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P. Wheatley-Price



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    GR 04 - Problems in Advanced Metastatic Disease (ID 18)

    • Event: WCLC 2015
    • Type: Grand Rounds
    • Track: Treatment of Advanced Diseases - NSCLC
    • Presentations: 1
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      GR04.03 - Systemic Treatment with Organ Failure (ID 1846)

      14:15 - 15:45  |  Author(s): P. Wheatley-Price

      • Abstract
      • Presentation

      Abstract:
      For patients with lung cancer, choices of systemic therapy are informed by clinical research. These guide the patient and clinician as to the gold standard options when facing their disease. However many patients seen day to day in the clinic are not eligible for clinical trials due to one factor or another, and therefore the applicability of standard of care options has a less solid evidence base. In a recent analysis of 528 newly diagnosed stage 4 NSCLC patients seen in consultation by medical oncologists, only 55% received systemic treatment [1]. Further, when simple and limited generic clinical trial inclusion criteria were applied to these patients, only 27% would have been ‘trial eligible’ [2]. In a review of selected recent practice changing chemotherapy, targeted therapy and immunotherapy trials, patients with significant renal impairment, hepatic impairment or cardiac impairment would have been excluded [3-6]. Therefore how should clinicians and patients approach making decisions about systemic therapy in the presence of organ failure, given the lack of available evidence? This abstract seeks to provide guidance on a reasonable approach to patients with lung cancer and organ failure. These issues should be discussed in a multi-disciplinary format, with specific interaction with specialists related to the particular organ failure (nephrology, hepatology, cardiology etc.), in addition to a specialist oncology pharmacist if the decision is made to proceed with therapy. Patients should be fully informed regarding relative benefits and harms from therapy, the consequences of declining therapy, and that proceeding with treatment will almost certainly not be based on level one evidence. Consideration should be given to early palliative care specialist input, and advance care planning. Understanding the cause and prognosis of the organ failure is self-evidently important. This abstract restricts discussion to patients with pre-existing organ failure, rather than organ failure secondary to the malignancy. In a recent review of clinical indicators of 6-month mortality in advanced non-cancer illnesses, Salpeter and colleagues evaluated heart failure, dementia, geriatric failure-to-thrive syndrome, hepatic cirrhosis, chronic obstructive pulmonary disease and end-stage renal disease. This list represented approximately 70% of the non-cancer diagnoses on admission to hospice [7]. Clearly not all patients with these conditions die within 6 months, and the authors identified common and disease specific prognostic indicators, including poor PS, malnutrition, comorbid illness and organ dysfunction. In the cancer clinic, the clinician must understand the natural course of the organ failure pathology. For patients with liver, kidney or heart failure who may be waiting for organ transplantation, the diagnosis of lung cancer makes them ineligible for the transplant program. Regarding prognosis of advanced organ failure, the United States Renal Data System (USRDS) Annual Report for patients receiving hemodialysis for end-stage renal disease, describes 3-year survival as 52%, and 61% for patients receiving peritoneal dialysis. The risk of death is particularly high in the first year of hemodialysis, with rates reported up to 25%. The Canadian Organ Replacement Register Annual Report describes a 5-year survival for patients on dialysis of approximately 43% (www.cihi.ca/corr ). For patients with end-stage heart failure, the 1-year survival is approximately 50% [8], which is not dramatically different to patients with stage 4 NSCLC receiving 1[st] line chemotherapy. The prognosis of patients with liver cirrhosis is variable, depending on severity, etiology and the presence or absence of complications. The MELD score (Model for End-Stage Liver Disease) is used to assess the severity of chronic liver disease [9], as an alternative to the Child-Pugh scoring system. Salpeter et al reported patients with decompensated liver failure (the presence of complications of cirrhosis) may have a median survival <6 months if associated with high MELD scores. An understanding of competing morbidities therefore clearly plays an important role in understanding the role systemic therapy plays in lung cancer. In assessing the need for adjuvant chemotherapy in patients with early stage disease, for patients with organ failure it is highly likely that any benefit from chemotherapy (approximately 5%) will be outweighed by the competing risks of the comorbid condition. After assessing patients with lung cancer, in the multi-disciplinary context and taking into account the issues discussed, the decision may still be to proceed with therapy. This should be on the understanding of the relative lack of data, and then a choice of regimen based on an understanding of the drug metabolism, with appropriate dose adjustments after dialogue with an oncology pharmacist. Table 1 outlines common lung cancer drugs and their route of elimination, and recommendations on use in renal or hepatic impairment. For patients receiving dialysis, there is variation in advice as to timing of adminstration relative to dialysis. This information and tabular information is taken from product monographs and selected references [10,11]. Data on efficacy for these drugs in these scenarios is largely limited to case reports. In conclusion, lung cancer patients with organ failure represent a population excluded from clinical trials and with a limited evidence base. The competing morbidity and mortality significantly mitigate against potential benefits from anti-cancer systemic therapy. The newer generations of targeted therapies and immunotherapies may be easier to deliver, but again limited data exists. Clinicians should discuss these cases in a multi-disciplinary environment, and early intervention from palliative care specialists may be particularly appropriate.

