Is routine admission to a critical care setting following hyperthermic intraperitoneal chemotherapy for ovarian cancer necessary?

INTRODUCTION: Hyperthermic intraperitoneal chemotherapy (HIPEC) is increasingly being used in patients with stage III ovarian cancer undergoing interval cytoreductive surgery (CRS). It is uncertain whether routine postoperative admission to a critical care setting after CRS-HIPEC is necessary. This study aims to estimate the incidence of patients requiring critical care, and to create a prediction model to identify patients who may forego admission to a critical care setting. METHODS: We analyzed 154 patients with primary ovarian cancer undergoing interval CRS-HIPEC at two Dutch centers between 2007 and 2021. Patients were routinely admitted to a critical care setting for 12-24 h. Patients that received critical support as defined by pre-specified definitions were retrospectively identified. Logistic regression analysis with backward selection was used to predict the need for critical care and the model was validated using bootstrapping. RESULTS: Thirty-eight percent of patients received postoperative critical care, consisting mainly of hemodynamic interventions. Independent predictors of critical care were blood loss, norepinephrine dose during surgery, and age (bootstrapped AUC = 0.76). Using a probability cut-off of 20%, one-third of patients are defined as low-risk for requiring critical care, with a negative predictive value of 0.88. CONCLUSIONS: The majority of patients,primarily undergoing low to intermediate complexity surgeries, did not receive critical care interventions after CRS-HIPEC. Selective admission to a critical care setting may be warranted and its feasibility and safety needs to be evaluated prospectively. Our prediction model can help identify patients in whom admission to a critical care setting may be omitted. Hospital costs and burden on critical care units will benefit from patient selection.

Evaluation of external validity of the OVHIPEC-1 trial in a real-world population.

OBJECTIVE: The OVHIPEC-1 trial (Phase III randomised clinical trial for stage III ovarian carcinoma randomising between interval cytoreductive surgery with or without hyperthermic intraperitoneal chemotherapy) showed improved survival when interval cytoreductive surgery (CRS) was combined with hyperthermic intraperitoneal chemotherapy in patients with stage III epithelial ovarian cancer (EOC). The authors compared the control arm of the trial with a real-world population treated in the Netherlands during the same period to explore generalizability of the trial results. METHODS: For this nationwide comparative cohort study, all patients with EOC undergoing interval CRS between 2007 and 2016 were identified from the Netherlands Cancer Registry if they fulfilled the eligibility criteria of OVHIPEC-1 (n = 1376). Patient and treatment characteristics, and overall survival (OS) were compared between trial and real-world populations. RESULTS: Age, comorbidity, BRCA status, histologic subtype, and residual disease were similar in trial and real-world patients. Trial patients had a better performance status, higher socioeconomic status, and underwent bowel surgery more often. In a real-world setting, patients more often received more than six cycles. The difference in OS between the trial and the real-world populations was not statistically significant (unadjusted hazard ratio, 1.09 [95% confidence interval, 0.87-1.37]; P = 0.44). CONCLUSION: Despite differences in patient characteristics, OS of patients treated in the control arm of OVHIPEC-1 was similar to patients treated outside the trial. The trial population accurately represents real-world patients with stage III EOC undergoing interval CRS in terms of outcome.

Hyperthermic intraperitoneal chemotherapy for epithelial ovarian cancer: A meta-analysis.

