Small bowel adenocarcinoma (SBA) is rare despite the fact that the small bowel represents the longest part and has the largest surface of all alimentary tract sections. Its incidence is 50-fold lower ...than that of colorectal carcinoma. It is often diagnosed at an advanced stage due to atypical and late symptoms, its low index of suspicion, difficult endoscopic access and poor detection by radiological imaging, resulting in impaired outcome. Due to its rarity and being molecularly a unique intestinal cancer, data regarding its optimal management are relatively sparse.
A PubMed search was performed to identify relevant manuscripts that were recently published. Emerging data regarding the pathogenesis, the diagnosis and the treatment of SBA that resulted from recent research are discussed in this comprehensive review.
Genomic analysis has demonstrated that SBA is a molecularly unique intestinal cancer. Double balloon enteroscopy and capsule endoscopy are novel techniques which may result in earlier diagnosis and consequently in improvement of the generally poor prognosis. For clinically localized disease, the quality of surgery has recently been defined, with removal of at least 8-10 lymph nodes correlating with improved prognosis. Moreover, adjuvant chemotherapy seems to improve outcome of stage III disease. The combination of a fluoropyrimidine and oxaliplatin appears to be the most effective systemic chemotherapy for disseminated disease. Genomic profiling can identify potentially targetable genomic alterations in a significant proportion of SBA patients. The role of administration of targeted agents or immune checkpoint inhibitors is still unknown and subject of ongoing clinical trials. In the common case of peritoneal metastases, recent studies have shown that cytoreductive surgery and intraoperative hyperthermic intraperitoneal chemotherapy may be an attractive treatment option in selected patients.
SBA is a rare and unique malignancy, whose diagnostic approach and treatment are evolving, resulting in improved outcome.
Background
Careful selection of patients with colorectal peritoneal metastases (PM) for cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC) is crucial. It remains ...unknown whether the time of onset of colorectal PM (synchronous vs metachronous) influences surgical morbidity and survival outcomes after CRS with HIPEC.
Methods
Patients with histologically proven colorectal PM who underwent CRS with HIPEC between February 2006 and December 2017 in two Dutch tertiary referral hospitals were retrospectively included from a prospectively maintained database. The onset of colorectal PM was classified as synchronous (PM diagnosed at the initiational presentation with colorectal cancer) or metachronous (PM diagnosed after initial curative colorectal resection). Major postoperative complications (Clavien–Dindo grade ≥ 3), overall survival (OS), and disease-free survival (DFS) were compared between patients with synchronous colorectal PM and those with metachronous colorectal PM using Kaplan–Meier analyses, proportional hazard analyses, and a multivariate Cox regression analysis.
Results
The study enrolled 433 patients, of whom 231 (53%) had synchronous colorectal PM and 202 (47%) had metachronous colorectal PM. The major postoperative complication rate and median OS were similar between the patients with synchronous colorectal PM and those with metachronous colorectal PM (26.8% vs 29.7%;
p
= 0.693 and 34 vs 33 months, respectively;
p
= 0.819). The median DFS was significantly decreased for the patients with metachronous colorectal PM and those with synchronous colorectal PM (11 vs 15 months; adjusted hazard ratio, 1.63; 95% confidence interval, 1.18–2.26).
Conclusions
Metachronous onset of colorectal PM is associated with early recurrence after CRS with HIPEC compared with synchronous colorectal PM, without a difference in OS or major postoperative complications. Time to onset of colorectal PM should be taken into consideration to optimize patient selection for this major procedure.
Background
Electrostatic pressurized intraperitoneal aerosol chemotherapy (ePIPAC) is a palliative treatment for unresectable peritoneal metastases from various primary cancers. However, little is ...known about the systemic pharmacokinetics of oxaliplatin after ePIPAC.
Methods
Twenty patients with unresectable colorectal peritoneal metastases were treated with repetitive ePIPAC monotherapy with oxaliplatin (92 mg/m
2
) and a simultaneous intravenous bolus of leucovorin (20 mg/m
2
) and 5-fluorouracil (400 mg/m
2
). Samples were collected during each ePIPAC: whole blood at
t
= 0,
t
= 5,
t
= 10,
t
= 20,
t
= 30,
t
= 60,
t
= 120,
t
= 240,
t
= 360 and
t
= 1080 min for plasma and plasma ultrafiltrate concentrations; urine at
t
= 0,
t
= 1,
t
= 3,
t
= 5 and
t
= 7 days. Samples were analyzed using atomic absorption spectrometry. Pharmacokinetics were analyzed using nonlinear mixed-effects modeling.
