Neutrophil-to-lymphocyte and platelet-to-lymphocyte ratios as predictive and prognostic markers in patients with locally advanced rectal cancer treated with neoadjuvant chemoradiation.

BACKGROUND: A standard therapy for locally advanced rectal cancer (LARC) includes fluoropyrimidine (FP)-based neoadjuvant chemoradiation (nCRT). Previous studies have inconsistently demonstrated that baseline neutrophil- and platelet-to-lymphocyte ratios (NLR and PLR) are predictive of response to nCRT or prognostic of outcomes in LARC. METHODS: We reviewed patients with LARC undergoing nCRT followed by surgery from 2005 to 2013 across 8 Canadian cancer centres. Outcome measures of interest were pathological complete response (pCR), disease-free survival (DFS) and overall survival (OS). Logistic regression and Cox proportional hazard models were used to assess for associations between baseline hematologic variables and outcomes. RESULTS: Of 1527 identified patients, 1237 (81%) were included in the DFS/OS analysis. Median age was 62 (range 23-88), 69% were male, and 80% had performance status (PS) 0-1. Twenty-six percent had elevated NLR (≥ 4), and 66% had elevated PLR (≥ 150). Ninety-seven percent of patients received FP-based nCRT, with 96% receiving ≥44 Gy. 81% completed neoadjuvant chemotherapy and 95% completed neoadjuvant radiotherapy, with a pCR rate of 18%. After a median follow-up time of 71 months, 8% developed local recurrence, 22% developed distant recurrence and 24% died. 5-year DFS and OS were 69% (95% CI 66-72%) and 79% (95% CI 77-82%), respectively. In multivariate analyses, elevated baseline NLR and PLR were neither prognostic for DFS and OS nor predictive of pCR. CONCLUSIONS: NLR and PLR were not found to be independently prognostic for DFS or OS and did not predict for pCR in patients with LARC undergoing nCRT followed by surgery.

Immediate-term cognitive impairment following intravenous (IV) chemotherapy: a prospective pre-post design study.

BACKGROUND: Cognitive impairment is commonly reported in patients receiving chemotherapy, but the acuity of onset is not known. This study utilized the psychomotor vigilance test (PVT) and trail-making test B (TMT-B) to assess cognitive impairment immediately post-chemotherapy. METHODS: Patients aged 18-80 years receiving first-line intravenous chemotherapy for any stage of breast or colorectal cancer were eligible. Patient symptoms, peripheral neuropathy and Stanford Sleepiness Scale were assessed. A five-minute PVT and TMT-B were completed on a tablet computer pre-chemotherapy and immediately post-chemotherapy. Using a mixed linear regression model, changes in reciprocal transformed PVT reaction time (mean 1/RT) were assessed. A priori, an increase in median PVT reaction times by > 20 ms (approximating PVT changes with blood alcohol concentrations of 0.04-0.05 g%) was considered clinically relevant. RESULTS: One hundred forty-two cancer patients (73 breast, 69 colorectal, median age 55.5 years) were tested. Post-chemotherapy, mean 1/RT values were significantly slowed compared to pre-chemotherapy baseline (p = 0.01). This corresponded to a median PVT reaction time slowed by an average of 12.4 ms. Changes in PVT reaction times were not correlated with age, sex, cancer type, treatment setting, or use of supportive medications. Median post-chemotherapy PVT reaction time slowed by an average of 22.5 ms in breast cancer patients and by 1.6 ms in colorectal cancer patients. Post-chemotherapy median PVT times slowed by > 20 ms in 57 patients (40.1%). Exploratory analyses found no statistically significant association between the primary outcome and self-reported anxiety, fatigue or depression. TMT-B completion speed improved significantly post-chemotherapy (p = 0.03), likely due to test-retest phenomenon. CONCLUSIONS: PVT reaction time slowed significantly immediately post-chemotherapy compared to a pre-chemotherapy baseline, and levels of impairment similar to effects of alcohol consumption in other studies was seen in 40% of patients. Further studies assessing functional impact of cognitive impairment on patients immediately after chemotherapy are warranted.

