Nayyer Iqbal

Advances in the management of colorectal cancer: from biology to treatment

BackgroundColorectal cancer (CRC) is the third most common malignant neoplasm worldwide and the fourth leading cause of cancer-related deaths. This article reviews the epidemiology, risk factors, pathogenesis, and prognosis of CRC with special emphasis on advances in the management of CRC over the past decade.MethodsA review of the published English literature was conducted using the search engines PubMed, Medline, EMBASE, and Google Scholar. A total of 127 relevant publications were identified for further review.ResultsMost CRC are sporadic and are due to genetic instability and multiple somatic mutations. Approximately 80 % of cancers are diagnosed at the early stage and are curable. The pathologic stage at presentation is the most important predictor of outcome after resection of early stage cancer. Surgery is the primary treatment modality for localized CRC. Advances in (neo)adjuvant chemotherapy and radiation have reduced the disease recurrence and increased survival in high risk diseases. Although recent advancements in combination chemotherapy and target agents have increased the survival of incurable CRC, it is remarkable that only selected patients with advanced CRC can be cured with multimodality therapy.ConclusionOver the past decade, there has seen substantial progress in our understanding of and in the management of CRC.

Surgical Management of the Primary Tumor in Stage IV Colorectal Cancer: A Confirmatory Retrospective Cohort Study.

Background: Observational studies have suggested that patients with stage IV colorectal cancer who undergo surgical resection of the primary tumor (SRPT) have better survival. Yet the results are not confirmed in the setting of a randomized controlled trial. Lack of randomization and failure to control prognostic variables such as performance status are major critiques to the findings of the observational studies. We previously have shown that SRPT, independent of chemotherapy and performance status, improves survival of stage IV CRC patients. The current study aims to validate our findings in patients with stage IV CRC who were diagnosed during the period of modern chemotherapy. Methods: A cohort of 569 patients with stage IV CRC diagnosed during 2006-2010 in the province of Saskatchewan was evaluated. Cox regression model was used for the adjustment of prognostic variables. Results: Median age was 69 years (59-95) and M: F was 1.4:1. Fifty-seven percent received chemotherapy, 91.4% received FOLFIRI or FOLFOX & 67% received a biologic agent. Median overall survival (OS) of patients who underwent SRPT and received chemotherapy was 27 months compared with 14 months of the non-resection group (p<0.0001). Median OS of patients who received all active agents and had SRPT was 39 months (95%CI: 25.1-52.9). On multivariate analysis, SRPT, hazard ratio (HR):0.44 (95%CI: 0.35-0.56), use of chemotherapy, HR: 0.33 (95%CI: 0.26-0.43), metastasectomy, HR: 0.43 (95%CI: 0.31-0.58), second line therapy, HR: 0.50 (95%CI: 0.35-0.70), and third line therapy, HR: 0.58 (95%CI: 0.41-0.83) were correlated with superior survival. Conclusions: This study confirms our findings and supports a favorable association between SRPT and survival in patients with stage IV CRC who are treated with modern therapy.

Reflections on multiple strategies to reduce transfusion in cancer patients: A joint narrative

Transfusion of red blood cells, platelets and plasma is widely used in the management of anemia and coagulopathy in cancer patients undergoing surgery, chemotherapy, and radiation. The decision to transfuse should not be made lightly as exposure to transfused blood, whether from an allogeneic or even autologous source, is not without risk and the long-term effect of blood transfusion on cancer outcomes remains questionable. Recognition of anemia associated with nutritional deficiency should be promptly corrected while avoiding the use of erythropoiesis stimulating agents. Minimizing blood loss and the prompt control of bleeding, coupled with a restrictive transfusion strategy, seem to be a reasonable approach that does not appear to be associated with long-term sequelae. Limiting platelet transfusion to patients with severe hypo-proliferative thrombocytopenia, and implementation of local hemostatic measures, together with the use of fractionated coagulation factor concentrates, as an alternative to frozen plasma transfusion, may reduce the exposure of cancer patients to potentially harmful thrombogenic and pro-inflammatory cellular microparticles. This joint narrative highlights current opinions for minimizing blood usage in patients with cancer.

