Abstract
Epithelial ovarian cancer (EOC) remains a significant challenge in gynecologic oncology. This study aimed to evaluate the outcomes of multivisceral resection in advanced EOC, focusing on the effect of surgical complexity on post-operative morbidity, time to adjuvant treatment, and overall survival. This single-arm study included 74 patients with advanced EOC who underwent multivisceral resection between January 2018 and December 2021 at the Regional Cancer Centre, Thiruvananthapuram. The study introduced a modified version of Aletti’s Surgical Complexity Scoring system to classify surgeries as intermediate or high complexity. Post-operative morbidity was assessed using the Clavien-Dindo scoring system. Time to adjuvant treatment and overall survival were also analyzed. Of the 74 patients, 80% underwent intermediate complexity surgeries, while 20% had high complexity procedures. Major morbidity (Clavien-Dindo grades 3 and 4) occurred in 10.9% of patients, with no significant difference between intermediate and high complexity surgeries (p = 0.86). Adjuvant chemotherapy was initiated within 6 weeks for 89.2% of patients. The overall 12-month and 18-month survival probabilities were 94% and 85%, respectively. Complete cytoreduction (CC-0) was achieved in 93.3% of cases, with significantly lower mortality rates compared to non-CC-0 cases (18.8% vs. 60%). Multivisceral resection in advanced EOC demonstrates favorable outcomes with acceptable morbidity rates, regardless of surgical complexity. The high rate of complete cytoreduction and impressive survival probabilities underscore the potential benefits of aggressive surgical approaches in advanced EOC. Although the subset analysis favored primary cytoreduction, further research with larger sample sizes is needed to confirm these findings and explore the impact of primary versus interval debulking surgery on long-term outcomes.
Keywords: Carcinoma ovary, multivisceral resection, primary cytoreduction, interval cytoreduction; Multivisceral resection; Primary cytoreduction; Interval cytoreduction
Introduction
As per the Global cancer statistics (2012), ovarian cancer is the second most common gynecologic malignancy in resource-rich countries and the third most common gynecologic malignancy in resource-limited countries.
The National Cancer Institute states that the lifetime risk for epithelial ovarian cancer is 1.28% or 1 in every 78 women. The median age at diagnosis of EOC (epithelial ovarian cancer) is between 60 and 64 years, but more than one-third of cases occur in patients aged 65 years or older [1].
It has been one and a half decades since the milestone paper of Aletti et al. was published emphasizing the importance of extensive surgical resection in the treatment of carcinoma ovary, showing that complete cytoreduction, even if amounting to more complex surgical resection, held a survival advantage irrespective of age and morbidity ( as calculated by the ASA score) [2].
Surgery has evolved a lot since then, with enhanced and sophisticated tools and a better understanding of perioperative physiology, and more precise ICU care; the surgical complexity has further evolved. This has led to the cytoreduction becoming more extensive, including more organs being resected, beyond the purview of the Surgical Complexity Score devised by Aletti et al. [2]. Also, since the treatment of advanced ovarian carcinoma is essentially multimodal, the effect of morbidity in the delay of adjuvant treatment and thus its effect on survival are also needed to be assessed.
This called for a revision of the score so that it can incorporate the increased extensivity of the resection and also to see whether it is still translating to survival benefit. These were the study objectives.
Materials and Methods
Study Design and Inclusion Criteria
Since this was a single-arm study, which included both primary cases and interval cytoreduction cases, there was no comparison arm. All patients with a diagnosis of advanced epithelial OC who underwent multivisceral resection between January 2018 and December 2021, at Regional Cancer Centre, Thiruvananthapuram, were included. Preoperative classification of the patients as per American Society of Anesthesiologists (ASA) score was done, using it as a marker for performance status. The decision to undertake a patient for multivisceral resection primarily or post-NACT was based on clinico-radiological features, the performance status of the patients, and surgeons ability to attain CC-0 (complete cytoreduction). Procedures performed, post-neoadjuvant or primary surgery status, and residual disease and time taken to starting adjuvant treatment were recorded.
Objectives of the Study
The primary objective was to study the effect of complexity of multivisceral resection on post-op morbidity (Clavien-Dindo scoring). Secondary objectives were to ascertain the delay in time to starting adjuvant treatment and overall survival (OS) in cases who underwent multivisceral resection.
Definitions
Multivisceral resection was defined as any resection of any organ, over and above TAH, BSO, omentectomy, lymph node dissection, and appendectomy. Complexity of surgery was graded using Modified Aletti’s Surgical Complexity Scoring System, where sleeve gastrectomy, partial cystectomy, cholecystectomy, and ureteric implant were added (suggesting the Trivandrum modification of Aletti Scoring system) and scoring given as per their added complexity (Table 1). Surgeries were classified as low/intermediate/high complexity surgeries based on the score. Since this study considered only multivisceral resection, all surgeries were of intermediate or high complexity grade (Table 1).
