Giovanni Aletti

Lymphadenectomy in early-stage ovarian cancer: is there still a role?

The role of systematic pelvic and para-aortic lymphadenectomy in presumed early-stage ovarian cancer remains controversial due to the lack of high-quality prospective evidence. No therapeutic benefit has been confirmed for systematic lymphadenectomy during surgical staging for apparent early-stage ovarian cancer. Lymphadenectomy may improve progression-free survival but has demonstrated no impact on overall survival, except for clear cell ovarian cancer, where a potential survival benefit has been suggested in retrospective studies. Systematic lymphadenectomy retains a diagnostic role in identifying occult nodal metastases (9% to 30% across series) undetected on pre-operative imaging or intra-operative assessment. The decision to perform lymphadenectomy should be individualized based on several factors, including histological sub-type, tumor grade, stage, and biomarker profile. Key considerations include the anticipated risk of lymph node metastasis, the opportunity to tailor adjuvant treatment by either omitting chemotherapy or offering maintenance targeted therapy, peri-operative morbidity, long-term sequelae impacting quality of life (eg, lower limb lymphedema), and cost-effectiveness. Systematic lymphadenectomy is guideline-recommended for high-grade tumors, including high-grade serous, high-grade endometrioid, and clear cell histologies, whereas it can be omitted in low-grade endometrioid and expansile mucinous sub-types. Its significance in low-grade serous and infiltrative mucinous ovarian cancers remains unclear, although guidelines frequently advocate for lymphadenectomy in these cases. To optimize patient selection, large-scale prospective studies with proper stratification by histotype and molecular profile are required. Emerging approaches to lymph node assessment, such as sentinel lymph node biopsy, artificial intelligence-assisted pre-operative imaging, and liquid biopsy, hold promise for improving staging accuracy.

Hyperthermic Intraperitoneal Chemotherapy in Platinum-Sensitive Recurrent Ovarian Cancer: A Randomized Trial on Survival Evaluation (HORSE; MITO-18)

PURPOSE To investigate whether the addition of hyperthermic intraperitoneal chemotherapy (HIPEC) to secondary cytoreductive surgery (SCS) without neoadjuvant chemotherapy has a benefit on progression-free survival (PFS), as opposed to SCS alone in patients with platinum-sensitive recurrent epithelial ovarian cancer (platinum-free interval, >6 months). METHODS This was a multicenter randomized phase III study. Random assignment was performed at the time of surgery in cases with residual tumor ≤0.25 cm. HIPEC with cisplatin (CDDP) 75 mg/m 2 for 60 minutes at 41.5°C was administered at the end of surgery in the experimental arm. Both groups received postoperative platinum-based chemotherapy. The primary end point was PFS. The safety profile and postrecurrence survival (PRS) were the secondary end points. RESULTS A total of 167 patients underwent random assignment, 82 patients to SCS plus HIPEC (experimental arm) and 85 to SCS alone (control arm). The median follow-up was 83 months (IQR, 64-102). The median PFS was 23 months (95% CI, 17 to 29) in the group that underwent surgery alone and 25 months (95% CI, 18 to 32) in the group that underwent cytoreductive surgery with HIPEC. The probability of PRS at 5 years was 61.6% (95% CI, 50.8 to 72.4) in the SCS group and 75.9% (95% CI, 66.5 to 85.3) in the SCS plus HIPEC group. The incidence of postoperative adverse events of any grade was similar between the two groups. CONCLUSION The addition of HIPEC to complete or nearly complete primary SCS did not confer a benefit in terms of PFS in patients with platinum-sensitive peritoneal recurrence.

