Abstract
Background
The presence of mesorectal fascia (MRF) invasion, grade 4 extramural venous invasion (EMVI), tumour deposits (TD) or extensive or bilateral extramesorectal (lateral) lymph nodes ...(LLN) on MRI has been suggested to identify patients with indisputable, extensive locally advanced rectal cancer (LARC), at high risk of treatment failure. The aim of this study is to evaluate whether or not intensified chemotherapy prior to neoadjuvant chemoradiotherapy improves the complete response (CR) rate in these patients.
Methods
This multicentre, single-arm, open-label, phase II trial will include 128 patients with non-metastatic high-risk LARC (hr-LARC), fit for triplet chemotherapy. To ensure a study population with indisputable, unfavourable prognostic characteristics, hr-LARC is defined as LARC with on baseline MRI at least one of the following characteristics; MRF invasion, EMVI grade 4, enlarged bilateral or extensive LLN at high risk of an incomplete resection, or TD. Exclusion criteria are the presence of a homozygous DPD deficiency, distant metastases, any chemotherapy within the past 6 months, previous radiotherapy within the pelvic area precluding standard chemoradiotherapy, and any contraindication for the planned treatment. All patients will be planned for six two-weekly cycles of FOLFOXIRI (5-fluorouracil, leucovorin, oxaliplatin and irinotecan) prior to chemoradiotherapy (25 × 2 Gy or 28 × 1.8 Gy with concomitant capecitabine). A resection will be performed following radiological confirmation of resectable disease after the completion of chemoradiotherapy. A watch and wait strategy is allowed in case of a clinical complete response. The primary endpoint is the CR rate, described as a pathological CR or a sustained clinical CR one year after chemoradiotherapy. The main secondary objectives are long-term oncological outcomes, radiological and pathological response, the number of resections with clear margins, treatment-related toxicity, perioperative complications, health-related costs, and quality of life.
Discussion
This trial protocol describes the MEND-IT study. The MEND-IT study aims to evaluate the CR rate after intensified chemotherapy prior to concomitant chemoradiotherapy in a homogeneous group of patients with locally advanced rectal cancer and indisputably unfavourable characteristics, defined as hr-LARC, in order to improve their prognosis.
Trial registration
Clinicaltrials.gov:
NCT04838496
, registered on 02–04-2021 Netherlands Trial Register: NL9790.
Protocol version
Version 3 dd 11–4-2022.
The majority of patients with locally recurrent rectal cancer (LRRC) present with extensive metastatic disease or an unresectable recurrence, and will be treated palliatively. Only a minority of ...patients will be eligible for potential cure by surgical treatment. The aim of this study is to evaluate the long-term outcome of surgical treatment and non-surgical treatment of patients with LRRC.
All patients with LRRC referred to our tertiary institute between 2000 and 2015 were retrospectively analysed. Patients were discussed in a multidisciplinary tumour board (MDT) and eventually received curative surgical or non-surgical treatment. Overall survival (OS) was compared by resection margin status and non-surgical treatment.
A total of 447 patients were discussed in our MDT of which 193 patients underwent surgical treatment and 254 patients received non-surgical treatment. Surgically treated patients were significantly younger, received less neoadjuvant therapy for the primary tumour, had less metastasis at diagnosis and more central recurrences. The 5-year OS was 51% for R0-resections and 34% for R1-resections. Although numbers with R2-resections were too small to implicate prognostic significance, there was no difference in 5-year OS between R2-resections and non-surgical treatment (10% vs. 4%, p = 0.282). In a subgroup analysis the OS of R2-patients was even poorer compared to optimal palliative treated patients with combined chemotherapy and radiotherapy (22 vs 29 months, p = 0.413).
R2-resections do not result in a survival benefit compared to non-surgical treatment in this non-randomized series. Patients with a high chance on a R2-resection could be offered non-surgical treatment, without local resection.
