Hyperthermic Intraperitoneal Chemotherapy in Ovarian Cancer van Driel, Willemien J; Koole, Simone N; Sikorska, Karolina ...
New England journal of medicine/The New England journal of medicine,
01/2018, Volume:
378, Issue:
3
Journal Article
Peer reviewed
Open access
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.
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.
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).
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 .).
The OVHIPEC-1 trial previously showed that the addition of hyperthermic intraperitoneal chemotherapy (HIPEC) to interval cytoreductive surgery resulted in improved progression-free and overall ...survival compared with cytoreductive surgery alone at 4·7 years of follow-up in patients with stage III epithelial ovarian cancer who were ineligible for primary cytoreduction. We report the final survival outcomes after 10 years of follow-up.
In this open-label, randomised, controlled, phase 3 trial, patients with primary epithelial stage III ovarian cancer were recruited at eight HIPEC centres in the Netherlands and Belgium. Patients were eligible if they were aged 18–76 years, had not progressed during at least three cycles of neoadjuvant carboplatin plus paclitaxel, had a WHO performance status score of 0–2, normal blood counts, and adequate renal function. Patients were randomly assigned (1:1) to undergo interval cytoreductive surgery without HIPEC (surgery group) or with HIPEC (100 mg/m2 cisplatin; surgery-plus-HIPEC group). Randomisation was done centrally by minimisation with a masked web-based allocation procedure at the time of surgery when residual disease smaller than 10 mm diameter was anticipated, and was stratified by institution, previous suboptimal cytoreductive surgery, and number of abdominal regions involved. The primary endpoint was progression-free survival and a secondary endpoint was overall survival, analysed in the intention-to-treat population (ie, all randomly assigned patients). This study is registered with ClinicalTrials.gov, NCT00426257, and is closed.
Between April 1, 2007, and April 30, 2016, 245 patients were enrolled and followed up for a median of 10·1 years (95% CI 8·4–12·9) in the surgery group (n=123) and 10·4 years (95% CI 9·5–13·3) in the surgery-plus-HIPEC group (n=122). Recurrence, progression, or death occurred in 114 (93%) patients in the surgery group (median progression-free survival 10·7 months 95% CI 9·6–12·0) and 109 (89%) patients in the surgery-plus-HIPEC group (14·3 months 12·0–18·5; hazard ratio HR 0·63 95% CI 0·48–0·83, stratified log-rank p=0·0008). Death occurred in 108 (88%) patients in the surgery group (median overall survival 33·3 months 95% CI 29·0–39·1) and 100 (82%) patients in the surgery-plus-HIPEC group (44·9 months 95% CI 38·6–55·1; HR 0·70 95% CI 0·53–0·92, stratified log-rank p=0·011).
These updated survival results confirm the long-term survival benefit of HIPEC in patients with primary stage III epithelial ovarian cancer undergoing interval cytoreductive surgery.
Dutch Cancer Foundation (KWF Kankerbestrijding).
The efficacy of programmed cell death protein 1 (PD-1) blockade in metastatic triple-negative breast cancer (TNBC) is low
, highlighting a need for strategies that render the tumor microenvironment ...more sensitive to PD-1 blockade. Preclinical research has suggested immunomodulatory properties for chemotherapy and irradiation
. In the first stage of this adaptive, non-comparative phase 2 trial, 67 patients with metastatic TNBC were randomized to nivolumab (1) without induction or with 2-week low-dose induction, or with (2) irradiation (3 × 8 Gy), (3) cyclophosphamide, (4) cisplatin or (5) doxorubicin, all followed by nivolumab. In the overall cohort, the objective response rate (ORR; iRECIST
) was 20%. The majority of responses were observed in the cisplatin (ORR 23%) and doxorubicin (ORR 35%) cohorts. After doxorubicin and cisplatin induction, we detected an upregulation of immune-related genes involved in PD-1-PD-L1 (programmed death ligand 1) and T cell cytotoxicity pathways. This was further supported by enrichment among upregulated genes related to inflammation, JAK-STAT and TNF-α signaling after doxorubicin. Together, the clinical and translational data of this study indicate that short-term doxorubicin and cisplatin may induce a more favorable tumor microenvironment and increase the likelihood of response to PD-1 blockade in TNBC. These data warrant confirmation in TNBC and exploration of induction treatments prior to PD-1 blockade in other cancer types.
