Are ESA's safe enough for cancer patients?

Earlier this year the FDA held a fourth session with the Oncologic Drugs Advisory Committee (ODAC) to review erythropoietin stimulating agents (ESA's). In 1993, ESA's were approved to reduce the number of red blood cells transfusions in cancer patients who have chemotherapy induced anemia. There is no doubt that the drugs do reduce the number of transfusions. They are also believed to alleviate symptoms such as fatigue and improve quality of life associated with the anemia, although the FDA has said that these remain 'unproven'.

The biggest challenge facing ODAC and the FDA though, is deciding whether ESA's very benefit in anemia is also a negative in terms of increased mortality and/or tumour progression. Eight controlled clinical trials suggest that there is evidence of increased risk of mortality and tumour progression in patients who have head & neck cancer, breast cancer, non-small cell lung cancer (NSCLC) and cervical cancer. According to the FDA, the new studies are either much larger than the original ones used to establish safety of the ESA's or have a different underlying histology.

In addition, the FDA claims that there is insufficient data to rule out mortality, shorter time to progression or lower loco-regional control in cancer other than NSCLC. As a result, FDA have asked ODAC to consider the following options:

- Remove the indication to treat anemia caused by cancer chemotherapy
- Restrict the indication to only patients who will not be cured by treatment intervention and contraindicate in adjuvant therapy
- Restrict use to specific cancer sub-types where safety has been adequately assessed (only NSCLC)
- Contraindicate use where harmful effected have been demonstrated (breast and head & neck cancers)
- Mandate risk management strategies

What is clear is that ESA's do offer a valuable clinical benefit in chemotherapy-induced anemia when used appropriately to avoid transfusions. The question is really one of risk-benefit because the very mechanism by which they work might also induce negative consequences.

It will be interesting to see what happens; The ESA market is worth several billion a year and sales are likely dropping with the repeated FDA discussions about risk benefit and safety.