Liquid biopsy in the management of advanced lung cancer: Implementation and practical aspects.

Non-small-cell lung cancer (NSCLC) is a major cause of cancer-related death worldwide. In recent years, the discovery of actionable molecular alterations has changed the treatment paradigm of the disease. Tissue biopsies have been the gold standard for the identification of targetable alterations but present several limitations, calling for alternatives to detect driver and acquired resistance alterations. Liquid biopsies reveal great potential in this setting and also in the evaluation and monitoring of treatment response. However, several challenges currently hamper its widespread adoption in clinical practice. This perspective article evaluates the potential and challenges associated with liquid biopsy testing, considering a Portuguese expert panel dedicated to thoracic oncology point of view, and providing practical insights for its implementation based on the experience and applicability in the Portuguese context.

Evaluation of Current Antiemetic Therapy Response in Patients Undergoing MEC or HEC Regimens in Portugal.

Chemotherapy-induced nausea and vomiting (CINV) negatively impact cancer patients' quality of life and treatment outcomes. This study evaluated the achievement of complete response to CINV prophylaxis during the first five days after chemotherapy in adult outpatient cancer clinics with solid malignant tumours receiving Moderate or Highly Emetogenic Chemotherapy (MEC or HEC) in Portugal. During the study, patients completed three evaluations, and nausea severity and CINV impact on patients' daily life was assessed. A complete response (no emetic episodes, no use of rescue antiemetic medication, and no more than mild nausea) was observed in 72% of the cycles (N = 161) throughout the five days after chemotherapy. Amongst the patient population, 25% classified their CINV episodes as severe. Though more than half of the patients achieved a complete response, suggesting that a therapeutic effort is being made to minimise this side effect, the overall scenario is barely optimistic. Significantly, new CINV-control measures in MEC/HEC patients should be adopted, specifically avoiding the single use of dexamethasone and 5-HT3 and raising awareness of using NK1-RAs. Thus, it is critical to improve CINV prophylactic treatment and implement practical international antiemetic guidelines in Portuguese clinical practice, envisaging the improvement of supportive care for cancer patients.

Lung cancer screening in clinical practice: identification of high-risk chronic obstructive pulmonary disease patients.

OBJECTIVE: The NELSON study demonstrated a positive association between computed tomography scanning and reduced mortality associated with lung cancer. The COPD-LUCSS-DLCO is a tool designed to improve screening selection criteria of lung cancer for chronic obstructive pulmonary disease patients. The aim of this study was to examine and compare the discriminating value of both scores in a community-based cohort of chronic obstructive pulmonary disease patients. METHODS: A retrospective study of chronic obstructive pulmonary disease patients followed in pulmonology consultation for a period of 10 years (2009-2019) was conducted. The NELSON criteria and COPD-LUCSS-DLCO score were calculated for each patient at the time of the study inclusion. The lung cancer incidence was calculated for each of the subgroups during the follow-up period. RESULTS: A total of 103 patients were included in the study (mean age 64.7±9.2 years, 88.3% male). Applying the COPD-LUCSS-DLCO score, high-risk patients have a 5.9-fold greater risk of developing lung cancer versus the low risk. In contrast, there was no significant association between NELSON selection criteria and lung cancer incidence. The area under the curve was 0.69 for COPD-LUCSS-DLCO and 0.59 for NELSON criteria. Comparing test results showed no differences. CONCLUSIONS: The use of the COPD-LUCSS-DLCO score in clinical practice can help to detect chronic obstructive pulmonary disease patients in greater risk of developing lung cancer with better performance than NELSON criteria. Therefore, models that include a risk biomarker strategy can improve selection criteria and consequently can enhance a better lung cancer prediction.