Results
Four patients received one ePIPAC, three patients received two ePIPAC, and thirteen patients received ≥ 3 ePIPAC. The population pharmacokinetic models adequately described the pharmacokinetics of oxaliplatin after ePIPAC. The plasma ultrafiltrate
C
max
of oxaliplatin reached 1.36–1.90 µg/mL after 30 min with an AUC
0–24 h
of 9.6–11.7 µg/mL * h. The plasma
C
max
reached 2.67–3.28 µg/mL after 90 min with an AUC
0–24 h
of 49.0–59.5 µg/mL * h. The absorption rate constant (Ka) was 1.13/h. Urine concentrations of oxaliplatin rapidly decreased to less than 3.60 µg/mL in 90% of the samples at day 7.
Discussion
Systemic exposure to oxaliplatin after ePIPAC seemed comparable to that after systemic chemotherapy, as described in other literature. Since this is an indirect comparison, future research should focus on the direct comparison between the systemic exposure to oxaliplatin after ePIPAC and after systemic chemotherapy.
Trial registration:
NCT03246321, Pre-results; ISRCTN89947480, Pre-results; NTR6603, Pre-results; EudraCT: 2017-000927-29, Pre-results.
Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) is a viable option for selected patients with peritoneal metastases (PM) from colorectal origin, resulting in ...long-term survival and even cure in some cases. However, adequate patient selection for this treatment is currently one of the major challenges. The aim of this review is to provide a comprehensive overview of clinically relevant factors associated with overall survival. This may help to guide clinicians through the complex interplay of patient, tumor, and treatment characteristics to adequately select patients who benefit the most from this extensive surgical treatment. First, basic principles of colorectal PM and the CRS and HIPEC treatment will be discussed. According to available literature, especially extent of peritoneal disease, completeness of cytoreduction, and signet ring cell histology have great influence on the outcome after CRS and HIPEC. Other factors that seem to have a negative prognostic value are the presence of liver metastases and the absence of treatment with neo-adjuvant systemic therapy. Prognostic models combining the above-mentioned factors, such as the Colorectal Peritoneal Metastases Prognostic Surgical Score nomogram, may provide clinically relevant tools to use in everyday practice.
Limitations of the PRODIGE 7 trial Rovers, Koen P; Kok, Niels F M; Punt, Cornelis J A ...
The lancet oncology,
20/May , Letnik:
22, Številka:
5
Journal Article
Recenzirano
...the trial report does not provide data on the potentially relevant proportion of these patients who did not proceed to cytoreductive surgery and subsequent trial enrolment for reasons such as ...progressive disease. ...it is unclear whether these patients differed from the 265 patients who were eventually enrolled in the PRODIGE 7 trial. Of the 219 patients who received preoperative systemic therapy, only one discontinued systemic treatment because of progressive disease. ...the PRODIGE 7 trial probably enrolled a selected population with favourable tumour biology, which is reflected by the unexpectedly high survival rates. ...the suggested inefficacy of oxaliplatin-based HIPEC, or HIPEC in general (as prematurely concluded by others3), should not be automatically extrapolated to patients undergoing upfront cytoreductive surgery, which is the standard of care for newly diagnosed resectable colorectal peritoneal metastases in many hospitals and countries due to the absence of prospective, high-quality data on the value of preoperative or perioperative systemic therapy in this setting.4,5 Therefore, additional randomised trials evaluating innovative, evidence-based intraperitoneal drug regimens after upfront cytoreductive surgery are warranted.
Background/purpose: Peritoneal metastases (PM) affect approximately one third of patients with metastatic small bowel adenocarcinoma (SBA). Treatment options are (1) systemic therapy ± palliative ...surgery and (2) cytoreductive surgery with intraperitoneal chemotherapy (CRS + IPC). Due to scarce evidence, PM from SBA represents a therapeutic challenge. This narrative review summarised and discussed the evidence that investigated available treatment options.
Methods: Studies were discussed if they investigated first line systemic therapy for advanced SBA or CRS + IPC for PM from SBA. Extracted outcomes were objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), disease-free survival (DFS), overall survival (OS), and grade III-V toxicity/morbidity.
