Perioperative systemic therapy and cytoreductive surgery with HIPEC versus upfront cytoreductive surgery with HIPEC alone for isolated resectable colorectal peritoneal metastases: protocol of a multicentre, open-label, parallel-group, phase II-III, randomised, superiority study (CAIRO6)

BACKGROUND: Upfront cytoreductive surgery with HIPEC (CRS-HIPEC) is the standard treatment for isolated resectable colorectal peritoneal metastases (PM) in the Netherlands. This study investigates whether addition of perioperative systemic therapy to CRS-HIPEC improves oncological outcomes. METHODS: This open-label, parallel-group, phase II-III, randomised, superiority study is performed in nine Dutch tertiary referral centres. Eligible patients are adults who have a good performance status, histologically or cytologically proven resectable PM of a colorectal adenocarcinoma, no systemic colorectal metastases, no systemic therapy for colorectal cancer within six months prior to enrolment, and no previous CRS-HIPEC. Eligible patients are randomised (1:1) to perioperative systemic therapy and CRS-HIPEC (experimental arm) or upfront CRS-HIPEC alone (control arm) by using central randomisation software with minimisation stratified by a peritoneal cancer index of 0-10 or 11-20, metachronous or synchronous PM, previous systemic therapy for colorectal cancer, and HIPEC with oxaliplatin or mitomycin C. At the treating physician's discretion, perioperative systemic therapy consists of either four 3-weekly neoadjuvant and adjuvant cycles of capecitabine with oxaliplatin (CAPOX), six 2-weekly neoadjuvant and adjuvant cycles of 5-fluorouracil/leucovorin with oxaliplatin (FOLFOX), or six 2-weekly neoadjuvant cycles of 5-fluorouracil/leucovorin with irinotecan (FOLFIRI) followed by four 3-weekly (capecitabine) or six 2-weekly (5-fluorouracil/leucovorin) adjuvant cycles of fluoropyrimidine monotherapy. Bevacizumab is added to the first three (CAPOX) or four (FOLFOX/FOLFIRI) neoadjuvant cycles. The first 80 patients are enrolled in a phase II study to explore the feasibility of accrual and the feasibility, safety, and tolerance of perioperative systemic therapy. If predefined criteria of feasibility and safety are met, the study continues as a phase III study with 3-year overall survival as primary endpoint. A total of 358 patients is needed to detect the hypothesised 15% increase in 3-year overall survival (control arm 50%; experimental arm 65%). Secondary endpoints are surgical characteristics, major postoperative morbidity, progression-free survival, disease-free survival, health-related quality of life, costs, major systemic therapy related toxicity, and objective radiological and histopathological response rates. DISCUSSION: This is the first randomised study that prospectively compares oncological outcomes of perioperative systemic therapy and CRS-HIPEC with upfront CRS-HIPEC alone for isolated resectable colorectal PM. TRIAL REGISTRATION: Clinicaltrials.gov/ NCT02758951 , NTR/ NTR6301 , ISRCTN/ ISRCTN15977568 , EudraCT/ 2016-001865-99 .

Watchful Waiting Versus Surgery of Mildly Symptomatic or Asymptomatic Inguinal Hernia in Men Aged 50 Years and Older: A Randomized Controlled Trial.

OBJECTIVE: To compare if watchful waiting is noninferior to elective repair in men aged 50 years and older with mildly symptomatic or asymptomatic inguinal hernia. BACKGROUND: The role of watchful waiting in older male patients with mildly symptomatic or asymptomatic inguinal hernia is still not well-established. METHODS: In this noninferiority trial, we randomly assigned men aged 50 years and older with mildly symptomatic or asymptomatic inguinal hernia to either elective inguinal hernia repair or watchful waiting. Primary endpoint was the mean difference in a 4-point pain/discomfort score at 24 months of follow-up. Using a 0.20-point difference as a clinically relevant margin, it was hypothesized that watchful waiting was noninferior to elective repair. Secondary endpoints included quality of life, event-free survival, and crossover rates. RESULTS: Between January 2006 and August 2012, 528 patients were enrolled, of whom 496 met the inclusion criteria: 234 were assigned to elective repair and 262 to watchful waiting. The mean pain/discomfort score at 24 months was 0.35 [95% confidence interval (CI) 0.28-0.41)] in the elective repair group and 0.58 (95% CI 0.52-0.64) in the watchful waiting group. The difference of these means (MD) was -0.23 (95% CI -0.32 to -0.14). In the watchful waiting group, 93 patients (35·4%) eventually underwent elective surgery and 6 patients (2·3%) received emergent surgery for strangulation/incarceration. Postoperative complication rates and recurrence rates in these 99 operated individuals were comparable with individuals originally assigned to the elective repair group (8.1% vs 15.0%; P = 0.106, 7.1% vs 8.9%; P = 0.668, respectively). CONCLUSIONS: Our data could not rule out a relevant difference in favor of elective repair with regard to the primary endpoint. Nevertheless, in view of all other findings, we feel that our results justify watchful waiting as a reasonable alternative compared with surgery in men aged 50 years and older.