Lung cancer screening in clinical practice: identification of high-risk chronic obstructive pulmonary disease patients

SUMMARY OBJECTIVE: The NELSON study demonstrated a positive association between computed tomography scanning and reduced mortality associated with lung cancer. The COPD-LUCSS-DLCO is a tool designed to improve screening selection criteria of lung cancer for chronic obstructive pulmonary disease patients. The aim of this study was to examine and compare the discriminating value of both scores in a community-based cohort of chronic obstructive pulmonary disease patients. METHODS: A retrospective study of chronic obstructive pulmonary disease patients followed in pulmonology consultation for a period of 10 years (2009-2019) was conducted. The NELSON criteria and COPD-LUCSS-DLCO score were calculated for each patient at the time of the study inclusion. The lung cancer incidence was calculated for each of the subgroups during the follow-up period. RESULTS: A total of 103 patients were included in the study (mean age 64.7±9.2 years, 88.3% male). Applying the COPD-LUCSS-DLCO score, high-risk patients have a 5.9-fold greater risk of developing lung cancer versus the low risk. In contrast, there was no significant association between NELSON selection criteria and lung cancer incidence. The area under the curve was 0.69 for COPD-LUCSS-DLCO and 0.59 for NELSON criteria. Comparing test results showed no differences. CONCLUSIONS: The use of the COPD-LUCSS-DLCO score in clinical practice can help to detect chronic obstructive pulmonary disease patients in greater risk of developing lung cancer with better performance than NELSON criteria. Therefore, models that include a risk biomarker strategy can improve selection criteria and consequently can enhance a better lung cancer prediction.

Metronomic oral vinorelbine in a real-world population of advanced non-small cell lung cancer patients.

INTRODUCTION: An increasing body of evidence from clinical trials and real-world studies suggests that metronomic oral vinorelbine (VNR) is a promising treatment option for elderly and unfit advanced non-small cell lung cancer (NSCLC) patients. The aim of this multicenter study was to present real-world data about the experience in treatment of NSCLC with metronomic VNR in Portugal. MATERIAL AND METHODS: Retrospective data from NSCLC patients not eligible for conventional chemotherapy or tyrosine kinase inhibitors who received oral metronomic VNR irrespective of treatment line and dose was retrieved from 19 Portuguese Oncology Centers between 2016 and 2018. RESULTS: A total of 293 patients were included, with a median of 76 (39 - 94) years; 71% were ≥70 years old. Patients had a median of 3 comorbidities and predominantly (61%) ECOG PS 2. Most (42%) received metronomic oral VNR as first-line treatment. Overall response rate was 18%, with 42 (18%) partial and no (0%) complete responses. A total of 54% of patients experienced stable disease and 28% of patients, disease progression. Disease control rate was 72%. Patients were a median of 4 (1 - 40) months on treatment. Treatment discontinuation was observed in 90%, mostly (67%) due to disease progression, followed by death (16%). Adverse events leading to treatment discontinuation were only reported in 5% of patients. Female gender (HR 0.601, 95% CI 0.434 - 0.832; p = 0.002) and ECOG PS 1 (HR 0.625, 95% CI [0.443 - 0.881]; p = 0.007) were significantly associated with a lower risk of metronomic oral VNR discontinuation. Overall, 21% of patients experienced G3/4 toxicity. CONCLUSION: The present real-world results agree with what has been previously reported by other international Centers and support the concept that metronomic scheduling is a relevant and safe approach to treat advanced NSCLC patients.

Monitoring and Managing Lorlatinib Adverse Events in the Portuguese Clinical Setting: A Position Paper.

Rearrangements in the anaplastic lymphoma kinase (ALK) and proto-oncogene tyrosine-protein kinase ROS (ROS1) genes characterise two distinct molecular subsets of non-small cell lung cancer (NSCLC) tumours. Lorlatinib is a third-generation ALK/ROS1 tyrosine kinase inhibitor (TKI) shown to have systemic and intracranial activity in treatment-naive patients and in those who progressed on first- and second-generation TKIs. Despite being generally well tolerated, lorlatinib has a unique and challenging safety profile that includes hyperlipidaemia and central and peripheral nervous system adverse events (AEs). This article summarises a set of strategies designed to monitor and manage lorlatinib-related AEs that were agreed upon by a multidisciplinary panel of specialists in a meeting held in July 2020. Among the recommendations hereby described, special emphasis was placed on communication: prescribing physicians should inform patients and their families/caregivers about the likelihood and nature of lorlatinib AEs, encouraging them to report any symptoms, while at the same time reassuring them that most events are manageable and resolve spontaneously and have little to no interference with cancer treatment. Importantly, all patients should undergo a set of baseline assessments, including biochemical analysis, evaluation of cardiovascular risk, electrocardiogram (ECG), neurological evaluation and contrast-enhanced magnetic resonance imaging of the brain, which should be repeated regularly during lorlatinib treatment. Supportive medications to treat or relieve lorlatinib AEs were also discussed, as were the conditions requiring specialist consultations and/or adjustments in lorlatinib therapy. The overall goal of this article is to serve as a practical guide for oncologists to systematically and effectively approach lorlatinib AEs.