The addition of hyperthermic intraperitoneal chemotherapy (HIPEC) with cisplatin to interval cytoreductive surgery improves recurrence‐free (RFS) and overall survival (OS) in patients with stage III ...ovarian cancer. Homologous recombination deficient (HRD) ovarian tumors are usually more platinum sensitive. Since hyperthermia impairs BRCA1/2 protein function, we hypothesized that HRD tumors respond best to treatment with HIPEC. We analyzed the effect of HIPEC in patients in the OVHIPEC trial, stratified by HRD status and BRCAm status. Clinical data and tissue samples were collected from patients included in the randomized, phase III OVHIPEC‐1 trial. DNA copy number variation (CNV) profiles, HRD‐related pathogenic mutations and BRCA1 promotor hypermethylation were determined. CNV‐profiles were categorized as HRD or non‐HRD, based on a previously validated algorithm‐based BRCA1‐like classifier. Hazard ratios (HR) and corresponding 99% confidence intervals (CI) for the effect of RFS and OS of HIPEC in the BRCAm, the HRD/BRCAwt and the non‐HRD group were estimated using Cox proportional hazard models. Tumor DNA was available from 200/245 (82%) patients. Seventeen (9%) tumors carried a pathogenic mutation in BRCA1 and 14 (7%) in BRCA2. Ninety‐one (46%) tumors classified as BRCA1‐like. The effect of HIPEC on RFS and OS was absent in BRCAm tumors (HR 1.25; 99%CI 0.48‐3.29), and most present in HRD/BRCAwt (HR 0.44; 99%CI 0.21‐0.91), and non‐HRD/BRCAwt tumors (HR 0.82; 99%CI 0.48‐1.42), interaction P value: 0.024. Patients with HRD tumors without pathogenic BRCA1/2 mutation appear to benefit most from treatment with HIPEC, while benefit in patients with BRCA1/2 pathogenic mutations and patients without HRD seems less evident.
What's new?
Serous ovarian cancers that are homologous recombination deficient (HRD) often are sensitive to platinum‐containing chemotherapy. Whether hyperthermic intraperitoneal chemotherapy (HIPEC) with cisplatin benefits patients with HRD tumors, however, remains unclear. In this study, an algorithm‐based HRD classifier was validated using data and tissue derived from the randomized, phase III OVHIPEC‐1 trial. Interval cytoreductive surgery and HIPEC was found to prolong recurrence‐free and overall survival moin patients with HRD/BRCA1 wild‐type ovarian cancers. Responses of BRCA1/2‐mutated and HR‐proficient ovarian cancers to HIPEC were less pronounced. The HRD classifier is a promising tool for identifying ovarian cancer patients who may benefit from HRD relying treatment modalities.
Background
The added value of surgery in breast cancer patients with pathological complete response (pCR) after neoadjuvant systemic therapy (NST) is uncertain. The accuracy of imaging identifying ...pCR for omission of surgery, however, is insufficient. We investigated the accuracy of ultrasound-guided biopsies identifying breast pCR (ypT0) after NST in patients with radiological partial (rPR) or complete response (rCR) on MRI.
Methods
We performed a multicenter, prospective single-arm study in three Dutch hospitals. Patients with T1–4(N0 or N +) breast cancer with MRI rPR and enhancement ≤ 2.0 cm or MRI rCR after NST were enrolled. Eight ultrasound-guided 14-G core biopsies were obtained in the operating room before surgery close to the marker placed centrally in the tumor area at diagnosis (no attempt was made to remove the marker), and compared with the surgical specimen of the breast. Primary outcome was the false-negative rate (FNR).
Results
Between April 2016 and June 2019, 202 patients fulfilled eligibility criteria. Pre-surgical biopsies were obtained in 167 patients, of whom 136 had rCR and 31 had rPR on MRI. Forty-three (26%) tumors were hormone receptor (HR)-positive/HER2-negative, 64 (38%) were HER2-positive, and 60 (36%) were triple-negative. Eighty-nine patients had pCR (53%; 95% CI 45–61) and 78 had residual disease. Biopsies were false-negative in 29 (37%; 95% CI 27–49) of 78 patients. The multivariable associated with false-negative biopsies was rCR (FNR 47%; OR 9.81, 95% CI 1.72–55.89;
p
= 0.01); a trend was observed for HR-negative tumors (FNR 71% in HER2-positive and 55% in triple-negative tumors; OR 4.55, 95% CI 0.95–21.73;
p
= 0.058) and smaller pathological lesions (6 mm vs 15 mm; OR 0.93, 95% CI 0.87–1.00;
p
= 0.051).
Conclusion
The MICRA trial showed that ultrasound-guided core biopsies are not accurate enough to identify breast pCR in patients with good response on MRI after NST. Therefore, breast surgery cannot safely be omitted relying on the results of core biopsies in these patients.
