Incidence, treatment, and survival trends in older versus younger women with epithelial ovarian cancer from 2005 to 2018: A nationwide Danish study.

OBJECTIVE: To examine clinical trends in Denmark for younger and older epithelial ovarian cancer (EOC) patients, focusing on incidence, treatment, and survival changes. METHODS: We included a nationwide cohort diagnosed with EOC from 2005 to 2018. We described age-standardized incidence, surgical patterns, residual disease trends, and cancer-specific survival stratified by age (<70 and ≥ 70 years), stage, and period (2005-09, 2010-13, 2014-18). RESULTS: We included 7522 patients. The incidence decreased from 16.3 (2005) to 11.4 (2018) per 100,000 woman-years, driven by the younger cohort. While the proportion of patients with stage IIIC-IV disease undergoing primary debulking surgery (PDS) decreased, the proportion of patients having interval debulking surgery (IDS) and no debulking surgery increased significantly. In 2014-18, 36% and 24% had PDS for younger and older patients, respectively, compared to 72% and 62% in 2005-09. In both age cohorts, the proportion of patients debulked to no residual disease increased significantly among patients with stage IIIC-IV and in the total cohort. Two-year cancer-specific survival increased from 75% (2005-09) to 84% (2014-18) for younger patients and from 53% to 66% for older patients. After adjusting for potential confounders, age ≥ 70 was associated with a 1.4-fold increased risk of cancer-specific death (95% confidence interval: 1.2,1.5). CONCLUSIONS: The proportion of patients with advanced EOC not undergoing PDS or IDS increased significantly. During the same period, patients debulked to no residual disease, and cancer-specific survival increased. However, a survival gap in favor of the younger patients remains after adjusting for potential confounders.

Adoption of minimally invasive surgery after neoadjuvant chemotherapy in women with metastatic uterine cancer.

OBJECTIVE: Utilization of neoadjuvant chemotherapy (NACT) for advanced stage uterine cancer is increasing. We analyzed the use and outcomes of open versus minimally invasive surgery (MIS) for women with stage IV uterine cancer who received NACT and underwent IDS. METHODS: The National Cancer Database was used to identify women with stage IV uterine cancer diagnosed from 2010 to 2017 and treated with NACT. Among women who underwent IDS, overall survival (OS) was compared between those who underwent laparotomy vs a minimally invasive approach. To account for imbalances in confounders, a propensity score analysis using inverse probability of treatment weighting (IPTW) was performed. RESULTS: A total of 1618 women were identified. Minimally invasive IDS was performed in 31.1% and increased from 16.2% in 2010 to 40.4% in 2017 (P < 0.001). More recent year of diagnosis and performance of surgery at a comprehensive cancer center were associated with increased use of MIS (P < 0.05). Women with serous and clear cell tumors, and carcinosarcomas (compared to endometrioid tumors), as well as Medicaid coverage (compared to commercial insurance) were less likely to undergo an MIS approach (P < 0.05). The median OS was 28 months (95% CI 23.7-30.7) and 24.3 months (95% CI 22.3-26.1) for MIS and laparotomy, respectively. After propensity score balancing, there was no association between the use of MIS and survival (HR = 0.90, 95% CI 0.71-1.14). CONCLUSIONS: Among women with stage IV uterine cancer treated with NACT performance of minimally invasive debulking surgery is increasing. Compared to laparotomy, MIS does not appear to negatively impact survival.

Trends in extent of surgical cytoreduction for patients with ovarian cancer.

PURPOSE: To identify patient and hospital characteristics associated with extended surgical cytoreduction in the treatment of ovarian cancer. METHODS: A retrospective analysis using the National Inpatient Sample (NIS) database identified women hospitalized for surgery to remove an ovarian malignancy between 2013 and 2017. Extended cytoreduction (ECR) was defined as surgery involving the bowel, liver, diaphragm, bladder, stomach, or spleen. Chi-square and logistic regression were used to analyze patient and hospital demographics related to ECR, and trends were assessed using the Cochran-Armitage test. RESULTS: Of the estimated 79,400 patients undergoing ovarian cancer surgery, 22% received ECR. Decreased adjusted odds of ECR were found in patients with lower Elixhauser Comorbidity Index (ECI) scores (OR 0.61, p<0.001 for ECI 2, versus ECI≥3) or residence outside the top income quartile (OR 0.71, p<0.001 for Q1, versus Q4), and increased odds were seen at hospitals with high ovarian cancer surgical volume (OR 1.25, p<0.001, versus low volume). From 2013 to 2017, there was a decrease in the proportion of cases with extended procedures (19% to 15%, p<0.001). There were significant decreases in the proportion of cases with small bowel, colon, and rectosigmoid resections (p<0.001). Patients who underwent ECR were more likely treated at a high surgical volume hospital (37% vs 31%, p<0.001) over the study period. For their hospital admission, patients who underwent ECR had increased mortality (1.6% vs. 0.5%, p<0.001), length of stay (9.6 days vs. 5.2 days, p<0.001), and mean cost ($32,132 vs. $17,363, p<0.001). CONCLUSIONS: Likelihood of ECR was associated with increased medical comorbidity complexity, higher income, and undergoing the procedure at high surgical volume hospitals. The proportion of ovarian cancer cases with ECR has decreased from 2013-17, with more cases performed at high surgical volume hospitals.

