Side Effects and Toxicity

As dramatically effective as the new arsenal of anti-cancer weapons can be, their very newness presents practitioners with a quandary.

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“There are unknowns in so many areas in terms of what’s best for an individual patient,” said Elizabeth Buchbinder, MD, a medical oncologist at the Dana-Farber Cancer Institute and instructor at Harvard Medical School in Boston, Massachusetts. “These therapies are so new, what are long-term side effects of these? Are we going to have people down the line having strange toxicities or side effects that we don’t even know about yet because we’ve been giving these therapies for only so many years?”

There’s also the immediate question of selecting the first line of treatment for patients. While the targeted therapies are powerful agents for stalling the growth of or shrinking tumors, that’s true only for patients who are BRAF-mutation positive. The immune checkpoint inhibitors, on the other hand, aren’t limited to that subset of melanoma patients.

“In the past we used to say that patients with very advanced, high tumor burdens should be treated if they were BRAF positive with BRAF and MEK inhibitors,” Dr Olszanski said, “but that paradigm is changing because we now have high response rates, again, with dual immunotherapy applications. Such that the response rates are not that dissimilar compared to treating with the BRAF and MEK inhibitor.

“We have to have a meaningful discussion with our patients. Do they want a convenient tablet and a very high likelihood of response, but with the knowledge that the response they enjoy is likely time-limited, or do they want to use their own immune system, through the use of immunotherapy, and potentially enjoy a long-lasting response?”

Then comes the issue of toxicity. Both classes of treatment are linked to a variety of side effects. The targeted therapies are commonly associated with cutaneous adverse effects including rash, keratoacanthoma, cutaneous squamous cell carcinoma, and photosensitivity, as well as arthralgia, diarrhea and fatigue.3 The checkpoint inhibitors result in their own, unique side effects, which include dermatologic, gastrointestinal, endocrine, and hepatic toxicities.4 Used in combination, the immunotherapies are significantly more toxic, Dr Buchbinder said, with grade 3 and 4 adverse events occurring in 55% to 60% of patients.

While there are still no studies directly comparing the effectiveness and toxicity of the 2 types of treatment, a new meta-analysis of 12 randomized controlled trials involving 6207 patients found that the “anti-CTLA4 monoclonal antibodies (RR [relative risk], 1.65; CI: 1.07-2.54) and the combination of anti-CTLA4 and PD1 monoclonal antibodies (RR, 3.39; CI: 1.94-5.93) were associated with significantly higher incidence of severe adverse events…than standard chemotherapy.”5

The meta-analysis also found that the “treatment combination was also more toxic than both anti-CTLA4 (RR, 2.06; CI: 1.45-2.93) and anti-PD1 (RR, 3.67; CI: 2.27-5.96) monoclonal antibodies alone.”

And, while the BRAF inhibitors were associated with higher toxicities, the analysis found, they also showed greater efficacy with BRAF-positive patients. The analysis’s corresponding author, Dr Simone Mocellin of the University of Padua in Italy, said via email, “we found that targeted therapy (with special regard to the combination of BRAF and MEK inhibitors) performs better than immunotherapy in terms of survival advantage provided to patients. On the other hand, physicians and patients should be aware of the fact that immunotherapy is less toxic as compared to targeted therapy: therefore, patients undergoing target therapy are expected to experience more side effects, which might lead them even to stop treatment.”

Even with the many caveats, the results of the 2 treatment tracks and the promise of ongoing research lead practitioners to anticipate even greater breakthroughs in the near future.

RELATED: Adjuvant Ipilimumab and HRQoL in High-risk Stage III Melanoma

“There is so much going on in melanoma right now,” said Dr Buchbinder. “So many new therapies. So many exciting things on the horizon. Vaccines, injectable therapies, new immune therapies, combination therapies. That is just an incredibly exciting time in melanoma. And I think we are going to start seeing huge advances in the next several years as we learn more and more about how to harness the immune system and really use it in the best way to fight melanoma.


  1. Eggermont AM, Robert C. New drugs in melanoma: it’s a whole new world. Eur J Cancer. 2011;47(14):2150-7. doi: 10.1016/j.ejca.2011.06.052 [Epub ahead of print]
  2. Olszanski AJ. Current and future roles of targeted therapy and immunotherapy in advanced melanoma. J Manag Care Spec Pharm. 2014;20(4):346-56. doi: 10.18553/jmcp.2014.20.4.346
  3. Welsh SJ, Corrie PG. Management of BRAF and MEK inhibitor toxicities in patients with metastatic melanoma. Ther Adv Med Oncol. 2015;7(2):122-36. doi: 10.1177/1758834014566428
  4. Linardou H, Gogas H. Toxicity management of immunotherapy for patients with metastatic melanoma. Ann Transl Med. 2016;4(14):272. doi: 10.21037/atm.2016.07.10
  5. Pasquali S, Chiarion-Sileni V, Rossi CR, Mocellin S. Immune checkpoint inhibitors and targeted therapies for metastatic melanoma: a network meta-analysis. Cancer Treat Rev. 2017;54:34-42. doi: 10.1016/j.ctrv.2017.01.006 [Epub ahead of print]