Therapeutic drug monitoring of neoadjuvant mFOLFIRINOX in resected pancreatic ductal adenocarcinoma.

BACKGROUND: Despite a potentially curative treatment, the prognosis after upfront surgery and adjuvant chemotherapy for patients with resectable pancreatic ductal adenocarcinoma (PDAC) is poor. Modified FOLFIRINOX (mFOLFIRINOX) is a cornerstone in the systemic treatment of PDAC, including the neoadjuvant setting. Pharmacokinetic-guided (PKG) dosing has demonstrated beneficial effects in other tumors, but scarce data is available in pancreatic cancer. METHODS: Forty-six patients with resected PDAC after mFOLFIRINOX neoadjuvant approach and included in an institutional protocol for anticancer drug monitoring were retrospectively analyzed. 5-Fluorouracil (5-FU) dosage was adjusted throughout neoadjuvant treatment according to pharmacokinetic parameters and Irinotecan (CPT-11) pharmacokinetic variables were retrospectively estimated. RESULTS: By exploratory univariate analyses, a significantly longer progression-free survival was observed for patients with either 5-FU area under the curve (AUC) above 28 mcg·h/mL or CPT-11 AUC values below 10 mcg·h/mL. In the multivariate analyses adjusted by age, gender, performance status and resectability after stratification according to both pharmacokinetic parameters, the risk of progression was significantly reduced in patients with 5-FU AUC ≥28 mcg·h/mL [HR = 0.251, 95% CI 0.096-0.656; p = 0.005] and CPT-11 AUC <10 mcg·h/mL [HR = 0.189, 95% CI 0.073-0.486, p = 0.001]. CONCLUSIONS: Pharmacokinetically-guided dose adjustment of standard chemotherapy treatments might improve survival outcomes in patients with pancreatic ductal adenocarcinoma.

Liver Resection and Transplantation Following Yttrium-90 Radioembolization for Primary Malignant Liver Tumors: A 15-Year Single-Center Experience.

Radioembolization (RE) may help local control and achieve tumor reduction while hypertrophies healthy liver and provides a test of time. For liver transplant (LT) candidates, it may attain downstaging for initially non-candidates and bridging during the waitlist. METHODS: Patients diagnosed with HCC and ICC treated by RE with further liver resection (LR) or LT between 2005-2020 were included. All patients selected were discarded for the upfront surgical approach for not accomplishing oncological or surgical safety criteria after a multidisciplinary team assessment. Data for clinicopathological details, postoperative, and survival outcomes were retrospectively reviewed from a prospectively maintained database. RESULTS: A total of 34 patients underwent surgery following RE (21 LR and 13 LT). Clavien-Dindo grade III-IV complications and mortality rates were 19.0% and 9.5% for LR and 7.7% and 0% for LT, respectively. After RE, for HCC and ICC patients in the LR group, 10-year OS rates were 57% and 60%, and 10-year DFS rates were 43.1% and 60%, respectively. For HCC patients in the LT group, 10-year OS and DFS rates from RE were 51.3% and 43.3%, respectively. CONCLUSION: Liver resection after RE is safe and feasible with optimal short-term outcomes. Patients diagnosed with unresectable or high biological risk HCC or ICC, treated with RE, and rescued by LR may achieve optimal global and DFS rates. On the other hand, bridging or downstaging strategies to LT with RE in HCC patients show adequate recurrence rates as well as long-term survival.

Impact on the Nutritional Status and Inflammation of Patients with Cancer Hospitalized after the SARS-CoV-2 Lockdown.

Many studies have demonstrated that malnutrition has a negative impact on quality of life and mortality in patients with cancer. During the SARS-CoV-2 lockdown, dietary intake changes were detected in the Spanish population, reflecting an increase in the consumption of fruit, bread, flours, and eggs. The present study analyzed the nutritional status of 728 patients with cancer admitted once the SARS-CoV-2 lockdown finished, comparing it with the previous year as well as with mortality rates. The Malnutrition Universal Screening Tool (MUST) was applied in the first 24 h after admission. Age, gender, days of stay, circulating concentrations of albumin, cholesterol, C-reactive protein (CRP), lymphocytes, prealbumin, and mortality data were analyzed. Patients with cancer admitted between June and December of 2020 exhibited no statistical differences in BMI, age, or gender as compared to patients admitted in 2019. Statistically significant differences in nutritional status (p < 0.05), albumin (p < 0.001), and CRP (p = 0.005) levels regarding lockdown were observed in relation with a small non-significant reduction in mortality. In conclusion, following the SARS-CoV-2 lockdown, an improved nutritional status in cancer patients at admission was observed with a decrease in the percentage of weight loss and CRP levels together with an increase in albumin levels compared to oncological patients admitted the previous year.