The changing landscape of systemic therapy in metastatic renal cell carcinoma: an update.

Treatment options for metastatic renal cell carcinoma (RCC) continue to expand. Three recent phase III trials, Checkmate 214, Keynote-426, and Javelin Renal 101, have led to FDA approval of three new regimens for patients with clear cell RCC: nivolumab plus ipilimumab, pembrolizumab plus axitinib, and avelumab plus axitinib, respectively. At the same time, the dearth of treatment options for non-clear cell RCC has changed very little. The role of cytoreductive nephrectomy has also come into question after the publication of the CARMENA and SURTIME trials. This review will examine recent changes in therapeutic options in clear cell RCC and non-clear RCC, and the role of surgery in the treatment of metastatic RCC.

Is ovarian cancer surgery stuck in the dark ages?: a commentary piece reviewing surgical technologies.

Ovarian cancer surgery endeavours to remove all visible tumour deposits, and surgical technologies could potentially facilitate this aim. However, there appear to be barriers around the adoption of new technologies, and we hope this article provokes discussion within the specialty to encourage a forward-thinking approach to new-age surgical gynaecological oncology.

National trends in bowel and upper abdominal procedures in ovarian cancer surgery.

OBJECTIVES: In the United States, trends in the initial treatment approach for ovarian cancer reflect a shift in paradigm toward the increased use of neoadjuvant chemotherapy and interval cytoreductive surgery. The aim of this study was to evaluate the trends in surgical cytoreductive procedures in ovarian cancer patients who underwent either primary or interval cytoreductive surgery. METHODS: This retrospective, population-based study examined patients with stage III/IV ovarian cancer diagnosed between January 2000 and December 2013 identified using SEER-Medicare. Small or large bowel resection, ostomy creation, and upper abdominal procedures were identified using relevant billing codes and compared over time. A 1:1 primary and interval cytoreductive propensity matched cohort was created using demographic and clinical variables. 30-day complications and the use of acute care services were compared. RESULTS: A total of 5417 women were identified. 34% underwent bowel resections, 16% ostomy creation, and 8% upper abdominal procedures. There was an increase in bowel resections and upper abdominal procedures from 2000 to 2013 in patients who underwent primary cytoreductive surgery. Compared with patients who received primary cytoreduction, patients who underwent interval cytoreductive surgery were less likely to undergo bowel resection (OR=0.50; 95% CI [0.41, 0.61]) or ostomy creation (OR=0.48; 95% CI [0.42, 0.56]). Upper abdominal procedures did not differ between groups. For patients who underwent primary cytoreductive surgery, these procedures were associated with intensive care unit stay (4.6% vs <2%, P<0.01). In both primary and interval cytoreductive surgery patients, the receipt of bowel and upper abdominal procedures was associated with multiple 30-day postoperative complications and higher rates of readmission and emergency room visits. CONCLUSIONS: The performance of upper abdominal procedures in ovarian cancer patients increased from 2000 to 2013. Interval cytoreductive surgery was associated with decreased likelihood of bowel surgery. In matched primary and interval cytoreductive surgery cohorts, the receipt of these procedures were associated with the increased likelihood of postoperative complications and use of acute care services.

Trends in the surgical management of malignant ovarian germcell tumors.