The Evolution of Metastatic Colorectal Cancer Clinical Trials: Application of the ASCO Framework for Assessing Value.

Background: Phase III trials in metastatic colorectal cancer (mCRC) have collectively led to progressive advancements in patient outcomes over the past decades. This study characterizes the evolution of mCRC phase III trials through assessing the value of cancer therapy, as measured by the ASCO Value Framework. Methods: Phase III trial results of systemic therapy for mCRC published between 1980 and 2015 were identified, and their outcome, statistical significance, journal impact factor, and citation by the 2016 NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for CRC were recorded. For each trial, the net health benefit (NHB) score was calculated using the June 2015 (original) and May 2016 (revised) ASCO Value Framework: Advanced Disease. Results: There were 114 mCRC phase III trials eligible for calculation of the NHB score. Using the revised framework, the median NHB score was 4.6 (range, -30 to 43.5); 12% of trials received bonus points. Trials with statistically significant results had higher NHB scores compared with nonsignificant trials (median NHB score, 21.6 vs 2.9; P<.0001). Clinical trials cited in the NCCN Guidelines had higher NHB scores than those not cited (median score, 8.0 vs 0.3; P=.02). In multivariate linear regression analysis, the only significant predictor of high NHB score was statistically significant studies. Conclusions: The median NHB score for mCRC phase III trials was 4.6. Higher NHB scores are associated with statistically significant studies and are cited in the NCCN Guidelines, a surrogate for practice-changing trials. The 2016 ASCO Value Framework may not fully capture the benefits on an individual patient level.

PROSPECT Eligibility and Clinical Outcomes: Results From the Pan-Canadian Rectal Cancer Consortium.

BACKGROUND: The PROSPECT trial (N1048) is evaluating the selective use of chemoradiation in patients with cT2N1 and cT3N0-1 rectal cancer undergoing sphincter-sparing low anterior resection. We evaluated outcomes of PROSPECT-eligible and -ineligible patients from a multi-institutional database. PATIENTS AND METHODS: Data from patients with locally advanced rectal cancer who received chemoradiation and low anterior resection from 2005 to 2014 were retrospectively collected from 5 Canadian centers. Overall survival, disease-free survival (DFS), recurrence-free survival (RFS), and time to local recurrence (LR) were estimated using the Kaplan-Meier method, and a multivariate analysis was performed adjusting for prognostic factors. RESULTS: A total of 566 (37%) of 1531 patients met the PROSPECT eligibility criteria. Eligible patients were more likely to have better PS (P = .0003) and negative circumferential resection margin (P < .0001). PROSPECT eligibility was associated with improved DFS (hazard ratio [HR], 0.75; 95% confidence interval [CI], 0.61-0.91), overall survival (HR, 0.73; 95% CI, 0.57-0.95), and RFS (HR, 0.68; 95% CI, 0.54-0.86) in univariate analyses. In multivariate analysis, only RFS remained significantly improved for PROSPECT-eligible patients (HR, 0.75; 95% CI, 0.57-1.00, P = .0499). The 3-year DFS and freedom from LR for PROSPECT-eligible patients were 79.1% and 97.4%, respectively, compared to 71.1% and 96.8% for PROSPECT-ineligible patients. CONCLUSION: Real-world data corroborate the eligibility criteria used in the PROSPECT study; the criteria identify a subgroup of patients in whom risk of recurrence is lower and in whom selective use of chemoradiation should be actively examined.

Acute liver failure and seizures as a consequence of regorafenib exposure in advanced rectal cancer.

