Use of the epidermal growth factor receptor inhibitors gefitinib,erlotinib, afatinib,dacomitinib, and icotinib in the treatment of non-small-cell lung cancer: a systematic review

Introduction

This systematic review addresses the use of epidermal growth factor receptor (egfr) inhibitors in three populations of advanced non-small-cell lung cancer (nsclc) patients—unselected, selected, and molecularly selected—in three treatment settings: first line, second line, and maintenance.

Methods

Ninety-six randomized controlled trials found using the medline and embase databases form the basis of this review.

Results

In the first-line setting, data about the efficacy of egfr tyrosine kinase inhibitors (tkis) compared with platinum-based chemotherapy are inconsistent. Results from studies that selected patients based on clinical characteristics are also mixed. There is high-quality evidence that an egfr tki is preferred over a platinum doublet as initial therapy for patients with an activating mutation of the EGFR gene. The egfr tkis are associated with a higher likelihood of response, longer progression-free survival, and improved quality of life. Multiple trials of second-line therapy have compared an egfr tki with chemotherapy. Meta-analysis of those data demonstrates similar progression-free and overall survival. There is consequently no preferred sequence for second-line egfr tki or second-line chemotherapy. The egfr tkis have also been evaluated as switch-maintenance therapy. No molecular marker could identify patients in whom a survival benefit was not observed; however, the magnitude of the benefit was modest.

Conclusions

Determination of EGFR mutation status is essential to making appropriate treatment decisions in patients with nsclc. Patients who are EGFR mutation–positive should be treated with an egfr tki as first-line therapy. An egfr tki is still appropriate therapy in patients who are EGFR wild-type, but the selected agent should be administered as second- or third-line therapy.     

Cost-effectiveness of first-line treatments for patients with KRAS wild-type metastatic colorectal cancer

Background

Combinations of chemotherapy regimens and monoclonal antibodies have been demonstrated to improve clinical outcomes in patients with metastatic colorectal cancer (mcrc). Although these combination treatment strategies are safe and effective in first-line treatment for mcrc, little is known about their economic consequences and resource allocation implications. In the present study, we evaluated the cost-effectiveness of bevacizumab plus folfiri, cetuximab plus folfiri, and panitumumab plus folfiri for patients with KRAS wild-type mcrc.

Methods

A Markov model simulated the lifetime patient outcomes and costs of each first-line treatment strategy and subsequent lines of treatment from the perspective of the health care payer in Ontario. The model was parameterized using data from the Ontario Cancer Registry, Ontario health administrative databases, and published randomized control trials. Patient outcomes were measured in quality-adjusted life years (qalys), and costs were measured in monetary terms. Costs and outcomes were both discounted at 5% and expressed in 2012 Canadian dollars.

Results

For mcrc patients with KRAS wild-type disease, the treatment strategy of bevacizumab plus folfiri was found to dominate the other two first-line treatment strategies. Sensitivity analyses revealed that the incremental cost-effectiveness ratio values were sensitive to the effectiveness of treatment, the costs of bevacizumab and cetuximab, and health utility values.

Conclusions

Evidence from Ontario showed that bevacizumab plus folfiri is the cost-effective first-line treatment strategy for patients with KRAS wild-type mcrc. The panitumumab plus folfiri and cetuximab plus folfiri options were both dominated, but the cetuximab plus folfiri strategy must be further investigated given that, in the sensitivity analyses, the cost-effectiveness of that strategy was found to be superior to that of bevacizumab plus folfiri under certain ranges of parameter values.     

Should noncurative resection of the primary tumour be performed in patients with stage iv colorectal cancer? A systematic review and meta-analysis

Purpose

Surgical resection of the primary tumour in patients with advanced colorectal cancer (crc) remains controversial. This review compares survival in patients with advanced crc who underwent surgical resection of the primary tumour with that in patients not undergoing resection, and determines rates of post-operative mortality and nonfatal complications, the primary tumour complication rate, the non-resection surgical procedures rate, and quality of life (qol).

Methods

Reports in the central, medline, and embase databases were searched for relevant studies, which were selected using pre-specified eligibility criteria. The search was also restricted to publication dates from 1980 onward, the English language, and studies involving human subjects. Screening, evaluation of relevant articles, and data abstraction were performed in duplicate, and agreement between the abstractors was assessed. Articles that met the inclusion criteria were assessed for quality using the Newcastle–Ottawa Scale. Data were collected and synthesized per protocol.

Results

From among the 3379 reports located, fifteen retrospective observational studies were selected. Of the 12,416 patients in the selected studies, 8620 (69%) underwent surgery. Median survival was 15.2 months (range: 10–30.7 months) in the resection group and 11.4 months (range: 3–22 months) in the non-resection group. Hazard ratio for survival was 0.69 [95% confidence interval (ci): 0.61 to 0.79] favouring surgical resection. Mean rates of postoperative mortality and nonfatal complications were 4.9% (95% ci: 0% to 9.7%) and 25.9% (95%ci: 20.1% to 31.6%) respectively. The mean primary tumour complication rate was 29.7% (95% ci: 18.5% to 41.0%), and the non-resection surgical procedures rate in the non-resection group was 27.6% (95 ci: 15.4% to 39.9%). No study provided qol data.

