Karolina Sikorska

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.)

Chemotherapy versus chemoradiotherapy after surgery and preoperative chemotherapy for resectable gastric cancer (CRITICS): an international, open-label, randomised phase 3 trial

BACKGROUNDnBoth perioperative chemotherapy and postoperative chemoradiotherapy improve survival in patients with resectable gastric cancer from Europe and North America. To our knowledge, these treatment strategies have not been investigated in a head to head comparison. We aimed to compare perioperative chemotherapy with preoperative chemotherapy and postoperative chemoradiotherapy in patients with resectable gastric adenocarcinoma.nnnMETHODSnIn this investigator-initiated, open-label, randomised phase 3 trial, we enrolled patients aged 18 years or older who had stage IB- IVA resectable gastric or gastro-oesophageal adenocarcinoma (as defined by the American Joint Committee on Cancer, sixth edition), with a WHO performance status of 0 or 1, and adequate cardiac, bone marrow, liver, and kidney function. Patients were enrolled from 56 hospitals in the Netherlands, Sweden, and Denmark, and were randomly assigned (1:1) with a computerised minimisation programme with a random element to either perioperative chemotherapy (chemotherapy group) or preoperative chemotherapy with postoperative chemoradiotherapy (chemoradiotherapy group). Randomisation was done before patients were given any preoperative chemotherapy treatment and was stratified by histological subtype, tumour localisation, and hospital. Patients and investigators were not masked to treatment allocation. Surgery consisted of a radical resection of the primary tumour and at least a D1+ lymph node dissection. Postoperative treatment started within 4-12 weeks after surgery. Chemotherapy consisted of three preoperative 21-day cycles and three postoperative cycles of intravenous epirubicin (50 mg/m2 on day 1), cisplatin (60 mg/m2 on day 1) or oxaliplatin (130 mg/m2 on day 1), and capecitabine (1000 mg/m2 orally as tablets twice daily for 14 days in combination with epirubicin and cisplatin, or 625 mg/m2 orally as tablets twice daily for 21 days in combination with epirubicin and oxaliplatin), received once every three weeks. Chemoradiotherapy consisted of 45 Gy in 25 fractions of 1·8 Gy, for 5 weeks, five daily fractions per week, combined with capecitabine (575 mg/m2 orally twice daily on radiotherapy days) and cisplatin (20 mg/m2 intravenously on day 1 of each 5 weeks of radiation treatment). The primary endpoint was overall survival, analysed by intention-to-treat. The CRITICS trial is registered at ClinicalTrials.gov, number NCT00407186; EudraCT, number 2006-004130-32; and CKTO, 2006-02.nnnFINDINGSnBetween Jan 11, 2007, and April 17, 2015, 788 patients were enrolled and randomly assigned to chemotherapy (n=393) or chemoradiotherapy (n=395). After preoperative chemotherapy, 372 (95%) of 393 patients in the chemotherapy group and 369 (93%) of 395 patients in the chemoradiotherapy group proceeded to surgery, with a potentially curative resection done in 310 (79%) of 393 patients in the chemotherapy group and 326 (83%) of 395 in the chemoradiotherapy group. Postoperatively, 233 (59%) of 393 patients started chemotherapy and 245 (62%) of 395 started chemoradiotherapy. At a median follow-up of 61·4 months (IQR 43·3-82·8), median overall survival was 43 months (95% CI 31-57) in the chemotherapy group and 37 months (30-48) in the chemoradiotherapy group (hazard ratio from stratified analysis 1·01 (95% CI 0·84-1·22; p=0·90). After preoperative chemotherapy, in the total safety population of 781 patients (assessed together), there were 368 (47%) grade 3 adverse events; 130 (17%) grade 4 adverse events, and 13 (2%) deaths. Causes of death during preoperative treatment were diarrhoea (n=2), dihydropyrimidine deficiency (n=1), sudden death (n=1), cardiovascular events (n=8), and functional bowel obstruction (n=1). During postoperative treatment, grade 3 and 4 adverse events occurred in 113 (48%) and 22 (9%) of 233 patients in the chemotherapy group, respectively, and in 101 (41%) and ten (4%) of 245 patients in the chemoradiotherapy group, respectively. Non-febrile neutropenia occurred more frequently during postoperative chemotherapy (79 [34%] of 233) than during postoperative chemoradiotherapy (11 [4%] of 245). No deaths were observed during postoperative treatment.nnnINTERPRETATIONnPostoperative chemoradiotherapy did not improve overall survival compared with postoperative chemotherapy in patients with resectable gastric cancer treated with adequate preoperative chemotherapy and surgery. In view of the poor postoperative patient compliance in both treatment groups, future studies should focus on optimising preoperative treatment strategies.nnnFUNDINGnDutch Cancer Society, Dutch Colorectal Cancer Group, and Hoffmann-La Roche.