BACKGROUND: Regorafenib is a multi-targeted tyrosine kinase inhibitor approved for use in refractory colorectal cancer. We report the first case of seizures secondary to acute liver failure, shortly after initiation of regorafenib in a patient with advanced rectal carcinoma. CASE PRESENTATION: A 64 year-old Caucasian female presented with confusion and generalized tonic-clonic seizures, 5 days after initiation of regorafenib for advanced rectal cancer. Investigations revealed significant elevations in bilirubin and alanine aminotransferase. No other cause for seizures and liver dysfunction were found. After interruption of regorafenib, no further seizures occurred, the symptoms of confusion resolved and liver function returned to normal. CONCLUSIONS: We report the first case of regorafenib-induced acute liver failure resulting in seizures. We suggest early monitoring for side effects, both clinically and biochemically after initiation of regorafenib.

Predictors of Pathologic Complete Response After Neoadjuvant Treatment for Rectal Cancer: A Multicenter Study.

BACKGROUND: Pathologic complete response (pCR) to neoadjuvant chemoradiation (CRT) for rectal cancer is associated with better long-term outcomes, and is used as an early indicator of response to novel agents. To assess the rate and predictors of pCR, we performed a retrospective multicenter study involving 5 Canadian cancer centers. PATIENTS AND METHODS: Cancer registries identified consecutive patients with locally advanced rectal adenocarcinoma from the Tom Baker Cancer Centre, Cross Cancer Institute, British Columbia Cancer Agency, Ottawa Hospital Cancer Centre, and the Dr H. Bliss Murphy Cancer Centre who received fluoropyrimidine-based CRT and had curative intent surgery from 2005 to 2012. Patient, tumor, and therapy characteristics were correlated with response. RESULTS: Of the 891 patients included, 885 patients had pCR data available. Of the included patients, 161 (18.2%) had a pCR to CRT, and 724 (81.8%) did not. Patients with a pCR had a lower pretreatment carcinoembryonic antigen (CEA) level, and higher hemoglobin level in univariate analysis. In multivariable analysis, statin use at baseline (odds ratio [OR], 1.7; 95% confidence interval [CI], 1.02-2.92; P = .04), lower pretreatment CEA level (OR, 1.03; 95% CI, 1.01-1.06; P = .03), and distance closer to anal verge (OR, 1.07; 95% CI, 1.01-1.15; P = .04) were significant predictors of pCR. The 3-year disease-free survival was 86% in those with a pCR versus 62.5% in those without a pCR (P < .0001) and pCR was associated with improved overall survival (hazard ratio, 0.29; 95% CI, 0.17-0.51; P < .0001). CONCLUSION: Lower pretreatment CEA level, proximity to anal verge, and statin use are predictors of pCR in our large retrospective cohort. Clinical trials to investigate statins combined with neoadjuvant CRT might be warranted.

Cardiac safety of the adjuvant Trastuzumab in a Moroccan population: observational monocentric study of about 100 patients.

BACKGROUND: Trastuzumab is a humanized monoclonal antibody that binds to the extracellular domain of the human epidermal growth factor receptor 2 (HER 2) and inhibits carcinoma cellular proliferation. Its use as an adjuvant for a period of one year is currently an internationally recognised standard for the treatment of localized breast cancer. Its use is generally well tolerated, with the most salient side effect being a particular cardiotoxicity that is typically manifested by an asymptomatic decrease in the left ventricular ejection fraction (LVEF) requiring careful monitoring before and during treatment. To evaluate the cardiac safety of trastuzumab we conducted a retrospective observational study of patients with HER2-positive localized breast cancer treated with trastuzumab between May 2008 and May 2010 in Morocco. FINDINGS: The study comprised of 100 patients. The average in LVEF before the start of trastuzumab was 70%, and at the end of treatment 66%, a decrease in absolute terms of 4%; this difference was statistically significant. 38% of the patients exhibited cardiotoxicity. 97% of our patients have completed treatment, of whom 23% with a provisional arrest because of a regressive fall in LVEF. A final arrest has been made in 3% of cases due to a non regressive reduction in LVEF. A symptomatic heart failure was found in three patients. Analysis of risk factors toxicity found a baseline LVEF higher in the patients who met cardiotoxicity than the rest of our sample. CONCLUSIONS: The cardiac safety in our study seems comparable with the literature data but located in the upper range of levels of toxicity. Cardiotoxicity is the major complication of Trastuzumab, of which LV dysfunction is the most common. Most instances are transient, asymptomatic and reversible.