Higher incidence rates than previously known in tenosynovial giant cell tumors.

Background and purpose - Tenosynovial giant cell tumors (TGCT) are rare, benign tumors, arising in synovial lining of joints, tendon sheaths, or bursae. 2 types are distinguished: localized, either digits or extremity, and diffuse lesions. Current TGCT incidence is based on 1 single US-county study in 1980, with an incidence of 9 and 2 per million person-years in localized (including digits) and diffuse TGCT, respectively. We aim to determine nationwide and worldwide incidence rates (IR) in TGCT affecting digits, localized-extremity TGCT and diffuse-type TGCT. Material and methods - Over a 5-year period, the Dutch Pathology Registry (PALGA) identified 4,503 pathology reports on TGCT. Reports affecting digits were solely used for IR calculations. Reports affecting extremities were clinically evaluated. Dutch IRs were converted to world population IRs. Results - 2,815 (68%) digits, 933 (23%) localized-extremity and 390 (9%) diffuse-type TGCT were identified. Dutch IR in digits, localized-extremity, and diffuse-type TGCT was 34, 11 and 5 per million person-years, respectively. All 3 groups showed a female predilection and highest number of new cases in age category 40-59 years. The knee joint was most often affected: localized-extremity (46%) and diffuse-type (64%) TGCT, mostly treated with open resection: localized (65%) and diffuse (49%). Reoperation rate due to local recurrence for localized-extremity was 9%, and diffuse TGCT 23%. Interpretation - This first nationwide study and detailed analyses of IRs in TGCT estimated a worldwide IR in digits, localized-extremity and diffuse TGCT of 29, 10, and 4 per million person-years, respectively. Recurrence rate in diffuse type is 2.6 times higher, compared with localized extremity. TGCT is still considered a rare disease; however, it is more common than previously understood.

Importance of circulating tumor cells in newly diagnosed colorectal cancer.

Presence of circulating tumor cells (CTC) is associated with poor prognosis in patients with metastatic colorectal cancer (CRC). The present study was conducted to determine if the presence of CTC prior to surgery and during follow­up in patients with newly diagnosed non-metastatic CRC can identify patients at risk for disease recurrence. In a prospective single center study 183 patients with newly diagnosed non-disseminated CRC, scheduled for surgery, were enrolled and followed-up for a median of 5.1 years. CTC were enumerated with the CellSearch system in 4 aliquots of 7.5 ml of blood before surgery and at several time-points during follow-up after surgery. The results showed that ≥1 CTC/30 ml of blood were detected in 44 (24%) patients before surgery. Patients with CTC before surgery had a significant decrease in recurrence-free survival (RFS, log-rank test p=0.014) and colon cancer related survival (CCRS, p=0.002). The 5-year RFS dropped from 75 to 61% and the 5-year CCRS from 83 to 69% for patients with CTC before surgery. The presence of CTC and positive lymph nodes remained significant factors in multivariate analysis for recurrence-free survival (RFS). Surprisingly, the presence of CTC weeks after surgery was not significantly associated with RFS and CCRD whereas CTC 2-3 years after surgery was again significantly associated with RFS and CCRD. The presence of CTC in patients with stage I-III CRC before surgery is associated with a significant reduction in RFS and CCRS. These findings suggest a role of CTC detection to assess which patients need adjuvant treatment.

Circulating tumor cells before and during follow-up after breast cancer surgery.