Predictive Factors of the Use of Systemic Therapy in Stage IV Colorectal Cancer: Who Gets Chemotherapy?

Background: Chemotherapy improves survival in patients with stage IV colorectal cancer (CRC). Although in a clinical trial setting, strict eligibility criteria are used for chemotherapy, little is known about the use of chemotherapy in the general population. The study aims to assess clinicopathological variables that correlate with the use of chemotherapy in patients with stage IV CRC. Methods: A retrospective cohort study involving patients with stage IV CRC, diagnosed between 1992 and 2005, in the province of Saskatchewan was carried out. A logistic regression analysis was performed to assess the correlation of various clinicopathological factors with the use of chemotherapy. Results: A total of 1,237 eligible patients were identified. Their median age was 70 years (range: 22-98) and the male:female ratio was 1.3:1. 23.8% had an ECOG performance status (PS) of ≥2 and 61.8% of the patients had a comorbid illness. 46.8% of the patients received chemotherapy. The multivariate logistic regression analysis revealed that an age of <65 years [odds ratio (OR) 3.82, 95% CI: 2.59-5.63], metastasectomy (OR 3.60, 95% CI: 1.82-7.10), normal albumin (OR 3.26, 95% CI: 2.44-4.36), no comorbid illness (OR 2.87, 95% CI: 1.34-6.16), ECOG PS of <2 (OR 2.72, 95% CI: 1.94-3.82), normal blood urea nitrogen (OR 2.24, 95% CI: 1.40-3.59), palliative radiation (OR 2.03, 95% CI: 1.38-2.99), primary tumor resection (OR 2.00, 95% CI: 1.47-2.73), and the time period (OR 1.85, 95% CI: 1.41-2.42) were significantly correlated with the use of chemotherapy. Conclusions: The use of chemotherapy appears to be increasing in stage IV CRC. Patients treated with curative intention or who underwent primary tumor resection were more likely to receive chemotherapy. Despite a known benefit of chemotherapy in elderly patients, a differential use of chemotherapy was noted in this population.

Red blood cell transfusion and outcome in cancer

Oncology services utilize about 15% of the blood transfusion resources in the USA. Red blood cell transfusion is performed immediately before, during or after major surgery to compensate for blood loss and hemodilution. However, a lack of evidence-based guidelines leads to variable transfusion practices among clinicians. The benefits of transfusing blood products are obvious in life-threatening low blood cell counts or bleeding, but it is becoming apparent that deliberate blood transfusion in some cancer patients can trigger negative clinical impacts. This review attempts to provide an overview of the impact of red blood cell transfusion in patients suffering from various types of oncologic pathologies.

Travel distance and use of salvage palliative chemotherapy in patients with metastatic colorectal cancer

Background Salvage palliative chemotherapy in metastatic colorectal cancer has been associated with significant improvement in survival. However, not all patients receive all available therapies. Travel burden can affect patient access and use of future therapy. The present study aims to determine relationship between travel distance (TD) and salvage palliative chemotherapy in patients with metastatic colorectal cancer. Method A patient cohort diagnosed with metastatic colorectal cancer during 2006-2010 in the province of Saskatchewan, Canada was studied. Logistic regression analyses were performed to assess relationship between travel distance and subsequent line therapies. Results The median age of 264 eligible patients was 62 years [interquartile range (IQR): 53-72]. The patients who received salvage systemic therapy had a median distance to travel of 60.0 km (IQR: 4.7-144) compared with 88.1 km (IQR: 4.8-189) if they did not receive second- or third-line therapy (P=0.06). In multivariate analysis distance to the cancer center <100 km, odds ratio (OR) 1.69 (95% CI: 1.003-2.84), no metastasectomy, OR 1.89 (95% CI: 1.03-3.46), and absence of comorbid illness as per Charlson comorbid index, OR 1.45 (95% CI: 1.19-1.77) were correlated with the use of second- and subsequent line therapies. Conclusions Our result revealed that travel distance to the cancer center greater than 100 km was associated less frequent use of second or subsequent line therapies in patients with metastatic colorectal cancer.