Limitations and perceived delays for diagnosis and staging of lung cancer in Portugal: A nationwide survey analysis.

BACKGROUND: We aimed to identify the perception of physicians on the limitations and delays for diagnosing, staging and treatment of lung cancer in Portugal. METHODS: Portuguese physicians were invited to participate an electronic survey (Feb-Apr-2020). Descriptive statistical analyses were performed, with categorical variables reported as absolute and relative frequencies, and continuous variables with non-normal distribution as median and interquartile range (IQR). The association between categorical variables was assessed through Pearson's chi-square test. Mann-Whitney test was used to compare categorical and continuous variables (Stata v.15.0). RESULTS: Sixty-one physicians participated in the study (45 pulmonologists, 16 oncologists), with n = 26 exclusively assisting lung cancer patients. Most experts work in public hospitals (90.16%) in Lisbon (36.07%). During the last semester of 2019, responders performed a median of 85 (IQR 55-140) diagnoses of lung cancer. Factors preventing faster referral to the specialty included poor articulation between services (60.0%) and patients low economic/cultural level (44.26%). Obtaining National Drugs Authority authorization was one of the main reasons (75.41%) for delaying the begin of treatment. The cumulative lag-time from patients' admission until treatment ranged from 42-61 days. Experts believe that the time to diagnosis could be optimized in around 11.05 days [IQR 9.61-12.50]. Most physicians (88.52%) started treatment before biomarkers results motivated by performance status deterioration (65.57%) or high tumor burden (52.46%). Clinicians exclusively assisting lung cancer cases reported fewer delays for obtaining authorization for biomarkers analysis (p = 0.023). Higher waiting times for surgery (p = 0.001), radiotherapy (p = 0.004), immunotherapy (p = 0.003) were reported by professionals from public hospitals. CONCLUSIONS: Physicians believe that is possible to reduce delays in all stages of lung cancer diagnosis with further efforts from multidisciplinary teams and hospital administration.

Post-infective bronchiectasis by measles prior infection - A case report.

Bronchiectasis (BE) refers to an abnormal and irreversible dilatation of the bronchi. Post-infectious etiology still remains an important and frequent cause. Associated the anti-vaccine movement, measles resurfaces and with all the outcomes that comes from the disease. The present case illustrates one of the possible complication of measles - BE, underlining the importance of vaccination.

Six versus fewer planned cycles of first-line platinum-based chemotherapy for non-small-cell lung cancer: a systematic review and meta-analysis of individual patient data.