Feasibility and patency of echoendoscopic anastomoses with lumen apposing metal stents depending on the gastrointestinal segment involved.

EUS-guided anastomoses with LAMS have emerged as a therapeutic option for patients with obstruction of the digestive tract. However, the long-term permeability of these anastomoses remains unknown. Most of the published cases involve the gastric wall and experience in distal obstruction is limited to few case reports. We review our series of patients treated with LAMS for gastrointestinal obstruction and describe the technical success according to the anastomotic site and the long-term follow-up in those cases in which the stent migrated spontaneously or was removed. Out of 30 cases treated with LAMS, EUS-guided anastomosis did not involve the gastric wall in 6 patients. These procedures were technically more challenging as two failures were recorded (2/6, 33%) while technical success was achieved in 100% of the cases in which the stent was placed through the gastric wall. In two of the patients, one with entero-enteric and another with recto-colic anastomosis, stent removal after spontaneous displacement was followed by long term permeability of the EUS-guided anastomosis (172 and 234 days respectively). In a EUS-guided gastroenterostomy the stent was removed at 118 days, but closure of the fistula was confirmed 26 days later. Our experience suggests that LAMS placement between bowel loops is feasible and might allow the creation of an anastomosis with long-term patency. As compared to LAMS placement between bowel loops, when LAMS are placed through the gastric wall, removal of the LAMS seems to lead to closure of the fistula.

Neoadjuvant therapy for locally advanced gastric cancer patients. A population pharmacodynamic modeling.

BACKGROUND: Perioperative chemotherapy (CT) or neoadjuvant chemoradiotherapy (CRT) in patients with locally advanced gastric (GC) or gastroesophageal junction cancer (GEJC) has been shown to improve survival compared to an exclusive surgical approach. However, most patients retain a poor prognosis due to important relapse rates. Population pharmacokinetic-pharmacodynamic (PK/PD) modeling may allow identifying at risk-patients. We aimed to develop a mechanistic PK/PD model to characterize the relationship between the type of neoadjuvant therapy, histopathologic response and survival times in locally advanced GC and GEJC patients. METHODS: Patients with locally advanced GC and GEJC treated with neoadjuvant CT with or without preoperative CRT were analyzed. Clinical response was assessed by CT-scan and EUS. Pathologic response was defined as a reduction on pTNM stage compared to baseline cTNM. Metastasis development risk and overall survival (OS) were described using the population approach with NONMEM 7.3. Model evaluation was performed through predictive checks. RESULTS: A low correlation was observed between clinical and pathologic TNM stage for both T (R = 0.32) and N (R = 0.19) categories. A low correlation between clinical and pathologic response was noticed (R = -0.29). The OS model adequately described the observed survival rates. Disease recurrence, cTNM stage ≥3 and linitis plastica absence, were correlated to a higher risk of death. CONCLUSION: Our model adequately described clinical response profiles, though pathologic response could not be predicted. Although the risk of disease recurrence and survival were linked, the identification of alternative approaches aimed to tailor therapeutic strategies to the individual patient risk warrants further research.

A randomized phase II clinical trial of dendritic cell vaccination following complete resection of colon cancer liver metastasis.

Surgically resectable synchronic and metachronic liver metastases of colon cancer have high risk of relapse in spite of standard-of-care neoadjuvant and adjuvant chemotherapy regimens. Dendritic cell vaccines loaded with autologous tumor lysates were tested for their potential to avoid or delay disease relapses (NCT01348256). Patients with surgically amenable liver metastasis of colon adenocarcinoma (n = 19) were included and underwent neoadjuvant chemotherapy, surgery and adjuvant chemotherapy. Fifteen patients with disease-free resection margins were randomized 1:1 to receive two courses of four daily doses of dendritic cell intradermal vaccinations versus observation. The trial had been originally designed to include 56 patients but was curtailed due to budgetary restrictions. Follow-up of the patients indicates a clear tendency to fewer and later relapses in the vaccine arm (median disease free survival -DFS-) 25.26 months, 95% CI 8.74-n.r) versus observation arm (median DFS 9.53 months, 95% CI 5.32-18.88).