BACKGROUND: The value of hyperthermic intraperitoneal chemotherapy (HIPEC) at the time of cytoreductive surgery (CRS) for epithelial ovarian cancer (EOC) is controversial and its use remains experimental in most national and international guidelines. We wished to systematically evaluate all available evidence. METHODS: A comprehensive review of data from MEDLINE, EMBASE, and Cochrane Library databases was conducted from the first report on HIPEC in EOC till April 3, 2022. Progression-free survival (PFS) and overall survival (OS) were compared between the HIPEC and control groups. This meta-analysis was registered with PROSPERO (CRD42021265810). RESULTS: Fifteen studies (10 case-control studies and 5 randomized controlled trials [RCTs]) were included in the present meta-analysis. Based on the time interval between the last systemic chemotherapy exposure and timing of CRS +/- HIPEC, all studies and patients' cohorts we classified into recent (<6 months; n = 9 studies/patients cohorts) and non-recent (≥6 months, n = 8 studies/patients cohorts) chemotherapy exposure groups. In the recent chemotherapy exposure group, HIPEC was associated with improvement of both PFS (HR, 0.585; 95% CI, 0.422-0.811) and OS (HR, 0.519; 95% CI, 0.346-0.777). On the contrary, in the non-recent chemotherapy exposure group, HIPEC failed to significantly affect PFS (HR, 1.037; 95% CI, 0.684-1.571) or OS (HR, 0.932; 95% CI, 0.607-1.430). Consistent results were observed in subsequent sensitivity analyses. CONCLUSION: Our present meta-analysis demonstrates that the value of HIPEC at CRS for EOC appears to depend on the timing of the last systemic chemotherapy exposure. Future trials are awaited to define the role of HIPEC in EOC.

Translational and pharmacological principles of hyperthermic intraperitoneal chemotherapy for ovarian cancer.

The long-term survival of advanced-stage ovarian cancer patients remains poor, despite extensive cytoreductive surgery, chemotherapy, and the recent addition of poly (ADP-ribose) polymerase inhibitors (PARPi). Hyperthermic intraperitoneal chemotherapy (HIPEC) has shown survival benefit by specifically targeting peritoneal metastases, the primary site of disease recurrence. Different aspects of how HIPEC exerts its effect remain poorly understood. Improved understanding of the effects of hyperthermia on ovarian cancer cells, the synergy of hyperthermia with intraperitoneal chemotherapy, and the pharmacological and pharmacokinetic properties of intraperitoneally administered cisplatin may help identify ways to optimize the efficacy of HIPEC. This review provides an overview of these translational and pharmacological principles of HIPEC and aims to expose knowledge gaps that may direct further research to optimize the HIPEC procedure and ultimately improve survival for women with advanced ovarian cancer.

Pathologic response of ductal carcinoma in situ to neoadjuvant systemic treatment in HER2-positive breast cancer.

PURPOSE: The presence of extensive ductal carcinoma in situ (DCIS) adjacent to HER2-positive invasive breast cancer (IBC) is often a contra-indication for breast-conserving surgery, even in case of excellent treatment response of the invasive component. Data on the response of DCIS to neoadjuvant systemic treatment (NST) are limited. Therefore, we estimated the response of adjacent DCIS to NST-containing HER2-blockade in HER2-positive breast cancer patients and assessed the association of clinicopathological and radiological factors with response. METHODS: Pre-NST biopsies were examined to determine presence of DCIS in all women with HER2-positive IBC treated with trastuzumab-containing NST ± pertuzumab between 2004 and 2017 in a comprehensive cancer center. When present, multiple DCIS factors, including grade, calcifications, necrosis, hormone receptor, and Ki-67 expression, were scored. Associations of clinicopathological and radiological factors with complete response were assessed using logistic regression models. RESULTS: Adjacent DCIS, observed in 138/316 patients with HER2-positive IBC, was eradicated after NST in 46% of patients. Absence of calcifications suspicious for malignancy on pre-NST mammography (odds ratio (OR) 3.75; 95% confidence interval (95% CI) 1.72-8.17), treatment with dual HER2-blockade (OR 2.36; 95% CI 1.17-4.75), a (near) complete response on MRI (OR 3.55; 95% CI 1.31-9.64), and absence of calcifications (OR 3.19; 95% CI 1.34-7.60) and Ki-67 > 20% in DCIS (OR 2.74; 95% CI 1.09-6.89) on pre-NST biopsy were significantly associated with DCIS response. CONCLUSIONS: As DCIS can respond to NST containing HER2-blockade, the presence of extensive DCIS in HER2-positive breast cancer before NST should not always indicate a mastectomy. The predictive factors we found could be helpful when considering breast-conserving surgery in these patients.