      Drug Elimination Liver Renal
      Cisplatin Renal N/A ↓ depending on CrCl
      Caboplatin Renal N/A Calvert Formula
      Docetaxel Liver Adjust N/A
      Pemetrexed Renal Caution in severe dysfunction avoid if CrCl <45
      Paclitaxel Liver Adjust N/A
      Gemcitabine Urine (inactive) Adjust by Bilirubin Caution
      Vinorelbine Liver Adjust by Bilirubin N/A
      Gefitinib Liver Caution Caution if CrCl <20
      Erlotinib Liver Caution N/A
      Afatinib Liver Caution Caution if CrCl <30
      Crizotinib Liver Adjust Caution if CrCl <30
      Ceritnib Liver Adjust Caution if CrCl <30
      Bevacizumab Reticulo-endothelial system Not involved Not involved
      Nivolumab Biochemical degradation No effect in mild impairment no effect if CrCl>/=15
      References : 1. Brule S, Al-Baimani K, Jonker H, et al: Palliative chemotherapy (CT) for advanced non-small cell lung cancer (NSCLC): Investigating disparities between patients who are treated versus those who are not. J Clin Oncol 33, 2015 2. Al-Baimani K, Jonker H, Zhang T, et al: Are clinical trial eligibility criteria an accurate reflection of a real world population of advanced lung cancer patients, World Conference on Lung Cancer. Denver, 2015, pp Abstract 1398 3. Gettinger SN, Horn L, Gandhi L, et al: Overall Survival and Long-Term Safety of Nivolumab (Anti-Programmed Death 1 Antibody, BMS-936558, ONO-4538) in Patients With Previously Treated Advanced Non-Small-Cell Lung Cancer. J Clin Oncol 33:2004-12 4. Mok TS, Wu YL, Thongprasert S, et al: Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med 361:947-57, 2009 5. Schiller JH, Harrington D, Belani CP, et al: Comparison of four chemotherapy regimens for advanced non-small-cell lung cancer. N Engl J Med 346:92-8, 2002 6. Shaw AT, Kim DW, Nakagawa K, et al: Crizotinib versus chemotherapy in advanced ALK-positive lung cancer. N Engl J Med 368:2385-94 7. Salpeter SR, Luo EJ, Malter DS, et al: Systematic review of noncancer presentations with a median survival of 6 months or less. Am J Med 125:512 e1-6 8. Friedrich EB, Bohm M: Management of end stage heart failure. Heart 93:626-31, 2007 9. Kamath PS, Kim WR: The model for end-stage liver disease (MELD). Hepatology 45:797-805, 2007 10. Janus N, Thariat J, Boulanger H, et al: Proposal for dosage adjustment and timing of chemotherapy in hemodialyzed patients. Ann Oncol 21:1395-403 11. Brandes JC, Grossman SA, Ahmad H: Alteration of pemetrexed excretion in the presence of acute renal failure and effusions: presentation of a case and review of the literature. Cancer Invest 24:283-7, 2006

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    MINI 29 - Meta Analyses and Trial Conduct (ID 156)

    • Event: WCLC 2015
    • Type: Mini Oral
    • Track: Treatment of Advanced Diseases - NSCLC
    • Presentations: 1
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      MINI29.06 - Are Clinical Trial Eligibility Criteria an Accurate Reflection of a Real World Population of Advanced Lung Cancer Patients? (ID 1398)

      18:30 - 20:00  |  Author(s): P. Wheatley-Price

      • Abstract
      • Presentation
      • Slides

      Background:
      Modern systemic treatment options for advanced NSCLC have largely been established from clinical trials (CTs). It is estimated that less than 10% of cancer patients enter a CT, but this subgroup drives oncology practice and impacts treatment decisions for other cancer patients. The advantage of CTs comes from solid internal validity and stringent methodology. Nonetheless, the generalizability of CTs could be questioned due to the high selectivity of eligibility criteria. We investigated clinical trial eligibility in an unselected NSCLC population

