Historically the standard treatment approach for advanced ovarian cancer has been to perform up-front primary cytoreduction surgery or primary “debulking” surgery (PDS) followed by adjuvant chemotherapy. The goal of surgery was to establish cytoreduction of the tumor to optimal (<1 cm3 disease) or, ideally, complete (no gross residual disease). While PDS has long been considered the default treatment approach, neoadjuvant chemotherapy (NACT) followed by interval cytoreductive surgery, typically after three or four cycles of chemotherapy, was the alternative strategy if it was anticipated or known that an “optimal” cytoreduction was not possible, feasible, or associated with acceptable morbidity. However, NACT was, and to some degree still is, widely considered the inferior strategy, reserved for patients with the worst prognosis. While mounting data challenges the inherent superiority of PDS, it still largely remains the default.
Why was PDS considered superior?
Dr. Emma C. Rossi
Why was PDS for advanced ovarian cancer considered a superior sequencing when it is so rarely considered appropriate for other disseminated cancers? This was born from the observation among retrospective data showing that survival was best when surgery was performed first, and when surgery was able to remove most or all visible disease (“complete” or “optimal” cytoreduction), NACT was performed.1 Several theories were proposed to explain the observations. These included the theory that bulky tumors contained avascular regions that would be less well accessed by chemotherapy, as well as the notion that chemotherapy exerts a constant fraction of kill on tumor cells, and if there is a lower burden of tumor cells to begin with, fewer cycles of chemotherapy will be necessary to eliminate all cells. Coupled with this was the notion that, if fewer cycles of chemotherapy are necessary, there would be less opportunity for development of drug resistance. Other theories such as the inflammatory effects of surgery impacting immune-mediated kill of malignant cells also are reported. These theories were largely found in the pages of textbooks, only supported by heavily biased observational series and not in the results of elegant translational studies. Of course, the observed superiority of PDS in these cohort studies was not surprising given that the patients who were historically selected for NACT had their treatment course chosen specifically for their poor prognostic factors (large volume, unresectable disease, poor performance status, and comorbidities). These “studies” were self-fulfilling prophecies.
Anecdotally I can attest that most patients are enthusiastic about a primary surgical approach to their advanced cancer. There is something concretely satisfying for patient and surgeon alike in the physical act of removing disease. As surgeons, if we believe that our added surgical effort will be rewarded with better outcomes for the patients, we will “try harder” in the operating room in order for them to do better. However, mounting data challenges whether it is our aggressive surgical effort as much as it is primary tumor biology that is the driver of prognosis in this disease. And aggressive primary surgery may add little other than perioperative morbidity.
Why that perspective may be changing
A culmination of many years of sophisticated translational research led by Anil Sood, MD, from the University of Texas MD Anderson Cancer Center, Houston, established there are fundamental biologic differences in the tumors of patients with ovarian cancer whose disease is amenable or not to a complete cytoreduction with PDS.2 In their work, the researchers sampled tumors from patients with advanced ovarian cancer who had been triaged either to PDS or NACT based on a standardized, validated laparoscopic algorithm that predicted a high probability of complete surgical resection. They performed pretreatment biopsies in both groups of patients and conducted a range of “omics” analyses to stratify these two subsets of patients – those who had a disease burden amenable to complete surgical resection versus those whose presenting disease burden exceeded an acceptable surgical effort). They identified several key molecular differences in the pretreatment biopsies of these two groups of patients, including alterations which might explain better or worse responses to therapy. These results suggest that the tumors of patients who go on to have successful PDS to no gross residual disease have different tumor biology to begin with. Otherwise said, perhaps it is favorable tumor biology that is associated with both a disease burden that is more amenable to both primary complete cytoreduction and better oncologic outcomes, rather than the surgical effort in and of itself.
This finding is supported by a study in which ovarian cancer survival outcomes were stratified by disease burden, surgical complexity scores, and postoperative residual disease among patients who were enrolled in GOG-182.3 Investigators led by Neil Horowitz, MD, created scores for surgical complexity, disease burden, and residual disease. They observed that the radicality of surgery (complexity score) was not an independent determinant of survival, but rather, patients who presented with a lower disease burden that required a less radical surgery had the best oncologic outcomes.
If the complexity of surgery does not influence outcomes as much as the predetermined, unmodifiable tumor biology, how should surgeons make decisions about the sequencing of treatment? Over the past 10 years, four randomized trials have been completed including more than 1,600 patients randomized to either PDS or NACT.4-7 All four have found no difference in the oncologic outcomes (progression-free or overall survival) between patients when randomized to PDS or NACT. While the statistical designs vary slightly, some being designed to look for noninferiority and others for superiority, they all showed that the sequence in which surgery and chemotherapy was performed mattered less than whether optimal cytoreduction was achieved when surgery was performed. As stated above, this phenomenon seems to be best determined by unmodifiable tumor biology. Unsurprisingly, these studies also have consistently found that perioperative outcomes (e.g., surgical complications, length of stay, death) were worse with PDS because of the higher surgical complexity that it demands. In the most recent SCORPION trial, rates of major postoperative complications in the PDS group were 25.9%, compared with only 7.6% in the NACT group (P < .0001) and all of the deaths from postoperative complications occurred in the PDS group at a rate of 8.3% (7 of 84 patients).7
Therefore, the wealth of data supports that oncologic outcomes are equivalent, and perioperative outcomes are improved for patients who undergo NACT for advanced, bulky ovarian cancer.