Conclusions

Although this review supports primary tumour resection in advanced crc, the results have significant biases. Randomized trials are warranted to confirm the findings.     

Bevacizumab in combination with FOLFIRI chemotherapy in patients with metastatic colorectal cancer: an assessment of safety and efficacy in the province of Newfoundland and Labrador

Background

In 2005, bevacizumab was approved by Health Canada for patients with metastatic colorectal cancer (mcrc). Newfoundland and Labrador was one of the first Canadian provinces to fund this agent in combination with folfiri (irinotecan, 5-fluorouracil, leucovorin) chemotherapy. In this analysis, the entire provincial bevacizumab sample for the first 2 years was assessed for overall safety and efficacy.

Methods

The medical records of 43 patients with mcrc who had received folfiri with bevacizumab were identified and reviewed. The longitudinal data collection format that was adopted assessed occurrences of adverse events after each cycle of treatment. Toxicity outcomes such as gastrointestinal (gi) perforations, bleeding, diarrhea, myelosuppression, proteinuria, and venous thromboembolic events (vtes) were collected and graded using the U.S. National Cancer Institute’s Common Terminology Criteria for Adverse Events, version 3.0. Time to treatment failure (ttf) and overall survival (os) were determined using the Kaplan–Meier method.

Results

Overall, the 43 study patients received 398 cycles of anticancer therapy (median: 6 cycles; range: 1–24 cycles). No gi perforations were identified. However, 4 bleeding events occurred (9.3%), 3 requiring permanent discontinuation of bevacizumab. Also, 6 grade 3 or 4 vtes occurred (14.0%), 3 of which required a hospital admission. In addition, grades 3 and 4 diarrhea, febrile neutropenia, and proteinuria showed cumulative incidences of 11.6%, 2.3%, and 2.3% respectively. Median ttf was 6.3 months; median os was 24.4 months.

Conclusions

Bevacizumab in combination with folfiri appears to be well tolerated, and efficacy is consistent with trial reports. However, patients should be closely monitored to avoid potentially serious events such as bleeding and vtes.     

Colorectal cancer screening in Canada: results from the first round of screening for five provincial programs

Background

Early implementation of programmatic colorectal cancer (crc) screening for average-risk individuals 50–74 years of age in Canada has used fecal occult blood tests [fts (guaiac or immunochemical)] and colonoscopy for follow-up of abnormal fts. This paper presents results of an evaluation of this crc screening.

Methods

Five Canadian provincial programs provided aggregated data for individuals with a first-round ft processed between January 1, 2009, and December 31, 2011.

Results

The 104,750 people who successfully completed a first round of screening represented 16.1% of those who had access to the programs between January 1, 2009, and December 31, 2011 (mean age: 61.2 years; men: 61.4 years; women: 61.1 years). Of those participants, 4661 had an abnormal ft (4.4%). Uptake of colonoscopy within 180 days after an abnormal ft was 80.5%, ranging from 67.8% to 89.5% by program. The positive predictive value (ppv) for adenoma was 35.9% for guaiac ft and 50.6% for immunochemical ft. Adenoma and crc detection rates were, respectively, 16.9 and 1.8 per 1000 screened. Of invasive crcs detected, 64.6% were stage i or ii.

Conclusions

Considering the variation in characteristics and stage of implementation of each provincial program, the collaboration of the provinces leading to this report on the early performance of crc screening in Canada is a major milestone. Targets are met or nearly met for significant indicators such as ppv for adenoma and cancer detection rate. Participation is expected to increase as programs are fully implemented in the provinces. Additional effort may be needed to improve timely access to follow-up colonoscopy.     

The role of the epidermal growth factor receptor tyrosine kinase inhibitors as therapy for advanced,metastatic, and recurrent non-small-cell lung cancer: a Canadian national consensus statement

Purpose

To provide consensus recommendations on the use of epidermal growth factor receptor tyrosine kinase inhibitors (egfr-tkis) in patients with advanced or meta-static non-small-cell lung cancer (nsclc).

Methods

Using a systematic literature search, phase ii trials, randomized phase iii trials, and meta-analyses were identified for inclusion.

Results

A total of forty-six trials were included. Clear evidence is available that egfr-tkis should not be administered concurrently with platinum-based chemotherapy as first-line therapy in advanced or metastatic nsclc. Evidence is currently insufficient to recommend single-agent egfr-tkis as first-line therapy either in unselected populations or in populations selected on the basis of molecular or clinical characteristics. Following failure of platinum-based chemotherapy, the evidence suggests that second-line egfr-tkis or second-line chemotherapy result in similar survival. Quality of life and symptom improvement for patients treated with an egfr-tki appear better than they do for patients treated with second-line docetaxel. Sequence of therapy may not appear to be important, but if survival is the outcome of interest, the goal should be to optimize the number of patients receiving three lines of therapy. Based on available data, molecular markers and clinical characteristics do not appear to be predictive of a differential survival benefit from an egfr-tki and therefore those factors should not be used to select patients for egfr-tki therapy.

