The goal of advanced ovarian cancer surgery is to remove all gross disease, or all visible and palpable disease implants. This became the established standard when improved survival was consistently observed among patients who had undergone complete surgical resection. Traditionally, definitions of no gross residual disease have been left in the hands, and eyes, of the surgeon. However, new technology has emerged which affords surgeons the ability to visualize ovarian cancer deposits that are imperceptible to the naked eye. But will this improve upon the poor cure rates for advanced ovarian cancer?
Many are familiar with the traditional definitions of “optimal” (less than 1 cm–sized deposits at any one location) and “suboptimal” (greater than 1 cm–sized deposits remaining) when referring to surgical cytoreduction of ovarian cancer. This nomenclature was introduced to define, categorize, and prognosticate patient groups after surgery. In recent years we have moved away from these descriptive definitions of ovarian cancer resection, borrowing from surgical oncology measures of surgical outcomes where “R0” defines surgical resection with negative margins, “R1” includes resection with positive microscopic margins (negative for tumor intraoperatively, but positive on microscopic pathology), and “R2” refers to macroscopic residual disease remaining.1
Dr. Emma C. Rossi
In ovarian cancer, surgeons have adopted the expression R0 to include patients in whom there is no gross visible or palpable residual disease, a special, favorable subgrouping of the previous “optimal” group. R1 is applied to patients with macroscopic, residual disease that fits within the traditional “optimal” cytoreduction classification (<1 cm in any one location). Obviously, these are significant variations to the traditional surgical oncology definitions, but not without supporting data. For example, patients with no gross residual disease (now defined as “R0”) have been observed to have improved survival, compared with patients who are “optimally” debulked but with R1 (<1 cm) residual disease.2 Therefore, this new goal of complete surgical resection has replaced the previous standard of “optimal” cytoreduction in which small macroscopic residual disease was acceptable.
Whether or not a surgery is completed with no gross residual disease is a subjective assessment made by the surgeon, and in practice, highly inaccurate. When a posttrial ad hoc analysis of 1,873 patients with advanced ovarian cancer who had been enrolled in a Gynecologic Oncology Group cooperative trial correlated surgeons’ assessments of “optimal” cytoreduction with objective postoperative radiographic findings (performed, on average, less than 1 month postoperatively) they found that postoperative CT scans identified lesions >1 cm in 40% of cases that had been characterized by surgeons as an “optimal” cytoreduction.3 Most commonly, discrepant lesions were identified in the upper abdominal quadrants and retroperitoneal aortic nodal regions. Therefore, surgeons’ subjective assessment of cytoreduction is prone to error, and given how important the completeness of cytoreduction is for clinical outcomes, there is interest in discovering methods to improve upon surgeons’ ability to discriminate volume of disease.
Pafolacianine (Cytalux, On Target Laboratories) is a novel drug that binds a fluorescent molecule to folic acid targeting the folate alpha receptors which are overexpressed on nonmucinous epithelial ovarian cancer cells compared with adjacent nonmalignant tissues.4 The drug is intravenously infused preoperatively and then visualized with companion near-infrared imaging devices during surgery to visualize its fluorescent signal where it is bound to ovarian cancer implants. In a phase 2 study of 178 patients with confirmed or suspected ovarian cancer, pafolacianine was able to detect implants of ovarian cancer in 26.9% of cases where the surgeon’s visual inspection was negative.5 Of note, the false-positive rate of this drug was not trivial, at 20%. Based on this efficacy data, the drug has been granted FDA approved for use in ovarian cancer surgery to augment the surgeon’s visualization of cancer. However, important questions remain unanswered by these preliminary data.
Will removal of additional microscopic ovarian cancer implants, only seen by pafolacianine, improve the survival of patients with ovarian cancer, and what effect will the addition of this extra surgery have on their surgical morbidity and risk? The use of pafolacianine to augment ovarian cancer debulking surgeries pivots on the premise that ovarian cancer outcomes are determined by surgical “effort” more than the biology of the disease. Otherwise said: The more we surgically remove, the more we cure. But this seems an old-fashioned notion, increasingly challenged by data. It has been shown that, when ovarian cancer debulking surgeries are necessarily more radical because of extensive disease distribution, prognosis is worse, compared with those patients with less extensive disease distribution.6 The effect of surgical effort contributes less than that of predetermined patterns of disease presentation. Additionally, genomic traits are different in tumors that are objectively determined to be not amenable to optimal cytoreduction, compared with resectable tumors.7 These data suggest that it is the disease, more than the surgeon, that most influences outcomes.
Additionally, the question of whether surgical removal of microscopic disease improves ovarian cancer survival has already been addressed with negative findings. The LION trial randomized 647 women with advanced ovarian cancer to primary cytoreductive surgery either with or without routine lymphadenectomy of clinically negative nodes.8 This study found no survival benefit to resecting clinically negative, microscopically positive nodes. In light of these data, it is difficult to imagine that there would be different results with the resection of microscopic peritoneal disease implants identified by pafolacianine.
While pafolacianine promises to move us closer to a true “R0” (negative margins) resection of ovarian cancer, is this even a feasible goal in a disease that is widely metastatic, particularly in the peritoneal cavity? What do “negative margins” mean in the peritoneal cavity? The sensitivity of pafolacianine in detecting microscopic disease is obviously not so high that it can guarantee patients a complete resection of a disseminated disease, and we still do not know what absolute benefit is derived from moving a little bit further on the continuum of surgical resection.
Perhaps augmentation of debulking is not the only, or best, use of pafolacianine for ovarian cancer surgery. Perhaps it might serve a role in diagnostics or staging of the disease rather than for a therapeutic purpose. In the meantime, we await ongoing clinical trials in this space to better inform clinicians what benefits, or harms, they might expect from the addition of this new drug as we continue to define the “optimal” surgical procedure for advanced ovarian cancer.
Dr. Emma Rossi is assistant professor in the division of gynecologic oncology at the University of North Carolina at Chapel Hill. She has no conflicts of interest.
References
1. Hermanek P, Wittekind C. Semin Surg Oncol 1994;10:12-20.
2. Elattar A et al. Cochrane Database Syst Rev 2011 Aug 10;2011(8):CD007565.
3. Eskander RN et al. Gynecol Oncol 2018;149:525-30.
4. Randall LM et al. Gynecol Oncol 2019;155:63-8.
5. Food and Drug Administration. FDA approves pafolacianine for identifying malignant ovarian cancer lesions. 2021 Dec 1.
6. Horowitz NS et al. J Clin Oncol 2015;33:937-43.
7. Lee S et al. Cell Rep. 2020;31:107502.
8. Harter P et al. N Engl J Med 2019;380:822-32.