Iron Surveillance and Management in Gastro-Intestinal Oncology Patients: A National Physician Survey.

PURPOSE: Iron deficiency (ID) is a complication of gastrointestinal (GI) cancers that may manifest as iron deficiency anemia (IDA). Serum ferritin monitoring and oral iron supplementation have the limitations of being falsely elevated and poorly absorbed, respectively. This study aims to assess the discordance in surveillance, treatment practices, and awareness of ID/IDA in GI cancer patients by Canadian physicians treating these patients. METHODS: From February 2020 to September 2021, a 22-question electronic survey was sent to medical oncologists (MOs), surgical oncologists (SOs), and gastroenterologists (GEs). The survey collected information about four domains: physician demographics, surveillance practices, treatment practices, and awareness of ID/IDA in GI cancer patients and ASCO/ASH guidelines. RESULTS: A total of 108 (34 MOs, 19 SOs, and 55 GEs) of the 872 (12.4%) invited physicians completed the survey. Of these, 26.5% of MOs, 36.8% of SOs, and 70.9% of GEs measured baseline iron parameters, with few continuing surveillance throughout treatment. Ferritin was widely measured by MOs (88.9%), SOs (100%), and GEs (91.4%). Iron was supplemented if ID/IDA was identified pre-treatment by 66.7% of MOs, 85.7% of SOs, and 94.2% of GEs. Parenteral iron was prescribed by SOs (100%), while oral iron was prescribed by MOs (83.3%) and GEs (87.9%). Only 18.6% of physicians were aware of the ASCO/ASH guidelines regarding erythropoiesis-stimulating agents with parenteral iron for treating chemotherapy-induced anemia. CONCLUSION: Results illustrate variations in practice patterns for IDA management across the different physician specialties. Moreover, there appeared to be gaps in the knowledge and care surrounding evidence-based IDA management principles which may contribute to poor clinical outcomes.

Long-term outcomes following salvage surgery for locally recurrent rectal cancer: A 15-year follow-up study.

BACKGROUND: Locally recurrent rectal cancer (LRRC) is a complex problem requiring multidisciplinary consultation and specialized surgical care. Given the paucity of published longer-term survival data, skepticism persists regarding the benefit of major extirpative surgery. We investigated ultra-long-term (~15 years) outcomes following radical resection of LRRC and sought relevant clinicopathologic prognostic variables. METHODS: A cohort of 52 consecutive patients who underwent resection of LRRC at our institution between 1997 and 2005 were followed with serial exams and imaging up to the point of death, or 30/06/2019. RESULTS: Median follow-up time was 16.5 years (9.9-18.3) for patients who were alive at last follow-up; only one patient was lost to follow-up, at 9.9 years. For the entire cohort of 52 patients, disease-specific survival (DSS) at 5, 10, and 15 years following salvage surgery was 41%, 33%, and 31%, respectively. All patients who had distant metastatic disease at the time of LRRC resection (n = 6) subsequently died of cancer, at a median of 21 months (4-46). In those without distant metastases at time of salvage surgery (n = 46), DSS at 5, 10, and 15 years was 47%, 38%, and 35%, respectively, median 60 months. Negative resection margin (R0) was independently predictive of superior outcomes. In patients with M0 disease who had R0 resection (n = 37), DSS at 5, 10 and 15 years was 58%, 47%, and 44%, respectively, median 73 months. No patient developed re-recurrence after 5.5 years. CONCLUSIONS: This study demonstrates exceptionally durable long-term cancer-free survival following salvage surgery for LRRC, indicating that cure is possible.

Multicenter Validation Study to Implement Plasma Epidermal Growth Factor Receptor T790M Testing in Clinical Laboratories.

