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Challenges and Opportunities in Liver Cancer

Challenges and Opportunities in Liver Cancer

Rod J. Nault
Anesthesia residency, Anesthesiology Institute, Cleveland Clinic, Cleveland, Ohio; Department of OUTCOMES RESEARCH, Cleveland Clinic, Cleveland, Ohio

Quinton Riter
Anesthesia residency, Anesthesiology Institute, Cleveland Clinic, Cleveland, Ohio; Department of OUTCOMES RESEARCH, Cleveland Clinic, Cleveland, Ohio

Daniel I. Sessler
Anesthesia residency, Anesthesiology Institute, Cleveland Clinic, Cleveland, Ohio; Department of OUTCOMES RESEARCH, Cleveland Clinic, Cleveland, Ohio

Abstract

Cancer is the second-leading cause of death worldwide. The initial treatment for nearly all solid cancers is surgical resection of a primary tumor. While tumors can usually be grossly removed, surgical interventions release tumor cells into the lymphatics and vascular beds1. Whether circulating tumor cells develop into clinical metastases depends largely on host defense, mostly natural killer cell function2,3.

Surgery and opioids have the potential to shift the disease-patient relationship towards cancers via at least three major avenues. One is the surgical intervention itself that depresses cell-mediated immunity, reduces concentrations of anti-angiogenic factors, and increases pro-angiogenic factors and release of growth factors that stimulate cancer cells1,3-8. Another factor is general anesthesia, which impairs the function of several immune cells important for anti-metastatic immune activity9. A third factor is the use of opioids for pain management which inhibit cellular and humoral immunity, and might even promote angiogenesis and tumor growth10-12.

Regional anesthesia and analgesia techniques attenuate perioperative tumor-promoting effects by blocking afferent signaling to the central nervous system. Thus, regional techniques might reduce the neuroendocrine response to surgery more effectively than general anesthesia. Furthermore, regional analgesia decreases the need for volatile anesthetics and opioids. Regional analgesia might thus help maintain perioperative anti-cancer immune function, notably natural killer cell activity, and thus reduce the risk of circulating tumor cells developing into clinical metastases13-16.

Potential benefit of regional analgesia for cancer recurrence is supported by animal investigations. For example, a study in rats compared halothane alone combined with either systemic morphine or with spinal block using bupivacaine with morphine. General anesthesia alone increased tumor retention in the lungs by up to 17-fold.  Additionally, natural killer cell activity was depressed by general anesthesia7. Another study compared general anesthesia with sevoflurane alone versus spinal blocks combining bupivacaine and morphine. Addition of the spinal block to general anesthesia attenuated suppression of tumoricidal liver mononuclear cells and consequently reduced promotion of tumor metastasis17. Animal evidence is thus largely consistent in suggesting benefit from regional analgesia and from reducing volatile anesthesia and opioid use.

Subsequent retrospective analyses in humans were encouraging. One compared combined general anesthesia with paravertebral analgesia versus general with morphine analgesia for breast cancer and reported that paravertebral analgesia reduced cancer recurrence18.  Another retrospective analysis reported that epidural analgesia reduced biochemical recurrence of prostate cancer by 57%19. However, many other retrospective analyses found no association between regional anesthesia and cancer outcomes20-23, leaving the overall record mixed.

Because purpose-designed trials of cancer recurrence naturally take a long time, investigators initially re-purposed previous randomized trials that were conducted for other purposes. For example, a team re-evaluated patients who participated in the MASTER trial.24 They identified 503 patients who had surgery for cancer and were able to obtain long-term follow-up information in 446 of them. Two other re-analyses evaluated 99 patients who had prostatectomies for prostate cancer comparing general to general plus epidural analgesia and 132 patients who had intra-abdominal surgery via midline or bilateral subcostal incisions for non-benign cancer resection comparing general anesthesia with epidural blocks versus with fentanyl analgesia followed by continuous subcutaneous morphine. None of these trials demonstrated notable differences in cancer-associated outcomes25,26. The only exception was a re-analysis that compared survival in patients randomized to general anesthesia with and without epidural supplementation for colon cancer surgery. A post hoc subgroup analysis implausibly found enhanced survival in the epidural group only in patients without metastasis before 1.5 years27. Analyses of trials conducted for other purposes thus provide little support for a benefit of regional analgesia for reducing cancer recurrence.