BACKGROUND: Platinum-based chemotherapy is the standard first-line treatment for patients with advanced non-small-cell lung cancer. However, the optimum number of treatment cycles remains controversial. Therefore, we did a systematic review and meta-analysis of individual patient data to compare the efficacy of six versus fewer planned cycles of platinum-based chemotherapy. METHODS: All randomised trials comparing six versus fewer planned cycles of first-line platinum-based chemotherapy for patients with advanced non-small-cell lung cancer were eligible for inclusion in this systematic review and meta-analysis. The primary endpoint was overall survival. Secondary endpoints were progression-free survival, proportion of patients with an objective response, and toxicity. Statistical analyses were by intention-to-treat, stratified by trial. Overall survival and progression-free survival were compared by log-rank test. The proportion of patients with an objective response was compared with a Mantel-Haenszel test. Prespecified analyses explored effect variations by trial and patient characteristics. FINDINGS: Five eligible trials were identified; individual patient data could be collected from four of these trials, which included 1139 patients-568 of whom were assigned to six cycles, and 571 to three cycles (two trials) or four cycles (two trials). Patients received cisplatin (two trials) or carboplatin (two trials). No evidence indicated a benefit of six cycles of chemotherapy on overall survival (median 9·54 months [95% CI 8·98-10·69] in patients assigned to six cycles vs 8·68 months [8·03-9·54] in those assigned to fewer cycles; hazard ratio [HR] 0·94 [95% CI 0·83-1·07], p=0·33) with slight heterogeneity between trials (p=0·076; I(2)=56%). We recorded no evidence of a treatment interaction with histology, sex, performance status, or age. Median progression-free survival was 6·09 months (95% CI 5·82-6·87) in patients assigned to six cycles and 5·33 months (4·90-5·62) in those assigned to fewer cycles (HR 0·79, 95% CI 0·68-0·90; p=0·0007), and 173 (41·3%) of 419 patients assigned to six cycles and 152 (36·5%) of 416 patients assigned to three or four cycles had an objective response (p=0·16), without heterogeneity between the four trials. Anaemia at grade 3 or higher was slightly more frequent with a longer duration of treatment: 12 (2·9%) of 416 patients assigned to three-to-four cycles and 32 (7·8%) of 411 patients assigned to six cycles had severe anaemia. INTERPRETATION: Six cycles of first-line platinum-based chemotherapy did not improve overall survival compared with three or four courses in patients with advanced non-small-cell lung cancer. Our findings suggest that fewer than six planned cycles of chemotherapy is a valid treatment option for these patients. FUNDING: None.

Primary pulmonary melanoma: the unexpected tumour.

A 62-year-old woman was referred to our pulmonology team with exertional dyspnoea and chest tightness of 2 months duration. Her medical history included cervical cancer and thyroid nodules. Imaging studies showed collapse of left upper lobe. Fiberoptic bronchoscopy unveiled an endoluminal lesion and bronchial biopsy displayed features of melanoma. She denied a history of melanoma or excision of lesions of skin, mucous membranes or the eye. A thorough evaluation including combined positron emission tomography with CT scan excluded other possible sites of primary melanoma, but there was a metastasis in a thoracic vertebra. Palliative radiotherapy of the spine was performed. Chemotherapy initiation with dacarbazine was postponed by the appearance of a malignant pleural effusion, confirmed by pleural fluid cytology. After four cycles chemotherapy was discontinued due to disease progression. The patient is still alive with a follow-up of 12 months, currently on best supportive care.

Phase II, double-blinded, randomized study of enzastaurin plus pemetrexed as second-line therapy in patients with advanced non-small cell lung cancer.

INTRODUCTION: We examined the efficacy of enzastaurin plus pemetrexed as second-line therapy in patients with advanced (stage IIIA/B or IV) non-small cell lung cancer in a double-blinded, randomized, phase II study. METHODS: Patients received pemetrexed 500 mg/m intravenously on day 1 of 21-day cycles (day 8 in cycle 1) plus oral enzastaurin (250 mg two times per day; combination arm) or placebo (pemetrexed arm). Both arms received supplementation with vitamin B12, folic acid, and dexamethasone. An interim analysis was conducted to determine whether efficacy would warrant a phase III study. RESULTS: The interim analysis showed no evidence of improved progression-free survival with enzastaurin. At final analysis (N = 160, 80 in each arm), baseline characteristics were well balanced. There was no significant difference in progression-free survival (3.0 months, p = 0.544) or overall survival (9.6 months in combination arm and 7.4 months in pemetrexed arm, p = 0.171). Drug-related serious adverse events included cerebrovascular accident, palpitations, and renal failure (n = 1, each) in combination arm and neutropenic sepsis, thrombocytopenia, and panniculitis (n = 1, each) in pemetrexed arm. Nonhematologic drug-related grade 3/4 toxicities were similar in both arms. Grade 3/4 hematologic toxicities were higher with the combination, specifically leukopenia (6.3% versus 0%), neutropenia (15.2% versus 5.0%), and thrombocytopenia (8.9% versus 1.3%). Of the 26 deaths reported on-study or within 30 days of discontinuation (10 in combination arm and 16 in pemetrexed arm), none were drug related. CONCLUSION: The combination regimen of enzastaurin and pemetrexed is well tolerated but does not improve efficacy over pemetrexed and placebo as second-line treatment of unselected patients with advanced non-small cell lung cancer.