Measuring the impact of specific surgical complications after ovarian cancer cytoreductive surgery on short-term outcomes

Objective We sought to measure the impact of specific peri-operative complications after primary cytoreductive surgery on relevant patient outcomes and use of resources. Methods A cohort of patients with advanced ovarian cancer who underwent primary cytoreductive surgery at two institutions (2006–2016) were studied. Specific known complications (‘exposures’) within 30 days of surgery were evaluated to determine the impact on outcomes. Exposures included bowel leak, superficial surgical site infection, deep surgical site infection, venous thromboembolic event, and cardiac event. Outcomes were prolonged lengths of stay, readmission or non-home discharge, reoperation, organ failure, delay to adjuvant chemotherapy, and 90-day mortality. Population attributable risk (PAR) was used to estimate the proportion of adverse outcomes that could be prevented by elimination of a causal exposure and considers both the strength of the association and the prevalence of the complication; adjusted PARs (aPAR) were calculated using adjusted relative risks (aRR) adjusted for stage (IIIC vs IV) and American Society of Anesthesiology score (<3 vs ≥3). Results A cohort of 892 patients was included. Each of the evaluated exposures had an impact on readmission/non-home discharge (aPAR range 5.3 to 13.5). A venous thromboembolic event was significantly associated with 90-day mortality (aRR=2.9 (95% CI 1.3 to 6.7); aPAR=8.6 (95% CI −1.8 to 19.1)) and organ failure (aRR=4.7 (95% CI 2.3 to 9.5); aPAR=13.9 (95% CI 2.8 to 25.1)). Similarly, a cardiac event was most strongly associated with organ failure and was very impactful (aPAR=19.0 (95% CI 6.8 to 31.1)). Bowel leak was a major contributor to poor outcome, including reoperation (aPAR=45.5 (95% CI 34.3 to 56.6)), organ failure (aPAR=13.6 (95% CI 2.6 to 24.6)), readmission/non-home discharge (aPAR=5.3 (95% CI 1.6 to 9.0)), delay to adjuvant chemotherapy (aPAR=5.9 (95% CI 2.3 to 9.4)), and prolonged lengths of stay (aPAR=13.0 (95% CI 9.1 to 16.9)). Conclusion Going beyond reporting complications using common scales to measure their genuine impact provides important information for providers, patients, and payers. We report that less frequent exposures, including a venous thromboembolic event, cardiac events, and bowel leaks, have a high impact on patients and use of resources.

Primary versus interval cytoreductive surgery in patients with rare epithelial or non-epithelial ovarian cancer

The standard treatment for advanced epithelial ovarian cancer is primary cytoreductive surgery, with the goal of achieving no residual disease. Neoadjuvant chemotherapy and interval cytoreductive surgery can be viable treatment options for patients with extensive disease that precludes complete tumor removal during initial surgery, or when significant comorbidities increase the surgical risk without adversely impacting overall survival rates. However, published studies mostly included patients with high-grade serous ovarian cancer, with an underrepresentation of non-high-grade serous epithelial and non-epithelial cancers. This review aimed to provide an overview of the available data on the outcomes of primary cytoreductive surgery versus interval cytoreduction in patients with rare ovarian cancer histotypes. Published literature on primary versus interval cytoreductive surgery in non-high-grade serous ovarian cancers from 2004 to 2024 was searched using PubMed, EMBASE, and Google Scholar and reported for each histological subtype. The outcomes of patients with low-grade serous, endometrioid, clear-cell, and mucinous carcinomas after neoadjuvant chemotherapy were reviewed. Furthermore, the results following neoadjuvant chemotherapy in non-epithelial ovarian cancers, such as ovarian germ cell tumors, sex cord-stromal tumors, and small-cell carcinoma of the ovary, have also been reported. Most data were derived from retrospective studies, with heterogeneity in design. Several ovarian cancer histotypes, including low-grade serous and mucinous carcinomas, may be less responsive than high-grade serous carcinomas to neoadjuvant chemotherapy. Consequently, primary cytoreduction with maximal surgical effort may confer a survival advantage. Other tumors responded well to neoadjuvant chemotherapy, allowing for interval fertility-sparing surgeries. Additional evidence is required because no prospective studies are currently available. Given the low incidence of these diseases, randomized controlled trials may not be feasible. However, national or international registries could play a pivotal role in determining the optimal approach for managing patients with these rare histotypes.