Adjuvant Therapy for Colon Cancer: Genes, Genes and the Patient in the Center.

Although molecular subtype-based stratification and genomic signatures of increasing complexity are becoming a new strategy to guide therapeutic decisions in stage II/III colon cancer, several prognostic factors that can be easily obtained from formalin-fixed paraffin-embedded (FFPE) specimens should be considered to create combined models that better define individual patients' needs. Clin Cancer Res; 24(16); 3787-9. ©2018 AACRSee related article by Kandimalla et al., p. 3867.

Role of histological regression grade after two neoadjuvant approaches with or without radiotherapy in locally advanced gastric cancer.

BACKGROUND: The degree of histopathological response after neoadjuvant therapy in locally advanced gastric cancer (GC) is a key determinant of patients' long-term outcome. We aimed to assess the pattern of histopathological regression after two neoadjuvant approaches and its impact on survival times. METHODS: Regression grade of the primary tumour (Becker criteria) and the degree of nodal response by a 4-point scale (grades A-D) were assessed. Grade A-true negative lymph nodes (LNs); grade B and C-infiltrated LNs with any or little evidence of nodal response; and grade D-complete pathological response in a previously infiltrated LN. A favourable pathological response was defined as Becker Ia-b and grade D. RESULTS: From 2004 to 2014, 80 patients with GC (cT3-4/N+ by CT-scan/EUS) were treated with either preoperative chemotherapy (ChT, n=34) or chemoradiation (CRT, n=46). Patients in the CRT group had a higher likelihood of achieving a Becker Ia-b response (58 vs 32%, P=0.001), a grade D nodal regression (30 vs 6%, P=0.009) and a favourable pathological response (23 vs 3%; P=0.019). Patients with a grade D nodal response had a longer 5-year PFS and OS compared with those with a grade B or C response. Patients with a baseline negative LN status had similar outcomes irrespective of the preoperative therapy received (5-year OS; ChT vs CRT, 58 vs 51%, P=0.92). CONCLUSIONS: Preoperative chemoradiation increases the likelihood of achieving favourable histopathological features that correlate with a 5-year OS>70% in GC patients.

Long-term oncologic results in cancer of the rectum treated by preoperative chemoradiotherapy and surgery: An analysis of 500 cases.

BACKGROUND: The standard treatment for locally advanced cancer of the rectum (LACR) and selective cases of stage IV disease is preoperative chemoradiotherapy (CRT) followed by total mesorectal excision (TME). Despite reductions in local recurrence, disease-free survival (DSF) has remained stable in recent years. OBJECTIVE: The objective of this study is to analyze patterns of recurrence, long-term survival and prognostic factors in a program of neoadjuvant CRT and surgery in LACR. METHODS: Between January 1992 and December 2011, 446 patients with LACR and 54 patients (with single metastases) were treated with pre-operative long course CRT and surgery. Three hundred forty four (66.8%) anterior resections of the rectum and 123 (24.6%) abdomino-perineal resections were performed. RESULTS: With a mean follow-up of 70.06 months, local recurrence was 4.8% and distant recurrence 25.5%. No differences were found in the histopathologic prognostic factors across the three groups studied depending on distance (cm) from the analmargin. Involvement of the circumferential resection margin (CRM+) was significantly greater in tumors in the distal third of the rectum (8.5%; p = 0.04). 67 patients (13.4%) showed a complete pathologic response. DSF at 5 and 10 years was significantly lower in patients with tumors affecting the distal third as compared to the middle third of the rectum (61.9% vs. 57.7%; p = 0.04). Tumors at this distal location resulted in a significantly higher incidence of lung metastases (p = 0.016).

Radioembolization of hepatocellular carcinoma activates liver regeneration, induces inflammation and endothelial stress and activates coagulation.

