Chemotherapy and Targeted Therapy Strategies in Patients with Unresectable or Borderline Resectable Metastatic Colorectal Cancer: Evidence for a Lack of Focus on Resection Rates.

BACKGROUND AND AIMS: Chemotherapy (CTx) with targeted therapy (TT) have increased the overall response rate (ORR) and improved survival in unresectable or borderline resectable metastatic colorectal cancer (mCRC). However, the resection rate is an endpoint with often suboptimal expert involvement. The aim was to investigate whether the improvements in ORR have translated to improved resection rates (RR). STUDY DESIGN: A systematic literature search was performed using the PICO process. STATISTICAL ANALYSIS: Odds ratios, and 95% confidence intervals (OR, 95% CI) were analyzed for ORR and RR using dichotomous values with the Mantel-Haenszel method. Progression-free survival (PFS) and overall survival (OS) were analyzed using the inverse-variance method and displayed as hazard ratios and 95% confidence intervals (HR, 95% CI). RESULTS: The literature search returned 469 records. Sixteen articles with 5724 patients were selected for analysis. The qualitative analysis revealed low and moderate risk of bias endpoints. Higher ORR was observed with CTx + TT versus CTx only (OR: 0.62 [95% CI 0.45; 0.82], p = 0.002) and with triplet CTx + TT versus doublet CTx + TT (OR: 0.61 [95% CI 0.46; 0.81], p < 0.001). PFS and OS were improved by use of TT (HR: 0.68-0.84; p < 0.001 to 0.04). The overall RR was low (< 15%) and did not improve in the same way as the other endpoints. CONCLUSION: The ORR and survival rates in unresectable and borderline resectable mCRC were improved by modern CTx and TT that did not translate into higher RR, mostly due to the lack of expert involvement.

The evaluation of follow-up strategies of watch-and-wait patients with a complete response after neoadjuvant therapy in rectal cancer.

AIM: Many of the current follow-up schedules in a watch-and-wait approach include very frequent MRI and endoscopy examinations to ensure early detection of local regrowth (LR). The aim of this study was to analyse the occurrence and detection of LR in a watch-and-wait cohort and to suggest a more efficient follow-up schedule. METHOD: Rectal cancer patients with a clinical complete response after neoadjuvant therapy were prospectively and retrospectively included in a multicentre watch-and-wait registry between 2004 and 2018, with the current follow-up schedule with 3-monthly endoscopy and MRI in the first year and 6 monthly thereafter. A theoretical comparison was constructed for the detection of LR in the current follow-up schedule against four other hypothetical schedules. RESULTS: In all, 50/304 (16%) of patients developed a LR. The majority (98%) were detected at ≤2 years, located in the lumen (94%) and were visible on endoscopy (88%). The theoretical comparison of the different hypothetical schedules suggests that the optimal follow-up schedule should focus on the first 2 years with 3-monthly endoscopy and 3-6 monthly MRI. Longer intervals in the first 2 years will cause delays in diagnosis of LR ranging from 0 to 5 months. After 2 years, increasing the interval from 6 to 12 months did not cause important delays. CONCLUSION: The optimal follow-up schedule for a watch-and-wait policy in patients with a clinical complete response after chemoradiation for rectal cancer should include frequent endoscopy and to a lesser degree MRI in the first 2 years. Longer intervals, up to 12 months, can be considered after 2 years.

Surgical treatment of breast cancer in patients aged 80 years or older--how much is enough?

BACKGROUND: The population of elderly people is increasing and so is the population of breast cancer patients aged ≥80 years. The aim of our retrospective study was to identify independent prognostic factors for the duration of breast cancer-specific survival of surgically treated patients aged ≥80 years. The secondary aim was to determine the appropriate surgical treatment of breast cancer in patients aged ≥80 years. METHODS: We reviewed the medical records of 154 patients aged ≥80 years with early-stage breast cancer (mean age 83 years) who underwent surgery at the tertiary cancer center in the period from 2000 to 2008. Tumor stage was pT1/pT2 and pT3/pT4 in 75% and 25%, respectively. Surgical treatment comprised: quadrantectomy (in 27%), mastectomy (in 73%), axillary dissection (in 57%), and sentinel lymph node biopsy (in 18%), while 25% of patients had no axillary surgery. RESULTS: During a median follow-up of 5.3 years, 31% of patients died of breast cancer, while 28% of patients died of other causes. Half of our patients with poorly differentiated breast cancer or estrogen receptor-negative tumor died of breast cancer. Multivariate statistical analysis showed that the pathological T-stage, pathological N-stage and estrogen receptors were independent prognostic factors for the duration of breast cancer-specific survival of patients. CONCLUSION: Short breast cancer-specific survival indicates that, in patients aged ≥80 years, breast cancer with metastases in axillary lymph nodes can be an aggressive disease.