Conclusions

The egfr-tkis represent an additional therapy in the treatment of advanced or metastatic nsclc. The results of ongoing clinical trials may define the optimal role for these agents and the effectiveness of combinations of these agents with other targeted agents.     

Fertility risk discussions in young patients diagnosed with colorectal cancer

Purpose

In 2006, the American Society of Clinical Oncology established guidelines on fertility preservation in cancer patients, but recent data suggest that the guidelines are not widely followed. To identify the frequency of fertility discussions and the characteristics that influence the rate of discussion, we performed a retrospective chart review for patients less than 40 years of age with newly diagnosed colorectal cancer (crc).

Methods

Charts of patients aged 18–40 years with newly diagnosed crc presenting to the Juravinski Cancer Centre from 2000 to 2009 were reviewed for documentation of discussions regarding fertility risks with treatment and reproductive options available. The influences of sex, age, year of diagnosis, stage of cancer, and type of treatment on the frequency of discussions were explored.

Results

The review located 59 patients (mean age: 35 years) who met the criteria for inclusion. A fertility discussion was documented in 20 of those patients [33.9%; 95% confidence interval (ci): 22.1% to 47.4%]. In the multivariate analysis, the odds of fertility being addressed was higher for patients receiving radiation [odds ratio (or): 9.31; 95% ci: 2.49 to 34.77, p < 0.001) and lower by age (or: 0.86; 95% ci: 0.74 to 0.99; p = 0.040). Of patients less than 35 years of age undergoing radiation treatment, 85% had a documented fertility discussion. We observed no significant difference in the frequency of discussions after 2006, when the American Society of Clinical Oncology guidelines were published (31.4% for 2000–2006 vs. 37.5% for 2007–2009, p = 0.63).

Conclusions

Discussions about fertility risks associated with crc treatment occur infrequently among young adults with newly diagnosed crc. However, discussions occur more frequently in younger patients and in those undergoing radiation. Further investigations assessing barriers and physician attitudes to fertility risk discussion and reproductive options are planned.     

Epidermal growth factor receptor targeted therapy in stages III and IV head and neck cancer

Question

What are the benefits associated with the use of anti–epidermal growth factor receptor (anti-egfr) therapies in squamous cell carcinoma of the head and neck (hnscc)? Anti-egfr therapies of interest included cetuximab, gefitinib, lapatinib, zalutumumab, erlotinib, and panitumumab.

Perspectives

Head-and-neck cancer includes malignant tumours arising from a variety of sites in the upper aerodigestive tract. The most common histologic type is squamous cell carcinoma, and most common sites are the oral cavity, the oropharynx, the hypopharynx, and the larynx. Worldwide, hnscc is the sixth most common neoplasm, and despite advances in therapy, long-term survival in hnscc patients is poor. Primary surgery followed by chemoradiation, or primary chemoradiation, are the standard treatment options for patients with locally advanced (stages iii–ivb) hnscc; however, meta-analytic data indicate that the benefit of concurrent platinum-based chemotherapy disappears in patients over the age of 70 years.Cetuximab is a monoclonal antibody approved for use in combination with radiation in the treatment of patients with untreated locally advanced hnscc and as monotherapy for patients with recurrent or metastatic (stage ivc) hnscc who have progressed on platinum-based therapy.Given the interest in anti-egfr agents in advanced hnscc, the Head and Neck Cancer Disease Site Group (dsg) of Cancer Care Ontario’s Program in Evidence-Based Care (pebc) chose to systematically review the literature pertaining to this topic so as to develop evidence-based recommendations for treatment.

Outcomes

Outcomes of interest included overall and progression-free survival, quality of life, tumour response rate and duration, and the toxicity associated with the use of anti-egfr therapies.

Methodology

The medline, embase, and Cochrane Library databases, the American Society of Clinical Oncology online conference proceedings, the Canadian Medical Association InfoBase, and the National Guidelines Clearinghouse were systematically searched to locate primary articles and practice guidelines. The reference lists from relevant review articles were searched for additional trials. All evidence was reviewed, and that evidence informed the development of the clinical practice guideline. The resulting recommendations were approved by the Report Approval Panel of the pebc, and by the Head and Neck Cancer dsg. An external review by Ontario practitioners completed the final phase of the review process. Feedback from all parties was incorporated to create the final practice guideline.

Results

The electronic search identified seventy-four references that were reviewed for inclusion. Only four phase iii trials met the inclusion criteria for the present guideline. No practice guidelines, systematic reviews, or meta-analyses were found during the course of the literature search.The randomized controlled trials (rcts) involved three distinct patient populations: those with locally advanced hnscc being treated for cure, those with incurable advanced recurrent or metastatic hnscc being treated with first-line platinum-based chemotherapy, and those with incurable advanced recurrent or metastatic hnscc who had disease progression despite, or who were unsuitable for, first-line platinum-based chemotherapy.

Practice Guideline

These recommendations apply to adult patients with locally advanced (nonmetastatic stages iii–ivb) or recurrent or metastatic (stage ivc) hnscc.

