Adjuvant Therapy for Patients with a Tumor-Positive Resection Margin After Neoadjuvant Chemoradiotherapy and Esophagectomy.

BACKGROUND: Approximately 4-9% of patients have a tumor-positive resection margin after neoadjuvant chemoradiotherapy (nCRT) and esophagectomy. Although it is associated with decreased survival, Western guidelines do not recommend adjuvant treatment. OBJECTIVE: The aim of this study was to assess the proportion of patients who received adjuvant therapy, and to evaluate overall survival (OS) after esophagectomy in patients with a tumor-positive resection margin. METHODS: Patients diagnosed with resectable (cT2-4a/cTxN0-3/NxM0) esophageal cancer between 2015 and 2022, and treated with nCRT followed by irradical esophagectomy, were selected from the Netherlands Cancer Registry. The primary outcome was the proportion of patients with a tumor-positive resection margin who started adjuvant treatment ≤16 weeks after esophagectomy, including chemotherapy/radiotherapy, immunotherapy, or targeted therapy. OS was calculated from the date of surgery until the date of death or last day of follow-up. RESULTS: Overall, 376 patients were included in our study, of whom 357 were treated with nCRT. Of these 357 patients, 98.3% had a microscopically irradical resection and 1.7% had a macroscopically irradical resection. Approximately 72.3% of tumors showed a partial response (Mandard 2-3) and 11.8% showed little/no pathological response (Mandard 4-5) to nCRT. One of 357 patients underwent adjuvant chemoradiotherapy and 39 patients (61%) underwent adjuvant immunotherapy (nivolumab). The median and 5-year OS rate of all patients was 16.4 months (95% confidence interval 13.1-19.8) and 21%, respectively. CONCLUSION: Real-world population-level data showed that no patients with a tumor-positive resection margin underwent adjuvant therapy following nCRT and esophagectomy prior to 2021. Interestingly, 61% of patients were treated with adjuvant nivolumab in 2021-2022. OS after irradical esophagectomy is poor and long-term data will explore the added value of nivolumab.

Stereotactic ablative radiotherapy or best supportive care in patients with localized pancreatic cancer not receiving chemotherapy and surgery (PANCOSAR): a nationwide multicenter randomized controlled trial according to a TwiCs design.

BACKGROUND: Significant comorbidities, advanced age, and a poor performance status prevent surgery and systemic treatment for many patients with localized (non-metastatic) pancreatic ductal adenocarcinoma (PDAC). These patients are currently treated with 'best supportive care'. Therefore, it is desirable to find a treatment option which could improve both disease control and quality of life in these patients. A brief course of high-dose high-precision radiotherapy i.e. stereotactic ablative body radiotherapy (SABR) may be feasible. METHODS: A nationwide multicenter trial performed within a previously established large prospective cohort (the Dutch Pancreatic cancer project; PACAP) according to the 'Trial within cohorts' (TwiCs) design. Patients enrolled in the PACAP cohort routinely provide informed consent to answer quality of life questionnaires and to be randomized according to the TwiCs design when eligible for a study. Patients with localized PDAC who are unfit for chemotherapy and surgery or those who refrain from these treatments are eligible. Patients will be randomized between SABR (5 fractions of 8 Gy) with 'best supportive care' and 'best supportive care' only. The primary endpoint is overall survival from randomization. Secondary endpoints include preservation of quality of life (EORTC-QLQ-C30 and -PAN26), NRS pain score response and WHO performance scores at baseline, and, 3, 6 and 12 months. Acute and late toxicity will be scored using CTCAE criteria version 5.0: assessed at baseline, day of last fraction, at 3 and 6 weeks, and 3, 6 and 12 months following SABR. DISCUSSION: The PANCOSAR trial studies the added value of SBRT as compared to 'best supportive care' in patients with localized PDAC who are medically unfit to receive chemotherapy and surgery, or refrain from these treatments. This study will assess whether SABR, in comparison to best supportive care, can relieve or delay tumor-related symptoms, enhance quality of life, and extend survival in these patients. TRIAL REGISTRATION: Clinical trials, NCT05265663 , Registered March 3 2022, Retrospectively registered.