PURPOSE: Plasma detection of EGFR T790M mutations is an emerging alternative to tumor rebiopsy in acquired epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor resistance. Validation of analytical sensitivity and clinical utility is required before routine diagnostic use in clinical laboratories. PATIENTS AND METHODS: Sixty-three patients with advanced EGFR-mutant lung cancer at 7 Canadian centers, who were being screened for the ASTRIS trial (ClinicalTrials.gov identifier: NCT02474355), participated in this companion study. Plasma T790M mutation was detected using droplet digital polymerase chain reaction, Cobas (Roche Diagnostics, Indianapolis, IN), or next-generation sequencing in 4 laboratories. T790M concordance was assessed between plasma and tumor samples. RESULTS: Assessment of T790M in tumor biopsy tissue was successful in 81% of patients; 49% had confirmed T790M results (tumor or plasma) for ASTRIS. Plasma testing in this companion study yielded T790M results in 97% of patients; 62% had T790M-positive results, 36% had negative results, and 2% had indeterminate results. Of 38 patients with negative or indeterminate biopsy results, 55% had positive plasma T790M results, increasing the proportion with T790M-positive results to 73%. Sensitivity of plasma T790M testing was 75%. Overall concordance between tissue and plasma was 64%, and concordance among laboratories was 90.3%. Response to osimertinib and duration of therapy were similar irrespective of testing method (overall response rate, 62.5% for tissue, 66.7% for plasma, and 70.6% for both). CONCLUSION: This multicenter validation study demonstrates that plasma EGFR T790M testing can identify significantly more patients than biopsy alone who may benefit from targeted therapy.

Molecular Profiling of Patients With Advanced Colorectal Cancer: Princess Margaret Cancer Centre Experience.

BACKGROUND: Molecular aberrations in KRAS, NRAS, BRAF, and PIK3CA have been well-described in advanced colorectal cancer. The incidences of other mutations are less known. We report results of molecular profiling of advanced colorectal cancer in an academic cancer center. PATIENTS AND METHODS: Patients with advanced colorectal were enrolled in an institution-wide molecular profiling program. Profiling was performed on formalin-fixed paraffin embedded archival tissues using a customized MassArray panel (23 genes, 279 mutations) or the Illumina MiSeq TruSeq Cancer Panel (48 genes, 212 amplicons, ≥ 500× coverage) in a Clinical Laboratory Improvement Amendments-certified laboratory. PTEN was determined by immunohistochemistry. RESULTS: From March 2012 to April 2014, 245 patients were enrolled. At least one mutation was found in 54% (97/178) and 91% (61/67) of patients using MassArray or MiSeq platforms, respectively (P < .01). Of all patients, KRAS G12/13 mutation was identified in 39%, and non-G12/13 KRAS, BRAF, or NRAS mutations were present in 9%, 6%, and 4%, respectively. Other common mutations included TP53 (68.7%), APC (41.8%), and PIK3CA (13.5%). Co-mutation with KRAS, NRAS, or BRAF was found in 75% of patients with PIK3CA mutation. Of 106 patients with known PTEN immunohistochemistry status, 16% were negative. A higher average number of mutations were observed in right versus left colorectal cancer (P < .01), with 13 of 14 BRAF mutations located in right colon cancer. CONCLUSION: Mutations are common in advanced colorectal cancer. Right colon cancers harbor more genetic aberrations than left colon or rectal cancers. These aberrations may contribute to differential outcomes to anti-epidermal growth factor receptor therapy among patients with right colon, left colon, or rectal cancers.

Bevacizumab in Colorectal Cancer: Current Role in Treatment and the Potential of Biosimilars.

Colorectal cancer (CRC) is a leading cause of tumor-related morbidity and mortality worldwide, with mortality most often attributable to metastatic disease. Bevacizumab, a humanized monoclonal antibody targeting vascular endothelial growth factor, has a significant role in the treatment of metastatic CRC (mCRC). However, patient access to bevacizumab may be limited in some regions or circumstances, owing to factors related to insurance coverage, reimbursement, patient out-of-pocket costs, or availability. As a result, outcomes for patients with mCRC may be worsened. Additionally, counterfeit bevacizumab has infiltrated legitimate supply chains, exposing patients to risk. Oncologists may also be affected detrimentally, since resolving access issues can be time-consuming and demoralizing. The imminent expiry of patents protecting bevacizumab provides other manufacturers with the opportunity to produce highly similar versions known as biosimilars. High-quality, safe, and effective biosimilars have the potential to expand access to bevacizumab. Most of the bevacizumab biosimilars currently in development are in clinical trials in patients with non-small-cell lung cancer, and future authorization for mCRC indications will, therefore, be based on extrapolation. This article reviews the current role of bevacizumab in the management of mCRC, the possible barriers associated with diminished access to bevacizumab, and the potential bevacizumab biosimilars in development. How biosimilars may impact the treatment of mCRC is also discussed.

Evolution of Symptom Burden of Advanced Lung Cancer Over a Decade.