High-Dose Chemotherapy With Hematopoietic Stem Cell Transplant in Patients With High-Risk Breast Cancer and 4 or More Involved Axillary Lymph Nodes: 20-Year Follow-up of a Phase 3 Randomized Clinical Trial.

Importance: Trials of adjuvant high-dose chemotherapy (HDCT) have failed to show a survival benefit in unselected patients with breast cancer, but long-term follow-up is lacking. Objective: To determine 20-year efficacy and safety outcomes of a large trial of adjuvant HDCT vs conventional-dose chemotherapy (CDCT) for patients with stage III breast cancer. Design, Setting, and Participants: This secondary analysis used data from a randomized phase 3 multicenter clinical trial of 885 women younger than 56 years with breast cancer and 4 or more involved axillary lymph nodes conducted from August 1, 1993, to July 31, 1999. Additional follow-up data were collected between June 1, 2016, and December 31, 2017, from medical records, general practitioners, the Dutch national statistical office, and nationwide cancer registries. Analysis was performed on an intention-to-treat basis. Statistical analysis was performed from February 1, 2018, to October 14, 2019. Interventions: Participants were randomized 1:1 to receive 5 cycles of CDCT consisting of fluorouracil, 500 mg/m2, epirubicin, 90 mg/m2, and cyclophosphamide, 500 mg/m2, or HDCT in which the first 4 cycles were identical to CDCT and the fifth cycle was replaced by cyclophosphamide, 6000 mg/m2, thiotepa, 480 mg/m2, and carboplatin, 1600 mg/m2, followed by hematopoietic stem cell transplant. Main Outcomes and Measures: Main end points were overall survival and safety and cumulative incidence risk of a second malignant neoplasm or cardiovascular events. Results: Of the 885 women in the study (mean [SD] age, 44.5 [6.6] years), 442 were randomized to receive HDCT, and 443 were randomized to receive CDCT. With 20.4 years median follow-up (interquartile range, 19.2-22.0 years), the 20-year overall survival was 45.3% with HDCT and 41.5% with CDCT (hazard ratio, 0.89; 95% CI, 0.75-1.06). The absolute improvement in 20-year overall survival was 14.6% (hazard ratio, 0.72; 95% CI, 0.54-0.95) for patients with 10 or more invoved axillary lymph nodes and 15.4% (hazard ratio, 0.67; 95% CI, 0.42-1.05) for patients with triple-negative breast cancer. The cumulative incidence risk of a second malignant neoplasm at 20 years or major cardiovascular events was similar in both treatment groups (20-year cumulative incidence risk for second malignant neoplasm was 12.1% in the HDCT group vs 16.2% in the CDCT group, P = .10), although patients in the HDCT group more often had hypertension (21.7% vs 14.3%, P = .02), hypercholesterolemia (15.7% vs 10.6%, P = .04), and dysrhythmias (8.6% vs 4.6%, P = .005). Conclusions and Relevance: High-dose chemotherapy provided no long-term survival benefit in unselected patients with stage III breast cancer but did provide improved overall survival in very high-risk patients (ie, with ≥10 involved axillary lymph nodes). High-dose chemotherapy did not affect long-term risk of a second malignant neoplasm or major cardiovascular events. Trial Registration: ClinicalTrials.gov Identifier: NCT03087409.

Complex challenges for patients with protracted incurable cancer: an ethnographic study in a comprehensive cancer centre in the Netherlands.