OBJECTIVE: To evaluate trends in the surgical management of young women and pediatric patients with malignant ovarian germ cell tumors (MOGCTs) and associated survival outcomes. MATERIALS AND METHODS: Using the Surveillance, Epidemiology, and End Results database we identified patients under 40 years who underwent surgery between 1994 and 2014. The Joinpoint Regression Program was employed to investigate the presence of temporal trends and calculate average annual percent change (AAPC) rates. For analysis purposes two age groups were formed; pediatric/adolescent (≤21 yrs) and young adult (22-40 yrs). Histology was categorized into dysgerminoma, immature teratoma, yolk-sac tumor, mixed germ cell tumor and other histology. Cancer specific survival was compared using log-rank tests. RESULTS: A total of 2238 patients were identified, with median age 21 years. Only 12.4% underwent hysterectomy. One third underwent omentectomy, and one half underwent lymphadenectomy (LND). A decrease in the rate of omentectomy (AAPC: -2.15, 95% CI: -3.4, -0.9) and hysterectomy (AAPC: -3.31, 95% CI: -6.1, -0.4) was observed. There was no change in the rate of LND (AAPC: 0.17, 95% CI: -0.7, 1.1). Pediatric patients were less likely to undergo omentectomy (30.2% vs 35.5%, p < 0.001), hysterectomy (3.5% vs 22%, p < 0.001) and LND (45.6% vs 54.7%, p < 0.001). There were no apparent survival differences according to the performance of hysterectomy, omentectomy or LND, when stratified by early (stage I) and advanced stage (II-IV), (p > 0.05). CONCLUSIONS: Pediatric patients with MOGCTs undergo less extensive surgical staging. A trend towards less extensive surgical procedures for young women over time was observed, without an apparent detrimental effect on cancer specific survival.

Trends in the indications for and short-term outcomes of cytoreductive surgery with hyperthermic intraperitoneal chemotherapy.

BACKGROUND: Cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC) is an increasingly utilized strategy for patients with peritoneal surface malignancies (PSM). METHODS: The US HIPEC Collaborative was retrospectively reviewed to compare the indications and perioperative outcomes of patients who underwent CRS ±â€¯HIPEC between 2000 and 2012 (P1) versus 2013-2017 (P2). RESULTS: Among 2,364 patients, 39% were from P1 and 61% from P2. The most common primary site was appendiceal (64%) while the median PCI was 13 and most patients had CCR 0 (60%) or 1 (25%). Over time, median estimated blood loss, need for transfusion, and length of hospital stay decreased. While the incidence of any (55% vs. 57%; p = 0.426) and Clavien III/IV complications did not change over time, there was a decrease in 90-day mortality (5% vs. 3%; p = 0.045). CONCLUSION: CRS-HIPEC is increasingly performed for PSM at high-volume centers. Despite improvements in some perioperative outcomes and a reduction in postoperative mortality, morbidity rates remain high.

Utilization and Treatment Patterns of Cytoreduction Surgery and Intraperitoneal Chemotherapy in the United States.

INTRODUCTION: Cytoreductive surgery (CRS) and intraperitoneal chemotherapy (IPC) is an effective treatment option for selected patients with peritoneal metastases (PM), but national utilization patterns are poorly understood. The objectives of this study were to (1) describe population-based trends in national utilization of CRS/IPC; (2) define the most common indications for the procedure; and (3) characterize the types of hospitals performing the procedure. METHODS: The National Inpatient Sample (NIS) was used to identify patients from 2006 to 2015 who underwent CRS/IPC, and to calculate national estimates of procedural frequency and oncologic indication. Hospitals performing CRS/IPC were classified based on size and teaching status. RESULTS: The estimated annual number of CRS/IPC cases increased significantly from 189 to 1540 (p < 0.001). Overall, appendiceal cancer was the most common indication (25.7%), followed by ovarian cancer (23.3%), colorectal cancer (22.5%), and unspecified PM (15.0%). Remaining cases (13.5%) were performed for other indications. Most cases were performed in large teaching hospitals (65.9%), compared with smaller teaching hospitals (25.1%), large non-teaching hospitals (5.3%), or small non-teaching hospitals (3.2%). Patients were more likely to undergo CRS/IPC without a diagnosis based on level I evidence (appendiceal, ovarian, or colorectal) at large non-academic hospitals (odds ratio 2.00, 95% confidence interval 1.18-3.38, p = 0.010) compared with large academic hospitals. CONCLUSIONS: Utilization of CRS/IPC is increasing steadily in the US, is performed at many types of facilities, and often for a variety of indications that are not supported by high-level evidence. Given associated morbidity of CRS/IPC, a national registry dedicated to cases of IPC is necessary to further evaluate use and outcomes.

Association of trainee involvement in an acute pain service with postoperative opioid use in patients undergoing cytoreductive surgery with hyperthermic intraperitoneal chemotherapy.