Relation between body composition and severe diarrhea in patients treated with preoperative chemoradiation with capecitabine for rectal cancer: a single-centre cohort study.

BACKGROUND: Chemoradiation with capecitabine followed by surgery is standard care for locally advanced rectal cancer (LARC). Severe diarrhea is considered a dose-limiting toxicity of adding capecitabine to radiation therapy. The aim of this study was to describe the risk factors and the impact of body composition on severe diarrhea in patients with LARC during preoperative chemoradiation with capecitabine. METHODS: A single centre retrospective cohort study was conducted in a tertiary referral centre. All patients treated with preoperative chemoradiation with capecitabine for LARC from 2009 to 2015 were included. Patients with locally recurrent rectal cancer who received chemoradiation for the first time were included as well. Logistic regression analyses were performed to identify risk factors for severe diarrhea. RESULTS: A total of 746 patients were included. Median age was 64 years (interquartile range 57-71) and 477 patients (64%) were male. All patients received a radiation dosage of 25 × 2 Gy during a period of five weeks with either concomitant capecitabine administered on radiation days or continuously during radiotherapy. In this cohort 70 patients (9%) developed severe diarrhea. In multivariable logistic regression analyses female sex (OR: 4.42, 95% CI 2.54-7.91) and age ≥ 65 (OR: 3.25, 95% CI 1.85-5.87) were the only risk factors for severe diarrhea. CONCLUSIONS: Female patients and patients aged sixty-five or older had an increased risk of developing severe diarrhea during preoperative chemoradiation therapy with capecitabine. No relation was found between body composition and severe diarrhea.

The clinical relevance of indeterminate lung nodules in patients with locally recurrent rectal cancer.

AIM: To evaluate the clinical relevance of indeterminate lung nodules (ILN) in patients with locally recurrent rectal cancer (LRRC) treated in a tertiary referral centre. METHODS: All patients with LRRC diagnosed between 2000 and 2017 were retrospectively reviewed. Reports of staging chest CT-scans were evaluated for ILN. Patients with distant metastases including lung metastases at time of LRRC diagnosis were excluded. Overall (OS), progression-free survival (PFS) and the cumulative incidence of lung metastases were compared between patients with and without ILN. RESULTS: In total 556 patients with LRRC were treated during the study period. In the 243 patients eligible for analysis, 68 (28%) had ILN at LRRC diagnosis. Median OS was 37 months for both the patients with and without ILN (p = 0.37). Median PFS was 14 months for the patients with ILN and 16 months for patients without ILN (p = 0.80). After correction for potential confounding, ILN present at LRRC diagnosis was not associated with impaired OS or PFS (adjusted hazards ratio [95% confidence interval]: 0.81 [0.54-1.22] and 1.09 [0.75-1.59]). The 5-year cumulative incidence of lung metastases was 31% in patients with ILN and 28% in patients without ILN (p = 0.19). CONCLUSION: Our study shows that ILN are present in roughly a quarter of patients with LRRC. No differences in OS, PFS, or the cumulative incidence of lung metastases were found between patients with and without ILN at LRRC diagnosis. These results suggest that ILN are of little to no clinical relevance in patients with LRRC.

Locally recurrent rectal cancer; long-term outcome of curative surgical and non-surgical treatment of 447 consecutive patients in a tertiary referral centre.

INTRODUCTION: 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. METHODS: 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. RESULTS: 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). CONCLUSION: 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.

Treatment of Inguinal Lymph Node Metastases in Patients with Rectal Adenocarcinoma.

