The Escalating Need for Robust Decision Support in Oncology: Ovarian Cancer as an Example

There is little doubt that the rate of chance in cancer management of most disease entities has rapidly accelerated. Who would have considered, for example, as recently as a decade ago that manipulation of an individual’s immune system would be an effective strategy in inducing long-term remissions in metastatic non–small cell lung cancer?

Although such developments surely represent meaningful improvements in the standard of care for a substantial population of patients presenting with or subsequently developing advanced cancers, the speed at which new drugs, combination regimens, and novel approaches are being introduced into routine practice surely presents a vexing challenge for treating oncologists as they attempt to provide the best possible care for their patients. Unfortunately, it is critical to note that regulatory approvals, publications in high-impact medical journals, or impressive abstract presentations at major national/international cancer meetings do not necessarily help a busy clinician decide the optimal approach for the next patient being seen in the office.

In the not so distant past, with a slower pace for the introduction of novel therapeutics, it was easier for the oncology community to examine in the conduct of randomized trials the questions of optimal regimen sequencing, defining the potential for persistence of drug sensitivity to a previously administered single agent or combination regimen following disease recurrence or the relative clinical use of several alternative options. Today, such objective comparative data that might be helpful in decision support are increasingly scarce.

What follows is a brief discussion of current real-world concerns in the management of advanced epithelial ovarian cancer, the clinical and research interest of this commentator. However, it must be noted that similar issues are evident in multiple malignant disease entities.

The standard frontline chemotherapy regimen for ovarian cancer today, 6 cycles of carboplatin plus paclitaxel, is essentially the same drug regimen and dosing schedule that has been employed for the past several decades. This strategy was defined and remained as the standard based on findings from multiple single-arm studies or randomized trials that explored a variety of alternative options.1 These included the benefits of carboplatin vs cisplatin (carboplatin is equally effective but less toxic), higher doses of a platinum (no benefit), extending the duration of primary platinum-based therapy (no benefit), adding a third cytotoxic drug (no additional benefit), or substituting an agent for paclitaxel (equal efficacy, modest increase in toxicity).

Primary chemotherapy was generally proceeded by an attempt at maximal surgical cytoreduction, but an acceptable alternative has been shown to be delivery of several cycles of carboplatin plus paclitaxel followed by surgery (neoadjuvant chemotherapy) with the subsequent administration of additional chemotherapy cycles. The platinum might alternatively have been delivered intraperitoneally (generally cisplatin instead of carboplatin), and additional cycles of single-agent paclitaxel might have been administered as a maintenance approach.1

During this era, primary therapy was 2 drugs with 2 options for drug delivery (intravenous or regional) and a decision had to be made regarding the timing of surgery. Even with second-line therapy, there were relatively limited therapeutic questions to be addressed. The first related to the potential for reinstitution of platinum-based therapy, which was based on prior toxicity, response, and a calculation of the length of time from completion of initial treatment (more or less than 6 to 12 months).

Thus, patients’ cancers were defined as potentially platinum sensitive or platinum resistant. If the cancer was determined to be platinum resistant, a variety of single agents was offered in sequence, all with limited efficacy but differing toxicities. During this era, although knowledge of relevant individual comorbidities was essential, there were no other well-defined parameters (eg, molecular subtypes) required to be considered in the management of advanced epithelial ovarian cancer.

Let us turn briefly to the massive sea change in therapeutic options available today in this clinical entity. First, molecular testing, both somatic and germline, is a mandated standard of care. And although the specific implications of somatic testing are directed to the patient, germline analysis has potentially broader implications for the individual’s family.

Today, there are several different commercially available PARP inhibitors relevant for maintenance treatment both following primary and second-line platinum-based chemotherapy. Unfortunately, direct randomized trial comparisons between these agents or between the various molecular testing platforms or information regarding differences in survival outcomes based on the timing of use of these drugs (maintenance following primary or second-line chemotherapy) are currently not available, and it remains an open question as to whether such studies will ever be conducted.

In addition, a clinician caring for an individual with advanced ovarian cancer today would have to consider the multiple potential uses of bevacizumab (Avastin).1,2 It is a remarkable observation that this antiangiogenic agent combined with several cytotoxic regimens has been revealed to improve survival outcomes (progression free, overall, or both). Randomized phase 3 trial data in ovarian cancer have led to FDA approval of these bevacizumab-containing regimens in 3 different regulatory-defined disease management categories, including primary chemotherapy, recurrent potentially platinum-sensitive disease, and platinum-resistant disease.

It should be added that although not specifically recognized in the national drug approval process, phase 3 trial data have revealed the clinical use of retreatment with chemotherapy plus bevacizumab compared with chemotherapy alone in women with ovarian cancer who have previously received the antiangiogenic drug.3 Thus, it is relevant to consider retreatment of patients with bevacizumab plus chemotherapy who have previously received the drug as a component of management for primary or recurrent disease. In fact, it is simply unknown how many lines of systemic therapy might be favorably affected by the addition of the antiangiogenic agent.

Based on the preceding discussion, it is not difficult to appreciate the growing number of unresolved clinically meaningful issues in the management of ovarian cancer. Consider the following less than comprehensive list of issues:

When should bevacizumab or a PARP inhibitor be administered? Is there a preference for one of the commercially available PARP inhibitors? Which biomarkers would lead to a decision to recommend use of this maintenance therapy? Should a PARP inhibitor be reintroduced if a patient exhibits evidence of disease progression, for example, a year after primary maintenance therapy has been completed? If the answer to this question is “yes,” should a different PARP agent be utilized? If a PARP inhibitor is given as maintenance, how does this affect the definition of potentially “platinum-sensitive” recurrent disease? In the absence of direct comparative data to chemotherapy plus bevacizumab in “platinum-resistant” ovarian cancer, what is the relative efficacy of this approach vs any newly approved antineoplastic agent in this setting? Finally, how should the results of next-generation sequencing be incorporated into the standard management paradigm for the growing list of tumor-agnostic drug approvals?

Unfortunately, in the absence of objective data, there are no easy answers to the preceding (and many other) questions. Rather, what we have as decision support is so-called expert opinion and FDA-approved company marketing. One would hope that with the combined efforts of the cancer community, which includes providers, health care organizations and systems, regulators, researchers, payers, and patients and their families most importantly, we can do better than this.

References

1. Markman M. Pharmaceutical management of ovarian cancer: current status. Drugs. 2019;79(11):1231-1239. doi:10.1007/s40265-019-01158-1
2. Markman M. Antiangiogenic drugs in ovarian cancer. Expert Opin Pharmacother. 2009;10(14):2269-2277. doi:10.1517/14656560903120907
3. Pignata S, Lorusso D, Joly F, et al; MITO16b/MANGO–OV2/ENGOT–ov17 Investigators. Carboplatin-based doublet plus bevacizumab beyond progression versus carboplatin-based doublet alone in patients with platinum-sensitive ovarian cancer: a randomised, phase 3 trial. Lancet Oncol. 2021;22(2):267-276. doi:10.1016/S1470-2045(20)30637-9