Clinicopathological characteristics of multiple-classifier endometrial cancers: a cohort study and systematic review

Endometrial cancers with more than one molecular feature- To describe our cohort of multiple classifiers and to report the results of a review on their incidence and the techniques used to identify them. Multiple classifiers identified at the European Institute of Oncology, Milan, between April 2019 and Decmber 2022, were included. Clinicopathological, molecular characteristics, and oncologic outcomes were summarized and compared between single and multiple classifiers sharing common features. Studies on molecular classification of endometrial cancer were searched in the PubMed Database to collect data on the incidence of multiple classifiers and the techniques used for classification. Among 422 patients, 48 (11.4%) were multiple classifiers: 15 (3.6%) POLEmut-p53abn, 2 (0.5%) POLEmut-MMRd, 28 (6.6%) MMRd-p53abn, and 3 (0.7%) POLEmut-MMRd-p53abn. MMRd-p53abn and MMRd differed in histotype (non-endometrioid: 14.8% vs 2.0%, p=0.006), grade (high-grade: 55.6% vs 22.2%, p=0.001), and MMR proteins expression, whereas they differed from p53abn in histotype (non-endometrioid: 14.8% vs 50.0%, p=0.006). POLEmut-p53abn and POLEmut differed only in grade (high-grade: 66.7% vs 22.7%, p=0.008), while they differed from p53abn in age (56.1 vs 66.7 years, p=0.003), stage (advanced: 6.7% vs 53.4%, p=0.001), and histotype (non-endometrioid: 6.7% vs 50.0%, p=0.002). Two (7.1%) patients with MMRd-p53abn, 4 (4.0%) with MMRd, and 25 (34.3%) with p53abn had a recurrence. No recurrences were observed in POLEmut-p53abn and POLEmut. The characteristics of POLEmut-p53abn resembled those of POLEmut, whereas MMRd-p53abn appeared to be intermediate between MMRd and p53abn. The high proportion of multiple classifiers may be related to the methods used for molecular classification, which included both p53 immunohistochemistry and

The prognostic impact of molecular classification in endometrial cancer that undergoes fertility-sparing treatment

No biomarkers are available to predict treatment response in patients with endometrial cancers who undergo fertility-sparing treatment. Therefore, we aimed to evaluate the prognostic role of molecular classification. Patients with endometrial cancer who underwent fertility-sparing treatment with progestins between 2005 and 2021 were retrospectively identified. Polymerase epsilon (POLE), TP53/p53, and mismatch repair (MMR) proteins were assessed to assign patients to molecular groups: POLE mutated (POLEmut), MMR deficient (MMRd), no specific molecular profile (NSMP), and p53 abnormal (p53abn). Treatment response was classified as complete, partial, stable disease, or progressive. Response at 6 months, best response, and recurrence after complete response were evaluated by molecular class. In total, 33 patients were assigned to a molecular class and included in the analysis. Molecular testing detected 3 POLEmut (9%), 3 MMRd (9%), 25 NSMP (76%), and 2 p53abn (6%); 0 of 3 POLEmut (0%), 0 of 3 MMRd (0%), 6 of 25 NSMP (24%), and 1 of 2 p53abn (50%) achieved complete response within 6 months. In terms of best response during the entire treatment period, 2 of 3 POLEmut (67%), 2 of 3 MMRd (67%), 18 of 25 NSMP (72%), and 1 of 2 p53abn (50%) showed complete response. After complete response was achieved, 1 of 2 POLEmut (50%), 2 of 2 MMRd (100%), 14 of 18 NSMP (78%), and 0 of 1 p53abn (0%) had a recurrence. Although the small number of patients limits our findings, a lower proportion of MMRd responded to progestins than of NSMP.