• Platinum-based chemoradiation remains the current standard of care for treatment of locally advanced hnscc.
• In patients with locally advanced hnscc who are medically unsuitable for concurrent platinumbased chemotherapy or who are over the age of 70 years (because concurrent chemotherapy does not appear to improve overall survival in this patient population), the addition of cetuximab to radical radiotherapy should be considered to improve overall survival, progression-free survival, and time to local recurrence.Cetuximab in combination with platinum-based combination chemotherapy is superior to chemotherapy alone in patients with recurrent or metastatic hnscc, and is recommended to improve overall survival, progression-free survival, and response rate.
• The role of anti-egfr therapies in the treatment of locally advanced hnscc is currently under study in large randomized trials, and patients with hnscc should continue to be offered clinical trials of novel agents aimed at improving outcomes.

Qualifying Statements

Chemoradiation is the current standard of care for patients with locally advanced hnscc, and to date, there is no evidence that compares cetuximab plus radiotherapy with chemoradiation, or that examines whether the addition of cetuximab to chemoradiation is of benefit in these patients. However, five ongoing trials are investigating the effect of the addition of egfr inhibitors concurrently with, before, or after chemoradiotherapy; those trials should provide direction about the best integration of cetuximab into standard treatment.In patients with recurrent or metastatic hnscc who experience progressive disease despite, or who are unsuitable for, first-line platinum-based chemotherapy, gefitinib at doses of 250 mg or 500 mg daily, compared with weekly methotrexate, did not increase median overall survival [hazard ratio (hr): 1.22; 96% confidence interval (ci): 0.95 to 1.57; p = 0.12 (for 250 mg daily vs. weekly methotrexate); hr: 1.12; 95% ci: 0.87 to 1.43; p = 0.39 (for 500 mg daily vs. weekly methotrexate)] or objective response rate (2.7% for 250 mg and 7.6% for 500 mg daily vs. 3.9% for weekly methotrexate, p > 0.05). As compared with methotrexate, gefitinib was associated with an increased incidence of tumour hemorrhage (8.9% for 250 mg and 11.4% for 500 mg daily vs. 1.9% for weekly methotrexate).     

Role of oxaliplatin combined with 5-fluorouracil and folinic acid in the first- and second-line treatment of advanced colorectal cancer

Question

What is the role of oxaliplatin combined with 5-fluorouracil (5-fu) and folinic acid (fa) in the first- and second-line treatment of advanced (unresectable locally advanced or metastatic) colorectal cancer?

Perspectives

Evidence was selected and reviewed by two members of the Gastrointestinal Cancer Disease Site Group (gi dsg) of Cancer Care Ontario’s Program in Evidence-Based Care (pebc) and by a methodologist. The resulting practice guideline report has been reviewed and approved by the gi dsg, which comprises medical and radiation oncologists, surgeons, a pathologist, and patient representatives.External review by Ontario practitioners was obtained through a mailed survey. Final approval of the original guideline report was obtained from the Practice Guidelines Coordinating Committee.

Outcomes

Outcomes of interest were 1-year survival, response rates, and quality of life.

Methodology

The medline, cancerlit, embase, Guidelines International Network, and Cochrane Library databases were systematically searched for relevant studies. Recommendations were formed based on the evidence reviewed. Through a survey, these recommendations were appraised by Ontario clinicians; the recommendations were then revised by the gi dsg. The systematic review and modified recommendations were approved by a review body within pebc.

Results

The literature review found twenty-one randomized controlled trials and two meta-analyses. Evidence on first-line treatment found infusional 5-fu/fa/oxaliplatin (folfox) to be superior to bolus 5-fu/fa/irinotecan (ifl) for rates of median survival and tumour response, with lower incidences of most adverse effects except peripheral neuropathy. For second-line treatment after fluoropyrimidine monotherapy, folfox is a reasonable alternative for patients with contraindications to second-line irinotecan. After progression on infusional 5-fu/fa/irinotecan (folfiri), folfox is the preferred therapy. Evidence from a single randomized trial suggests that additional benefits can be expected with the addition of bevacizumab to the folfox regimen in second-line treatment.

Practice Guideline

These recommendations apply to adult patients with advanced colorectal cancer who have high performance status (Eastern Cooperative Oncology Group score 0–2).Refer to Appendix A for available treatment options and to Appendix b for recommended dosages and schedules.The folfox regimen is an important component of therapy for advanced colorectal cancer.

First-line Therapy

In one trial, folfox was shown to be superior to ifl. The folfox regimen has superior rates of median survival and tumour response. Compared with ifl, folfox has lower incidences of severe nausea, vomiting, diarrhea, and febrile neutropenia, but a higher incidence of peripheral neuropathy.Short-term infusional 5-fu/fa in combination with either oxaliplatin (folfox) or irinotecan (folfiri) are both acceptable alternatives for fit patients when combination therapy is the preferred treatment. Choice of first-line therapy may rely on patient factors and preferences—for example, less neuropathy with irinotecan versus less alopecia with oxaliplatin.