Unusual case of cavitary lung metastasis from squamous cell carcinoma of the uterine cervix.

Spontaneous excavation of primary lung cancer is common; however cavitation of metastatic lung lesions is rare and usually confused with benign lesions. In Moroccan context tuberculosis is the first suspected diagnosis of lung excavations. We report a rare case of cavitary lung metastasis of a uterine cervix cancer, treated initially as tuberculosis. A 40-year old non-smoking woman with a known history of squamous cell carcinoma of the uterine cervix since August 2005; presented on September 2008 with right chest pain without fever, hemoptysis or weight loss. CT scan showed a thin walled cavity. Empirical Antibiotic therapy was conducted 15 days with poor outcome. Then antibacillary treatment was started with no proof of mycobacterial infection. A month later, the patient presented with gynecological bleeding and a pneumothorax. Bronchoscopy with transbronchial biopsy of the cavitary mass was performed. Pathology demonstrated a metastatic squamous cell carcinoma. Pelvic examination and MRI showed a subsequent local cervix recurrence. Patient underwent 3 courses of systemic chemotherapy. She died on June 2009 due to progressive disease. Even cavitary lung metastases are rare and benign differential diagnosis are more common, clinician should be careful in neoplastic context and investigation should be done to eliminate a recurrence.

Triple negative breast cancer in Moroccan women: clinicopathological and therapeutic study at the National Institute of Oncology.

BACKGROUND: Triple-negative breast cancer (TNBC) is defined by the lack of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER-2) expression. This is an aggressive malignancy with a poor prognosis despite the high rates of response to chemotherapy. The aim of this study is to determine the clinicopathological, therapeutic features and outcomes associated with this type of breast cancer. METHODS: This is a retrospective study of confirmed triple negative breast cancer females collected at the National institute of oncology of Rabat in Morocco, between January 2007 and December 2008. Epidemiological, clinical, histological, therapeutic and evolutive data were analyzed. OS and DFS rates were estimated by Kaplan-Meier analysis. RESULTS: A total of one 152 patients with breast cancer, were identified as having triple-negative breast cancer (16,5%). The median age at diagnosis was 46 years. 130 patients (86%) had infiltrating ductal carcinoma and thirteen had medullar carcinoma (9%). 84 cases (55%) were grade III Scarff-Bloom-Richardson (SBR). 48 % had positive lymph nodes, and 5 % had distant metastases at diagnosis. According TNM staging, 12 patients (8%) had stage I, 90 patients (60%) had stage II and the 43(28%) had stage III. 145 patients received surgery. 41 (28%) had conservative surgery and 104 (72%) received radical mastectomy with axillary lymph nodes dissection. 14 patients with advanced tumors or inflammatory breast cancer have received neoadjuvant chemotherapy and four patients (28%) had complete pathologic response. From 131 patients how received adjuvant chemotherapy, 99 patients (75,5%) had Anthracycline based chemotherapy) and 27 patients (20,6%) had sequential Anthracycline and docetaxel,. Seven patients with metastatic disease received anthracycline-based regimen in the first line metastatic chemotherapy. The median follow-up time was 46 months (range 6,1 -60 months). Overall survival at 5 years for all patients was 76,5%. CONCLUSION: These results suggest that most TNBC characteristics in Moroccan patients are in accordance with literature data, especially concerning young age at diagnosis high grade tumors, advanced stage at diagnosis, and short time to relapse. Although the high response rate to chemotherapy, the overall prognosis of this subset of tumors remains poor.

Radiation induced esophageal adenocarcinoma in a woman previously treated for breast cancer and renal cell carcinoma.