Incidence of sentinel lymph node metastases in apparent early-stage endometrial cancer: a multicenter observational study

Ultrastaging is accurate in detecting nodal metastases, but increases costs and may not be necessary in certain low-risk subgroups. In this study we examined the risk of nodal involvement detected by sentinel lymph node (SLN) biopsy in a large population of apparent early-stage endometrial cancer and stratified by histopathologic characteristics. Furthermore, we aimed to identify a subgroup in which ultrastaging may be omitted. We retrospectively included patients who underwent SLN (with bilateral mapping and no empty nodal packets on final pathology) ± systematic lymphadenectomy for apparent early-stage endometrial cancer at two referral cancer centers. Lymph node status was determined by SLN only, regardless of non-SLN findings. The incidence of macrometastasis, micrometastasis, and isolated tumor cells (ITC) was measured in the overall population and after stratification by histotype (endometrioid vs serous), myometrial invasion (none, <50%, ≥50%), and grade (G1, G2, G3). Bilateral SLN mapping was accomplished in 1570 patients: 1359 endometrioid and 211 non-endometrioid, of which 117 were serous. The incidence of macrometastasis, micrometastasis, and ITC was 3.8%, 3.4%, and 4.8%, respectively. In patients with endometrioid histology (n=1359) there were 2.9% macrometastases, 3.2% micrometastases, and 5.3% ITC. No macro/micrometastases and only one ITC were found in a subset of 274 patients with low-grade (G1-G2) endometrioid endometrial cancer without myometrial invasion (all <1%). The incidence of micro/macrometastasis was higher, 2.8%, in 708 patients with low-grade endometrioid endometrial cancer invading <50% of the myometrium. In patients with serous histology (n=117), the incidence of macrometastases, micrometastasis, and ITC was 11.1%, 6.0%, and 1.7%, respectively. For serous carcinoma without myometrial invasion (n=36), two patients had micrometastases for an incidence of 5.6%. Ultrastaging may be safely omitted in patients with low-grade endometrioid endometrial cancer without myometrial invasion. No other subgroups with a risk of nodal metastasis of less than 1% have been identified.

Predictors of recurrence in early-stage cervical cancer without adjuvant treatment after radical surgery

The role of adjuvant radiotherapy after radical surgery for early-stage cervical cancer is controversial in the absence of high-risk factors. This study aimed to evaluate predictors of recurrence in patients with early-stage cervical cancer undergoing observation after radical surgery. Patients with FIGO 2018 stage I cervical cancer who underwent radical surgery without adjuvant therapy at the European Institute of Oncology, IEO (Milan, Italy) between 2010 and 2023 were retrospectively identified. Patients with high-risk factors for recurrence (positive margins, parametria, or lymph nodes) were excluded. Recurrence-free survival following surgery was estimated using the Kaplan-Meier method. Log-rank test and Cox regression analyses were performed to assess predictors of recurrence. A total of 340 patients were identified: 7 (2.0 %) stage IA1, 31 (9.1 %) IA2, 191 (56.2 %) IB1, 108 (31.8 %) IB2, and 3 (0.9 %) IB3. Twenty-two (6.5 %) patients had a recurrence. The estimated 5-year recurrence-free survival for the overall cohort was 93.5 % (95 % CI, 89.9-95.8). On multivariate analysis, factors associated with a higher risk of recurrence included tumor size ≥2 cm (HR 3.04, 95 % CI 1.26-7.35; p = 0.01) and grade 3 (HR 2.76, 95 % CI 1.1-6.9; p = 0.03). In the absence of high-risk factors, the risk of recurrence in patients with early-stage cervical cancer who did not receive adjuvant treatment after radical surgery was low overall. Patients with individual risk factors such as tumor size ≥2 cm or tumor grade 3 may be at higher risk of recurrence. Further research is warranted to redefine risk groups and tailor adjuvant treatment based on timely clinicopathological risk factors.