The consensus statements regarding first-line therapies in women with ovarian cancer, reached at the Fifth Ovarian Cancer Consensus Conference held in Tokyo, Japan, in November 2015 are reported. ...Three topics were reviewed and the following statements are recommended: (i) Surgery: the subgroups that should be considered in first-line ovarian cancer clinical trials should be (a) patients undergoing primary debulking surgery and (b) patients receiving neo-adjuvant chemotherapy. The amount of residual disease following surgery should further stratify patients into those with absent gross residual disease and others. (ii) Control arms for chemotherapy: for advanced stage ovarian cancer the standard is intravenous 3-weekly carboplatin and paclitaxel. Acceptable alternatives, which should be stratified variables in trials when more than one regimen is offered, include weekly paclitaxel plus 3-weekly carboplatin, the addition of bevacizumab to 3-weekly carboplatin and paclitaxel, and intraperitoneal therapy. (iii) Trial Endpoints: overall survival is the preferred primary endpoint for first-line clinical trials with or without a maintenance component. Progression-free survival (PFS) is an alternative primary endpoint, but if PFS is chosen overall survival must be measured as a secondary endpoint and PFS must be supported by additional endpoints, including predefined patient reported outcomes and time to first or second subsequent therapy. For neoadjuvant therapy, additional ‘window of opportunity’ endpoints should be included.
Alternatives to surgery are needed for the treatment of vulvar intraepithelial neoplasia. We investigated the effectiveness of imiquimod 5% cream, a topical immune-response modulator, for the ...treatment of this condition.
Fifty-two patients with grade 2 or 3 vulvar intraepithelial neoplasia were randomly assigned to receive either imiquimod or placebo, applied twice weekly for 16 weeks. The primary outcome was a reduction of more than 25% in lesion size at 20 weeks. Secondary outcomes were histologic regression, clearance of human papillomavirus (HPV) from the lesion, changes in immune cells in the epidermis and dermis of the vulva, relief of symptoms, improvement of quality of life, and durability of response. Reduction in lesion size was classified as complete response (elimination), strong partial response (76 to 99% reduction), weak partial response (26 to 75% reduction), or no response (< or =25% reduction). The follow-up period was 12 months.
Lesion size was reduced by more than 25% at 20 weeks in 21 of the 26 patients (81%) treated with imiquimod and in none of those treated with placebo (P<0.001). Histologic regression was significantly greater in the imiquimod group than in the placebo group (P<0.001). At baseline, 50 patients (96%) tested positive for HPV DNA. HPV cleared from the lesion in 15 patients in the imiquimod group (58%), as compared with 2 in the placebo group (8%) (P<0.001). The number of immune epidermal cells increased significantly and the number of immune dermal cells decreased significantly with imiquimod as compared with placebo. Imiquimod reduced pruritus and pain at 20 weeks (P=0.008 and P=0.004, respectively) and at 12 months (P=0.04 and P=0.02, respectively). The lesion progressed to invasion (to a depth of <1 mm) in 3 of 49 patients (6%) followed for 12 months (2 in the placebo group and 1 in the imiquimod group). Nine patients, all treated with imiquimod, had a complete response at 20 weeks and remained free from disease at 12 months.
Imiquimod is effective in the treatment of vulvar intraepithelial neoplasia. (Current Controlled Trials number, ISRCTN11290871 controlled-trials.com.).
Purpose
The shift from adjuvant to neoadjuvant treatment in colon cancer demands the radiological selection of patients for systemic therapy. The aim of this study was to evaluate the accuracy of the ...CT-based TNM stage and high-risk features, including extramural venous invasion (EMVI) and tumour deposits, in the identification of patients with histopathological advanced disease, currently considered for neoadjuvant treatment (T3-4 disease).
Methods
All consecutive patients surgically treated for non-metastatic colon cancer between January 2018 and January 2020 in a referral centre for colorectal cancer were identified retrospectively. All tumours were staged on CT according to the TNM classification system. Additionally, the presence of EMVI and tumour deposits on CT was evaluated. The histopathological TNM classification was used as reference standard.
Results
A total of 176 patients were included. Histopathological T3-4 colon cancer was present in 85.0% of the patients with CT-detected T3-4 disease. Histopathological T3-4 colon cancer was present in 96.4% of the patients with CT-detected T3-4 colon cancer in the presence of both CT-detected EMVI and CT-detected tumour deposits. Histopathological T0-2 colon cancer was present in 50.8% of the patients with CT-detected T0-2 disease, and in 32.4% of the patients without CT-detected EMVI and tumour deposits.