BACKGROUND: Several hospitals have implemented a multidisciplinary Acute Pain Service (APS) to execute surgery-specific opioid sparing analgesic pathways. Implementation of an anesthesia attending-only APS has been associated with decreased postoperative opioid consumption, time to ambulation, and time to solid food intake for patients undergoing cytoreductive surgery with hyperthermic intraperitoneal chemotherapy. In this study, we evaluated the impact of introducing an APS trainee on postoperative opioid consumption in patients undergoing hyperthermic intraperitoneal chemotherapy during POD 0-3. METHODS: We performed a retrospective propensity-matched cohort study where we compared opioid consumption and hospital length of stay among two historical cohorts: attending-only APS service versus service involving a regional anesthesia fellow. RESULTS: In the matched cohorts, the median postoperative day (POD) 0-3 opioid use [25%, 75% quartile] for the single attending and trainee involvement cohort were 38.5 mg morphine equivalents (MEQ) [14.1 mg, 106.3 mg] and 50.4 mg MEQ [28.4 mg, 91.2 mg], respectively. The median difference was -9.8 mg MEQ (95% CI -30.7-16.5 mg; P = 0.43). There was no difference in hospital length of stay between both cohorts (P = 0.67). CONCLUSIONS: We found that the addition of a regional anesthesia fellow to the APS team was not associated with statistically significant differences in total opioid consumption or hospital length of stay in this surgical population. The addition of trainees to the infrastructure, with vigilant supervision, is not associated with change in outcomes.

The evolving role of cytoreductive nephrectomy: incorporating genomics of metastatic renal cell carcinoma into treatment decisions.

PURPOSE OF REVIEW: Recent publications evaluating cytoreductive nephrectomy in the era of targeted therapy emphasize the importance of patient selection. We reviewed the predictive role of genetic alterations in patients with metastatic renal cell carcinoma (mRCC) undergoing cytoreductive nephrectomy. RECENT FINDINGS: Studies evaluating the association between genetic alterations and outcomes following systemic treatment for mRCC include mainly patients after cytoreductive nephrectomy. Expression of proangiogenic genes, single nucleotide polymorphisms involving genes of the vascular-endothelial growth factor (VEGF) pathway and somatic mutations of chromatin remodeling genes were associated with response to VEGF-targeted therapy. Outcomes following treatment with mammalian target of rapamycin (mTOR) inhibitors were initially associated with mTOR/TSC1/TSC2 mutations; however, subsequent studies did not validate these findings but rather found an association between loss of PTEN expression and PBRM1 mutations and improved outcomes. Loss of PBRM1 was initially linked to response to immunotherapy; however, larger studies question this association and showed high expression of T-effector gene signature predicted improved outcome. Primary tumors with low intratumor heterogeneity but elevated somatic copy-number alterations were associated with rapid progression at multiple sites. SUMMARY: Genetic alterations may help select patients for cytoreductive nephrectomy and optimize timing of treatment. Intratumor heterogeneity and genetic discordance between primary and metastatic tumors may limit clinical applicability. Future studies should evaluate approaches to overcome these limitations.

Evolving role of cytoreductive nephrectomy in metastatic renal cell carcinoma of variant histology.

PURPOSE OF REVIEW: Summarize current evidence for cytoreductive nephrectomy in patients with metastatic renal cell carcinoma (mRCC) of variant histology. RECENT FINDINGS: The mainstream treatment for advanced malignancy is systematic therapy, including chemotherapy, targeted therapy, and immunotherapy. Nonetheless, cytoreductive nephrectomy has been used in the management of mRCC including variant (nonclear cell) histology. Prospective data supported cytoreductive nephrectomy for clear cell mRCC in the cytokine immunotherapy era in the late 1990s. In the targeted therapy era, the practice of cytoreductive nephrectomy in nonclear and clear cell histology had been largely based on retrospective data, but a recent phase III trial showed that targeted therapy alone is noninferior to targeted therapy combined with cytoreductive nephrectomy, therefore, questioning the clinical benefit of cytoreductive nephrectomy in this context. However, this trial had excluded patient with nonclear cell histology. With the potential for checkpoint inhibitor combinations to achieve long-term complete durable response, cytoreductive nephrectomy is a subject of ongoing debate especially, in nonclear cell histology as those were excluded from prospective trials. SUMMARY: Data are very sparse in nonclear histology. Although retrospective data favor the use of cytoreductive nephrectomy in nonclear cell mRCC, clinicians must carefully select patients and balance risks of surgery and delayed systemic therapy.

Is cytoreductive nephrectomy relevant in the immunotherapy era?