BACKGROUND: Inguinal lymph node metastases (ILNM) from rectal adenocarcinoma are rare and staged as systemic disease. This study aimed to provide insight into the treatment and prognosis of ILNM from rectal adenocarcinoma. METHODS: All patients with a diagnosis of synchronous or metachronous ILNM from rectal adenocarcinoma between January 2005 and March 2017 were retrospectively reviewed. RESULTS: The study identified 27 patients with ILNM (15 with synchronous and 12 with metachronous disease). After discussion by a multidisciplinary tumor board, 19 patients were treated with curative intent, 17 of whom underwent inguinal lymph node dissection. Of the 17 patients, 12 had locally advanced rectal cancer (LARC) with isolated ILNM, 3 had LARC and metastases elsewhere, and 2 had locally recurrent rectal cancer (LRRC). The median overall survival (OS) for all the patients treated with curative intent was 27 months [95% confidence interval (CI) 11.6-42.4 months], with a 5-year OS rate of 34%. The median OS for the patients with LARC and isolated ILNM (n = 12) was 74 months (95% CI 18.0-130.0 months), with a 5-year OS rate of 52%. All the patients with metastases elsewhere (n = 3) or LRRC (n = 2) experienced recurrent systemic disease. Eight patients were treated with palliative intent. The median OS for this group was 13 months (95% CI 1.9-24.1 months), with a 3-year OS rate of 0%. CONCLUSION: Clinicians should not consider ILNM as an incurable systemic disease. Patients with primary rectal cancer and solitary ILNM who were eligible for curative surgical treatment had a 5-year survival rate of 52%. The prognosis for patients with additional systemic metastases or LRRC is worse, and the benefit of surgery is unclear.

The liver-first approach for locally advanced rectal cancer and synchronous liver metastases.

BACKGROUND: Patients with locally advanced rectal cancer (LARC) and synchronous liver metastases (sRLM) can be treated according to the liver-first approach. This study aimed to evaluate prognostic factors for completing treatment and in how many patients extensive lower pelvic surgery might have been omitted. METHODS: Retrospective analysis of all patients with LARC and sRLM treated at the Erasmus MC Cancer Institute according to the liver-first between 2003 and 2016. RESULTS: In total 129 consecutive patients were included. In 90 patients (70%) the liver-first was completed. Ten patients had a (near) complete response (ypT0-1N0) of their primary tumour. In 36 out of 39 patients not completing the liver-first protocol palliative rectum resection was withheld. Optimal cut-offs for CEA level (53.15 µg/L), size (3.85 cm) and number (4) of RLMs were identified. A preoperative CEA level above 53.15 µg/L was an independent predictor for non-completion of the liver-first protocol (p = 0.005). CONCLUSION: Ten patients had a (near) complete response of their primary tumour and, in retrospect, rectum sparing therapies could have been considered. Together with 36 patient in whom palliative rectum resection was not necessary this entails that nearly 40% patients with LARC and sRLM might be spared major pelvic surgery if the liver-first approach is applied. A predictor (CEA) was found for non-completion of the liver-first protocol. The majority of patients underwent resection of both primary tumour and hepatic metastasis with curative intent. These findings together entail that the liver-first approach may be considered in patients with LARC and sRLM.

Neoadjuvant chemoradiotherapy for resectable oesophageal cancer.

At present, treatment of potentially curable oesophageal cancer includes neoadjuvant chemoradiotherapy followed by oesophagectomy. Alternatively, neoadjuvant chemotherapy is used. To date, strong evidence on the superiority of one modality over the other has not been provided. Currently, up to one-third of patients show a pathologically complete response after neoadjuvant chemoradiotherapy. To optimise the efficacy of neoadjuvant treatment for individual patients, prediction of response to neoadjuvant treatment is highly desired. Therefore, several clinical diagnostic modalities have been investigated for early response evaluation, of which positron emission tomography (PET) has been studied most extensively. To identify patients who might benefit from postponing or even omitting surgery, recent advances have been made in evaluating response after completion of neoadjuvant chemoradiotherapy. This review provides an overview of current evidence and recent advances in neoadjuvant chemoradiotherapy for oesophageal cancer and discusses the use of neoadjuvant chemotherapy compared to chemoradiotherapy. Moreover, clinical response evaluation to neoadjuvant chemoradiotherapy is reviewed.