Second-line Therapy

After progression on first-line anti-thymidylate synthase monotherapy (for example, 5-fu/fa, capecitabine), irinotecan is standard second-line therapy. The folfox regimen is a reasonable alternative for patients with contraindications to the use of second-line irinotecan.After progression on both irinotecan and an anti-thymidylate synthase agent, folfox is the preferred therapy. Recent trials suggest that, as compared with folfox alone, folfox combined with bevacizumab provides additional survival benefits.

Qualifying Statements

The role of radiation therapy, either alone or in combination with chemotherapy, for locally advanced unresectable colorectal cancer is not addressed in this guideline.Use of chronomodulated regimens is a topic that intersects with the use of oxaliplatin/5-fu combinations, particularly chronomodulation of 5-fu in these combinations. Chronomodulation of oxaliplatin has not been extensively studied, and the topic of chronomodulation is beyond the scope of this guideline and is not addressed.Although data exist to support the use of bevacizumab in combination with folfox in second-line treatment, no first-line treatment data are available on which to make a recommendation.     

Perioperative chemotherapy for gastroesophageal cancer in British Columbia: a multicentre experience

Background

In 2006, perioperative epirubicin, cisplatin, and 5-fluorouracil (ecf), compared with surgery alone, demonstrated a significant survival benefit in resectable gastroesophageal cancers. We report the results of our experience with that protocol.

Methods

The BC Cancer Agency (bcca) is a multicentre institution that treats most oncology patients for the province. Characteristics of the 83 bcca patients with localized gastric, gastroesophageal junction, or lower esophageal cancer who initiated perioperative chemotherapy either ecf or epirubicin, cisplatin, and capecitabine (ecx) from 2008 to 2011 were abstracted to an anonymous database and analyzed.

Results

Of the 83 patients in the cohort [66 men; median age: 62 years (range: 37–79 years)], 87.9% completed 3 cycles of perioperative chemotherapy, and 93.9% (n = 78) underwent an attempt at surgery (2 patients died of chemotherapy toxicities, 1 refused surgery, and 2 developed disease progression before surgery). In 11 of the surgeries (14.1%), tumours could not be resected because of unresectability (n = 1), liver metastasis (n = 1), and peritoneal carcinomatosis (n = 9). One patient died of surgical complications. The 6 patients (7.2%) who achieved a pathologic complete response are all alive and recurrence-free. Of 46 patients (55.4%) who subsequently began postoperative chemotherapy, 44.5% completed 3 cycles. Estimated median survival was 40.3 months. Weight loss was the only significant prognostic factor for worse overall survival.

Conclusions

Our multicentre experience confirmed the feasibility of the magic protocol in a real-world scenario and showed that ecx is also an adequate regimen in the perioperative setting. Weight loss was the only significant prognostic factor for worse overall survival. All patients who achieved a pathologic complete response are recurrence-free after a median follow-up of 40.3 months.     

Prognostic factors associated with the response to sunitinib in patients with metastatic renal cell carcinoma

Objective

We investigated the prognostic clinicopathologic factors associated with overall survival (os) and progression-free survival (pfs) in the once-daily continuous administration of first-line sunitinib in a consecutive cohort of Turkish patients with metastatic renal cell carcinoma (rcc).

Methods

The study enrolled 77 Turkish patients with metastatic rcc who received sunitinib in a continuous once-daily dosing regimen between April 2006 and April 2011. Univariate analyses were performed using the log-rank test.

Results

Median follow-up was 18.5 months. In univariate analyses, poor pfs and os were associated with 4 of the 5 factors in the Memorial Sloan–Kettering Cancer Center (mskcc) score: Eastern Cooperative Oncology Group performance status of 2 or higher, low hemoglobin, high corrected serum calcium, and high lactate dehydrogenase. In addition to those factors, hypoalbuminemia, more than 2 metastatic sites, liver metastasis, non–clear cell histology, and the presence of sarcomatoid features on pathology were also associated with poor pfs; and male sex, hypoalbuminemia, prior radiotherapy, more than 2 metastatic sites, lung metastasis, nuclear grade of 3 or 4 for the primary tumour, and the presence of sarcomatoid features were also associated with poorer os. The application of the mskcc model distinctly separated the pfs and os curves (p < 0.001).

Conclusions

Our study identified prognostic factors for pfs and os with the use sunitinib as first-line metastatic rcc therapy and confirmed that the mskcc model still appears to be valid for predicting survival in metastatic rcc in the era of molecular targeted therapy.     

Retrospective practice review of treatment of metastatic non-small-cell lung cancer with second-line erlotinib

Background

Epidermal growth factor receptor tyrosine kinase inhibitors (egfr-tkis) and chemotherapy have both demonstrated efficacy in recurrent metastatic non-small-cell lung cancer (nsclc) following failure of first-line platinum-based chemotherapy. Although the 3 available therapeutic agents—docetaxel, erlotinib, and pemetrexed—have significantly changed the treatment landscape for recurrent nsclc, the optimal selection of second- and third-line therapy has not been established. This practice review examines the outcomes in clinical practice of using second-line erlotinib followed by third-line chemotherapy in the treatment of recurrent metastatic nsclc.