OBJECTIVE: Advances in oncology increasingly result in protracted disease trajectories for patients with incurable cancer. In this disease phase, patients are aware of the incurable nature of cancer although they are not yet approaching the last phase of life. We explored the challenges for patients confronted with protracted incurable cancer. DESIGN: Ethnographic study (2015-2017) based on conversations with patients, observations at a day-care unit and a selection of information from the medical records of patients who died during the study period. SETTING: The day-care unit of a comprehensive cancer centre in the Netherlands. PARTICIPANTS: Nineteen patients with stage IV breast cancer (in remission, >1 year after diagnosis) and 11 patients with stage IV lung-cancer (in remission, >6 months after diagnosis). RESULTS: In patients who had died during the study period, the treatment response often fluctuated between stable, remission and progression throughout the course of the disease. Patients reported that this fluctuation could be overwhelming. However, as patients grew accustomed to having protracted incurable cancer, the distress associated with fluctuations (perceived in scan results) slowly faded. Patients reported that cancer became part of who they were. At the day-care unit, most patients talked about their disease in an optimistic or neutral way and expressed delight in life. They often expressed gratefulness for the possible prolongation of life, expressed hope and tried to stay optimistic. This was frequently reinforced by optimistic doctors and nurses. Relatives, however, could downplay such optimism. Moreover, some patients acknowledged that hope was qualified by their personal challenges regarding their disease. CONCLUSIONS: In situations where tumours remained in remission or were stable for extended periods, patients grew accustomed to having cancer. At the day-care unit, medical professionals typically encouraged an attitude of being hopeful and optimistic, which could be downplayed by relatives. More research is warranted to explore this protracted disease phase and this optimistic view among healthcare professionals.

Hyperthermic intraperitoneal chemotherapy for ovarian cancer: The heat is on.

Patients with advanced epithelial ovarian cancer have a high incidence of peritoneal disease recurrence despite maximal efforts to surgically remove all visible tumor plus intravenous chemotherapy. The administration of intraperitoneal chemotherapy that specifically targets the peritoneal surface has been investigated in previous trials, but questions about the design of these studies has prevented this treatment from being widely adopted in clinical practice. Hyperthermic intraperitoneal chemotherapy (HIPEC) is a single intraoperative approach that also targets the peritoneal surface. A randomized phase 3 trial showed significant benefit in recurrence-free and overall survival when HIPEC was added to interval cytoreductive surgery (CRS) in patients who were not eligible for primary surgery because of the extent of their disease (OVHIPEC trial; NCT00426257). The trial showed no important differences in toxicity or patient-reported outcomes between the study groups. The extent of surgery and the number of bowel resections were also similar between the 2 study groups, and the effect of HIPEC was homogeneous across the levels of predefined and post hoc subgroups. Nevertheless, the design and the results of the OVHIPEC trial were critically assessed, and this resembles the reluctance to adopt the positive results of the earlier intraperitoneal chemotherapy studies. This overview discusses the design and results of the OVHIPEC trial. The evidence that is currently available points to a clinically relevant and cost-effective benefit of HIPEC added to interval CRS for patients with stage III ovarian cancer who are not eligible for primary surgery. Ongoing collaborative research will provide further evidence regarding the role of HIPEC in ovarian cancer.

Hyperthermic Intraperitoneal Chemotherapy in Ovarian Cancer.

BACKGROUND: Treatment of newly diagnosed advanced-stage ovarian cancer typically involves cytoreductive surgery and systemic chemotherapy. We conducted a trial to investigate whether the addition of hyperthermic intraperitoneal chemotherapy (HIPEC) to interval cytoreductive surgery would improve outcomes among patients who were receiving neoadjuvant chemotherapy for stage III epithelial ovarian cancer. METHODS: In a multicenter, open-label, phase 3 trial, we randomly assigned 245 patients who had at least stable disease after three cycles of carboplatin (area under the curve of 5 to 6 mg per milliliter per minute) and paclitaxel (175 mg per square meter of body-surface area) to undergo interval cytoreductive surgery either with or without administration of HIPEC with cisplatin (100 mg per square meter). Randomization was performed at the time of surgery in cases in which surgery that would result in no visible disease (complete cytoreduction) or surgery after which one or more residual tumors measuring 10 mm or less in diameter remain (optimal cytoreduction) was deemed to be feasible. Three additional cycles of carboplatin and paclitaxel were administered postoperatively. The primary end point was recurrence-free survival. Overall survival and the side-effect profile were key secondary end points. RESULTS: In the intention-to-treat analysis, events of disease recurrence or death occurred in 110 of the 123 patients (89%) who underwent cytoreductive surgery without HIPEC (surgery group) and in 99 of the 122 patients (81%) who underwent cytoreductive surgery with HIPEC (surgery-plus-HIPEC group) (hazard ratio for disease recurrence or death, 0.66; 95% confidence interval [CI], 0.50 to 0.87; P=0.003). The median recurrence-free survival was 10.7 months in the surgery group and 14.2 months in the surgery-plus-HIPEC group. At a median follow-up of 4.7 years, 76 patients (62%) in the surgery group and 61 patients (50%) in the surgery-plus-HIPEC group had died (hazard ratio, 0.67; 95% CI, 0.48 to 0.94; P=0.02). The median overall survival was 33.9 months in the surgery group and 45.7 months in the surgery-plus-HIPEC group. The percentage of patients who had adverse events of grade 3 or 4 was similar in the two groups (25% in the surgery group and 27% in the surgery-plus-HIPEC group, P=0.76). CONCLUSIONS: Among patients with stage III epithelial ovarian cancer, the addition of HIPEC to interval cytoreductive surgery resulted in longer recurrence-free survival and overall survival than surgery alone and did not result in higher rates of side effects. (Funded by the Dutch Cancer Society; ClinicalTrials.gov number, NCT00426257 ; EudraCT number, 2006-003466-34 .).

