targeted agents outside their indications on the basis of tumour molecular profiling . . . . . Our findings suggest that off-label use of molecularly targeted agents outside their indications should be discouraged, and enrolment into clinical trials encouraged," says Le Tourneau and his colleagues.
 

More research required

Hani Gabra, Professor of Medical Oncology and Head of Cancer, Imperial College London says, "SHIVA is important because it is the first randomized study carried out in this complex area of matching drugs to genomic profiles of tumours. Despite the fact that the results are negative we should continue research in this area because personalised medicine is a relatively new area. One thing to note is that the molecularly targeted agents used in SHIVA were single agents, which could increase resistance and reduce the agent’s efficacy. In clinical practice we tend to use several targeted agents in combination in order to counteract drug resistance. SHIVA tested specific agents and specific targets, which resulted in disappointing findings. This doesn’t necessarily negate the overall strategy, but it does suggest that more research is necessary to test the overall strategy, and this might be more challenging.”
 

Takeaways

SHIVA is one of several on going and proposed studies aimed at defining the role of targeting sequencing of tumours in an endeavour to enhance therapy. The SHIVA study did not uncover any new positive evidence to help in the management of advanced cancers. Le Tourneau and his colleagues suggest further studies in a subset of patients that have tumours with molecular alterations in the chain of proteins in the cell that communicates a signal from a receptor on the surface of the cell to the DNA in the nucleus of the cell. Oncologists, while disappointed by SHIVA’S results, still hold out hope for their patients and advocate further studies.

 
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joined 2 years, 11 months ago

Chiara Recchi

Senior Research Associate

Chiara Recchi graduated cum laude in Italy with a Master in the laboratory of Cesare Montecucco at the University of Padova. She then moved to France at the Pasteur Institute in the group of Brigitte Gicquel, where she obtained her PhD in Microbiology for her work on the virulence factors of Mycobacterium tuberculosis.

Later, she extended her interest to cell biology and she trained as a postdoc in the laboratory of Philippe Chavrier at the Curie Institute in Paris. Here she became involved in the study of intracellular trafficking and how this controls the metastatic properties of cancer cells.

She thus continued working in this field when in 2007 she moved to London, where she became research associate at the Imperial College in Miguel Seabra’s group. Here she developed her own project combining her expertise in intracellular trafficking with the lab’s experience in Rab proteins. This led to one of the first descriptions of Rab27a as key to tumour progression.

She now leads the Tumour Suppressor Group at the Ovarian Cancer Action Research Centre, directed by Hani Gabra, at Imperial College London.

Her main focus is to understand how the tumour suppressor protein OPCML controls trafficking and signalling of Receptor Tyrosine Kinases in ovarian cancer.


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