Methods

We conducted a retrospective review of nsclc patient charts at three Canadian institutions. Patients with recurrent nsclc who had received second-line erlotinib therapy followed by third-line chemotherapy were selected by census. A chart review assessed key outcomes that included time to progression (ttp), response, and change in performance status. Outcomes for specific patient subgroups were also examined.

Results

We identified 35 patients for this retrospective practice review. First-line platinum-doublet therapy demonstrated a mean ttp of 6.6 months and a 46% overall response rate (15 partial responses and 1 complete response). Second-line treatment with erlotinib produced the highest mean ttp of all lines of therapy (9.2 months) and an overall response rate of 40% (all being partial responses). In the third-line setting, in which most patients received docetaxel, the mean ttp was 4.3 months and the overall response rate was 18% (all being partial responses). Subgroup analysis showed that all patient subgroups demonstrated benefit from second-line erlotinib treatment; improved benefit was observed in patients who developed rash, in female patients, in never smokers, in Asian patients, in patients with positive egfr status, and in patients with adenocarcinoma histology.

Conclusions

For patients with advanced nsclc who progressed following first-line platinum-based chemotherapy, the data demonstrate that second-line egfr-tki treatment is efficacious and well-tolerated and that it does not appear to diminish the benefit of third-line chemotherapy.     

Patterns of presentation, referral, and treatment of hepatocellular carcinoma in a pre-sorafenib era: experience of a Canadian provincial cancer agency

Background

Systemic treatment options in hepatocellular carcinoma (hcc) are limited. Sorafenib, a multikinase inhibitor, has been shown to improve survival in patients with advanced hcc and adequate hepatic reserve. Currently, the proportion of referred patients with hcc that would be eligible for sorafenib therapy is unclear. We reviewed patterns in the presentation and management of referred patients with hcc at the BC Cancer Agency (bcca) before the availability of sorafenib.

Methods

Records of patients with hcc referred to the bcca from January 1, 2003, to December 31, 2007, were reviewed. Distributions were analyzed using frequency statistics.

Results

Of 518 patients reviewed, 77% were men and 45% were of Asian ethnicity; median age was 64 years. Histology confirmation was available in only 34% of the patients; 64% had an elevated level of alpha-fetoprotein at diagnosis. The Child–Pugh score at presentation could not be determined in 56%; the most common missing variable was albumin (44%). Among the 226 evaluable patients, the Child–Pugh classification was A in 140 (62%), B in 64 (28%), and C in 22 (10%). Eastern Cooperative Oncology Group performance status was not documented in 40% of patients. The TNM staging was recorded per agency protocol; however, it was incompletely documented in most patients. Distant metastases were recorded in 12% of patients, and 75 patients (15%) underwent hepatic resection before referral. After bcca referral, no further therapy was offered to 287 patients (54%), regional therapy was offered to 170 (33%), and chemotherapy was offered to 67 (13%).

Conclusions

In this era of targeted therapies, characterizing the proportion of patients with hcc that would be eligible for such therapies is important. In our experience, referred patients are commonly Asian men with an acceptable hepatic reserve by Child–Pugh score, who have been diagnosed by clinical criteria alone. Most patients were offered no further therapy. Moving forward, accurate and systematic documentation of staging, performance status, and Child–Pugh score per the Barcelona Clinic Liver Cancer staging protocol will be imperative to best identify patients who may benefit most from sorafenib or available clinical trials, and to subsequently evaluate the population-based impact of the introduction of such therapies in patients with advanced hcc.     

Risk factors for locoregional recurrence after postmastectomy radiotherapy in breast cancer patients with four or more positive axillary lymph nodes

Background

We investigated risk factors for locoregional recurrence (lrr) in breast cancer patients with 4 or more positive axillary lymph nodes receiving postmastectomy radiotherapy (pmrt).

Methods

Medical records (1998–2007) were retrospectively reviewed for the population of interest. The Kaplan–Meier method was used to calculate the survival rate; Cox regression models were used for univariate and multivariate analysis of predictors of breast cancer lrr.

Results

The study enrolled 439 patients. Median duration of follow-up was 54 months. The 5-year rates of locoregional recurrence-free survival (lrrfs), distant metastasis–free survival (dmfs), and breast cancer–specific survival (bcss) were 87.8%, 59.5%, and 70.7% respectively. In patients with lrr and no concomitant metastasis, and in those without lrr, the 5-year rates of dmfs were 21.1% and 65.7% respectively (p < 0.001), and the 5-year rates of bcss were 34.5% and 76.4% respectively (p < 0.001).Univariate analysis showed that menopausal status (p = 0.041), pN stage (p = 0.006), and positivity for her2 [human epidermal growth factor receptor 2 (p = 0.003)] or the triple-negative disease subtype (p < 0.001) were determinants of lrrfs. Multivariate analysis showed that pN3 stage [hazard ratio (hr): 2.241; 95% confidence interval (ci): 1.270 to 3.957; p = 0.005], her2 positivity (hr: 2.705; 95% ci: 1.371 to 5.335; p = 0.004), and triple-negative disease subtype (hr: 4.617; 95% ci: 2.192 to 9.723; p < 0.001) were independent prognostic factors of lrrfs.