The presence of circulating tumor cells (CTC) is an independent prognostic factor for progression-free and overall survival for patients with metastatic and newly diagnosed breast cancer. The present study was undertaken to explore whether the presence of CTC before and during follow-up after surgery is associated with recurrence free survival (RFS) and overall survival (OS). In a prospective single center study, CTC were enumerated with the CellSearch system in 30 ml of peripheral blood of 403 stage I-III patients before undergoing surgery for breast cancer (A) and if available 1 week after surgery (B), after adjuvant chemo- and/or radiotherapy or before start of long-term hormonal therapy (C), one (D), two (E) and three (F) years after surgery. Patients were stratified into unfavorable (CTC≥1) and favorable (CTC=0) prognostic groups. >1 CTC in 30 ml blood was detected in 75/403 (19%) at A, 66/367 (18%) at B, 40/263 (15%) at C, 30/235 (12%) at D, 18/144 (11%) at E and 11/83 (13%) at F. RFS and OS was significantly lower for unfavorable CTC as compared to favorable CTC before surgery (p=0.022 and p=0.006), after adjuvant therapy (p<0.001 and p=0.018) and one (p=0.006 and p=0.013) and two (p<0.001 and p=0.045) years after surgery, but not 1 week post-surgery. The presence of CTC in blood drawn pre and one and two years after surgery, but not post-surgery is associated with shorter RFS and OS for stage I-III breast cancer.

Circulating tumor cells, disease recurrence and survival in newly diagnosed breast cancer.

INTRODUCTION: The presence of circulating tumor cells (CTC) is an independent prognostic factor for progression-free survival and breast cancer-related death (BRD) for patients with metastatic breast cancer beginning a new line of systemic therapy. The current study was undertaken to explore whether the presence of CTC at the time of diagnosis was associated with recurrence-free survival (RFS) and BRD. METHODS: In a prospective single center study, CTC were enumerated with the CellSearch system in 30 ml of peripheral blood of 602 patients before undergoing surgery for breast cancer. There were 97 patients with a benign tumor, 101 did not meet the inclusion criteria of which there were 48 patients with DCIS, leaving 404 stage I to III patients. Patients were stratified into unfavorable (CTC ≥1) and favorable (CTC = 0) prognostic groups. RESULTS: ≥1 CTC in 30 ml blood was detected in 15 (15%) benign tumors, in 9 DCIS (19%), in 28 (16%) stage I, 32 (18%) stage II and in 16 (31%) patients with stage III. In stage I to III patients 76 (19%) had ≥1 CTC of whom 16 (21.1%) developed a recurrence. In 328 patients with 0 CTC 38 (11.6%) developed a recurrence. Four-year RFS was 88.4% for favorable CTC and 78.9% for unfavorable CTC (P = 0.038). A total of 25 patients died of breast cancer-related causes and 11 (44%) had ≥1 CTC. BRD was 4.3% for favorable and 14.5% for unfavorable CTC (P = 0.001). In multivariate analysis ≥1 CTC was associated with distant disease-free survival, but not for overall recurrence-free survival. CTC, progesterone receptor and N-stage were independent predictors of BRD in multivariate analysis. CONCLUSIONS: Presence of CTC in breast cancer patients before undergoing surgery with curative intent is associated with an increased risk for breast cancer-related death.

Preoperative staging with chest CT in patients with colorectal carcinoma: not as a routine procedure.

BACKGROUND: Preoperative staging of patients with colorectal carcinoma (CRC) has the potential benefit of altering treatment options when metastases are present. The clinical value of chest computed tomography (CT) in staging remains unclear. MATERIALS AND METHODS: All patients who undergo colorectal surgery in our hospital are prospectively registered, including patient, treatment, and histopathological characteristics; outcome; and follow-up. Since January 2007, routine preoperative staging CT of chest and abdomen for patients with CRC has been performed as part of our regional guidelines. In this observational cohort study, an analysis on outcome was done after inclusion of 200 consecutive patients. RESULTS: Synchronous metastases were present in 60 patients (30%). Staging chest CT revealed pulmonary metastases in 6 patients, with 1 false positive finding. In 50 patients indeterminate lesions were seen on chest CT (25%). These were diagnosed during follow-up as true metastases (n = 8), bronchus carcinoma (n = 2), benign lesions (n = 25), and remaining unknown (n = 15). Ultimately, synchronous pulmonary metastases were diagnosed in 13 patients (7%), in 6 patients confined to the lung (3%). In none of the patients the treatment plan for the primary tumor was changed based on the staging chest CT. CONCLUSION: The low incidence of pulmonary metastases and minimal consequences for the treatment plan limits the clinical value of routine staging chest CT before operation. It has several disadvantages such as costs, radiation exposure, and prolonged uncertainty because of the frequent finding of indeterminate lesions. Based on this study, a routine staging chest CT in CRC patients is not advocated.