Bevacizumab combined with docetaxel, oxaliplatin, and capecitabine, followed by maintenance with capecitabine and bevacizumab, as first-line treatment of patients with advanced HER2-negative gastric cancer: A multicenter phase 2 study.

The current study was a multicenter, single‐arm, phase 2 study performed to investigate the feasibility and efficacy of bevacizumab combined with docetaxel, oxaliplatin, and capecitabine (B‐DOC) in patients with advanced human epidermal growth factor receptor 2 (HER2)‐negative, previously untreated, gastric or gastroesophageal adenocarcinoma.

Trastuzumab and bevacizumab combined with docetaxel, oxaliplatin and capecitabine as first-line treatment of advanced HER2-positive gastric cancer: a multicenter phase II study.

SummaryObjective To investigate the efficacy of bevacizumab and trastuzumab combined with docetaxel, oxaliplatin, and capecitabine (B-DOCT) as first-line treatment of advanced human epidermal growth factor receptor 2 (HER2)-positive gastric cancer (GC). Methods In this multicentre, single-arm, phase II study, tumor HER2 status was determined centrally prior to treatment. Patients with advanced HER2-positive adenocarcinoma of the stomach or gastroesophageal junction (immunohistochemistry 3+ or immunohistochemistry 2+/silver in-situ hybridization positive) were treated with six cycles of bevacizumab 7.5xa0mg/kg (day 1), docetaxel 50xa0mg/m2 (day 1), oxaliplatin 100xa0mg/m2 (day 1), capecitabine 850xa0mg/m2 b.i.d. (days 1–14), and trastuzumab 6xa0mg/kg (day 1) every three weeks, followed by maintenance with bevacizumab, capecitabine, and trastuzumab until disease progression. The primary objective was to demonstrate an improvement of progression-free survival (PFS) to >7.6xa0months (observed in the ToGA trial) determined according to the lower limit of the 95xa0% confidence interval (CI). Secondary endpoints were safety, objective response rate (ORR), and overall survival (OS). Results Twenty-five patients with HER2-positive tumors were treated with B-DOCT between March 2011 and September 2014. At a median follow-up of 17xa0months, median PFS was 10.8xa0months (95%CI: 9.0–NA), OS was 17.9xa0months (95%CI: 12.4–NA). One-year PFS and OS were 52xa0% and 79xa0%, respectively. The ORR was 74xa0% (95%CI: 52–90xa0%). Two patients became resectable during treatment with B-DOCT and achieved a pathological complete response. The most common treatment-related gradexa0≥xa03 adverse events were: neutropenia (16xa0%), diarrhoea (16xa0%), and hypertension (16xa0%). Conclusions B-DOCT is a safe and active combination in HER2-positive GC, supporting further investigations of DOC with HER2/vascular endothelial growth factor (VEGF) inhibition in HER2-positive GC.

Dermatography (Medical Tattooing) for Scars and Skin Grafts in Head and Neck Patients to Improve Appearance and Quality of Life