INTRODUCTION: Lung cancer is associated with higher levels of symptom distress and unmet needs than other cancer types. We assessed changes in symptoms, function, understanding, and preferences of patients with advanced lung cancer over a 10-year period. MATERIALS AND METHODS: A 26-item self-administered questionnaire was used to assess symptom burden, functional impairment, knowledge of disease and treatment, and information preferences. The survey was administered to consecutive outpatients with advanced lung cancer first in 2002 and a second cohort in 2012. RESULTS: A total of 108 patients with advanced lung cancer were surveyed in 2002, and 100 in 2012. Rates of severe physical symptoms were similar over the 10-year period. The most common symptoms remained fatigue, cough, and dyspnea. One-third perceived major impairment of daily activities from lung cancer. Significant anxiety was reported by at least 20%; nearly a quarter reported being unable to meet family needs. More patients in 2012 received information on treatment benefits, side effects, and clinical trials. Only 40% reported having end-of-life wishes, and fewer than half had discussed these with their oncologist. Over time, more patients expressed a preference for treatment associated with increased survival even if it compromised quality of life. Half were interested in Internet-based resources, most in print media, and a growing number in telephone support. CONCLUSION: Patients with advanced lung cancer continue to experience significant symptom distress and unmet needs despite advances in treatment. Comprehensive assessment and symptom, psychological, financial, and information support remain key areas for improvement in the care of patients with advanced lung cancer.

Pan Canadian Rash Trial: A Randomized Phase III Trial Evaluating the Impact of a Prophylactic Skin Treatment Regimen on Epidermal Growth Factor Receptor-Tyrosine Kinase Inhibitor-Induced Skin Toxicities in Patients With Metastatic Lung Cancer.

PURPOSE: Erlotinib is an epidermal growth factor receptor inhibitor approved for patients with advanced non-small-cell lung cancer (NSCLC) whose epidermal growth factor receptor expression status is positive or unknown. Although it is efficacious, erlotinib can cause skin toxicity. This prospective, randomized phase III trial examined the effect of prophylactic treatment of erlotinib-induced skin rash. PATIENTS AND METHODS: Patients receiving erlotinib in the second- or third-line setting for advanced NSCLC were randomly assigned to prophylactic minocycline (100 mg twice per day for 4 weeks), reactive treatment (after rash developed, per grade of rash), or no treatment unless severe (grade 3). Rash incidence and severity, time to maximal rash, time to resolution, and overall survival (OS) were compared among treatment groups. RESULTS: In all, 150 patients were randomly assigned, 50 to each of three treatment arms. The incidence of skin toxicity was 84% regardless of treatment arm. Prophylactic treatment with minocycline significantly lengthened the time to the most severe grade of rash. Grade 3 rash was significantly higher in the no-treatment arm. OS was not significantly different among treatment arms, but patients receiving prophylactic or reactive treatments had a longer OS (7.6 and 8 months, respectively) than those who received no rash treatment (6 months). Rash was not self-limiting. CONCLUSION: The incidence of all grades of rash did not differ statistically among the three arms, so the trial was negative. The incidence of grade 3 skin toxicities was reduced in patients who were treated with prophylactic minocycline or reactive treatment. Efficacy was not compromised. Prophylactic minocycline and reactive treatment are both acceptable options for the necessary treatment of erlotinib-induced rash in the second- or third-line setting of metastatic NSCLC.

Collaborative Care in NSCLC; the Role of Early Palliative Care.

The management of non-small cell lung cancer (NSCLC) has evolved into a multidisciplinary team approach that traditionally has involved medical oncology, radiation oncology, and thoracic surgery. However, in the era of personalized medicine the importance of molecular diagnostics requires adequate tissue for histologic subtyping and molecular testing and thus requires the engagement of other subspecialties such as pathology, respirology, and interventional radiology. Unfortunately in 2014, the majority of patients presenting with NSCLC will succumb to their disease and the early integration of palliative care into the treatment strategy will improve the quality of life and end-of-life care of our patients and may in fact improve their overall survival.

A phase I/II study of GTI-2040 plus docetaxel as second-line treatment in advanced non-small cell lung cancer: a study of the PMH phase II consortium.