Cardiac Toxicity of HER2-Directed Therapy in Women with Breast Cancer: Epidemiology, Etiology, Risk Factors, and Management

The HER2-targeted therapy have profoundly changed the outcomes of women with HER2-positive breast cancers. Trastuzumab and pertuzumab, HER2-targeting monoclonal antibodies, lapatinib and Neratinib, small molecule inhibitors of HER2 and the epidermal growth factor receptor, and ado-trastuzumab emtansine, a HER2-positive directed antibody drug conjugate, are approved for the treatment of HER2-positive breast cancer. Cardiac toxicity is a known adverse effects of trastuzumab, and other HER2-directed therapy. In most cases it manifests as mild and reversible left ventricle dysfunction. Nevertheless, symptomatic heart failure is not rare. The incidence and severity of cardiac dysfunction is greatest among women who received HER2-directed therapy in combination with anthracycline-based therapy. In addition, a borderline low normal left ventricle ejection fraction; prior treatment with antihypertensive medication; and older age are other risk factors for trastuzumab-related cardiac dysfunction. HER2 signaling plays an important role in modulating myocardial response to treatment-related injury. Management of trastuzumab and the other HER2 targeted treatment-related cardiac dysfunction has two key components: withdrawal of HER2-directed therapy and treatment of underlying cardiac dysfunction. A multidisciplinary approach is recommended for an optimal outcome. This chapter reviews cardiac toxicity of trastuzumab and other HER2-directed therapy including epidemiology and pathophysiology of cardiac dysfunction, cardiac monitoring, treatment and prevention.

Outcomes and Drug Costs of Sunitinib Regimens for Metastatic Renal Cell Carcinoma: A Provincial Population-Based Study.

Micro‐Abstract Conventional sunitinib dosing in metastatic renal cell carcinoma administers 50 mg daily on a 4 weeks on/2 weeks off (4/2) schedule. Many patients undergo modifications to schedule, dose, or both. An adjusted‐dose regimen is associated with improved overall survival and progression‐free survival over standard intermittent dosing, with lower overall drug costs. Background: Conventional sunitinib dosing in metastatic renal cell carcinoma (mRCC) administers 50 mg daily on a 4 weeks on/2 weeks off (4/2) schedule. Not all patients tolerate this regimen and many undergo modifications to schedule, dose, or both. Material and Methods: All patients with mRCC treated with sunitinib by the Saskatchewan Cancer Agency between January 1, 2006, and January 1, 2013, were included. Regimens were categorized as standard intermittent dosing (SID), modified intermittent schedule (MIS), modified intermittent dosing (MID), combination of modified schedule and dosing (MSD), or continuous dosing (CD). The primary objective was to compare overall survival (OS) between regimens. Secondary outcomes included progression‐free survival (PFS), discontinuation due to adverse effects (AE), and medication cost. Results: Among 161 patients, 18.0%, 51.6%, and 30.4% had favorable, intermediate, and poor Heng risk prognoses, respectively. A total of 140 (87.0%) received sunitinib as first‐line therapy. MID was associated with longer OS compared with SID (estimated median 28.4 vs. 11.2 months). PFS was longer for MID, MSD, and CD compared with SID (estimated median 12.0, 9.0, and 8.0 months vs. 3.0 months, respectively). Adjustment for potential confounders did not negate these associations. SID also had higher average monthly drug costs than MIS, MID, and MSD. Overall discontinuation rate due to AE was high (24%). Conclusion: An adjusted‐dose sunitinib regimen is associated with improved OS and PFS over SID, with lower costs. The development of toxicities requiring dose reductions serves as a predictive biomarker for better outcomes.