External validation of the annual recurrence risk model for tailored surveillance strategy in patients with cervical cancer

The annual recurrence risk model (ARRM), developed by the Surveillance in Cervical Cancer consortium and endorsed by the European Society of Gynecological Oncology, predicts the annual risk of cervical cancer recurrence. However, it lacks an external validation, which we aimed to address in the current retrospective study. We included patients with pathology confirmed T1a to T2b cervical cancers who underwent radical surgery at the European Institute of Oncology, Milan from January 2010 to December 2022. Using the ARRM risk calculator, patients were assigned a score from 0 to 100 points, which allowed classification into 5 risk groups (0, 1-25, 26-50, 51-75, and 76-100 points). Differences in 5-year disease-free survival were evaluated through log-rank tests with pairwise comparisons. Annual risk of recurrence was calculated using conditional survival analysis. Overall, 411 patients with cervical cancers were included: 0 (0.0%) scored 0 points, 149 (36.3%) scored 1 to 25 points, 224 (54.5%) scored 26 to 50 points, 37 (9.0%) scored 51 to 75 points, and 1 (0.2%) scored 76 to 100 points. The patient from 76 to 100 points was excluded from further analyses. The 5-year disease-free survival rates were 96.3% (95% CI 90.0 to 98.6), 85.7% (95% CI 80.1% to 89.9%), and 66.6% (95% CI 47.3% to 80.2%) in groups 1 to 25, 26 to 50, and 51 to 75 points, respectively (p < .01). Compared with 26 to 50 and 51 to 75 points, the annual risk of recurrence was lower in the 1 to 25 points group, at around 1% from year 1 to 5. The ARRM tool confirmed its validity in stratifying cervical cancer into groups with significantly different disease-free survival rates in an independent large population from a tertiary center. The annual risk of recurrence should be carefully considered when tailoring follow-up, always taking into account the patient's perspective.

Para-aortic lymph node recurrence in surgically treated early-stage cervical cancer without para-aortic lymph node surgical staging

The standard treatment for early-stage cervical cancer includes radical hysterectomy with pelvic lymph node staging ± bilateral salpingo-oophorectomy. Para-aortic lymphadenectomy may be considered; however, its role remains controversial. The objective of this study was to assess the para-aortic lymph node recurrence rate in patients undergoing surgery for apparent early-stage cervical cancer without para-aortic lymph node surgical staging. This is a retrospective cohort study including all consecutive patients with presumed early-stage (International Federation of Gynecology and Obstetrics (FIGO) 2018 IA1-IB2, IIA1) cervical cancer who underwent radical surgery at the European Institute of Oncology, Milan, Italy. Pelvic lymph node assessment included sentinel lymph node biopsy and/or systematic pelvic lymphadenectomy. Patients who underwent para-aortic lymphadenectomy or had an indication to receive adjuvant para-aortic radiotherapy were excluded. The Kaplan-Meier method was used to estimate 5-year recurrence-free survival. Overall, 432 patients were included. The median age was 43.7 years (IQR 38.1-51.6). Sixteen (3.7%) patients were staged IA1 at diagnosis, 24 (5.6%) IA2, 208 (48.1%) IB1, 177 (41%) IB2, and 7 (1.6%) IIA1. At final pathology, the stage distribution was as follows: 36 (8.3%) stage IA1-IA2, 323 (74.8%) stage IB1-IB3, 17 (3.9%) stage II, and 56 (13%) stage IIIC1. Eighty-two patients (19%) underwent concurrent pelvic chemoradiotherapy, 20 (4.6%) radiotherapy alone, and 3 (0.7%) chemotherapy alone. Thirty-eight (8.8%) patients experienced a recurrence with a median time of 18 months (IQR 12-29). The median follow-up time for the remaining 394 (91.2%) patients was 70 months (IQR 36-98). Two patients (0.5%) had a recurrence in the para-aortic lymph nodes. The 5-year recurrence-free survival in the overall cohort was 90% (95% CI 87.4% to 93.3%). Given the low rate of para-aortic lymph node recurrence in surgically treated early-stage cervical cancer and the well-established peri-operative complications associated with para-aortic lymphadenectomy, our study aligns with recent evidence supporting the omission of this procedure in such patients.