INTRODUCTION: GTI-2040, an antisense oligonucleotide, targets the ribonucleotide reductase R2 subunit, critical for DNA synthesis. This study determined the recommended phase II dose (RP2D) of docetaxel plus GTI-2040, toxicity, and response rate in advanced non-small cell lung cancer (NSCLC). PATIENTS AND METHODS: Advanced solid tumor patients, preferably with platinum-treated NSCLC, performance status 0 to 2, no symptomatic central nervous system metastases, adequate organ and bone marrow function, and >or=1 prior chemotherapy regimen were treated with escalating doses of GTI-2040 given by 14-day continuous intravenous infusion (CVI) plus docetaxel every 21 days. RESULTS: Twenty-nine patients were treated, (24 NSCLC, 3 hormone-refractory prostate cancer, 1 head and neck, and 1 small cell lung cancer). GTI-2040 5 mg/kg as CVI for 14 days plus docetaxel 75 mg/m(2) intravenously every 21days was determined as the RP2D. Dose-limiting toxicity was not seen. Two patients at RP2D developed grade 4/5 febrile neutropenia. One prostate specific antigen response was seen in phase I, but no objective tumor responses in the NSCLC patients. Median time to progression was 3.4 months, 3.2 months in the NSCLC patients treated at RP2D. CONCLUSIONS: Activity of the combination at RP2D, GTI-2040 5 mg/kg/d x 14 days by CVI plus docetaxel 75 mg/m(2) does not seem superior to docetaxel alone in previously treated NSCLC.

Prognostic significance of mesenteric tumor nodules in patients with stage III colorectal cancer.

BACKGROUND: Tumor nodules are occasionally found in adjacent mesentery of colorectal cancer specimens and are felt to reflect a worse prognosis. The clinical significance of mesenteric tumor nodules was investigated. METHODS: A review of 786 patients with stage III colorectal cancer referred between 1995 and 1999 was undertaken. TNM staging was standardized by considering mesenteric nodules separately and not assigning them to T or N categories. Survival analyses were performed. RESULTS: Mesenteric tumor nodules were found in 116 (14.8%) patients: 48 (41.4%) with colon cancer and 68 (58.6%) rectal cancer. Mean age at surgery was 63 years. Adjuvant chemotherapy was given to 84.8% of colon cancer patients. Two (2.9%) rectal cancer patients received neoadjuvant chemoradiation, and 63 (92.6%) received adjuvant therapy (chemotherapy and/or radiation). In the cohort with mesenteric nodules, the median time to progression was 23.1 months, the median 5-year disease-free survival was 35%, and the median overall survival (OS) was 47.9 months, with 44% OS at 5 years. In the 19 (16.4%) patients with mesenteric nodules and no lymph nodes the 5-year OS was 60% (SEER stage II 5-year survival 82.5%), whereas in 97 patients who were lymph node-positive the 5-year OS was 40% (SEER 5-year survival stage IIIc 44.3%; stage IV 8.1%). CONCLUSIONS: In comparison to SEER survival data, the presence of mesenteric nodules appears to worsen the prognosis of any T/N0 disease to that of overall stage III disease. Mesenteric nodules with any T/N+ disease had prognosis similar to that of stage IIIC disease, but the prognosis was better than M1 disease. .

Natural history and chemotherapy effectiveness for advanced adenocarcinoma of the small bowel: a retrospective review of 113 cases.

BACKGROUND: Small bowel adenocarcinoma is a rare cancer that has generally been considered resistant to chemotherapy, although little has been published on the role of chemotherapy. A retrospective analysis was conducted of patients with advanced small bowel adenocarcinoma to explore chemotherapy use, and gain knowledge for ongoing management and future clinical trials. PATIENTS AND METHODS: All patients with advanced adenocarcinoma of the small bowel treated at Princess Margaret Hospital (PMH) between 1986 and 2004 were identified through the cancer registry. The medical records were reviewed for patient characteristics, treatment and outcome data. Survival statistics were estimated using the Kaplan Meier survival curves and Cox proportional regression model. RESULTS: Data on 113 patients was reviewed. Forty-four patients received palliative chemotherapy with an overall response rate (ORR) of 36% during a first or second line regimen (9% complete responses and 27% partial responses). Newer chemotherapy regimens including gemcitabine and irinotecan combinations appeared to have higher ORR, than older fluorouracil-based regimens. Some patients responded to more than one line of chemotherapy. Palliative chemotherapy predicted for overall survival (OS) in a multivariate analysis (HR 0.47, P = 0.035). CONCLUSION: Chemotherapy appears to have activity in adenocarcinoma of the small bowel. Prospective trials evaluating patient benefit are required to confirm this activity using newer systemic therapies, until such time retrospective reviews such as this will continue to guide treatment decisions.