      Methods:
      With ethics approval, a retrospective chart review was performed of patients with de novo advanced NSCLC assessed by medical oncologists at a large academic cancer centre, serving a mixed urban and rural population, between September 2009 and September 2012. Data collected included patient demographics, stage, performance status, histology, treatment details and outcome. Two sets (A and B) of arbitrary eligibility criteria were created using common criteria from phase 3 CTs. These criteria were applied to this cohort to identify the proportions of patient who would hypothetically qualify for CT enrollment. Criteria A required: ECOG 0 or 1, absence of brain metastases, Creatinine < 120 and the absence of second malignancy. Criteria B, allowing broader inclusion, only required ECOG 0-2 and Creatinine < 120. We investigated survival among eligible/ineligible and treated/untreated patients.

      Results:
      528 patients were included: 55% male; 50% ECOG 0-1; 58% adenocarcinoma, 22% squamous cell; 7% stage IIIB and 93% stage IV. Using the strict CT criteria (A), only 144 (27%) patients were considered eligible. Of those, 79% actually received systemic therapy. From 384 patients who would have been ineligible for the CT, 178 patients (46%) still received systemic therapy. There was a trend to longer median overall survival (mOS) in the eligible treated compared to eligible non-treated patients (11.6 vs 8.1 months p=0.12). mOS was significantly longer in the non-treated eligible cohort compared to the non-treated ineligible cohort (8.1 vs 3.8 months p=0.003). The eligible treated and non-eligible treated had similar mOS ( 11.6 vs 10.2 months, p= 0.10). When less strict eligibility criteria (B) were applied, 343 patients (65%) would have been eligible, of whom 240 patients (70%) actually received systemic therapy. From the remaining ineligible 185 patients, only 51 (28%) received treatment. The mOS was similar in the treated patient whether eligible or ineligible (10.9 vs 10.1 months, p=0.57). As seen in criteria A, significantly longer mOS was observed in the eligible untreated compared to the ineligible untreated ( 4.9 vs 3.5 months p<0.001).

      Conclusion:
      While clinical trial criteria restrict study entry to the fittest patients, these results suggest that they do not reflect the broader patient population, as many ‘ineligible’ patients received therapy. Extrapolation of treatment paradigms to non-trial eligible populations is common, and may be reasonable based on these results. We observed similar survival among treated patients, whether trial eligible or not. This suggests that clinical judgement is more important than trial eligibility. In order to broaden trial participation, we could hypothesize that trial eligibility criteria could be relaxed.

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    ORAL 12 - Quality of Life and Trials (ID 96)

    • Event: WCLC 2015
    • Type: Oral Session
    • Track: Advocacy
    • Presentations: 1
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      ORAL12.05 - Impact of Time to Drug Approval on Potential Years of Life Lost: The Compelling Need for Improved Trial and Regulatory Efficiency (ID 1547)

      10:45 - 12:15  |  Author(s): P. Wheatley-Price

      • Abstract
      • Presentation
      • Slides

      Background:
      Survival of incurable cancer patients is improving gradually. Several hundred new therapies are under development. However, internationally, regulatory complexity slows progress by increasing drug development costs (hence, fewer drugs can be assessed with available resources) and by producing numerous speed bumps that delay approval of useful drugs and that increase resources required to document that other agents are ineffective.

      Methods:
      We assessed cancer therapies undergoing phase III trials between 2001 and 2015. To be included, trials had to document statistically significant improvement in overall survival. We excluded adjuvant trials and trials in uncommon malignancies. To determine the number of life-years potentially lost per year required for drug approval, we multiplied the improvement in median survival in years by the estimated number of patients (North American and worldwide) dying annually from the relevant malignancy.

      Results:
      In the Table, we present the life-years lost per year required for approval for 21 therapies in 10 malignancies. When the combined impact of all tumor sites and drugs are considered together, there were 29 life-years lost in North America per hour of delay in therapy approval (1 for every 2 minutes of delay) and 260 life-years lost worldwide per hour of delay (1 for every 14 seconds of delay). These numbers do not take into account impact of drugs non-evaluable due to cross-over or missing survival data, drugs that were prematurely abandoned, drugs still undergoing investigation, or approaches for non-malignant lethal diseases. Figure 1



      Conclusion:
      Clearly, the survival gains associated with the foregoing drugs are only modest. Despite this, there would be a large negative impact associated with approval delays even if factors such as co-morbidities, performance status, ability to pay, etc, limit the number of patients treated to a fraction of the total dying from a specific malignancy. There are numerous opportunities to improve efficiency of cancer drug approval without sacrificing safety or data integrity. This requires urgent attention.

