When complete debulking is feasible, primary debulking surgery (PDS) may be superior to neoadjuvant chemotherapy (NACT) in women with high-grade serous ovarian carcinoma (HGSC) because upfront surgery eliminates chemo-resistant cells more effectively than NACT, a mathematical model simulating the clinical course of HGSC predicted.
According to Shengqing Gu, PhD, Princess Margaret Hospital, Toronto, Ontario, and colleagues, whose work was published in the Proceedings of the National Academy of Sciences, the model predicted that a typical HGSC patient has low numbers of chemo-resistant cells at the time of diagnosis.
PDS may dramatically decrease the number of both chemo-sensitive and chemo-resistant cancer cells, as both are equally likely to be removed at surgery. Follow-up chemotherapy in turn would reduce any remaining chemo-sensitive cells to very low numbers or, potentially, eradicate them altogether, the authors suggested.
In contrast, NACT could dramatically enrich the tumor bed with chemo-resistant cells, killing only the chemo-sensitive cells, the team argued. Consequently, chemo-resistant cells could make up a large proportion of the total tumor burden following NACT, at which point it would become virtually impossible for interval debulking surgery to fully eradicate these cells.
“Our model, combined with earlier clinical data, suggests that for patients who can undergo complete debulking, surgery offers the best chance of long-term survival or even cure,” co-senior author Benjamin Neel, MD, PhD, director of Perlmutter Cancer Center at NYU Langone Health, New York, said in a statement. “Our model also provides some insight about optimal early detection and treatment intervals.”
Two independent cohorts were used to train and evaluate the mathematical model.
“The first dataset contains information on 148 patients who were treated by PDS or NACT at the University Health Network (UHN) between March 2003 and November 2011,” the authors explained. Complete debulking—defined as <1 mm of residual tumor—was achieved in 97 patients in this group, whereas the remaining 51 patients had 1 to 10 mm of residual tumor. Among the complete debulking group, 40 received upfront surgery followed by six cycles of platinum and taxane-based chemotherapy—referred to as the PDS <1 mm group—while remaining patients were treated with upfront chemotherapy followed by interval surgery after the first three to four chemotherapy cycles—referred to as the NACT <1mm group. The remaining patients in the UHN dataset also underwent debulking surgery but were left with residual tumor of between 1 and 10 mm in diameter.
The second dataset involved 137 patients who participated in the CAN-CCTG-OV16 trial (the CCTG cohort), all of whom received upfront surgery, followed by eight cycles of carboplatin plus paclitaxel chemotherapy. Only 20 patients in the CCTG cohort achieved a debulking status of <1 mm residual tumor, while 36 patients were left with 1 to 10 mm of residual tumor and 81 patients were left with residual tumor in excess of 10 mm.
“We then explored why the predicted superiority of PDS over NACT depends on residual tumor burden post-surgery,” Gu and colleagues wrote.
By evaluating the expected distribution of chemo-sensitive and chemo-resistant cell numbers after first-line therapy, they found that “PDS with <1 mm residual tumor potentially can deplete all cancer cells in a significant proportion of HGSC patients”—which would account for the considerable survival difference between PDS and NACT patients with less than 1 mm of residual tumor, they noted.
In contrast, in patients with more than 1 mm residual remaining tumor, “neither PDS nor NACT depletes all malignant cells.” As a result, “almost all patients with >1 mm residual tumor are predicted to relapse and eventually die because of the inability of current agents to kill chemo-resistant cells,” Gu and colleagues argued. Residual tumor mass is thus a key determinant of survival after PDS, but not NACT.
Using the same model, the team also predicted the effects of altering current treatment regimens on patient outcomes.
“For PDS with < 1 mm residual tumor, earlier initiation of chemotherapy might prolong survival whereas longer treatment delay might worsen outcomes (P<0.001),” the group suggested.
On the other hand, for PDS patients with >1 mm residual tumor or for NACT-treated patients left with any amount of residual tumor, treatment delay is unlikely to have any effect on patient outcomes because in both scenarios, it’s unlikely that all cancer cells will be depleted, irrespective of treatment delay.
Investigators also used the same model to evaluate the potential benefits of earlier diagnosis.
“Contrary to the intuitive notion that earlier diagnosis of recurrence should be advantageous, we find that CA-125-based earlier diagnosis is not expected to improve survival,” the authors wrote, “[so] our model predicts no advantage in patient survival if recurrence is detected earlier.”
Earlier diagnosis followed by prompt re-initiation of chemotherapy may deplete chemo-sensitive cells more effectively; however, it does little to affect chemo-resistant cells that have already been enriched by first-line therapy, ultimately hastening patient death.
The team also explored the potential benefit of detecting treatment-naïve tumors earlier, when it is likely that smaller, less disseminated tumors would be detected, increasing the likelihood that patients will be a candidate for complete debulking.
“Our analysis argues that earlier diagnosis of treatment-naïve cancer, with concomitant prompt intervention, can improve patient survival compared to regular diagnosis when controlled for residual cancer cell number post-surgery,” they report.
For PDS with complete debulking, the survival benefit with earlier diagnosis of treatment-naïve cancer could be dramatic because a lower volume and less diffuse tumor on diagnosis would increase the likelihood of surgeons being able to eradicate the disease.
In contrast, the survival benefit in patients treated with NACT with complete debulking was predicted to be limited.
“PDS that leaves minimal residual tumor is the optimal treatment strategy for patients who can tolerate the surgery and who do not have overwhelming or inaccessible disease burden at presentation,” the authors concluded. “…If debulking surgery removes all chemo-resistant cells, the PDS regimen can [also] be curative.”
- Primary debulking surgery followed by adjuvant chemotherapy is predicted to be superior to neoadjuvant chemotherapy in women with high-grade serous ovarian cancer.
- Earlier detection of primary tumor could extend ovarian cancer survival; however, earlier detection of ovarian cancer relapse is unlikely to be beneficial with current therapies, the study authors found.
Pam Harrison, Contributing Writer, BreakingMED™
The study was supported by the National Institutes of Health among others.
Neel is a co-founder, holds equity in and has received consulting feels from Navire Pharmaceuticals, Northern Biologics and Jengu Therapeutics. He has also received consulting fees from Avrinas as well as from MPM Capital and has equity in Recursion Pharma.
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