Effect of Low-Intensity Physical Activity and Moderate- to High-Intensity Physical Exercise During Adjuvant Chemotherapy on Physical Fitness, Fatigue, and Chemotherapy Completion Rates: Results of the PACES Randomized Clinical Trial.

PURPOSE: We evaluated the effectiveness of a low-intensity, home-based physical activity program (Onco-Move) and a moderate- to high-intensity, combined supervised resistance and aerobic exercise program (OnTrack) versus usual care (UC) in maintaining or enhancing physical fitness, minimizing fatigue, enhancing health-related quality of life, and optimizing chemotherapy completion rates in patients undergoing adjuvant chemotherapy for breast cancer. PATIENTS AND METHODS: We randomly assigned patients who were scheduled to undergo adjuvant chemotherapy (N = 230) to Onco-Move, OnTrack, or UC. Performance-based and self-reported outcomes were assessed before random assignment, at the end of chemotherapy, and at the 6-month follow-up. We used generalized estimating equations to compare the groups over time. RESULTS: Onco-Move and OnTrack resulted in less decline in cardiorespiratory fitness (P < .001), better physical functioning (P ≤ .001), less nausea and vomiting (P = .029 and .031, respectively) and less pain (P = .003 and .011, respectively) compared with UC. OnTrack also resulted in better outcomes for muscle strength (P = .002) and physical fatigue (P < .001). At the 6-month follow-up, most outcomes returned to baseline levels for all three groups. A smaller percentage of participants in OnTrack required chemotherapy dose adjustments than those in the UC or Onco-Move groups (P = .002). Both intervention groups returned earlier (P = .012), as well as for more hours per week (P = .014), to work than the control group. CONCLUSION: A supervised, moderate- to high-intensity, combined resistance and aerobic exercise program is most effective for patients with breast cancer undergoing adjuvant chemotherapy. A home-based, low-intensity physical activity program represents a viable alternative for women who are unable or unwilling to follow the higher intensity program.

Marking axillary lymph nodes with radioactive iodine seeds for axillary staging after neoadjuvant systemic treatment in breast cancer patients: the MARI procedure.

OBJECTIVE: The MARI procedure [marking the axillary lymph node with radioactive iodine (I) seeds] is a new minimal invasive method to assess the pathological response of nodal metastases after neoadjuvant systemic treatment (NST) in patients with breast cancer. This method allows axilla-conserving surgery in patients responding well to NST. METHODS: Prior to NST, proven tumor-positive axillary lymph nodes were marked with a I seed. This marked lymph node is the so-called MARI-node. After NST, the MARI node was selectively removed using a γ-detection probe. A complementary axillary lymph node dissection was performed in all patients to assess whether pathological response in the MARI node was indicative for the pathological response in the additional lymph nodes. RESULTS: A tumor-positive axillary lymph node was marked with a I seed in 100 patients. The MARI node was successfully identified in 97 of these 100 patients (identification rate 97%). Two patients did not undergo subsequent axillary lymph node dissection, leaving 95 patients for further analysis. The MARI node contained residual tumor cells in 65 of these 95 patients. In the other 30 patients, the MARI node was free of tumor, but additional positive lymph nodes were found in 5 patients. Thus, the MARI procedure correctly identified 65 of 70 patients with residual axillary tumor activity (false negative rate 5/70 = 7%). CONCLUSIONS: This study shows that marking and selectively removing metastatic lymph nodes after neoadjuvant systemic treatment has a high identification rate and a low false negative rate. The tumor response in the marked lymph node may be used to tailor further axillary treatment after NST.

