The Highs and Lows of Targeted Therapies

OncologyOncology Vol 29 No 5
Volume 29
Issue 5

In order for there to be a truly clinically significant breakthrough in targeted therapy, we need to further explore the tumorigenesis of gynecologic malignancies and identify the initiators and true drivers of these cancers.

Cancer chemotherapy has undergone a vast and interesting evolution since its origins. Mustard gas–based agents were first used in the early 20th century, and they resulted in dramatic responses in patients with deadly cancers. Platinums, vinca alkaloids, taxanes, and other agents were subsequently developed, all of which were engineered based on the intrinsic cell growth cycle that is exhibited by both normal and cancer cells-although the speed at which the cycle is completed differs significantly between the two types of cells. These “untargeted” therapies can potentially attack all cells in the body, but our hope in using them is that they will preferentially eliminate the more rapidly growing cancer cells before they cause irreparable damage to healthy cells. Multiple combinations of these agents, as well as varying dosing schedules and delivery methods, have been tested in an effort to improve patient responses and outcomes. With improvements, however, often and unfortunately have come associated toxicities, which our patients have bravely withstood in the hope of prolonging life. A good-and quite recent-example of both the promise and the perils of untargeted therapy might be the Gynecologic Oncology Group (GOG) study[1] that showed that intraperitoneal cisplatin in combination with intraperitoneal and intravenous paclitaxel resulted in a nearly 1.5-year overall survival improvement in women with ovarian carcinoma, compared with outcomes in women given these agents intravenously only. This represents a phenomenal improvement in overall survival, not just progression-free survival, in modern cytotoxic therapy trials. However, the use of intraperitoneal therapy is still debated because of a lack of knowledge of the ideal way to deliver it, and because of major concerns over toxicity.

In this issue of ONCOLOGY, Drs. Liu, Cripe, and Tewari offer an elegant review of anti-angiogenesis therapy in gynecologic malignancies,[2] a paper that can help us better understand the molecular pathways involved in cancer development, growth, and progression. Knowledge of such pathways forms the basis for the development of “targeted” therapies. In theory, targeted therapies should prevent and eliminate cancer cells while simultaneously preserving healthy ones, in essence minimizing collateral damage. One of the first targeted therapies, imatinib, provided proof of this concept, resulting in dramatic and unprecedented responses in patients with gastrointestinal stromal tumor and chronic myeloid leukemia, with relatively fewer reported side effects compared with conventional untargeted therapies. Most importantly, imatinib prolonged both progression-free and overall survival.

Since the success of imatinib, there has been an explosion of such targeted therapies. Our goal has been to mimic imatinib’s success in other tumor types, but unfortunately we are unaware of the driving and initiating molecular pathways in most other cancers. The improvements in outcomes seen with many other targeted therapies have been modest at best, and have consisted mostly of improvements in progression-free and not overall survival. We are still looking for that imatinib-style knockout punch against most cancers.

Newer targeted therapies now often block multiple targets and are at times not as “targeted” against the cancer cells as we would like them to be. They can attack healthy cells and do cause significant toxicities. The financial cost of these agents is significant as well. Thus, we must seriously consider whether the 2- to 4-month differences seen in progression-free survival, while highly statistically significant, are as exciting clinically as we want them to be, especially when no benefit in overall survival is seen. Even overall survival improvements of 2 to 4 months are, frankly, of limited clinical importance. And worse yet, even in cases where targeted therapies have resulted in a remarkable response, cancer cells continue to outsmart even the smartest of us humans, adapting and forging novel pathways that enable them ultimately to resist these new therapies as well.

In order for there to be a truly clinically significant breakthrough in targeted therapy, we need to further explore the tumorigenesis of gynecologic malignancies and identify the initiators and true drivers of these cancers.

Financial Disclosure:The author has no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.


1. Armstrong DK, Bundy B, Wenzel L, et al. Intraperitoneal cisplatin and paclitaxel in ovarian cancer. N Engl J Med. 2006;354:34-43.

2. Liu FW, Cripe J, Tewari KS. Anti-angiogenesis therapy in gynecologic malignancies. Oncology (Williston Park). 2015;29:350-60.

Related Videos
Brian Slomovitz, MD, MS, FACOG discusses the use of new antibody drug conjugates for treating patients with various gynecologic cancers.
Developing novel regimens may continue to improve survival outcomes of patients with advanced cervical cancer following the FDA approval of pembrolizumab and chemoradiation, says Jyoti S. Mayadev, MD.
Treatment with pembrolizumab plus chemoradiation appears to be well tolerated with no detriment to quality of life among those with advanced cervical cancer.
Jyoti S. Mayadev, MD, says that pembrolizumab in combination with chemoradiation will be seamlessly incorporated into her institution’s treatment of those with FIGO 2014 stage III to IVA cervical cancer following the regimen’s FDA approval.
Domenica Lorusso, MD, PhD, says that paying attention to the quality of chemoradiotherapy is imperative to feeling confident about the potential addition of pembrolizumab for locally advanced cervical cancer.
Guidelines from the Society of Gynecologic Oncology may help with managing the ongoing chemotherapy shortage in the treatment of patients with gynecologic cancers, according to Brian Slomovitz, MD, MS, FACOG.
Brian Slomovitz, MD, MS, FACOG, notes that sometimes there is a need to substitute cisplatin for carboplatin, and vice versa, to best manage gynecologic cancers during the chemotherapy shortage.
Findings from the phase 3 MIRASOL trial support mirvetuximab soravtansine as a standard treatment option for platinum-resistant ovarian cancer, according to Ritu Salani, MD.
Trastuzumab deruxtecan appears to elicit ‘impressive’ responses among patients with HER2-positive gynecologic cancers regardless of immunohistochemistry in the phase 2 DESTINY-PanTumor02 trial.
Ritu Salani, MD, highlights the possible benefit of a novel targeted therapy and autologous tumor vaccine in patients with platinum-resistant ovarian cancer, and in the maintenance setting after treatment for platinum-sensitive disease.
Related Content