Conclusion
The diagnostic accuracy of CT-based staging was comparable with previous studies. The presence of high-risk features on CT increased the probability of histopathological T3-4 colon cancer. However, a substantial part of the patients without CT-detected EMVI and tumour deposits was diagnosed with histopathological T3-4 disease. Hence, more accurate selection criteria are required to correctly identify patients with locally advanced disease.
Background
As part of a randomized phase II trial in patients with isolated resectable colorectal peritoneal metastases (CPMs), the present study compared patient-reported outcomes (PROs) of patients ...treated with perioperative systemic therapy versus cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS–HIPEC) alone. Also, PROs of patients receiving perioperative systemic therapy were explored.
Patients and Methods
Eligible patients were randomized to perioperative systemic therapy (experimental) or CRS–HIPEC alone (control). PROs were assessed using EORTC QLQ-C30, QLQ-CR29, and EQ-5D-5L questionnaires at baseline, after neoadjuvant treatment (experimental), and at 3 and 6 months postoperatively. Linear mixed modeling was used to compare five predefined PROs (visual analog scale, global health status, physical functioning, fatigue, C30 summary score) between arms and to longitudinally analyze PROs in the experimental arm.
Results
Of 79 analyzed patients, 37 (47%) received perioperative systemic therapy. All predefined PROs were comparable between arms at all timepoints and returned to baseline at 3 or 6 months postoperatively. The experimental arm had worsening of fatigue mean difference (MD) + 14,
p
= 0.001, loss of appetite (MD + 15,
p
= 0.003), hair loss (MD + 18,
p
< 0.001), and loss of taste (MD + 27,
p
< 0.001) after neoadjuvant treatment. Except for loss of appetite, these PROs returned to baseline at 3 or 6 months postoperatively.
Conclusions
In patients with resectable CPM randomized to perioperative systemic therapy or CRS–HIPEC alone, PROs were comparable between arms and returned to baseline postoperatively. Together with the trial’s previously reported feasibility and safety data, these findings show acceptable tolerability of perioperative systemic therapy in this setting.
Clinically staged T1-3 rectal cancer (cT1-3) is generally treated by total mesorectal excision(TME) with or without neoadjuvant therapy and sometimes requires beyond TME-surgery, whereas cT4 rectal ...cancer often requires both. This study evaluates the outcome of cT1-3 and cT4 rectal cancer according to hospital volume.
Patients undergoing rectal cancer surgery between 2005 and 2013 in the Netherlands were included from the National Cancer Registry. Hospitals were divided into low(1–20), medium(21–50) and high(>50 resections/year) volume for cT1-3 and low(1–4), medium(5–9) and high(≥10 resections/year) volume for cT4 rectal cancer. Cox-proportional hazards model was used for multivariable analysis of overall survival (OS).
A total of 14.050 confirmed cT1-3 patients and 2.104 cT4 patients underwent surgery. In cT1-3 rectal cancer, there was no significant difference in 5-year OS related to high, medium and low hospital volume (70% vs. 69% vs. 69%). In cT4 rectal cancer, treatment in a high volume cT4 hospital was associated with a survival benefit compared to low volume cT4 hospitals (HR 0.81 95%CI 0.67–0.98) adjusted for non-treatment related confounders, but this was not significant after adjustment for neoadjuvant treatment. Patients with cT4-tumours treated in high volume hospitals had a significantly lower age, more synchronous metastases, more patients treated with neoadjuvant therapy and a higher pT-stage.
Hospital volume was not associated with survival in cT1-3 rectal cancer. In cT4 rectal cancer, treatment in high volume cT4 hospitals was associated with improved survival compared to low volume cT4 hospitals, although this association lost statistical significance after correction for neoadjuvant treatment.
ABSTRACT
Background
Failure of chemoradiotherapy (CRT) for anal squamous cell carcinoma (SCC) results in persistent or recurrent anal SCC. Treatment with salvage abdominoperineal resection (APR) can ...potentially achieve cure. The aims of this study are to analyze oncological and surgical outcomes of our 30-year experience with salvage APR for anal SCC after failed CRT and identify prognostic factors for overall survival (OS).
Methods
All consecutive patients who underwent salvage APR between 1990 and 2016 for histologically confirmed persistent or recurrent anal SCC after failed CRT were retrospectively analyzed.