Conclusions

In breast cancer patients with 4 or more positive axillary lymph nodes who undergo pmrt for breast cancer, lrr significantly influences survival. Patients who developed lrr carried a high risk for distant metastasis and death. Pathologic stage (pN3), her2 positivity, and the triple-negative disease subtype are risk factors that significantly influence lrrfs.     

Bevacizumab-based therapy for colorectal cancer: experience from a large Canadian cohort at the Jewish General Hospital between 2004 and 2009

Background

Before its regulatory approval in Canada, bevacizumab to treat patients with colorectal cancer (crc) was accessed through the Bevacizumab Expanded Access Trial and a special-access program at the Jewish General Hospital. We retrospectively evaluated patient outcomes in that large cohort.

Methods

All patients (n = 196) had metastatic crc, were bevacizumab-naïve, and received bevacizumab in combination with chemotherapy at the Jewish General Hospital between 2004 and 2009. We collected patient demographics and clinical characteristics; relevant medical history, disease stage and tumour pathology at diagnosis; type, duration, and line of therapy; grades 3 and 4 adverse events (aes), time to disease progression (ttp), and overall survival (os) from diagnosis.

Results

Median follow-up was 36.0 months. Median ttp was 8.0 months [95% confidence interval (ci): 7.0 to 9.0 months). Median os was 41.0 months (95% ci: 36.0 to 47.0 months). Of the 40 grades 3 and 4 bevacizumab-related aes experienced by 38 patients (19.4%), the most common were thrombocytopenia (n = 17), deep-vein thrombosis (n = 6), pulmonary embolism (n = 4), and hypertension (n = 3).

Conclusions

In an expanded access setting, our data reflect the efficacy and safety of bevacizumab-based therapy in the controlled post-registration clinical trial setting.     

Making lifestyle changes after colorectal cancer: insights for program development

Background

Healthy lifestyle behaviours may improve outcomes for people with colorectal cancer (crc), but the intention to take action and to change those behaviours may vary with time and resource availability. We aimed to estimate the prevalence of current lifestyle behaviours in people with and without crc in our community, and to identify their desire to change and their resource preferences.

Methods

A mixed-methods survey was completed by people diagnosed with crc who were pre-treatment (n = 54), undergoing treatment (n = 62), or done with treatment for less than 6 months (n = 67) or for more than 6 months (n = 178), and by people without cancer (n = 83).

Results

Current lifestyle behaviours were similar in all groups, with the exception of vigorous physical activity levels, which were significantly lower in the pre-treatment and ongoing treatment respondents than in cancer-free respondents. Significantly more crc respondents than respondents without cancer had made lifestyle changes. Among the crc respondents, dietary change was the change most frequently made (39.3%), and increased physical activity was the change most frequently desired (39.1%). Respondents wanted to use complementary and alternative medicine (cam), reading materials, self-efficacy, and group activities to make future changes.

Conclusions

Resources for lifestyle change should be made available for people diagnosed with crc, and should be tailored to address physical activity, cam, and diet. Lifestyle programs offered throughout the cancer trajectory and beyond treatment completion might be well received by people with crc.     

18F-Fluorodeoxyglucose positron-emission tomography could have a prognostic role in patients with advanced hepatocellular carcinoma

Introduction

We set out to evaluate the prognostic value of ¹⁸F-fluorodeoxyglucose positron-emission tomography (pet) in patients with advanced (non-transplant-eligible) hepatocellular carcinoma (hcc) and to evaluate the correlation between standardized uptake values (suvs) and survival outcomes.

Methods

We identified patients with hcc who, from 2005 to 2013, underwent pet imaging before any treatment. This retrospective study from our hcc database obtained complete follow-up data for the 63 identified patients.

Results

Of the 63 patients, 10 underwent surgical resection, and 59 underwent locoregional therapy. In this cohort, 28 patients were pet-positive (defined as any lesion with a suv ≥ 4.0) before any therapy was given, and 35 patients were pet negative (all lesions with a suv < 4.0). On survival analysis, median survival was greater for the pet-negative than for the pet-positive patients: 29 months (range: 16.3–41.1 months) versus 12 months (range: 4.0–22.1 months) respectively, p = 0.0241. The pet-positive patients more often had large tumours (≥5 cm), poor differentiation, and extrahepatic disease, reflecting more aggressive tumours. On multivariate analysis, only pet positivity was associated with poor survival (p = 0.049).

Conclusions

Compared with pet-positive patients, pet-negative patients with hcc experienced longer survival. Imaging by pet can be of value in early prognostication for patients with hcc, especially patients receiving locoregional therapy for whom pathologic tumour differentiation is rarely available. This potential role for pet requires further validation in a prospective study.     

Serum C-reactive protein predicts poor prognosis in patients with locoregionally advanced nasopharyngeal carcinoma treated with chemoradiotherapy

Background

We aimed to evaluate the association of serum C-reactive protein (crp) with prognosis in patients with locoregionally advanced nasopharyngeal carcinoma treated with chemoradiotherapy.