[Cost of cancer care in Portugal]. / Custo do tratamento do cancro em Portugal.

INTRODUCTION: Cancer is the second most important cause of death in Portugal, following cardiovascular diseases (CVD), and shows a constant progressive increase in the proportional share of total deaths. In Portugal, as in most countries, the health care budget is under constant cost-containment pressures. In this context it is necessary to verify if enough resources have been allocated to the disease in terms of health care expenditure. The main objective of this study is to estimate the cost of cancer care in Portugal and to compare it to similar data in Europe and the United States of America (USA), to the cost of CVD. The secondary objective is to evaluate the cost of pharmaceuticals used in the treatment of cancer in Portugal, both in relation to total pharmaceutical expenditure and to other therapeutic areas. METHODS: Three main sources of information were used: comprehensive literature review, primary and secondary data sources, and a modified Delphi Panel, which was used to fill in gaps in the information derived from the data sources and the literatura review. The burden of cancer was measured through the Disability-adjusted life-year (DALY) and, in order to determine the costs of cancer, detailed information on the costs of medical visits and of inpatient episodes based on Diagnosis Related Groups (DRG), in 2006, was used. To estimate the total cost of cancer, we used a combination of top down (breaking global expenditure data to specific levels) and bottom up methodology (based on the sum of different components). RESULTS: Based on 2006 data on direct medical care expenditures in Portugal, we found that 565 million euro were spent on cancer in comparison to 1 320 million on CVD representing 3.91% and 9.14% of total cost on health respectively. When we break down total expenditure on drugs by therapeutic area we find that CVD drugs represent about 21.6% of total drug costs in Portugal and cancer drugs represent about 5.6% of the total. Oncology drugs represent 32% of the total expenditure on cancer, while CVD drugs represent 54% of the total expenditure on CVD. In comparison, in terms of BoD in Portugal, 18.6% of DALY's were associated with CVD and 15.3% with cancer. CONCLUSION: Considering the burden of disease (BoD) of CVD and cancer in Portugal, we can state that the expenditure allocated to cancer is significantly lower than expected. Using the criterion of expenditure according to need, we observed that there is an imbalance of expense/BoD in oncology indicating that cancer seems to be underfunded in Portugal. Even considering that this shouldn't be the only criterion to determine the volume of expense in a certain therapeutic area, the differential observed in this study is sufficiently high to deserve attention from the decision-makers.

Phase II study of celecoxib with cisplatin plus etoposide in extensive-stage small cell lung cancer.

We performed a phase II trial to test whether a cyclooxygenase (COX-2) inhibitor, celecoxib, added to standard first-line combination chemotherapy (CT) and as maintenance therapy would improve outcomes in extensive-stage (ES) small-cell lung cancer (SCLC). This was a multicenter trial in CT-naive patients with ES-SCLC. They received standard cisplatin and etoposide (EP) up to 6 cycles and celecoxib 400 mg PO bid continuously until disease progression. Primary end points were response rate (RR), time to progression (TTP), and toxicity. Secondary were overall survival (OS) and quality of life. Of 74 expected patients, only 24 were enrolled and the study stopped earlier because of the published safety concerns about celecoxib. The patients, all male, were between 38 and 74 years. A total of 130 cycles of CT were administered. Toxicity associated with celecoxib was minimal. The RR was 56.5%. Median TTP and OS were 8.6 and 11.3 months, respectively. These data suggest that celecoxib may safely be combined with EP for treatment of ES-SCLC. This combination showed a promising activity and, despite the safety concerns regarding celecoxib, it would be interesting to further evaluate this regimen.

Pemetrexed in second line of non-small cell lung cancer. / Pemetrexed em segunda linha no carcinoma do pulmão de não pequenas células.