Table 1.
The suggested modified Aletti’s surgical complexity score
| TH-BSO | 1 |
| Omentectomy | 1 |
| Pelvic lymphadenectomy | 1 |
| Paraaortic lymphadenectomy | 1 |
| Pelvic peritoneum stripping | 1 |
| Rectosigmoidectomy | 3 |
| Large bowel resection | 2 |
| Diaphragm stripping/resection | 2 |
| Splenectomy | 2 |
| Liver resection | 2 |
| Small bowel resection | 1 |
| Cholecystectomya | 1 |
| Ureteric reimplanta | 2 |
| Partial cystectomya | 2 |
| Sleeve gastrectomya | 1 |
| Complexity score groups | Points |
| Low | Less than 4 |
| Intermediate | 4–7 |
| High | 8 or more |
aProcedures added beyond the original Aletti score
The post-op morbidity analyzed was the 30-day major morbidity which included the Clavien-Dindo grade 3 and 4 complications with respect to surgical complexity.
Time to starting adjuvant treatment was stratified into two groups: less than 6 weeks and more than 6 weeks, as various studies have shown that optimal time to initiate adjuvant treatment has been found to be 4–6 weeks [3].
The outcomes were compared with contemporary group of patients who did not undergo multivisceral resection as a part of primary or post NACT cytoreduction in our institution and with historical literature.
Statistical Analysis
The categorical variables were presented using frequencies and percentages. The continuous variables were summarized using mean, SD, median, and interquartile range. The association between categorical variables was done using chi-square or Fisher’s exact test. The survival probabilities were estimated using Kaplan–Meier methods, and comparisons were done using a log rank test. The risk for survival was estimated using Cox-regression analysis. A p-value < 0.05 was considered to be statistically significant.
Results
Seventy-four consecutive patients underwent multivisceral resection for carcinoma ovary. Eighteen patients were operated primarily, and 56 patients were taken up for surgery after neoadjuvant chemotherapy. Mean age of the total cohort was 53 years (range 21–75 years). Serous adenocarcinoma was the most common subtype in Table 2. About 80% of the surgeries done were of intermediate complexity; the rest were of high complexity.
Table 2.
Patient and tumor details
| Age | ||
| Mean | 53.43 | |
| Median | 53.50 | |
| Std. deviation | 10.555 | |
| Minimum | 21 | |
| Maximum | 75 | |
| Histopathology | Frequency | |
| Serous | 44 | |
| Mucinous | 4 | |
| Endometrioid | 3 | |
| Undifferentiated | 1 | |
| Others | 23 | |
| Incidence of intermediate and highly complex surgeries | ||
| Complexity grade | Frequency | Percent |
| Intermediate (Aletti score 4–7) | 61 | 82.4 |
| High (Aletti score 8 or more) | 13 | 17.6 |
In the 30-day post-op morbidity analysis, major morbidity (Clavien-Dindo grades 3 and 4) was experienced by eight patients (10.9%) (Table 3). Two out of 13 high complexity surgery patients (15.3%) and 6 out of 61 intermediate complexity patients ( 9.83%) patients experienced the major morbidity. But this was not statistically significant (p = 0.86).
Table 3.
Effect of surgical complexity on post-op morbidity
| Complexity grade | Clavien Dindo (CD) Grade of 30 days post op morbidity | |||||
|---|---|---|---|---|---|---|
| No complication | 1 | 2 | 3 | 4 | Total | |
| Intermediate (N= 61) | 45 | 2 | 8 | 4 | 2 | 61 |
| High (N=13) | 9 | 0 | 2 | 1 | 1 | 13 |
| Total | 54 | 2 | 10 | 5 | 3 | 74 |
| p value (for CD score 3,4) = 0.862 | ||||||
The delay in starting adjuvant chemotherapy was divided into two groups: Delay of up to 6 weeks or more than 6 weeks. For 66 patients, the chemotherapy was started within 6 weeks, while for 8 patients, it was delayed beyond 6 weeks. In the follow-up data, the delay failed to show any statistical significance in survival (p = 0.181) (Table 4).
Table 4.