BACKGROUND & AIMS: Radioembolization may rarely induce liver disease resulting in a syndrome that is similar to veno-occlusive disease complicating bone marrow transplantation where inflammation, endothelial cell activation and thrombosis are likely involved. We hypothesized that similar mechanisms could be implicated in radioembolization-induced liver disease (REILD). Moreover, lobar radioembolization may induce hypertrophy of the non-treated hemiliver most probably by inducing liver regeneration. METHODS: In patients with hepatocellular carcinoma, we prospectively studied serum levels of markers of liver regeneration, oxidative stress, pro-inflammatory pathways, endothelial activation and coagulation parameters over 2 months after radioembolization. RESULTS: Although REILD did not occur among 14 treated patients, a decrease in effective liver blood flow was observed. Radioembolization was followed by a persistent increase in pro-inflammatory (interleukin 6 and 8) and oxidative stress (malondyaldehide) markers, an induction of endothelial injury markers (vW factor and PAI-1) and an activation of the coagulation cascade (factor VIII, PAI-1, D-Dimer) as well as a significant increase in factors related to liver regeneration (FGF-19 and HGF). CONCLUSION: Radioembolization activates liver regeneration, produces oxidative stress, activates inflammatory cytokines and induces endothelial injury with partial activation of the coagulation cascade. These findings may have implications in the pathogenesis, prevention and therapy of REILD and in the development of new therapies to enhance hypertrophy with a surgical perspective.

Analysis of surgical complications of primary tumor resection after neoadjuvant treatment in stage IV colon cancer.

PURPOSE: Assess the surgical complications of primary tumor resection in stage IV colon cancer patients previously treated with neoadjuvant chemotherapy. METHODS: Between July 2001 and September 2010, 67 consecutive patients received preoperative chemotherapy. Clinical and surgical complications were obtained from the medical records. This study was retrospective in design. RESULTS: All patients were affected with liver metastasis, and 29.8% had metastasis in additional organs. Three different schemes of preoperative chemotherapy were employed, based on FOLFIRI, XELOXIRI or XELOX plus cetuximab. Eighteen patients (26.8%) reported some side effects to the chemotherapy, without contraindicating any intervention. All patients underwent colon surgery and within those, eight patients (11.9%), underwent liver surgery simultaneously. Median hospital admission was 8 [3-29] days. The perioperative complication rate was 16.2%, when the estimated physiological and operative severity score for the enumeration of mortality and morbidity (POSSUM) was 58.3%. There was not perioperative mortality, despite the mortality prediction for Portsmouth-POSSUM (P-POSSUM) being 5.07%. No differences were observed between the chemotherapy regimen (P=0.72) or the kind of the surgery-simple or combined (P=0.58). CONCLUSIONS: Neoadjuvant chemotherapy as a systemic treatment for stage IV colon cancer does not indicate surgery contraindication nor increases postoperative morbimortality by a significant amount.

Prognosis factors for recurrence in patients with locally advanced rectal cancer preoperatively treated with chemoradiotherapy and adjuvant chemotherapy.

BACKGROUND: Neoadjuvant chemoradiotherapy followed by total mesorectal excision has improved the outcome of locally advanced rectal carcinoma. OBJECTIVE: The aim of this study was to identify independent prognosis factors of disease recurrence in a group of patients treated with this approach. DESIGN AND PATIENTS: This study was retrospective in design. Data from patients with locally advanced rectal cancer who had completed treatment from 2000 to 2010 were reviewed. SETTINGS: The analysis was performed in a tertiary referral center. MAIN OUTCOME MEASURES: The primary outcomes measured were the recurrence risk factors. RESULTS: The cohort consisted of 228 patients; 69.3% of them were men, and median age was 59 years. Stage III rectal cancer was found in 64.9% of patients. The most frequently administered therapy was concurrent capecitabine, oxaliplatin, and 7-field radiotherapy, followed by 3-field radiotherapy and fluoropyrimidines. After a median follow-up of 49 months, 23.7% of the patients experienced disease recurrence: 2.6% had local recurrence, 21.1% had distant metastases, and 0.5% had both. Factors significantly correlated with recurrence risk in multivariate logistic regression were y-pathological stage (III vs I/II: OR = 2.51), tumor regression grade (1/2 vs 3+/4: OR = 3.34; 3 vs 3+/4: OR = 1.20), and low rectal location (OR = 2.36). The only independent prognosis factor for liver metastases was tumor regression grade (1/2 vs 3+/4: OR = 4.67; 3 vs 3+/4: OR = 1.41), whereas tumor regression grade (1-2 vs 3+/4: OR = 5.5; 3 vs 3+/4: OR = 1.84), low rectal location (OR = 3.23), and previous liver metastasis (OR = 7.73) predicted lung recurrence. LIMITATIONS: This is a single institutional experience, neoadjuvant combined therapy is not homogeneous, and the analysis has been performed in a retrospective manner. CONCLUSIONS: Patients with low third locally advanced rectal cancer with a poor response to neoadjuvant chemoradiotherapy (high y-pathological stage or low tumor regression grade) are at high risk of recurrence. Intense surveillance and the design of alternative therapeutic approaches aimed to lower the distant failure rate seem warranted.