Evaluation of perioperative management of advanced ovarian (tubal/peritoneal) cancer patients: a survey from MITO-MaNGO Groups

The European Society of Gynaecological Oncology (ESGO)-quality indicators (QIs) for advanced ovarian cancer (AOC) have been assessed only by few Italian centers, and data are not available on the proportion of centers reaching the score considered for a satisfactory surgical management. There is great consensus that the Enhanced Recovery After Surgery (ERAS) approach is beneficial, but there is paucity of data concerning its application in AOC. This survey was aimed at gathering detailed information on perioperative management of AOC patients within MITO-MaNGO Groups. A 66-item questionnaire, covering ESGO-QIs for AOC and ERAS items, was sent to MITO/MaNGO centers reporting to operate >20 AOC/year. Thirty/34 questionnaires were analyzed. The median ESGO-QIs score was 31.5, with 50% of centers resulting with a score ≥32 which provides satisfactory surgical management. The rates of concordance with ERAS guidelines were 46.6%, 74.1%, and 60.7%, respectively, for pre-operative, intra-operative, and post-operative items. The proportion of overall agreement was 61.3%, and with strong recommendations was 63.1%. Pre-operative diet, fasting/bowel preparation, correction of anaemia, post-operative feeding and early mobilization were the most controversial. A significant positive correlation was found between ESGO-QIs score and adherence to ERAS recommendations. This survey reveals a satisfactory surgical management in only half of the centers, and an at least sufficient adherence to ERAS recommendations. Higher the ESGO-QIs score stronger the adherence to ERAS recommendations, underlining the correlations between case volume, appropriate peri-operative management and quality of surgery. The present study is a first step to build a structured platform for harmonization within MITO-MaNGO networks.

Multimodal treatment for resectable neuroendocrine carcinoma of the cervix

Non-metastatic neuroendocrine carcinoma of the cervix (NECC) is a rare and aggressive disease. Lacking prospective studies, the optimal multimodal treatment approach has not yet been clearly defined. This study aims to assess the clinical outcomes of patients with non-metastatic NECC treated with surgery and (neo)adjuvant chemotherapy, according to pathologic prognostic factors and multimodal treatments received. We retrospectively examined data from patients with non-metastatic NECC candidate to receive surgery and (neo)adjuvant chemotherapy and discussed at the European Institute of Oncology’s Multidisciplinary Neuroendocrine Tumor Board, between January 2003 and December 2021. Primary endpoints were event-free survival and overall survival. A total of 27 consecutive patients were evaluated, 15 with early stage NECC and 12 with a locally advanced NECC. Eight patients received neoadjuvant and 19 adjuvant platinum-based chemotherapy; 14 received adjuvant pelvic radiotherapy, half with external-beam radiation therapy alone, and half combined with brachytherapy. No patients progressed or relapsed during (neo)adjuvant chemotherapy. The median event-free survival was 21.1 months and the median overall survival was 33.0 months. Pathological FIGO stage ≥ IIB, adjuvant external-beam radiation therapy with or without brachytherapy emerged as significant and independent prognostic factors for event-free survival. Brachytherapy was also prognostic for overall survival. Non-metastatic NECC requires a multimodal approach, mainly weighted on the FIGO stage. The addition of brachytherapy should be considered, especially in patients with locally advanced disease. Because of the scarcity of robust clinical data, treatment strategy should be discussed in multidisciplinary board, taking into account patient.

Hyperthermic Intra-peritoneal Chemotherapy (HIPEC) in Ovarian Cancer Recurrence

The purpose of this study is to determine the role of surgery followed by hyperthermic intra-peritoneal chemotherapy (HIPEC) versus surgery alone in patients with platinum-sensitive first recurrence of ovarian cancer. Moreover it is a prospective randomized multicenter trial, aimed to investigate the prognostic role of surgery plus HIPEC versus surgery alone in terms of progression free interval, overall survival, morbidity and mortality, second recurrence pattern, quality of life with EORTC QLQ-C30 and QLQ OV28 questionnaires.