Importance Dermatography (medical tattooing) is often overlooked as an adjuvant procedure to improve color mismatch in the head and neck area, and its effect on patient satisfaction and quality of life has not been evaluated, to our knowledge. Objective To analyze the effect of dermatography on the subjective perception of the appearance of scars and skin grafts and the quality of life in head and neck patients. Design, Setting, and Participants Case series of patients undergoing dermatography at the Netherlands Cancer Institute–Antoni van Leeuwenhoek Hospital, Amsterdam, between July 1, 2007, and April 1, 2015. Participants were invited to respond to 2 questionnaires measuring their scar or graft appearance and their quality of life before and after dermatography as an adjuvant treatment for benign or malignant head and neck tumors. Intervention Use of dermatography. Main Outcomes and Measures Two questionnaires evaluating a visual analog scale score (range, 0-10) and multiple questions on a 5-point scale focusing on satisfaction with the appearance and the quality of life. Results Among 76 patients, 56 (74%) were included in the study. The mean (SD) age of the study cohort was 56.5 (16.0) years, and 42 (75%) were female. The mean improvement in scar or skin graft perception on the visual analog scale of the modified Utrecht Questionnaire for Outcome Assessment in Aesthetic Rhinoplasty before and after dermatography was 4 points. On the modified Patient Scar Assessment Questionnaire, uniform improvement of approximately 1 point across 9 questions was observed. The answers to all patient satisfaction and quality-of-life questions on both questionnaires improved significantly after dermatography. Conclusions and Relevance Dermatography is an effectual adjuvant procedure to improve the subjective perception of scar and skin graft appearance and the quality of life in head and neck patients. Level of Evidence 4.

Survival is associated with complete response on MRI after neoadjuvant chemotherapy in ER-positive HER2-negative breast cancer

BackgroundPathological complete remission (pCR) of estrogen receptor (ER)-positive/human epidermal growth factor receptor 2 (HER2)-negative breast cancer is rarely achieved after neoadjuvant chemotherapy (NAC). In addition, the prognostic value of pCR for this breast cancer subtype is limited. We explored whether response evaluation by magnetic resonance imaging (MRI) is associated with recurrence-free survival after NAC in ER-positive/HER2-negative breast cancer.MethodsMRI examinations were performed in 272 women with ER-positive/HER2-negative breast cancer before, during and after NAC. MRI interpretation included lesion morphology at baseline, changes in morphology and size, and contrast uptake kinetics. These MRI features, clinical characteristics and final pathology were correlated with recurrence-free survival.ResultsThe median follow up time was 41 months. There were 35 women with events, including 19 breast-cancer-related deaths. On multivariable analysis, age younger than 50 years (hazard ratio (HR)u2009=u20092.55, 95 % confidence interval (CI) 1.3, 5.02, pu2009=u20090.007), radiological complete response after NAC (HRu2009=u200914.11, CI 1.81, 1818; pu2009=u20090.006) and smaller diameters of washout/plateau enhancement at MRI after NAC (HRu2009=u20091.02, CI 1.00, 1.04, pu2009=u20090.036) were independently associated with best recurrence-free survival. Pathological response was not significant; HRu2009=u20092.12, CI 0.86, 4.64, pu2009=u20090.096.ConclusionsMRI after NAC in ER-positive/HER2-negative tumors may be predictive of recurrence-free survival. A radiological complete response at MRI after NAC is associated with an excellent prognosis.

Radiation-induced dose-dependent changes of the spleen following postoperative chemoradiotherapy for gastric cancer.

BACKGROUND AND PURPOSEnAbdominal (chemo-)radiotherapy is associated with dose-limiting toxicity of various normal structures. The purpose of this retrospective study was to investigate radiation-induced changes of the spleen and their clinical consequences.nnnPATIENTS AND METHODSnIn gastric cancer patients treated with postoperative chemoradiotherapy, the spleen size and its functions were assessed at follow-up by spleen volume on CT-scan, serum leucocytes/thrombocytes, and the occurrence of infectious events consisting of pneumonia and fatal sepsis. To evaluate the effect of radiation dose, mixed effects and Cox regression models were used.nnnRESULTSnForty-six out of 90 consecutive patients treated from 2006 to 2011 were evaluable. All patients received 45 Gy in 25 fractions with concurrent capecitabine (n=8), and capecitabine/cisplatin (n=38). Median Dmean to the spleen was 40 Gy (range 32-46). Mean relative spleen volume reduced to 37% (95% CI 32-42%) at 4-year follow-up, which was most strongly associated to the V44 (p<0.001). Median follow-up time was 67 (95% CI 57-78) months. Eleven patients had 13 pneumonias and 3 fatal sepsis. No association with dosimetric parameters was observed.nnnCONCLUSIONSnIn postoperative chemoradiotherapy for gastric cancer, the spleen received a high radiation dose. This resulted in a progressive, radiation dose-dependent reduction of spleen volume. Pneumonia and fatal sepsis occurred frequently, possibly as a result of functional hyposplenia.