Prognostic factors and prevention of radioembolization-induced liver disease.

UNLABELLED: Radioembolization (RE)-induced liver disease (REILD) has been defined as jaundice and ascites appearing 1 to 2 months after RE in the absence of tumor progression or bile duct occlusion. Our aims were to study the incidence of REILD in a large cohort of patients and the impact of a series of changes introduced in the processes of treatment design, activity calculation, and the routine use of ursodeoxycholic acid and low-dose steroids (modified protocol). Between 2003 and 2011, 260 patients with liver tumors treated by RE were studied (standard protocol: 75, modified protocol: 185). REILD appeared only in patients with cirrhosis or in noncirrhosis patients exposed to systemic chemotherapy prior to RE. Globally, the incidence of REILD was reduced in the modified protocol group from 22.7% to 5.4% and the incidence of severe REILD from 13.3% to 2.2% (P<0.0001). Treatment efficacy was not jeopardized since 3-month disease control rates were virtually identical in both groups (66.7% and 67.2%, P=0.93). Exposure to chemotherapy in the 2-month period following RE and being treated by the standard protocol were independent predictors of REILD among noncirrhosis patients. In cirrhosis, the presence of a small liver (total volume<1.5 L), an abnormal bilirubin (>1.2 mg/dL), and treatment in a selective fashion were independently associated with REILD. CONCLUSION: REILD is an uncommon but relevant complication that appears when liver tissue primed by cirrhosis or prior and subsequent chemotherapy is exposed to the radiation delivered by radioactive microspheres. We designed a comprehensive treatment protocol that reduces the frequency and the severity of REILD.

Four-week neoadjuvant intensity-modulated radiation therapy with concurrent capecitabine and oxaliplatin in locally advanced rectal cancer patients: a validation phase II trial.

PURPOSE: To validate tolerance and pathological complete response rate (pCR) of a 4-week preoperative course of intensity-modulated radiation therapy (IMRT) with concurrent capecitabine and oxaliplatin (CAPOX) in patients with locally advanced rectal cancer. METHODS AND MATERIALS: Patients with T3 to T4 and/or N+ rectal cancer received preoperative IMRT (47.5 Gy in 19 fractions) with concurrent capecitabine (825 mg/m(2) b.i.d., Monday to Friday) and oxaliplatin (60 mg/m(2) on Days 1, 8, and 15). Surgery was scheduled 4 to 6 weeks after the completion of chemoradiation. Primary end points were toxicity and pathological response rate. Local control (LC), disease-free survival (DFS), and overall survival (OS) were also analyzed. RESULTS: A total of 100 patients were evaluated. Grade 1 to 2 proctitis was observed in 73 patients (73%). Grade 3 diarrhea occurred in 9% of the patients. Grade 3 proctitis in 18% of the first 50 patients led to reduction of the dose per fraction to 47.5 Gy in 20 treatments. The rate of Grade 3 proctitis decreased to 4% thereafter (odds ratio, 0.27). A total of 99 patients underwent surgery. A pCR was observed in 13% of the patients, major response (96-100% of histological response) in 48%, and pN downstaging in 78%. An R0 resection was performed in 97% of the patients. After a median follow-up of 55 months, the LC, DFS, and OS rates were 100%, 84%, and 87%, respectively. CONCLUSIONS: Preoperative CAPOX-IMRT therapy (47.5 Gy in 20 fractions) is feasible and safe, and produces major pathological responses in approximately 50% of patients.

Patterns of response after preoperative treatment in gastric cancer.