Total pelvic exenteration for locally advanced and locally recurrent rectal cancer in the elderly.

BACKGROUND: Total pelvic exenteration (TPE) is a radical approach for locally advanced rectal cancer (LARC) and locally recurrent rectal cancer (LRRC) in case of tumour invasion into the urogenitary tract. The aim of this study is to assess surgical and oncological outcomes of TPE for LARC and LRRC in elderly patients compared to younger patients. METHODS: All patients who underwent TPE for LARC and LRRC between January 1990 and March 2017 were retrospectively analyzed. Patients aged <70 years were classified as younger and ≥70 years as elderly patients. RESULTS: In total 126 patients underwent TPE, of whom 88 younger and 38 elderly patients. Elderly patients had a significantly higher number of ASA > II patients (p = 0.01). Indication for surgery LARC (n = 73) and LRRC (n = 53) did not differ significantly. The 30-day mortality rate was significantly higher (p = 0.01) in elderly (13%) compared to younger patients (3%). Elderly patients experienced more anastomotic leakage (p = 0.02). Median overall survival (OS) was 75 months [95%CI 37.1; 112.9] for elderly and 45 months [95%CI 22.4; 67.8] for younger patients (p = 0.77). The 5-year OS rate was 44% in both groups. Median disease specific survival (DSS) was 78 months [95%CI 69.1; 86.9] for elderly and 60 months [95%CI 36.6; 83.4] for younger patients (p = 0.34). The 5-year DSS rate was 57% and 49%, respectively. CONCLUSION: TPE is an invasive treatment for rectal cancer with high 30-day mortality in elderly patients. Oncological outcomes are similar in elderly and younger patients. Therefore, TPE should not be withheld because of high age only, but careful patient selection is needed.

Treatment selection of early stage non-small cell lung cancer: the role of the patient in clinical decision making.

BACKGROUND: The objective of this study is to investigate the role and experience of early stage non-small cell lung cancer (NSCLC) patient in decision making process concerning treatment selection in the current clinical practice. METHODS: Stage I-II NSCLC patients (surgery 55 patients, SBRT 29 patients, median age 68) were included in this prospective study and completed a questionnaire that explored: (1) perceived patient knowledge of the advantages and disadvantages of the treatment options, (2) experience with current clinical decision making, and (3) the information that the patient reported to have received from their treating physician. This was assessed by multiple-choice, 1-5 Likert Scale, and open questions. The Decisional Conflict Scale was used to assess the decisional conflict. Health related quality of life (HRQoL) was measured with SF-36 questionnaire. RESULTS: In 19% of patients, there was self-reported perceived lack of knowledge about the advantages and disadvantages of the treatment options. Seventy-four percent of patients felt that they were sufficiently involved in decision-making by their physician, and 81% found it important to be involved in decision making. Forty percent experienced decisional conflict, and one-in-five patients to such an extent that it made them feel unsure about the decision. Subscores with regard to feeling uninformed and on uncertainty, contributed the most to decisional conflict, as 36% felt uninformed and 17% of patients were not satisfied with their decision. HRQoL was not influenced by patient experience with decision-making or patient preferences for shared decision making. CONCLUSIONS: Dutch early-stage NSCLC patients find it important to be involved in treatment decision making. Yet a substantial proportion experiences decisional conflict and feels uninformed. Better patient information and/or involvement in treatment-decision-making is needed in order to improve patient knowledge and hopefully reduce decisional conflict.

Chemoradiation therapy for rectal cancer in the distal rectum followed by organ-sparing transanal endoscopic microsurgery (CARTS study).