There have been three major trials of regional analgesia on cancer recurrence. The first randomized 2,132 patients having potentially curative primary breast cancer surgery to paravertebral analgesia or conventional opioid analgesia. Cancer recurrence was similar in each group after a median follow-up time of 36 months (hazard ratio 0.97, 95% CI 0.74–1.28; p=0.84). The authors noted that breast surgery causes less operative stress and pain than major abdominal and thoracic surgery, and postulated that regional analgesia might yet be beneficial for such cases.28

The next trial therefore compared overall survival and cancer-free survival in patients randomized to combined general-epidural anesthesia versus general anesthesia alone for major abdominal cancer resections. In a total of 1,712 patients with a median follow-up duration of 66 months, there were no differences in terms of mortality (adjusted hazard ratio, 1.07; 95% CI, 0.92 to 1.24; P = 0.408) or recurrence-free survival (adjusted hazard ratio, 0.97; 95% CI, 0.84 to 1.12; P = 0.692)29.

The third major trial randomized 400 patients having video-assisted thoracoscopic lung cancer resection to general anesthesia alone or general anesthesia combined with thoracic epidural analgesia. At a median follow-up duration of 32 months, epidural analgesia did not reduce recurrence-free (adjusted hazard ratio, 0.90; 95% CI, 0.60 to 1.35; P = 0.608), overall (adjusted hazard ratio, 1.12; 95% CI, 0.64 to 1.96; P = 0.697), or cancer-specific survival (adjusted hazard ratio, 1.08; 95% CI, 0.61 to 1.91; P = 0.802).30 Thus, even when restricting analysis to patients experiencing high surgical stress and considerable postoperative pain, regional techniques failed to reduce cancer recurrence.

While regional anesthetic techniques have many benefits, three robust trials which randomized a total of 4,244 patients conclusively demonstrate that regional analgesia does not reduce recurrence of breast, abdominal, and lung cancer (Figure). Given the quality and diversity of evidence, further investigations into regional analgesia are unlikely to prove fertile. Case closed. Instead, perioperative investigators might better focus on comparisons between volatile and intravenous anesthesia31-33, and on adjuncts such as COX-2 inhibitors34,35 and lidocaine36.

Figure legend: Forest plot of hazard ratios for cancer recurrence and recurrence-free survival from three major trials of regional analgesia in patients having cancer surgery. There was no evidence of benefit in any of the trials.

Joao Seda Neto, MD, PHD
Hepatology and Liver Transplantation, Hospital Sírio-Libanês, São Paulo, SP, Brazil; Hepatology and Liver Transplantation A. C. Camargo Cancer Center, São Paulo, SP, Brazil

Flavia H. Feier, MD, PHD
Hepatology and Liver Transplantation, Hospital Sírio-Libanês, São Paulo, SP, Brazil

Renata Pugliese, MD, PHD
Hepatology and Liver Transplantation, Hospital Sírio-Libanês, São Paulo, SP, Brazil; Hepatology and Liver Transplantation A. C. Camargo Cancer Center, São Paulo, SP, Brazil

Helry L. Candido, MD
Hepatology and Liver Transplantation, Hospital Sírio-Libanês, São Paulo, SP, Brazil

Gilda Porta, MD, PHD
Hepatology and Liver Transplantation, Hospital Sírio-Libanês, São Paulo, SP, Brazil; Hepatology and Liver Transplantation A. C. Camargo Cancer Center, São Paulo, SP, Brazil

Irene K. Miura, MD, PHD
Hepatology and Liver Transplantation, Hospital Sírio-Libanês, São Paulo, SP, Brazil; Hepatology and Liver Transplantation A. C. Camargo Cancer Center, São Paulo, SP, Brazil

Paulo Chapchap, MD, PHD

Eduardo A. Fonseca, MD, PHD
Hepatology and Liver Transplantation, Hospital Sírio-Libanês, São Paulo, SP, Brazil; Hepatology and Liver Transplantation A. C. Camargo Cancer Center, São Paulo, SP, Brazil

Abstract

Background: The mainstays of irresectable hepatoblastoma (HB) treatment are surgical resection and cisplatin based (CB) chemotherapy (CHT). However, adequate patient selection is a key to achieve acceptable disease-free survival in patients with unresectable HB undergoing liver transplantation (LT).