Methods

We retrospectively reviewed 79 patients with locoregionally advanced nasopharyngeal carcinoma (cT3–4N0–3M0) treated with chemoradiotherapy. Chemoradiotherapy consisted of external-beam radiotherapy to the nasopharynx (70–80 Gy), the lymph node–positive area (60–70 Gy), and the lymph node–negative area (50–60 Gy) combined with 3 cycles of various platinum-based regimens delivered at 3-week intervals. Elevated crp was defined as more than 8 mg/L. The survival rate was calculated using the Kaplan–Meier method, and univariate and multivariate analyses (Cox proportional hazards model) were used to identify factors significantly associated with prognosis.

Results

During the median follow-up of 3.9 years (range: 1–5.5 years), 23 patients died from nasopharyngeal cancer. The 5-year cancer-specific survival (css) rate was 62.90%. Before chemoradiotherapy, 18 patients had high serum crp; the css rate in that subgroup was significantly worse than the rate in the remaining patients (p = 0.0002). Multivariate analysis showed that crp was an independent prognostic indicator of css, with a hazard ratio of 3.04 (95% confidence interval: 1.22 to 7.55; p = 0.017). Among the 18 patients with elevated serum crp, 9 achieved normal serum crp after chemoradiotherapy, of whom 5 remained living with no evidence of recurrence or metastasis during follow-up. By contrast, the remaining 9 patients in whom serum crp did not normalize after chemoradiotherapy died within 4.2 years.

Conclusions

Elevated serum crp before treatment predicts poor prognosis in patients with locoregionally advanced nasopharyngeal carcinoma treated with chemoradiotherapy.     

Histologic classification of non-small-cell lung cancer over time: reducing the rates of not-otherwise-specified

Background

The importance of histologic classification in selecting the appropriate systemic therapy for non-small-cell lung cancer (nsclc) came to attention in 2007. In British Columbia, that information was communicated through international and national meetings, our centralized cancer care program, and to the medical community at large in multidisciplinary forums. We examined the effects of those education programs on the categorization of nsclc and associated systemic treatment practices.

Methods

The BC Cancer Agency provides cancer care to 4.6 million residents of British Columbia. A retrospective review of all stage iiib and iv nsclc patients referred in 2007 and 2011 collected baseline characteristics, treatment, and outcomes. Histology was classified using the International Classification of Diseases for Oncology, 3rd edition, for the Canadian Cancer Registry.

Results

In 2007, 671 patients were referred, and 170 received chemotherapy; in 2011, the relevant figures were 680 and 197 respectively. Baseline characteristics in the cohorts were not statistically significantly different in 2007 and 2011. Histologic classifications in 2007 were 41% nonsquamous, 13% squamous, and 46% not otherwise specified (nos); in 2011, they were 63%, 17%, and 20% respectively. Exposure to pemetrexed in any line of therapy in 2007 was 22% for nonsquamous, 17% for squamous, and 10% for nos; in 2011, exposure was 39%, 3%, and 37% respectively. Exposure to epidermal growth factor receptor tyrosine kinase inhibitor (egfr tki) in 2007 was 36%, 22%, and 33%; in 2011, it was 64%, 60%, and 63%. Median overall survival duration, 2007 versus 2011, was 3.25 months versus 3.57 months with best supportive care, and 11.31 months versus 11.54 months with chemotherapy.

Conclusions

The specificity of nsclc histologic categorization improved in 2011 compared with 2007, with a reduction of 26 percentage points in the rate of nos disease. The proportion of patients treated with chemotherapy over time remained the same, but the use of pemetrexed and egfr tki increased. The increased accuracy in histologic classification resulted in more appropriate utilization of systemic drugs.     

Specialists' perceptions of hereditary colorectal cancer screening in Newfoundland and Labrador

Purpose

Colorectal cancer (crc) screening is particularly valuable in Newfoundland and Labrador (NL), where a substantial proportion of crc cases have a hereditary link. We examined the perceptions of gastroenterologists and general surgeons with respect to screening practices for patients with hereditary crc.

Methods

We surveyed all gastroenterologists and general surgeons in NL to determine demographic and professional practice characteristics and screening knowledge, practices, and attitudes for four groups of patients with hereditary crc.

Results

Of the 43 eligible physicians, 36 (83.7%) responded. Most of the physicians surveyed knew the correct age to start screening, preferred screening by colonoscopy, had a systematic means in their own practice of prioritizing patients for screening, and felt that family doctors or patients (or both) should be responsible for monitoring screening compliance. Most physicians reported that patients with hereditary nonpolyposis crc and familial adenomatous polyposis waited 3 months for screening; patients with a family history of crc or adenomatous polyp waited 6 months or longer. Although respondents agreed on the need for a province-wide crc registry [4.36 on a 5-point Likert scale (1 = strongly disagree; 5 = strongly agree)], they disagreed that wait times were reasonable (2.81) and that other health professionals should perform colonoscopies (2.86). They were equivocal about the need for centralized bookings (3.25) and about whether genetic testing is useful for prioritizing patients (3.25).

Conclusions

Gastroenterologists and general surgeons in NL were knowledgeable about screening, but had varying opinions about individual roles in screening, wait times, and the means for prioritizing and providing screening for patients with hereditary crc.