Induction chemotherapy with mitomycin, vindesine, and cisplatin for stage IIIA (T1-3, N2) unresectable non-small-cell lung cancer: final results of the Toronto phase II trial.

PURPOSE: This is a phase II study to assess the role of induction chemotherapy in the management of stage IIIA non-small-cell lung cancer (NSCLC). We are now reporting the long-term follow-up of the Toronto phase II trial. METHODS: Sixty five patients with mediastinoscopy proven stage IIIA NSCLC received two cycles of preoperative MVP or VLB/P followed by thoracotomy followed by two further courses of chemotherapy. RESULTS: The overall response rate was 67.7% with three complete and 41 partial responders. Forty seven patients went on to thoracotomy with 35 complete resections. Pathologically 4.6% of patients had no tumour remaining. There were three postop deaths as well as five chemotherapy related deaths. Of the 35 patients completely resected 19 have recurred including eight in brain. The median survival for the entire 65 patients is 18.6 months with a 1 year survival of 66%, 5 year survival of 29% and a 10 year survival of 22%. CONCLUSIONS: The long-term survival of induction chemotherapy is maintained. The high incidence of brain recurrences warrants assessment of the role of prophylactic cranial radiation. The role of surgery for stage IIIA NSCLC following induction chemotherapy awaits further study.

A phase I study of pegylated liposomal doxorubicin hydrochloride (Caelyx) in combination with cyclophosphamide and vincristine as second-line treatment of patients with small-cell lung cancer.

The purpose of this study was to determine the recommended phase II dose of liposomal doxorubicin (Caelyx ; Doxil in the United States) in combination with cyclophosphamide and vincristine for previously treated patients with good performance status with relapsed or refractory small-cell lung cancer. Twenty-one eligible patients were enrolled between November 1999 and September 2001 and received liposomal doxorubicin 25-40 mg/m2, cyclophosphamide 750-1000 mg/m2, and vincristine 1.2 mg/m2 intravenously (I.V.) every 21 days. At doses of liposomal doxorubicin 40 mg/m2, cyclophosphamide 750 mg/m2, and vincristine 1.2 mg/m2 I.V., 1 of 6 patients had dose-limiting neutropenia and fever in cycle 2 and 2 of 6 developed grade 3 hand-foot syndrome during cycle 3. Therefore, the recommended phase II doses are liposomal doxorubicin 35 mg/m2, cyclophosphamide 750 mg/m2, and vincristine 1.2 mg/m2 I.V. every 21 days. Antitumor activity was seen at all dose levels. This combination is well tolerated and has evidence of antitumor activity. A phase II evaluation is ongoing.

Economic analysis of the TAX 317 trial: docetaxel versus best supportive care as second-line therapy of advanced non-small-cell lung cancer.

PURPOSE: To determine the cost-effectiveness (CE) of second-line docetaxel compared with best supportive care (BSC) in the TAX 317 trial, a randomized clinical trial of second-line chemotherapy in non-small-cell lung cancer. METHODS: A retrospective CE analysis of the TAX 317 trial was undertaken, evaluating direct medical costs of therapy from the viewpoint of Canada's public health care system. Costs were derived in 1999 Canadian dollars, and resource use was determined through prospective trial data. RESULTS: The incremental survival benefit in the docetaxel arm over BSC was 2 months (P =.047). The CE of docetaxel was $57,749 per year of life gained. For patients treated with docetaxel 75 mg/m(2), the CE was $31,776 per year of life gained. In univariate sensitivity analyses, CE estimates were most sensitive to changes in survival, ranging from $18,374 to $117,434 with 20% variation in survival at the recommended dose. The largest cost center in both arms was hospitalization, followed by the cost of drugs, investigations, radiotherapy, and community care. BSC patients had fewer hospitalizations than patients in the chemotherapy arm and were more often palliated at home. CONCLUSION: Although the decision to treat should not be based on economic considerations alone, our CE estimate of $31,776 per year of life gained (at the currently recommended dose of docetaxel) is within an acceptable range of health care expenditures, and the total costs of therapy are similar to those of second-line palliative chemotherapy for other solid tumors.