Epithelial ovarian cancer (EOC) metastasizes intra-abdominally with often numerous, superficial, small-sized lesions. This so-called peritoneal carcinomatosis is difficult to treat, and peritoneal ...recurrences are frequently observed, leading to a poor prognosis. Underlying mechanisms of interactions between EOC and peritoneal cells are incompletely understood. This review summarizes and discusses the development of peritoneal carcinomatosis from a cell-biological perspective, focusing on characteristics of EOC and peritoneal cells. We aim to provide insight into how peritoneum facilitates tumor adhesion but limits size of lesions and depth of invasion. The development of peritoneal carcinomatosis is a multistep process that requires adaptations of EOC and peritoneal cells. Mechanisms that enable tumor adhesion and growth involve cadherin restructuring on EOC cells, integrin-mediated adhesion, and mesothelial evasion by mechanical forces driven by integrin-ligand interactions. Clinical trials targeting these mechanisms, however, showed only limited effects. Other factors that inhibit tumor growth and deep invasion are virtually unknown. Future studies are needed to elucidate the exact mechanisms that underlie the development and limited growth of peritoneal carcinomatosis. This review on development of peritoneal carcinomatosis of EOC summarizes the current knowledge and its limitations. Clarification of the stepwise process may inspire future research to investigate new treatment approaches of peritoneal carcinomatosis.
Background: Population-based data on borderline ovarian tumors (BOTs) are scarce and information regarding recent trends in incidence, treatment and survival is lacking. The purpose of this study was ...to analyze these trends in the Netherlands and to assess the risk of developing a subsequent invasive ovarian tumor.
Material and methods: All consecutive patients diagnosed with BOTs between 1993 and 2016 (n = 7113) were identified from the Netherlands Cancer Registry (NCR). Annual age-adjusted incidence rates were calculated. Relative survival (RS) analyses and multivariable analyses estimating excess mortality were conducted. Patients with a subsequent invasive ovarian tumor were identified by the NCR.
Results: Age-adjusted incidence increased from 2.1/100,000 person-years in 1993 to 4.2/100,000 in 2011, after 2011 the incidence declined. The proportion of bilateral tumors decreased over time from 16% in 1993-1998 to 11% in 2005-2010 and remained stable onwards. Survival improved over time (excess mortality ratio
adjusted
2011-2016 versus 1993-1998: 0.25; 95%CI: 0.13-0.47). Five-year RS increased from 91% in 1993-1998 to 98% in 2011-2016 and 10-year RS from 88% in 1993-1998 to 96% in 2005-2010. Fewer patients were treated with chemotherapy (4.4% in 1993-1998 versus 0.7% in 2011-2016). During a median follow-up time of 8 years, 0.9% developed a subsequent invasive ovarian carcinoma.
Conclusions: The incidence of BOTs increased over time from 1993 until 2010 but declined since 2011. This decline may be partly due to changes in the classification of gynecological tumors, as serous BOTs are now more often diagnosed as low grade serous ovarian cancers. Survival is high and has improved since 1993. The risk of a subsequent invasive ovarian carcinoma seems low.
Abstract
Background
An increasing number of breast cancer (BC) survivors are at risk of developing contralateral breast cancer (CBC). We aimed to investigate the influence of various adjuvant ...systemic regimens on, subtype-specific, risk of CBC.
Methods
This population-based cohort study included female patients diagnosed with first invasive BC between 2003 and 2010; follow-up was complete until 2016. Clinico-pathological data were obtained from the Netherlands Cancer Registry and additional data on receptor status through linkage with PALGA: the Dutch Pathology Registry. Cumulative incidences (death and distant metastases as competing risk) and hazard ratios (HRs) were estimated for all invasive metachronous CBC and CBC subtypes.
Results
Of 83 144 BC patients, 2816 developed a CBC; the 10-year cumulative incidence was 3.8% (95% confidence interval CI = 3.7% to 4.0%). Overall, adjuvant chemotherapy (HR = 0.70, 95% CI = 0.62 to 0.80), endocrine therapy (HR = 0.46, 95% CI = 0.41 to 0.52), and trastuzumab with chemotherapy (HR = 0.57, 95% CI = 0.45 to 0.73) were strongly associated with a reduced CBC risk. Specifically, taxane-containing chemotherapy (HR = 0.48, 95% CI = 0.36 to 0.62) and aromatase inhibitors (HR = 0.32, 95% CI = 0.23 to 0.44) were associated with a large CBC risk reduction. More detailed analyses showed that endocrine therapy statistically significantly decreased the risk of estrogen receptor (ER)-positive CBC (HR = 0.41, 95% CI = 0.36 to 0.47) but not ER-negative CBC (HR = 1.32, 95% CI = 0.90 to 1.93) compared with no endocrine therapy. Patients receiving chemotherapy for ER-negative first BC had a higher risk of ER-negative CBC from 5 years of follow-up (HR = 2.84, 95% CI = 1.62 to 4.99) compared with patients not receiving chemotherapy for ER-negative first BC.
Conclusion
Endocrine therapy, chemotherapy, as well as trastuzumab with chemotherapy reduce CBC risk. However, each adjuvant therapy regimen had a different impact on the CBC subtype distribution. Taxane-containing chemotherapy and aromatase inhibitors were associated with the largest CBC risk reduction.
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