Results
Forty-seven patients underwent salvage APR for either persistent (
n
= 24) or recurrent SCC (
n
= 23). Median OS was 47 months 95% confidence interval (CI) 10.0–84.0 months and 5-year survival was 41.6%, which did not differ significantly between persistent or recurrent disease (
p
= 0.551). Increased pathological tumor size (
p
< 0.001) and lymph node involvement (
p
= 0.014) were associated with impaired hazard for OS on multivariable analysis, and irradical resection only (
p
= 0.001) on univariable analysis. Twenty-one patients developed local recurrence after salvage APR, of whom 8 underwent repeat salvage surgery and 13 received palliative treatment. Median OS was 9 months (95% CI 7.2–10.8 months) after repeat salvage surgery and 4 months (95% CI 2.8–5.1 months) following palliative treatment (
p
= 0.055).
Conclusions
Salvage APR for anal SCC after failed CRT resulted in adequate survival, with 5-year survival of 41.6%. Negative prognostic factors for survival were increased tumor size, lymph node involvement, and irradical resection. Patients with recurrent anal SCC after salvage APR had poor prognosis, irrespective of performance of repeat salvage surgery, which never resulted in cure.
Neoadjuvant chemoradiotherapy (NACRT) has increased local control in locally advanced rectal cancer. Reduced skeletal muscle mass (sarcopenia), or ongoing muscle wasting, is associated with decreased ...survival in cancer. This study aims to assess the change in body composition during NACRT and its impact on outcome using computed tomography (CT) imaging in locally advanced rectal cancer (LARC) patients.
LARC patients treated with NACRT were selected from a prospectively maintained database and retrospectively analyzed. One-hundred twenty-two patients who received treatment between 2004 and 2012 with available diagnostic CT imaging obtained before and after NACRT were identified. Cross-sectional areas for skeletal muscle was determined, and subsequently normalized for patient height. Differences between skeletal muscle areas before and after NACRT were computed, and their influence on overall and disease-free survival was assessed.
A wide distribution in change of body composition was observed. Loss of skeletal muscle mass during chemoradiotherapy was independently associated with disease-free survival (HR0.971; 95% CI: 0.946–0.996; p = 0.025) and distant metastasis-free survival (HR0.942; 95% CI: 0.898–0.988; p = 0.013). No relation was observed with overall survival in the current cohort.
Loss of skeletal muscle mass during NACRT in rectal cancer patients is an independent prognostic factor for disease-free survival and distant metastasis-free survival following curative intent resection.
•Muscle wasting is observed during neoadjuvant chemoradiotherapy for rectal cancer.•This is associated with impaired disease-free survival after surgical resection.•Distant-metastases free survival is markedly reduced.•Despite effect on disease-free survival, overall survival is not impaired.
Rectal cancer surgery is accompanied with high morbidity and poor long term functional outcome. Screening programs have shown a shift towards more early staged cancers. Patients with early rectal ...cancer can potentially benefit significantly from rectal preserving therapy. For the earliest stage cancers, local excision is sufficient when the risk of lymph node disease and subsequent recurrence is below 5 %. However, the majority of early cancers are associated with an intermediate risk of lymph node involvement (5-20 %) suggesting that local excision alone is not sufficient, while completion radical surgery, which is currently standard of care, could be a substantial overtreatment for this group of patients.
In this multicentre randomised trial, patients with an intermediate risk T1-2 rectal cancer, that has been locally excised using an endoluminal technique, will be randomized between adjuvant chemo-radiotherapylimited to the mesorectum and standard completion total mesorectal excision (TME). To strictly monitor the risk of locoregional recurrence in the experimental arm and enable early salvage surgery, there will be additional follow up with frequent MRI and endoscopy. The primary outcome of the study is three-year local recurrence rate. Secondary outcomes are morbidity, disease free and overall survival, stoma rate, functional outcomes, health related quality of life and costs. The design is a non inferiority study with a total sample size of 302 patients.
The results of the TESAR trial will potentially demonstrate that adjuvant chemoradiotherapy is an oncological safe treatment option in patients who are confronted with the difficult clinical dilemma of a radically removed intermediate risk early rectal cancer by polypectomy or transanal surgery that is conventionally treated with subsequent radical surgery. Preserving the rectum using adjuvant radiotherapy is expected to significantly improve morbidity, function and quality of life if compared to completion TME surgery.
NCT02371304 , registration date: February 2015.
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