Results: Eighteen studies (15 observational, 3 phase II) that investigated systemic therapy and six observational studies that investigated CRS + IPC were reviewed. In studies that investigated systemic therapy, ORR, DCR, median PFS, median OS, and grade III-V toxicity ranged from 6% to 50%, 50% to 90%, 3 to 11 months, 8 to 20 months, and 10% to 68%, respectively. Fluoropyrimidine-oxaliplatin revealed favourable survival outcomes compared to fluoropyrimidine-irinotecan, fluoropyrimidine-cisplatin, fluoropyrimidine monotherapy, and other regimens. In studies that investigated CRS + IPC, median DFS, median OS, and grade III-V morbidity ranged from 10 to 12 months, 16 to 47 months, and 12% to 35%, respectively.
Conclusion: Based on available evidence, fluoropyrimidine-oxaliplatin should be regarded as optimal first line systemic treatment. In selected patients, CRS + IPC appears safe and may be more effective than systemic therapy as single treatment. Future studies should evaluate survival and morbidity of CRS + IPC in larger cohorts, as well as the value of chemotherapy with targeted agents in metastatic SBA with subgroup analysis for PM from SBA.
Background
CRC-PIPAC prospectively assessed repetitive oxaliplatin-based pressurized intraperitoneal aerosol chemotherapy (PIPAC-OX) as a palliative monotherapy (i.e., without concomitant systemic ...therapy in between subsequent procedures) for unresectable colorectal peritoneal metastases (CPM). The present study explored patient-reported outcomes (PROs) during trial treatment.
Methods
In this single-arm phase 2 trial in two tertiary centers, patients with isolated unresectable CPM received 6-weekly PIPAC-OX (92 mg/m
2
). PROs (calculated from EQ-5D-5L, and EORTC QLQ-C30 and QLQ-CR29) were compared between baseline and 1 and 4 weeks after the first three procedures using linear mixed modeling with determination of clinical relevance (Cohen’s
D
≥ 0.50) of statistically significant differences.
Results
Twenty patients underwent 59 procedures (median 3 range 1–6). Several PROs solely worsened 1 week after the first procedure (index value − 0.10,
p
< 0.001; physical functioning − 20,
p
< 0.001; role functioning − 27,
p
< 0.001; social functioning − 18,
p
< 0.001; C30 summary score − 16,
p
< 0.001; appetite loss + 15,
p
= 0.007; diarrhea + 15,
p
= 0.002; urinary frequency + 13,
p
= 0.004; flatulence + 13,
p
= 0.001). These PROs returned to baseline at subsequent time points. Other PROs worsened 1 week after the first procedure (fatigue + 23,
p
< 0.001; pain + 29,
p
< 0.001; abdominal pain + 32,
p
< 0.001), second procedure (fatigue + 20,
p
< 0.001; pain + 21,
p
< 0.001; abdominal pain + 20,
p
= 0.002), and third procedure (pain + 22,
p
< 0.001; abdominal pain + 22,
p
= 0.002). Except for appetite loss, all changes were clinically relevant. All analyzed PROs returned to baseline 4 weeks after the third procedure.
Conclusions
Patients receiving repetitive PIPAC-OX monotherapy for unresectable CPM had clinically relevant but reversible worsening of several PROs, mainly 1 week after the first procedure.
Trial registration
Clinicaltrials.gov: NCT03246321; Netherlands trial register: NL6426.
Complications after cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) result in impaired short- and long-term outcomes. However, financial consequences of ...complications after CRS and HIPEC in a European health care setting are unknown. This study aims to assess the consequences of complications on hospital costs after CRS and HIPEC.In this prospective observational cohort study, patients with colorectal peritoneal metastases treated with CRS and HIPEC were included. Financial information was collected according to the Dutch manual for costs analyses. Costs were compared between patients without complications (NC), minor complications (MC), or severe complications (SC), according to the Clavien-Dindo classification.One hundred and sixty-one patients were included, of whom 42% experienced NC, 27% MC and 31% SC. Mean hospital costs were 9.406 ± 2.235 in NC patients, 12.471 ± 3.893 in MC patients, and 29.409 ± 22.340 in SC patients. The 31% of patients with severe complications accounted for 56% of all hospital costs. Hospital admission costs in SC patients were 320% higher compared to NC patients. Costs of complications were estimated to be 43% of all admission costs.Severe postoperative complications have major influence on costs after CRS and HIPEC and result in a threefold increase of hospital costs in affected patients. This finding stresses the need for adequate risk assessment of developing severe complications after CRS and HIPEC.
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