Guiding breast-conserving surgery in patients after neoadjuvant systemic therapy for breast cancer: a comparison of radioactive seed localization with the ROLL technique.

BACKGROUND: Radioguided occult lesion localization (ROLL) with technetium-99 m colloid (ROLL-(99m)Tc) is commonly used to perform breast-conserving surgery in patients with nonpalpable breast tumors. Radioactive seed localization is a relatively new technique that localizes the tumor with a radioactive iodine-125 ((125)I) seed. The feasibility and outcome of these techniques after neoadjuvant systemic treatment has not been widely investigated. METHODS: All patients treated with neoadjuvant systemic treatment between 2007 and 2010 in the Netherlands Cancer Institute who underwent breast-conserving surgery with the ROLL-(99m)Tc technique (n = 83) or with (125)I seed localization (n = 71) were analyzed. The weight of the resected specimen, the margins, and the percentage of patients requiring a second surgical intervention as a result of positive margins were assessed. RESULTS: Patient and tumor characteristics and systemic treatment regimens were comparable between both groups. The median weight of the resected specimen (53 vs. 48 g), the median smallest margin (3.5 vs. 3.0 mm), and the risk for additional surgery for incomplete resections (7 vs. 8 %) did not differ significantly between patients treated with the ROLL-(99m)Tc technique and (125)I seed localization. CONCLUSIONS: The ROLL-(99m)Tc technique and (125)I seed localization demonstrate comparable results when used to perform breast-conserving surgery after neoadjuvant systemic treatment. Because (125)I seed localization does not require additional radiological localization shortly before surgery, it simplifies surgery scheduling. Therefore, we prefer (125)I seed localization to perform breast-conserving surgery after neoadjuvant systemic treatment.

SERPINA6, BEX1, AGTR1, SLC26A3, and LAPTM4B are markers of resistance to neoadjuvant chemotherapy in HER2-negative breast cancer.

Response rates to chemotherapy remain highly variable in breast cancer patients. We set out to identify genes associated with chemotherapy resistance. We analyzed what is currently the largest single-institute set of gene expression profiles derived from breast cancers prior to a single neoadjuvant chemotherapy regimen (dose-dense doxorubicin and cyclophosphamide). We collected, gene expression-profiled, and analyzed 178 HER2-negative breast tumor biopsies ("NKI dataset"). We employed a recently developed approach for detecting imbalanced differential signal (DIDS) to identify markers of resistance to treatment. In contrast to traditional methods, DIDS is able to identify markers that show aberrant expression in only a small subgroup of the non-responder samples. We found a number of markers of resistance to anthracycline-based chemotherapy. We validated our findings in three external datasets, totaling 456 HER2-negative samples. Since these external sets included patients who received differing treatment regimens, the validated markers represent markers of general chemotherapy resistance. There was a highly significant overlap in the markers identified in the NKI dataset and the other three datasets. Five resistance markers, SERPINA6, BEX1, AGTR1, SLC26A3, and LAPTM4B, were identified in three of the four datasets (p value overlap < 1 × 10(-6)). These five genes identified resistant tumors that could not have been identified by merely taking ER status or proliferation into account. The identification of these genes might lead to a better understanding of the mechanisms involved in (clinically) observed chemotherapy resistance and could possibly assist in the recognition of breast cancers in which chemotherapy does not contribute to response or survival.