Non small cell lung cancer (NSCLC), which is the leading cause of cancer mortality, is accounts for 85% of all cases of lung cancer. The majority of NSCLC patients present with advanced, unresectable disease. In advanced disease, chemotherapy with platinun (cisplatin or carbo-platin) in combination with a third-generation cytotoxic drug (gemcitabine, vinorelbine, paclitaxel or docetaxel) can provide a modest improvement in survival with quality of life. Response rates of 20%-40% can be expected with a median survival of 8-10 months and a 1 year survival rate of 30% - 40%. Pemetrexed, a multitargeted antifolate agent, has shown clear activity in mesothelioma and NSCLC. In a phase III trial, second line treatment with pemetrexed demonstrated overall survival comparable to docetaxel with a more manageable toxicity profile. Single agent pemetrexed have shown well tolerate in elderly patients, in combination with radiotherapy where we can use full dose pemetrexed. In second line, in nonsquamous NSCLC pemetrexed administrated with folic acid and vitamin B12, has a significant superior survival compared with docetaxel (9.3 vs 8.0months). Rev Port Pneumol 2008; XIV (Sup.2): S21-S26.

Erlotinib and brain metastases. / Erlotinib e metástases cerebrais.

We report two cases of brain metastases in context of non small cell lung cancer (NSCLC). After having progressed to chemotherapy they received erlotinib 150mg/m2 orally daily, with complete response of brain metastasis and partial response of thoracic lesions. Brain metastases are both prevalent and a major cause of mortality in NSCLC, with few systemic treatment options. Median survival after whole brain radiotherapy is 4-6 months and the role of systemic therapy for brain metastases is limited with the most drugs use to stage IV disease ineffective in this setting. This case demonstrates that brain metastases may be sensitive to erlotinib and give to us growing body of evidence that EGFR-associated tyrosine kinase inhibition is a feasible strategy in the management of NSCLC patients with brain metastases We propose further study into the continued use of this drug in the situation where there is a differential response. Rev Port Pneumol 2008; XIV (Supl 3): S35-S42.

[Mounier-Kuhn syndrome: a rare aetiology of recurrent respiratory infections]. / Síndroma de Mounier-Kuhn: Uma causa rara de infecções respiratórias de repetição.

The incidence of the syndrome may be greater than is suspected. Patients present with recurrent respiratory infections and bronchiectasis. The symptoms are non-specific and indistinguishable from those of other chronic respiratory diseases. The diagnosis is often made several years after the first clinical complaints. The authors perform a brief review of the literature and report two cases of Mounier-Kuhn syndrome. One of the patients was diagnosed in childhood and the other in the fourth deca- de of life.

[Small cell lung cancer--state of the art and future perspectives]. / Carcinoma do pulmão de pequenas células--Estado da arte e perspectivas futuras.

Lung cancer is the leading cause of cancer-related death in Portugal. Almost 3500 Portuguese are expected to be diagnosed with lung cancer in 2006; approximately 20% will have small cell lung cancer (SCLC). At presentation, 25% to 30% of patients will have local or regional disease, classified as limited stage disease. The concurrent chemovalidation therapy is the best choice. Once daily thoracic radiation therapy to doses in the range of 50 Gy to 60 Gy would reflect an accepted standard of care in daily practice. Because of the increase toxicity associated with hyper fractionated radiation, this approach is often limited to select patients. Etoposide plus cisplatin are synergistic, well tolerated and result in equal or superior survival compared with other regimens. This is the standard regimen for concomitant therapy in limited stage and for extensive disease SCLC. Despite good chemo sensitivity and radio sensitivity, the prognosis of SCLC is very poor because of the early development of resistance and the associated high tendency to recurrence, making second line treatment of SCLC a problem of real medical relevance. Topotecan now offers an effective and well tolerated monosubstance for second line therapy of recurrent SCLC. There has been a significant increase in median survival for patients with SCLC receiving topotecan plus symptomatic therapy versus symptomatic therapy. The efficacy of this drug is comparable to the efficacy of the three-drug combination CAV. The tolerability can be improved by means of toxicity-adapted dosing. In elderly and in patients with performance status 2, topotecan is also well tolerated and has good efficacy. Initial studies into weekly administration also demonstrate good efficacy. The combination of topotecan with cranial radiotherapy is well tolerated and effective in the treatment of cerebral metastases of SCLC. New classes of agents, such as antiangiogenic agents including bevacizumab, small molecule tyrosine kinase inhibitors and thalidomide are being evaluated with chemotherapy for patients with extensive stage SCLC.