Numerical mesoscale tissue model of electrochemotherapy in liver based on histological findings.

Electrochemotherapy (ECT) and irreversible electroporation (IRE) are being investigated for treatment of hepatic tumours. The liver is a highly heterogeneous organ, permeated with a network of macro- and microvasculature, biliary tracts and connective tissue. The success of ECT and IRE depends on sufficient electric field established in whole target tissue; therefore, tissue heterogeneity may affect the treatment outcome. In this study, we investigate electroporation in the liver using a numerical mesoscale tissue model. We numerically reconstructed four ECT experiments in healthy porcine liver and computed the electric field distribution using our treatment planning framework. We compared the computed results with histopathological changes identified on microscopic images after treatment. The mean electric field threshold that best fitted the zone of coagulation necrosis was 1225 V/cm, while the mean threshold that best fitted the zone of partially damaged liver parenchyma attributed to IRE was 805 V/cm. We evaluated how the liver macro- and microstructures affect the electric field distribution. Our results show that the liver microstructure does not significantly affect the electric field distribution on the level needed for treatment planning. However, major hepatic vessels and portal spaces significantly affect the electric field distribution, and should be considered when planning treatments.

Radiological findings of porcine liver after electrochemotherapy with bleomycin.

Background Radiologic findings after electrochemotherapy of large hepatic blood vessels and healthy hepatic parenchyma have not yet been described. Materials and methods We performed a prospective animal model study with regulatory approval, including nine grower pigs. In each animal, four ultrasound-guided electroporated regions were created; in three regions, electrodes were inserted into the lumen of large hepatic vessels. Two types of electrodes were tested; variable linear- and fixed hexagonal-geometry electrodes. Ultrasonographic examinations were performed immediately and up to 20 minutes after the procedure. Dynamic computed tomography was performed before and at 60 to 90 minutes and one week after the procedure. Results Radiologic examinations of the treated areas showed intact vessel walls and patency; no hemorrhage or thrombi were noted. Ultrasonographic findings were dynamic and evolved from hyperechogenic microbubbles along electrode tracks to hypoechogenicity of treated parenchyma, diffusion of hyperechogenic microbubbles, and hypoechogenicity fading. Contrast-enhanced ultrasound showed decreased perfusion of the treated area. Dynamic computed tomography at 60 to 90 minutes after the procedure showed hypoenhancing areas. The total hypoenhancing area was smaller after treatment with fixed hexagonal electrodes than after treatment with variable linear geometry electrodes. Conclusions Radiologic findings of porcine liver after electrochemotherapy with bleomycin did not show clinically significant damage to the liver, even if a hazardous treatment strategy, such as large vessel intraluminal electrode insertion, was employed, and thus further support safety and clinical use of electrochemotherapy for treatment of hepatic neoplasia.

Large Liver Blood Vessels and Bile Ducts Are Not Damaged by Electrochemotherapy with Bleomycin in Pigs.

The first clinical studies on the use of electrochemotherapy to treat liver tumours that were not amenable to surgery or thermal ablation techniques have recently been published. However, there is still a lack of data on the effects of electrochemotherapy on normal liver tissue. Therefore, we designed a translational animal model study to test whether electrochemotherapy with bleomycin causes clinically significant damage to normal liver tissue, with emphasis on large blood vessels and bile ducts. We performed electrochemotherapy with bleomycin or delivered electric pulses alone using a potentially risky treatment strategy in eight pigs. Two and seven days after treatment, livers were explanted, and histological analysis was performed. Blood samples were collected before treatment and again before euthanasia to evaluate blood biomarkers of liver function and systemic inflammatory response. We found no thrombosis or other clinically significant damage to large blood vessels and bile ducts in the liver. No clinical or laboratory findings suggested impaired liver function or systemic inflammatory response. Electrochemotherapy with bleomycin does not cause clinically significant damage to normal liver tissue. Our study provides further evidence that electrochemotherapy with bleomycin is safe for treatment of patients with tumours near large blood vessels in the liver.