Anterior resection of rectal cancer without bowel preparation and diverting stoma.

PURPOSE: Since the introduction of total mesorectal excision (TME) as the standard operation technique for rectal cancer, anastomotic leakage percentages of up to 18% have been reported. To prevent such leakage, the use of mechanical bowel preparation and also the construction of a diverting ileostoma or colostomy have been standard procedures for years. In our institute, however, all patients undergoing colorectal surgery are operated upon without these measures. The present study was undertaken to investigate the results of this strategy in terms of the occurrence of postoperative anastomotic leakage. METHODS: All patients who underwent an elective (low) anterior resection between January 1996 and December 2001 (n = 144) entered the study. The clinical and pathological records of these patients were reviewed retrospectively. The exclusion criteria were patients with fixed rectal carcinoma who received preoperative radiotherapy and/or a stoma only at operation, emergency operations, abdominoperoneal resections, and Hartmann's procedures. RESULTS: Anastomotic leakage occurred in 7 out of 144 patients (4.9%). There was a trend toward a higher leakage frequency in men, in patients with a distal anastomosis, in patients with a stapled anastomosis, and in patients with a T3-T4 tumor or with positive lymph nodes. None of these factors, however, had a significant prognostic value based on a univariate or multivariate analysis. Those who died after leakage tended to be older than those who did not (P < 0.05). CONCLUSION: A (low) anterior resection can be performed safely without mechanical bowel preparation or a diverting stoma, and results in an anastomotic leakage percentage of less than 5%. Appropriate selection of patients may be important, but none of the investigated patient- or tumor-related factors could be identified as decisive.

Synchronous tumours of the unilateral parotid gland: rare or undetected?

INTRODUCTION: Multiple tumours of the parotid gland with the same histological appearance may occur as synchronous unilateral tumours, but bilaterality has also been reported. Synchronous multiple unilateral parotid tumours with different histology remain rare. METHODS: Between January 1988 and May 2002, a total of 341 patients underwent parotidectomy in our department. Medical charts were reviewed retrospectively for synchronous multiple unilateral tumours. RESULTS: Fourteen patients had two or more tumours within the same specimen. The combinations encountered were two to four adenolymphomas (n=9), adenolymphoma plus pleomorphic adenoma (n=3), adenolymphoma plus MALT lymphoma (n=1), and pleomorphic adenoma plus acinic cell carcinoma (n=1). The outcome was clinical freedom from signs of tumour recurrence in any patient (mean follow-up = 51 months). CONCLUSION: Synchronous multiple unilateral parotid tumours usually include two or more adenolymphomas and might occur more often than previously realized. The possibility of a concomitant carcinoma, and the prevention of recurrent tumours, may warrant a more radical surgical excision of the parotid gland, accurate intraoperative examination of the resected specimen, and routine histological evaluation of the entire specimen. Preoperative radiological investigation may further increase the chances of finding multiple parotid tumours.

Local recurrence of rectal cancer after total mesorectal excision without preoperative radiotherapy.

BACKGROUND: At this moment, it is still debatable whether all patients with mobile rectal cancer who undergo surgical removal of the tumor should be treated with preoperative radiotherapy, since it is likely that only certain patients will benefit from this strategy. In this study, patients with mobile rectal cancer were immediately operated upon and only those with positive nodes or with incomplete resection received adjuvant radiotherapy. AIMS OF THE STUDY: To investigate the local recurrence rate after the use of a selective policy of adjuvant radiotherapy and to determine risk factors for local recurrence. METHODS: In a 5-yr-period, 178 patients with rectal cancer were referred to our institute. A total of 131 patients with mobile rectal cancer were treated with curative intent, which implied a microscopically radical resection and no signs of distant metastasis at operation. A retrospective analysis was undertaken to investigate the incidence of local recurrence in this curative group and to determine risk factors for local recurrence. RESULTS: The postoperative mortality in the curative group was 5.3%. Local recurrences were observed in 6 patients (4.6%) after a median period of 25 mo (range 11-37); two of them also had distant metastases detected at the same time. The highest local recurrence rates were seen in men (5.3%), in distal rectal cancers (6.9%), and in the node-positive group (8.7%). CONCLUSION: A low local recurrence rate can be achieved after total mesorectal excision (TME) without preoperative radiotherapy. Our results suggest using preoperative radiotherapy only for those patients who are at a higher risk for local recurrence. Staging techniques for selection of these patients are at this moments till inappropriate.