Procedure: This single-center retrospective analysis of 28 children with HB submitted to LDLT from 1996 to 2019 aimed at determining the pre-transplant factors associated with worse post-transplant event-free survival. The clinical variables collected were gender, age, PELD score (Pediatric End-Stage Liver Disease scoring system), type of neoadjuvant CHT (CB versus other regimens), pre- and post- CHT AFP levels, %AFP reduction post CHT (AFP pre-CHT – AFP post- CHT /AFP pre- CHT), PRETEXT stage, primary versus rescue LDLT, time between diagnosis and LDLT, presence of metastases at diagnosis, follow-up time.

Results: Patients were divided in groups according to the occurrence of the event (recurrence/death) after LDLT – 10 patients in the event-yes and 18 patients in the event-no. Probability of 5-y event-free survival was 63.9%. AFP reduction < 70% (HR=4.33, 95%CI 1.1 to 16.95, p=0.03), and time from diagnosis to LT > 12 months (HR=4.11, 95%CI 1.14 to 14.76, p=0.03) were associated with higher recurrence/death in the Cox regression analysis. Alpha-fetoprotein (AFP) reduction post-CHT > 70% had a good performance in determining disease-free survival, with a calculated AUC of 0.8.

Conclusion: LT for HB is the preferred treatment option for unresectable HB, with no distant metastasis and adequate response to CHT. AFP reduction < 70%, and time from diagnosis to LT > 12 months were associated with higher recurrence/death However, due to the limited number of patients in this study, a larger number of patients is required to corroborate these findings.

Omobolaji O. Ayandipo
Department of Surgery, College of Medicine, University of Ibadan, Ibadan; Department of Surgery, University College Hospital, Ibadan

Anuoluwapo O. Ajao
Department of Surgery, University College Hospital, Ibadan

Naomi A. Olagunju
Department of Surgery, University College Hospital, Ibadan

Oluwasanmi A. Ajagbe
Department of Surgery, College of Medicine, University of Ibadan, Ibadan

Adegbolahan J. Fakoya
Department of Surgery, College of Medicine, University of Ibadan, Ibadan

Gbolahan Obajimi
Department of Obstetrics &amp; Gynaecology University College Hospital, Ibadan

Abstract

Background: Breast cancer subtypes are often used as therapeutic and prognostic measures; however, it is unclear whether there is an association between molecular subtypes and site-specific metastasis. Our study aimed to evaluate the relationship between molecular subtypes and developing metastasis in specific sites.

Methods: We selected 118 breast cancer patients with immunohistochemistry confirmed molecular subtype diagnosed in 2020 and 2021 at the Department of Surgery, University College Hospital, Ibadan. We classified the molecular subtypes into four categories, HR+/HER2-, HR-/HER2+, HR+/HER2+, and triple negative (HR-/HER2-). The different sites of metastasis of interest were lungs, liver, brain, and bone. We used the chi-square test to determine the proportions and significance of the subtypes based on the different sites assessed.

Results: According to our study, 45.50%, 18.20%, and 36.40% of patients presented with lungs, liver, and other (multiple organs and contralateral breast) metastasis respectively. Additionally, HR+/HER2- and TNBC patients developed metastasis at a higher rate and account for a combined 90.10% of all metastases (the site-specific distribution was even between both subtypes).

Conclusion: Overall, while there are limitations in our study based on sample size, our data shows that some molecular subtypes are associated with a higher risk of metastasis. Additionally, while not significant in our study, breast cancer subtypes are associated with different metastatic sites.

Nwe Ni Than, Dr.

Abstract

Metabolic dysfunction associated steatotic liver disease (MASLD) or previously known Non-alcoholic fatty liver disease (NAFLD) is a common condition with an estimated global prevalence of around 30%.  It is becoming a public health concern due to its close association with type 2 diabetes mellitus and obesity. It is important to screen for those with inflammation and fibrosis to halt the progression to cirrhosis. Cirrhosis is associated with liver related complications and liver cancer. Currently, there are no targeted treatments for MASLD at this stage and most treatments are currently in clinical trials. The focus of treatment had been on managing underlying risk metabolic risk factors.