BACKGROUND: This prospective multicentre study was performed to quantify the number of patients with minimal residual disease (ypT0-1) after neoadjuvant chemoradiotherapy and transanal endoscopic microsurgery (TEM) for rectal cancer. METHODS: Patients with clinically staged T1-3 N0 distal rectal cancer were treated with long-course chemoradiotherapy. Clinical response was evaluated 6-8 weeks later and TEM performed. Total mesorectal excision was advocated in patients with residual disease (ypT2 or more). RESULTS: The clinical stage was cT1 N0 in ten patients, cT2 N0 in 29 and cT3 N0 in 16 patients. Chemoradiotherapy-related complications of at least grade 3 occurred in 23 of 55 patients, with two deaths from toxicity, and two patients did not have TEM or major surgery. Among 47 patients who had TEM, ypT0-1 disease was found in 30, ypT0 N1 in one, ypT2 in 15 and ypT3 in one. Local recurrence developed in three of the nine patients with ypT2 tumours who declined further surgery. Postoperative complications grade I-IIIb occurred in 13 of 47 patients after TEM and in five of 12 after (completion) surgery. After a median follow-up of 17 months, four local recurrences had developed overall, three in patients with ypT2 and one with ypT1 disease. CONCLUSION: TEM after chemoradiotherapy enabled organ preservation in one-half of the patients with rectal cancer.

Staging for locally advanced pancreatic cancer.

AIM: To address the role of a dedicated radiologist and high quality CT scanning in staging of patients referred with suspected locally advanced pancreatic cancer. Furthermore, the value of laparoscopy in detecting CT-occult metastases in these patients was assessed. METHODS: In a prospective cohort study, 116 patients with suspected unresectable pancreatic cancer referred from peripheral hospitals (107) or our own gastroenterology department (9) were analysed. CT scans from referral centres were reviewed and in case of locally advanced disease or uncertain metastatic disease, patients underwent a laparoscopy to detect CT-occult metastases. Patients without metastases were offered 5-FU based chemoradiotherapy. RESULTS: After reviewing 107 abdominal CT scans from referral centres, 73 (68%) scans had to be repeated due to unacceptable quality. Locally advanced disease was confirmed in 59 (55%) patients and metastatic disease was found in 24 patients (22%). During laparoscopy, metastases were found in 24/68 (35%) patients with locally advanced disease on CT scan and metastases were confirmed in 3/5 (60%) with suspected metastases. Overall, only 46/116 (40%) patients with suspected unresectable disease appeared to have locally advanced pancreatic cancer after adequate staging including laparoscopy in our centre. CONCLUSION: Correct staging is difficult in patients with suspected locally advanced pancreatic cancer and should preferably be performed in centres with technically advanced equipment and experienced radiologists. Laparoscopy should be offered to patients before locoregional therapy.

Total pelvic exenteration for primary locally advanced and locally recurrent rectal cancer.

AIMS: To report the role of total pelvic exenteration in a series of locally advanced and recurrent rectal cancers. METHODS: In the period 1994-2004, TPE was performed in 35 of 296 patients with primary locally advanced and recurrent rectal cancer treated in the Daniel den Hoed Cancer Center; 23 of 176 with primary locally advanced and 12 of 120 with recurrent rectal cancer. All but one patient received pre-operative External Beam Radiation Therapy (EBRT). After 1997, Intra Operative Radiotherapy (IORT) was performed in case of a resection margin less than 2 mm. RESULTS: Overall major complication rates were not significantly different between patients with primary and recurrent rectal cancer (26% vs. 50%, p=0.94). The hospital mortality rate was 3%. The 5-year local control and overall survival of patients with primary locally advanced rectal cancer were 88% and 52%, respectively. In patients with recurrent rectal cancer 3-year local control and survival rates were 60% and 32%, respectively. An incomplete resection, preoperative pain and advanced Wanebo stage for recurrent cancer were negative prognostic factors for both local control and overall survival. CONCLUSION: TPE in primary locally advanced rectal cancer enables good local control and acceptable overall survival, thereby justifying the use of the procedure. Patients with recurrent rectal cancer showed a high rate of major complications, a high distant metastasis rate, and a poor overall survival.