Outcomes after prophylactic gastrectomy for hereditary diffuse gastric cancer

Patients with hereditary diffuse gastric cancer and a CDH1 mutation have a 60–80 per cent lifetime risk of developing diffuse gastric cancer. Total prophylactic gastrectomy eliminates this risk, but is associated with considerable morbidity. The effectiveness (removal of all gastric mucosa) and outcomes of this procedure were evaluated retrospectively.

Pharmacogenetic variants associated with outcome in patients with advanced gastric cancer treated with fluoropyrimidine and platinum-based triplet combinations: a pooled analysis of three prospective studies

The main treatment for advanced gastric cancer is fluoropyrimidine and platinum-based chemotherapy. We investigated the clinical validitiy of 19 candidate pharmacogenetic variants in ENOSF1 (enolase superfamily member 1), TYMS, CDA, MTHFR, TYMP, DPYD, ERCC1, ERCC2, GSTP1, GSTT1, GSTM1, CYP3A4 and CYP3A5 in relation to overall survival (OS), progression-free survival, objective response rate (ORR) and toxicity in 185 patients receiving triplet chemotherapy. The formal significance threshold was P<0.0026. TYMS VNTR (variable number of 28-bp tandem repeats) 3u2009R/3u2009R genotype was formally associated with inferior ORR (odds ratio (OR) 0.3, P=0.0025), whereas ENOSF1 rs2612091 G/G was nominally associated with OS after adjustment for TYMS 3u2009R/3u2009R (hazard ratio (HR) 1.5, P=0.041). In a subgroup analysis of patients with locally advanced disease (n=33), ENOSF1 rs2612091 was strongly associated with OS (HR 6.5, P=0.001). CYP3A4*22/CYP3A5*3 genotype was nominally associated with grade 3/4 toxicity in patients receiving docetaxel-containing chemotherapy (P=0.0175). This is the first study suggesting that ENOSF1 rs2612091 is prognostic or predictive of OS in gastric cancer. This finding requires prospective validation.

The prognostic and potentially predictive value of the Laurén classification in oesophageal adenocarcinoma

AIMnTo investigate the histological subtypes of oesophageal adenocarcinoma according to the Laurén classification (intestinal/diffuse/mixed) in relation to tumour response to neoadjuvant treatment, and in relation to patients survival after potentially curative treatment.nnnMETHODSnData were collected from all oesophageal adenocarcinoma patients who underwent potentially curative treatment in our institute between 1998 and 2014. Treatment consisted of neoadjuvant chemoradiotherapy (36-50xa0Gy) followed by an oesophagectomy or definitive chemoradiotherapy (50-50.4xa0Gy). Clinical data were collected from patient records. All endoscopic biopsies and surgical resection specimens were reassessed to determine the histological subtype (intestinal, diffuse or mixed) and the Mandard tumour regression grade (TRG). The impact of the histological subtypes on survival was determined using a Cox model.nnnRESULTSnMedian follow-up was 68 months. Diffuse and mixed type cancers accounted for 25% of oesophageal adenocarcinomas. Median overall survival differed significantly between patients with intestinal (nxa0=xa0121, 39 months), diffuse (nxa0=xa028, 18 months) or mixed type (nxa0=xa011, 25 months) carcinomas (log rank, pxa0=xa00.023). In multivariable analysis, the diffuse type was associated with shorter survival (diffuse versusxa0intestinal: hazard ratios 2.06, pxa0=xa00.006). A pathologically (near) complete response (TRG 1 or 2) was seen less frequently in diffuse type than in intestinal type carcinomas (24% versusxa060%; pxa0=xa00.015).nnnCONCLUSIONSnPatients with diffuse type oesophageal adenocarcinomas had a significantly worse prognosis than those with intestinal type carcinomas. Intestinal type carcinomas showed a better response to neoadjuvant chemoradiotherapy than diffuse type carcinomas. These differences call for the exploration of differentiated approaches in the potentially curative treatment of oesophageal adenocarcinomas.