Primary Tumor Location and Survival in the General Population With Metastatic Colorectal Cancer

Background Recent evidence from clinical trials suggests that primary tumor location in patients with metastatic colorectal cancer correlates with differential outcomes, and patients with tumors originating in the right side of the colon have inferior survival. We conducted a large population‐based cohort study using individual patient data to confirm the prognostic importance of primary tumor location in the general population with metastatic colorectal cancer. Methods A cohort of 1947 patients who were diagnosed with metastatic colorectal cancer from 1992 to 2010 was studied. Ascending and transverse colon cancers were defined as right‐sided tumors. Cox proportional multivariate analyses were done to determine prognostic significance of primary tumor location. Results The median age was 70 years (interquartile range, 60‐78 years), and the male to female ratio was 1.3:1. Twenty‐nine percent had World Health Organization performance status of > 1. Seven‐hundred and seventy (39%) patients had right‐sided tumors, and 908 (47%) received chemotherapy. The median overall survival of patients with right‐sided tumors was 14 months (95% confidence interval [CI], 12.7‐15.3 months) compared with 20.5 months (95% CI, 18.5‐22.5 months) of patients with left‐sided tumors (P < .001). On multivariate analysis, right‐sided tumors (hazard ratio [HR], 1.40; 95% CI, 1.20‐1.60), no metastasectomy (HR, 2.40; 95% CI, 1.90‐2.90), intact primary tumor (HR, 1.60; 95% CI, 1.32‐1.90), an elevated carcinoembryonic antigen level (HR, 1.54; 95% CI, 1.30‐1.90), lack of combination chemotherapy (HR, 1.52; 95% CI, 1.31‐1.80), stage IVb disease (HR, 1.50; 95% CI, 1.17‐1.86), leukocytosis (HR, 1.44; 95% CI, 1.28‐1.73), and World Health Organization performance status > 1 (HR, 1.30; 95% CI, 1.10‐1.55) were correlated with inferior survival. Conclusions Our results confirm that individuals with metastatic colorectal cancer and right‐sided tumors who received chemotherapy have inferior survival independent of other known prognostic variables. Future studies are required to understand the underlying pathophysiology. Micro‐Abstract Recent evidence from clinical trials suggests that primary tumor location in patients with metastatic colorectal cancer correlates with differential outcomes. This large population‐based cohort study involving 1947 patients confirms that primary tumor location is an independent prognostic variable regardless of age, performance status, and comorbid illness in the real‐world patients with metastatic colorectal cancer. Patients with right‐sided tumor have inferior survival compared with patients whose tumors originate in the left side of the large intestine.

Effect of Surgery and Adjuvant Therapy in Reproductive and Sexual Dysfunction in Pre-menopausal Women with Breast Cancer

Breast cancer is one of the most common cancers in women. Approximately twenty five percent breast cancer occurs during the reproductive and perimenopausal years. Surgery is the primary treatment of breast cancer. In addition, based on stage and biology of the disease, chemotherapy, radiation, endocrine therapy and biologics are recommended to reduce recurrence and cancer-related mortality. Although survival rates of women with breast cancer has significantly improved, the potential late adverse effects of adjuvant treatment and their impact on quality of life of breast cancer survivors have become increasingly important. Among premenopausal women with breast cancer, management of sexual dysfunction and fertility presents a challenge. The principal mechanisms that systemic therapy affect sexual function and fertility in women with breast cancer is ovarian suppression. In addition, cancer therapy alters anatomy and causes mucosal or skin changes that result in impaired sexual and reproductive health. In this article we review the effect of surgery and adjuvant therapy on reproductive and sexual health of young breast cancer survivors and briefly discuss various treatment options.