Delay in starting adjuvant × survival crosstabulation
| Delay in starting adjuvant chemotherapy | |||||
|---|---|---|---|---|---|
| Time | Up to 6 weeks (N = 66) | > 6 weeks for (N = 8) | P-value | ||
| Surv Prob % | SE % | Surv Prob % | SE % | ||
| 12 | 93.7 | 3.1 | 100 | - | 0.181 |
| 18 | 83.9 | 4.7 | 100 | - | |
Post-op follow-up data of 3 years (range 1 to 6 years) was collected. Overall 12-month and 18-month survival probability of the cohort was 94 and 85%, respectively. Five of the cases had extensive disease infiltration, thus limiting optimal debulking rate (CC-1) (6.7%). Sixteen patients (21.6%) died of the disease during follow-up, of which three patients were those where CC-0 was not achieved. Cohorts where complete cytoreduction was achieved showed 18.8% mortality. Out of the five patients where CC-0 was not achieved, three had died during follow-up due to disease (60%).
The subset analysis of primary multivisceral resection patients and their comparison with post-NACT patients (Table 5) showed that the patients taken up for surgery primarily had better survival, and the patients operated after NACT had 1.8 times the probability of death than patients who underwent primary surgery (HR 1.8, CI 0.53–6.2). The wide confidence interval may be due to a limited sample size.
Table 5.
Survival probability: primary cytoreduction vs. post-NACT
| Time in months | Primary multivisceral resection (N = 18) | Post-NACT multivisceral resection (N = 56) | Total = 74 | ||
|---|---|---|---|---|---|
| Surv Prob % | SE %(Std error) | Surv Prob % | SE % | ||
| 12 | 100 | - | 92.4 | 3.7 | P-value = 0.326 |
| 24 | 86.7 | 8.8 | 71.7 | 6.9 | |
Discussion
Carcinoma ovary is one of the unconquered cancers in modern medicine that continues to elude us. With dismal survival outcomes, every percent increase in survival carries a lot of value. The study introduces a modified version of Aletti’s Surgical Complexity Scoring (SCS) system, incorporating additional procedures such as sleeve gastrectomy, partial cystectomy, cholecystectomy, and ureteric implant. This modification reflects the evolving nature of cytoreductive surgery in EOC. The results show that 80% of the surgeries were of intermediate complexity, with the remaining 20% classified as high complexity. Importantly, the study found no statistically significant difference in major morbidity (Clavien-Dindo grades 3 and 4) between intermediate and high complexity surgeries (9.83% vs. 15.3%, p = 0.86). This finding is encouraging, as it suggests that increased surgical complexity does not necessarily translate to significantly higher rates of major complications. This aligns with the findings of Aletti et al., who demonstrated that extensive surgical resection could provide a survival advantage regardless of age and morbidity [2]. Similar results were reported by Tozzi et al. in their study of 200 patients undergoing multivisceral resection for advanced ovarian cancer, where they found no significant increase in major complications with increased surgical complexity [4]. The majority of patients (89.2%) were able to start adjuvant chemotherapy within 6 weeks of surgery, which is considered optimal timing [3]. This suggests that multivisceral resection, even when complex, does not significantly delay the initiation of adjuvant treatment in most cases. The study reports impressive overall survival probabilities, with 94% at 12 months and 85% at 18 months. These outcomes are particularly noteworthy given that all patients in the study underwent multivisceral resection, indicating advanced disease. The results underscore the potential benefits of aggressive surgical approaches in advanced EOC. Similar favorable outcomes were reported in a large international cohort study by Harter et al., which found improved survival rates in patients undergoing complete cytoreduction with multivisceral resection [5]. The importance of complete cytoreduction is highlighted by the survival differences observed between patients who achieved complete cytoreduction (CC-0) and those who did not. The mortality rate was significantly lower in the CC-0 group (18.8%) compared to the non-CC-0 group (60%). An interesting finding from the subset analysis is that patients who underwent primary debulking surgery had better survival outcomes compared to those who received neoadjuvant chemotherapy (NACT) followed by interval debulking. Patients who underwent surgery after NACT had 1.8 times the probability of death compared to those who had primary surgery (HR 1.8, CI 0.53–6.2). While the wide confidence interval suggests caution in interpretation due to the limited sample size, this finding aligns with some studies that have shown superior outcomes with primary debulking surgery in selected patients [6]. For instance, a recent propensity-matched retrospective study of 36,000 patients found longer median survival in primary cytoreduction vs post NACT [7].
The limitation of this study is that It is a retrospective study. Being a single-arm study, there was no comparison group. It primarily aimed at assessing the feasibility of multivisceral resection with extended procedures beyond the complexity scoring, which showed positive results in terms of morbidity and survival was comparable with contemporary literature for both primary and post NACT cytoreductions.
Declarations
Conflict of Interest
The authors declare no competing interests.
Footnotes
Publisher's Note
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References
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