PURPOSE OF REVIEW: The recent approval of immune checkpoint inhibitors (ICI) revolutionized the treatment paradigm for metastatic renal cell carcinoma (mRCC). However, the role of cytoreductive nephrectomy is not well defined in this setting. Here, we review the contemporary role and timing of cytoreductive nephrectomy for advanced RCC in the era of immunotherapy. RECENT FINDINGS: Evidence concerning combination systemic therapy and cytoreductive nephrectomy in the multimodal management of mRCC is primarily limited to studies conducted in the targeted therapy era. The oncologic role of cytoreductive nephrectomy in the setting of ICI remains largely undefined and is supported primarily by case reports. Nonetheless, patient selection for cytoreductive nephrectomy is paramount, and appropriate candidacy in the ICI era will likely be refined as increasing evidence emerges. Until then, a cautious balance between perceived oncologic benefit and risks of intervention must be exercised. Several trials are ongoing to help shed light on patient selection, technical feasibility, and optimal timing of cytoreductive nephrectomy in the immunotherapy era. SUMMARY: Although the role and timing for cytoreductive nephrectomy remain to be further elucidated in the immunotherapy era, patient selection remains critical for treatment planning. Further studies are urgently needed to better define the role of cytoreductive nephrectomy in this setting.

The evolving role of cytoreductive nephrectomy in metastatic renal cell carcinoma.

PURPOSE OF REVIEW: To review the evidence related to cytoreductive nephrectomy in metastatic renal cell carcinoma (mRCC) treated in the targeted therapy era, with a focus on observational studies and randomized trials. RECENT FINDINGS: A number of retrospective observational studies exploring the role of cytoreductive nephrectomy have been reported. These have suggested an association between cytoreductive nephrectomy and survival, with hazard ratio estimates ranging from 0.39 to 0.68 in favour of cytoreductive nephrectomy. In contrast, the CARMENA randomized trial demonstrated that sunitinib alone was noninferior to cytoreductive nephrectomy followed by sunitinib in intermediate-risk and poor-risk patients. The results of the SURTIME trial suggest that initial sunitinib followed by a deferred cytoreductive nephrectomy may also be a reasonable approach in select patients. SUMMARY: On the basis of the evidence to date, there is still a role for cytoreductive nephrectomy in the multimodality treatment of mRCC. Careful patient selection is of paramount importance and discussion in multidisciplinary tumour boards is encouraged. As the treatment landscape of mRCC continues to change, the role of cytoreductive nephrectomy in the modern immuno-oncology era will need to be explored.

Ovarian Cancer Maintenance: Practice-Changing Data Calls for Changing Practice.

Staying current on the rapidly evolving therapeutic landscape in oncology is challenging for clinicians. This commentary discusses exciting practice­changing data specific to ovarian cancer.

Continuous improvement in primary Debulking surgery for advanced ovarian cancer: Do increased complete gross resection rates independently lead to increased progression-free and overall survival?

OBJECTIVES: To assess complete gross resection (CGR) rates and survival outcomes in patients with advanced ovarian cancer who underwent primary debulking surgery (PDS) during a 13-year period in which specific changes to surgical paradigm were implemented. METHODS: We identified all patients with stage IIIB-IV high-grade ovarian carcinoma who underwent PDS at our institution, with the intent of maximal cytoreduction, from 1/2001-12/2013. Patients were categorized by year of PDS based on the implementation of surgical changes to our approach to ovarian cancer debulking (Group 1, 2001-2005; Group 2, 2006-2009; Group 3, 2010-2013). RESULTS: Among 978 patients, 78% had stage IIIC disease and 89% had disease of serous histology. Carcinomatosis was found in 81%, and 60% had bulky upper abdominal disease (UAD). Compared to Group 1, those who underwent PDS during the latter 2 time periods had higher ASA scores (p < 0.001), higher-stage disease (p < 0.001), and more often had carcinomatosis (p = 0.015) and bulky UAD (p = 0.009). CGR rates for Groups 1-3 increased from 29% to 40% to 55%, respectively (p < 0.001). Five-year progression-free survival (PFS) rates increased over time (15%, 16%, and 20%, respectively; p = 0.199), as did 5-year overall survival (OS) rates (40%, 44%, and 56%, respectively; p < 0.001). On multivariable analysis, CGR was independently associated with PFS (p < 0.001) and OS (p < 0.001). CONCLUSIONS: Despite higher-stage disease and greater tumor burden, CGR rates, PFS and OS for patients who underwent PDS increased over a 13-year period. Surgical paradigm shifts implemented specifically to achieve more complete surgical cytoreduction are likely the reason for these improvements.