PURPOSE: To analyze the rate of pathologic response in patients with locally advanced gastric cancer treated with preoperative chemotherapy with and without chemoradiation at our institution. METHODS AND MATERIALS: From 2000 to 2007 patients were retrospectively identified who received preoperative treatment for gastric cancer (cT3-4/ N+) with induction chemotherapy (Ch) or with Ch followed by concurrent chemoradiotherapy (45 Gy in 5 weeks) (ChRT). Surgery was planned 4-6 weeks after the completion of neoadjuvant treatment. Pathologic assessment was used to investigate the patterns of pathologic response after neoadjuvant treatment. RESULTS: Sixty-one patients were analyzed. Of 61 patients, 58 (95%) underwent surgery. The R0 resection rate was 87%. Pathologic complete response was achieved in 12% of the patients. A major pathologic response (<10% of residual tumor) was observed in 53% of patients, and T downstaging was observed in 75%. Median follow-up was 38.7 months. Median disease-free survival (DFS) was 36.5 months. The only patient-, tumor-, and treatment-related factor associated with pathologic response was the use of preoperative ChRT. Patients achieving major pathologic response had a 3-year actuarial DFS rate of 63%. CONCLUSIONS: The patterns of pathologic response after preoperative ChRT suggest encouraging intervals of DFS. Such a strategy may be of interest to be explored in gastric cancer.

Improving disease control in advanced colorectal cancer: Panitumumab and cetuximab.

Colorectal cancer remains a major public health concern in Europe and North America. It is responsible for one million new cases and half a million deaths per year worldwide. During the past few years new effective treatments have evolved improving the outcome of patients with this disease. Several alternatives are currently available for advanced colorectal cancer patients including different chemotherapeutic regimens (fluoropyrimidines, irinotecan and oxaliplatin) and targeted therapies such as bevacizumab and cetuximab. Different combinations achieve a median survival of over 2 years. Intense efforts focus on identifying agents targeting growth factor receptors, signal transduction pathways or angiogenesis mediators. One of the last available drugs for the management of advanced colorectal cancer is panitumumab, a well-tolerated and effective anti-EGFR monoclonal antibody approved as a single agent in chemotherapy refractory patients. We discuss the current evidence supporting panitumumab for metastatic colorectal cancer treatment, potential predictive biomarkers and ongoing clinical trials with different combinations including panitumumab.

Liver disease induced by radioembolization of liver tumors: description and possible risk factors.

BACKGROUND: To the authors' knowledge, liver damage after liver radioembolization with yttrium90-labeled microspheres has never been studied specifically. METHODS: Using a complete set of data recorded prospectively among all patients without previous chronic liver disease treated by radioembolization at the authors' institution from September 2003 to July 2006, patterns of liver damage were identified and possible risk factors were analyzed. RESULTS: In all, 20% of patients developed a distinct clinical picture that appeared 4 to 8 weeks after treatment and was characterized by jaundice and ascites. Veno-occlusive disease was the histologic hallmark observed in the most severe cases. This form of sinusoidal obstruction syndrome was not observed among patients who never received chemotherapy or in those in whom a single hepatic lobe was treated. Relevant to treatment planning, a possible risk factor was a higher treatment dose in relation to the targeted liver volume. A transjugular intrahepatic stent shunt improved liver function in 2 patients with impending liver failure, although 1 of them eventually died from it. CONCLUSIONS: Radioembolization of liver tumors, particularly after antineoplastic chemotherapy, may result in an uncommon but potentially life-threatening form of hepatic sinusoidal obstruction syndrome that presents clinically with jaundice and ascites.

Assessment of the value of confirming responses in clinical trials in oncology.

The requirement for a second assessment to confirm initial tumour response is required by all response guidelines. Its rationale, however, is not clear. We have conducted this study to compare validity of response rate assessment determined with and without secondary confirmation. Using specified criteria, nine trials of one single cytotoxic drug including 416 patients were selected from a pharmaceutical database. Objective response rates were determined by a single determination and by two separate determinations. 81 responses (19.5%, [15.8-23.6%]) were scored by the confirmation method and 97 responses (23.3% [19.3-27.7%]) by the no-confirmation method. The Kappa (kappa) coefficient of 0.89 indicates good agreement between both methods. This is the first study that systematically compares response rates calculated with and without performing response confirmation. Results show good agreement between both methods. We suggest that assessing response without confirmation may be the preferred method. These results should be confirmed by additional studies in a variety of cancer settings.