BACKGROUND: Secondary radiation-induced cancers are rare but well-documented as long-term side effects of radiation in large populations of breast cancer survivors. Multiple neoplasms are rare. We report a case of esophageal adenocarcinoma in a patient treated previously for breast cancer and clear cell carcinoma of the kidney. CASE PRESENTATION: A 56 year-old non smoking woman, with no alcohol intake and no familial history of cancer; followed in the National Institute of Oncology of Rabat Morocco since 1999 for breast carcinoma, presented on consultation on January 2011 with dysphagia. Breast cancer was treated with modified radical mastectomy, 6 courses of chemotherapy based on CMF regimen and radiotherapy to breast, inner mammary chain and to pelvis as castration. Less than a year later, a renal right mass was discovered incidentally. Enlarged nephrectomy realized and showed renal cell carcinoma. A local and metastatic breast cancer recurrence occurred in 2007. Patient had 2 lines of chemotherapy and 2 lines of hormonotherapy with Letrozole and Tamoxifen assuring a stable disease. On January 2011, the patient presented dysphagia. Oesogastric endoscopy showed middle esophagus stenosing mass. Biopsy revealed adenocarcinoma. No evidence of metastasis was noticed on computed tomography and breast disease was controlled. Palliative brachytherapy to esophagus was delivered. Patient presented dysphagia due to progressive disease 4 months later. Jejunostomy was proposed but the patient refused any treatment. She died on July 2011. CONCLUSION: We present here a multiple neoplasm in a patient with no known family history of cancers. Esophageal carcinoma is most likely induced by radiation. However the presence of a third malignancy suggests the presence of genetic disorders.

Primary pleural leiomyosarcoma with rapid progression and fatal outcome: a case report.

INTRODUCTION: Leiomyosarcomas are neoplasms of smooth muscles that most commonly arise from the uterus, gastrointestinal tract, or soft tissue. Primary pleural leiomyosarcoma is extremely rare. To the best of our knowledge, only nine cases have been published to date. Because of the rarity of pleural leiomyosarcoma and its similarity (clinical and histological) to other pleural neoplasms, particularly sarcomatous mesothelioma, diagnosis is often difficult. CASE PRESENTATION: A 58-year-old North African man was admitted with complaints of dyspnea and chest pain to our hospital. Chest computed tomography revealed right pleural effusion and pleural thickening. A transthoracic needle biopsy yielded a diagnosis of leiomyosarcoma, and tumor cells were strongly and uniformly positive for vimentin, a smooth muscle actin at immunohistochemical analysis. A general examination did not show any metastatic lesions in other areas. One month after diagnosis, the tumor grew rapidly, with pulmonary invasion, and therefore he was treated only by palliative care. He died from respiratory failure one month later. Because no organ of origin of the leiomyosarcoma, other than the pleura, was detected, this case was diagnosed as a primary pleural leiomyosarcoma. CONCLUSIONS: Although leiomyosarcoma originating from the pleura is rare, this entity is increasingly described. The purpose of presenting this case report is to raise awareness among clinicians to consider this clinical entity as a differential diagnosis when a pleural mass is identified.

Classic Kaposi's sarcoma in Morocco: clinico-epidemiological study at the National Institute of Oncology.

