Rapid Accelerating Changes in Cancer Management Through the Lens of Ovarian Cancer

Maurie Markman, MD

The magnitude of changes in cancer management and the favorable effect on patient survival and quality of life over the past several decades cannot be overstated. The paradigm of care in the not-so-distant past for most cancers presumed at diagnosis to be localized to a single organ, or perhaps with only regional spread, was simply surgical resection. If this was not possible, external radiation was employed. Systemic antineoplastic therapy was limited to those settings where surgery or radiation was considered to be inappropriate because of the extent of local/regional spread, metastasis at diagnosis, or a malignancy that had recurred or progressed following an attempt at curative local treatment.

And even when more than 1 modality was used, the general concept was to deliver therapeutic options in sequence (eg, surgery, possibly followed by radiation to reduce risk of local recurrence, possibly followed by systemic therapy if there was a concern for microscopic metastatic disease or where more advanced cancer was discovered during curative-intent surgery).

Today, a planned multimodality treatment regimen devel-oped at the time of initial diagnosis is increasingly the norm rather than the exception in the management of local-ized or regionally advanced cancers. In contrast to standard past practices, surgery or radiation may now be reasonably employed in the setting of metastatic disease, not only as palliation but as a critically relevant component of a strategyto substantially extend survival.

Further, neoadjuvant chemotherapy has gained consid-erable traction in several malignancies as a way to reduce the extent of required tissue removal for surgery with curative intent. This not only makes it possible for a greater percentage of patients to achieve optimal cytoreduction, but also helps to determine the inherent sensitivity of the malignancy to the antineoplastic agents planned to be continued following surgery.

And in a most provocative preliminary observation, it has recently been shown that a group of carefully selected patients in a specific clinical setting—patients with stage II or III rectal cancer whose tumors possess unique molec-ular characteristics (eg, mismatch repair deficiency)—may have their advanced but still localized cancer controlled by immunotherapy as the sole management approach, poten-tially avoiding standard surgical resection completely with or without chemoradiotherapy.¹ Of course, it remains to be determined by studies with larger patient populations—and with longer follow-up—whether this truly novel approach to cancer management ultimately becomes a standard of care.

However, it is also critical to acknowledge that this accel-erating rate of change in disease management comes with a substantial cost. Here, this commentary is not refer-ring to serious concerns about the financial impact of new therapeutics, which is a most relevant topic to be discussed another time.

The cost being highlighted is the difficulty provid-ers experience when attempting to be knowledgeable and completely up-to-date regarding the numerous major devel-opments (eg, novel anticancer agents introduced into the clinic, new indications for existing drugs) and minor alter-ations (eg, recently reported rare toxicity associated with a particular therapeutic strategy) in disease management.

nant condition (eg, breast or lung cancer), the magnitude of changes associated with regular updates in standard guidelines (eg, those from the National Comprehensive Cancer Network, the American Society of Clinical Oncology, major national or regional insurers) can be formidable. But consider the effect of the current situation on the commu-nity oncology generalist who on a daily basis may see individuals with multiple tumor types, individuals who are receiving different adjuvant regimens, or individuals who are undergoing management of metastatic disease across the increasingly wide spectrum of the cancer journey.

To emphasize the specific point of this commentary, consider the recent past vs the current treatment options for patients with epithelial ovarian cancer. Two decades ago in the frontline setting, there was a platinum agent plus paclitaxel available.² In most situations, clinicians elected to administer carboplatin, rather than cisplatin, because of its more favorable toxicity profile, but there were no survival differences between the regimens. The standard treatment called for 5 or 6 cycles, with no evidence for the value of delivering additional courses, using more dose-intense or high-dose chemotherapy regimens (with bone marrow or peripheral stem cell support), or adding a third agent to the platinum-paclitaxel combination. Further, the most intense debate among investigators in the frontline treatment of patients with ovarian cancer during this era was not which antineoplastic drug strategy to use, but rather the role of regional (intraperitoneal) vs systemic drug delivery.

If a patient entered a clinical remission, treatment was discontinued until evidence of recurrence. There were no controlled trial data supporting continuation of treatment or maintenance therapy in the presence of chemo-responsive disease. If there was recurrence, a relatively simple formula based on the time a patient’s cancer was not exposed to chemotherapy—deemed platinum sensitive for recurrence and platinum resistant for nonresponsive disease—helped select patients who might benefit from rein-troduction of the same (or a similar) platinum program. And unfortunately, but of critical importance, there was little (if any) evidence for the clinical value of any therapeutic approach in the presence of platinum-resistant disease.

Today, although carboplatin plus paclitaxel remarkably remains the chemotherapy backbone for frontline systemic therapy, the paradigm for disease management has changed rather substantially. Phase 3 trial data from large cooperative groups and industry-sponsored studies have revealed the clinical benefit of neoadjuvant therapy in the manage-ment of advanced disease, as demonstrated in equivalent survival with less surgical morbidity and mortality in appropriately selected patients.²

Additionally, findings have highlighted the role of paclitaxel maintenance therapy, which has improved progression-free survival outcomes, but has a substantial risk of symptomatic neuropathy.² Other agents such as bevacizumab (Avastin), have demonstrated unequivocal value when combined with cytotoxic chemotherapy in the primary, platinum-sensitive recur-rent and platinum-resistant settings. PARP inhibitors have had a striking impact on disease outcomes when employed as maintenance therapy follow-ing first and later lines of chemotherapy and particularly in the presence of BRCA mutations or other molecular evidence of homologous recombi-nation deficiency.^2,3 The rapidly evolving management paradigm has not slowed, with a recent preliminary report that the delivery of mirvetuximab soravtansine-gynx (Elahere) in platinum-resistant ovarian cancers that strongly express the folate receptor α, improves survival compared with chemotherapy alone.⁴

There is little question that there is increasing potential for women with epithelial ovarian cancer to benefit greatly from objectively effective new therapeutics. But the speed of the developments realistically challenges physicians to have the time, knowledge, and experience to carefully consider the details of the multiple options. Unfortunately, the situation is only made more complex by the paucity of direct randomized comparisons between possible approaches.

And we are discussing here only 1 of multiple types of cancer an individual oncologist may see in their office today

References

1. Cercek A, Lumish M, Sinopoli J, et al. PD-1 blockade in mismatch repair-deficient, locally advanced rectal cancer. N Engl J Med. 2022;386(25):2363-2376. doi:10.1056/NEJMoa22014452.
2. Markman M. Pharmaceutical management of ovarian cancer: current status. Drugs. 2019;79(11):1231-1239. doi:10.1007/s40265-019-01158-13.
3. Tew WP, Lacchetti C, Ellis A, et al. PARP inhibitors in the management of ovarian cancer: ASCO guideline. J Clin Oncol. 2020;38(30):3468-3493. doi:10.1200/JCO.20.019244.
4. FDA grants accelerated approval to mirvetuximab soravtansine-gynx for FRα positive, platinum-resistant epithelial ovarian, fallopian tube, or peritoneal cancer. FDA. November 14, 2022. Accessed May 25, 2023. bit.ly/3F5Kqxg