The purpose of this review to inform the readers of the change in the nomenclature from NAFLD to MASLD. This review will also focus on the background of MASLD, the pathogenesis as well as assessment and treatment of patients with MASLD.

Joshua Samuel Alfred
St Helens and Knowsley Teaching Hospitals NHS Trust

Rachael Clifford
St Helens and Knowsley Teach-ing Hospitals NHS Trust

Steven Dixon
St Helens and Knowsley Teach-ing Hospitals NHS Trust

Ramya Kalaiselvan
St Helens and Knowsley Teach-ing Hospitals NHS Trust

Abstract

Introduction: There are over 42,000 new cases of colorectal cancer diagnosed every year in the UK alone, a third of those being rectal in origin. Although there has been significant progress in the treatment of rectal cancer, overall, 5-year survival can still be as low as 17% for those with advanced disease. We aimed to assess the impact on of overall survival and quality of life of primary tumour resection in the palliative setting.

Method: A literature search was performed using Pubmed and Cochrane databases in March 2022. Bias was assessed using the Joanna Briggs institute checklist.

Results: Seven papers were included in the review; all retrospective cohort. A total of 809 patients underwent rectal resection in the presence of metastatic disease +/- adjuvant therapy. The median age was 61years, 59.7% male. 68.6% of patients presented with liver metastasis at the time of diagnosis. The most commonly reported symptoms preoperatively were bleeding and tenesmus. 4-50% of patients in each cohort underwent neoadjuvant therapy. Highest 30-day mortality reported was 7.3%. Both studies comparing resection v none demonstrated a higher overall survival for those undergoing surgery, with one showing 1year overall

survival 65v20%. Quality of life was not addressed across the literature.

Conclusion: Although there is some evidence to show a favourable overall survival for patients undergoing primary tumour resection in the palliative setting, this data is mainly old and across a heterogeneous population. A larger scale prospective study would be required to assess its potential role and impact upon quality of life. 

Linda Ding, PhD
Department of Radiation Oncology, UMass Chan Medical School, Worcester, MA 01655, USA; Department of Radiation Oncology, UMass Memorial Health, Worcester, MA 01655 USA

Shirin Sioshansi, MD

Hesham Malik, MD

Elisa Franquet-Elia, MD
Department of Radiology, UMass Chan Medical School, Worcester, MA 01655, USA; Department of Radiology, UMass Memorial Health, Worcester, MA 01655, USA

Lacey McIntosh, DO, MPH
Department of Radiology, UMass Chan Medical School, Worcester, MA 01655, USA; Department of Radiology, UMass Memorial Health, Worcester, MA 01655, USA

Evan Ruppell, DO
Department of Radiology, UMass Chan Medical School, Worcester, MA 01655, USA, Department of Radiology, UMass Memorial Health, Worcester, MA 01655, USA

Robert Licho, MD
Department of Radiology, UMass Chan Medical School, Worcester, MA 01655, USA, Department of Radiology, UMass Memorial Health, Worcester, MA 01655, USA

Young Kim, MD
Department of Radiology, UMass Chan Medical School, Worcester, MA 01655, USA, Department of Radiology, UMass Memorial Health, Worcester, MA 01655, USA

Alan Goldstein, MD
Department of Radiology, UMass Chan Medical School, Worcester, MA 01655, USA, Department of Radiology, UMass Memorial Health, Worcester, MA 01655, USA

Kriti Mittal, MD
Department of Medicine, UMass Chan Medical School, Worcester, MA 01655, USA, Department of Medicine, UMass Memorial Health, Worcester, MA 01655 USA

Ming-Jin Wang, MD
Department of Medicine, UMass Chan Medical School, Worcester, MA 01655, USA, Department of Medicine, UMass Memorial Health, Worcester, MA 01655 USA

Patan Gultawatvichai, MD
Department of Medicine, UMass Chan Medical School, Worcester, MA 01655, USA, Department of Medicine, UMass Memorial Health, Worcester, MA 01655 USA

Savant Mehta, MD
Department of Medicine, UMass Chan Medical School, Worcester, MA 01655, USA, Department of Medicine, UMass Memorial Health, Worcester, MA 01655 USA

Kimberly Foley, NP
Department of Medicine, UMass Memorial Health, Worcester, MA 01655 USA