BACKGROUND: Classic Kaposi's sarcoma (CKS) is a rare disease likely associated with human herpes virus 8 (HHV-8) infection, and occurs predominantly in Jewish, Mediterranean and middle eastern men. There is a dearth of data in Moroccan patients with CKS regarding epidemiology, clinical characteristics and outcomes. This report examines a cohort of patients with CKS evaluated at the national institute of oncology over 11-year period. METHODS: A retrospective analysis of patients referred to the national institute of oncology with classical Kaposi sarcoma, between January 1998 and February 2008, was performed. Reviewed information included demographics, clinical and pathological staging, death or last follow-up. RESULTS: During the study period, 56 patients with a diagnosis of CKS have been referred to our hospital. There were 11 (19.7%) females and 45 (80.3%) males (male-to-female ratio: 4:1). Mean age at diagnosis was 61.7 ± 15 (range: 15-86 years). Nodules and/or plaques were the most frequent type of lesion. The most common location was the lower limbs, particularly the distal lower extremity (90%). In addition to skin involvement, visceral spread was evident in 9 cases. The most common visceral involvement sites were lymph nodes (44%), lung (22%), and gastrointestinal tract (22%). Associated lymphoedema was seen in 24 (42%) of the patients. There were 18 stage I patients (32.14%), 8: stage II (14.28%), 21 stage III (37.5%) and 9 stage IV (16.07%). A second primary malignancy was diagnosed in 6 cases (10.7%), none of the reticuloendothelial system. With a median follow-up of 45 months, 38 (67.8) patients are alive, of whom 25 (65.78%) patients with stable disease, five with progressive disease currently under systemic chemotherapy and 8 (21.05%) are alive and free of disease, over a mean interval of 5 years. CONCLUSION: This is the largest reported series in our context. In Morocco, CKS exhibits some special characteristics including a disseminated skin disease at diagnosis especially in men, a more common visceral or lymph node involvement and a less frequent association with second malignancies.

Spermatocytic seminoma at the National Institute of Oncology in Morocco.

BACKGROUND: Spermatocytic seminoma (SS) is a distinct testicular germ cell tumor, representing less than 1% of testicular cancers. The clinical features that distinguish ss from classical seminoma are an older age at presentation and a reduced propensity to metastasize. The aim of our work is to underline the epidemiological, clinical, histological, therapeutical and prognostic features of this tumor. FINDINGS: A retrospective analysis of patients referred to the national institute of oncology with seminoma, identified from the institutional tumor registry, between January 1996 and February 2009, was performed. Information reviewed included demographics, clinical, pathological staging, surgical management, adjuvant treatment and last follow-up. We studied four cases of spermatocytic seminoma, which represented 1% of testicular tumor and 6,4% of all seminoma treated at our institution during the study period. Median age at diagnosis was 45 years (range: 42-48). Mean delay before consulting was 9 months and the mean tumor size was 13,75 cm (10-18 cm). No patient had a history of maldescended testis. The main clinical complaint was unilateral testis mass with low progression. Pathology showed that tumors had a polymorphic appearance with small, intermediate and large cells. In all cases, the tumor was limited to the testis. immunohistochemical studies showed that tumors were negative for all the classical antibodies tested (LCA, cytokeratins, PLAP, lymphoid markers, CD117). Thoraco-abdomino-pelvic CT scan and tumor markers (AFP and hCG) were normal. All patients were Stage I. Treatment consisted on an orchidectomy associated with adjuvant radiotherapy in one patient. After a median follow-up of 6 years ranging from 2 to 15 years, we did not note any relapse or metastasis. CONCLUSION: The diagnosis of spermatocytic seminoma must be considered in all patients aged of more than 50 with testicular tumor. With only three cases of metastatic disease confirmed in the literature, this is a subgroup of patients in whom radiotherapy can safely be omitted.

[Intestinal non-Hodgkin lymphoma: "immunoproliferative small intestinal disease"]. / Lymphomes malins non hodgkiniens de l'intestin grêle de type "immunoproliferative small intestinal disease".

Immunoproliferative small intestinal disease (IPSID), also known as alpha chain disease, is a rare disease. In the recent WHO classification of hematopoietic and lymphoid tissue, IPSID is considered as a variant of extranodal mucosa-associated lymphoid tissue (MALT) lymphoma. Campylobacter jejuni is a specific pathogen, found to be related to IPSID. Diagnosis is based on histology and immunochemistry (± fluorescent in situ hybridization), with presence of many variable levels of abnormal immunoglobulin in the serum, identified to be truncated alpha-heavy chains. Early-stage disease is treated by antibiotics (tetracyclines). Chemotherapy is recommended up front for patients with advanced disease at presentation or refractory to antibiotics. The chemotherapy schedule used is the CHOP (cyclophosphamide, vincristine, doxorubicin, and prednisone) regimen.