Sean Wilson, MD
Department of Radiology, UMass Chan Medical School, Worcester, MA 01655, USA, Department of Radiology, UMass Memorial Health, Worcester, MA 01655, USA

Maryann L Bishop-Jodoin, MEd
Department of Radiation Oncology, UMass Chan Medical School, Worcester, MA 01655, USA

Thomas J FitzGerald, MD
Department of Radiation Oncology, UMass Chan Medical School, Worcester, MA 01655, USA Department of Radiation Oncology, UMass Memorial Health, Worcester, MA 01655 USA

Abstract

Yttrium-90 (Y-90) therapy has become an important component to the care of patients with primary hepatic malignancies and lesions that have metastasized to the liver. Therapy is administered through an intra-arterial procedure after an interventional procedure is performed using an albumin labeled product to ensure therapy will be delivered to the target volume of interest with minimal migration from the target of choice. In the past, dose to target has been measured by activity delivered and qualitative deposition of dose on metabolic imaging post application. Imaging tools such as single positron emission computer tomography (SPECT) and digital positron emission tomography have given us insight into quantitative dose to volumetric tumor target and dose to normal tissue. Recent validation of computational software has provided voxel-based dosimetry similar to applied processes established in radiation oncology planning systems. This development presents an opportunity to create dose volume analysis similar to teletherapy and brachytherapy dose delivery for Y-90 therapy. In this case report, we review Y-90 dosimetry on a patient with dual diagnosis of a locally advanced high-risk adenocarcinoma of the prostate which required treatment to the para-aortic lymph nodes located in the same axial plane with renal parenchyma. Although not clinically anticipated, hepatocellular carcinoma was serendipitously discovered at the time of staging for prostate cancer. Treatment dosimetry of the hepatocellular carcinoma is reviewed in retrospect with voxel-based commercial software. Same day SPECT study suggested dose localized to the liver, however voxel planning software confirmed unintentional dose to additional structures including the right kidney and uninvolved liver which influenced radiation therapy treatment planning for prostate carcinoma. With modern available tools, post therapy dosimetry for Y-90 can be performed in a manner similar to volumetric dosimetry used in radiation oncology and provide valuable dose volume analysis of dose delivered to target and additional tissue.

Kum Shiu Lam
The Humanity & Health GI & Liver Centre, Suite 2101, 9 Queen’s Road Central, Hong Kong.

George Ka Kit Lau
The Humanity & Health GI & Liver Centre, Suite 2101, 9 Queen’s Road Central, Hong Kong.

Abstract

Background and Aim: Gastric intestinal metaplasia (GIM) is precancerous with a worldwide prevalence of 25%. Eradicating Helicobacter pylori prevented about half of gastric cancers; failure to prevent the rest was attributed to GIM. GIM is irreversible and often extensive. There is no treatment. Existing endoscopic mucosal resection (EMR) is designed to treat early gastric cancer of usually <2 cm. A two‐endoscope technique of EMR for extensive GIM had been designed and successfully applied. Our aim is to describe the technique in detail.

Two-endoscope technique of endoscopic mucosal resection: Patients with histologically confirmed moderate to severe GIM (operative link on GIM [OLGIM] classification) received the treatment in a daycare center. Chromoendoscopy with methylene blue was first performed to disclose and mark the GIM. Submucosal saline injections were used to lift the stained mucosa to form multiple safety cushions, which were then transformed into artificial polyps by suction and ligation, using a cap for ligation of esophageal varices. EMRs were then achieved by snare polypectomy. By rotating two gastroscopes, one designated to perform lift and snare and the other to perform suction and ligation, cycles of lift–ligate–snare were carried out until all stained mucosa was removed. Assessment chromoendoscopy with ≥seven biopsies was performed at 6 months.

Results: A total of 227 EMRs were performed in 40 patients, with a median of 3.5 per patient. Bleeding was uncommon and minimal. Gastric perforation ascribable to loss of a safety cushion occurred in one patient. Chromoendoscopy at 6 months in 36 willing patients showed no recurrence of GIM.

Conclusion: The two‐endoscope technique of EMR for GIM was essentially safe and effective, with no recurrence at 6 months. It could be performed by endoscopists with standard skills.