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    P1.01 - Poster Session/ Treatment of Advanced Diseases – NSCLC (ID 206)

    • Event: WCLC 2015
    • Type: Poster
    • Track: Treatment of Advanced Diseases - NSCLC
    • Presentations: 1
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      P1.01-034 - Is There A "Physician Effect" in Medical Oncology? (ID 1408)

      09:30 - 17:00  |  Author(s): P. Wheatley-Price

      • Abstract
      • Slides

      Background:
      Non-small cell lung cancer (NSCLC) is the commonest cause of cancer death globally, with a 5-year survival of 16%. Known prognostic factors include stage, performance status (PS) and gender, but does the choice of physician affect patient outcome? We assessed practice variations of four medical oncologists treating advanced NSCLC, investigating this impact on overall survival (OS).

      Methods:
      Following ethics approval, a retrospective analysis was undertaken of all newly diagnosed stage 4 NSCLC patients seen in out-patient consultation at our institution between 2009 and 2012. All physicians accepted unselected lung cancer referrals and all patients are included. Baseline demographics, systemic therapy received, reasons for not receiving therapy, and OS data were collected. Cox regression analyses (univariate and multivariate) were employed to assess determinants of OS. The physicians were blinded to the results.

      Results:
      Overall 528 patients were included. Baseline characteristics are shown in table 1. A significant variation was noted in the proportion receiving any systemic chemotherapy (p≤0.01) [D(60%), L(65%), R(43%), M(52%)] (Figure 1A). However OS was not statistically significantly different among all patients (p=0.47), among treated patients (p=0.18) or among untreated patients (p=0.22)(Table and Figure 1B). In multivariate analysis, factors associated with survival were PS (p<0.01), weight loss (<5%, ≥5%)(p<0.01), WBC (<11, ≥11)(p=0.0588) and platelets (<400, ≥400)(p=0.0374).Figure 1

      Demographic Overall (n=528) Physician R (n=137) Physician M (n=118) Physician D (n=115) Physician L (n=158) p-value
      Median Age 68 70 68 67 67 0.23
      Gender (male) 55% 58% 58% 49% 56% 0.42
      PS (0-1) 50% 47% 48% 50% 55% 0.01
      Hg (<100) 6% 11% 3% 4% 4% 0.01
      LDH (<250) 28% 21% 30% 27% 33% 0.09
      Platelets (<400) 71% 64% 75% 78% 70% 0.12
      Weight loss (>5%) 48% 49% 48% 46% 49% 0.87
      WBC (<11) 62% 56% 68% 68% 60% 0.11
      Received ≥ 1 line systemic therapy 55% 43% 52% 60% 65% <0.01




      Conclusion:
      While practice size and proportion of patient treated did vary between oncologists, these did not translate into significantly different survival. There were statistically significant differences in the distribution of baseline characteristics between the 4 oncologists and this could cause the differences in proportion of patients treated. We hypothesize that as long as the oncologists are well trained and display good practice, survival is not dependant on the individual. This research does not measure other valuable characteristics or outcomes such as rapport, compassion, and quality of life, which may differ between physicians.

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    P2.01 - Poster Session/ Treatment of Advanced Diseases – NSCLC (ID 207)

    • Event: WCLC 2015
    • Type: Poster
    • Track: Treatment of Advanced Diseases - NSCLC
    • Presentations: 1
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      P2.01-033 - Patients with Advanced NSCLC Requiring Inpatient Oncology Consultation (ID 504)

      09:30 - 17:00  |  Author(s): P. Wheatley-Price

      • Abstract
      • Slides

      Background:
      Most newly diagnosed advanced lung cancer patients have an initial medical oncology consult as an outpatient. However, occasionally the initial referral occurs as an inpatient. We explored the characteristics of advanced NSCLC patients whose first medical oncology consultation occurred while hospitalized.

      Methods:
      With ethics approval, we performed a retrospective analysis of all advanced NSCLC patients at our institution whose initial consult occurred while hospitalized, from 2007 to 2012. Demographics, treatment and survival data were collected. This was an exploratory analysis. Multivariate survival analysis was performed using Cox regression models.

      Results:
      In total, 223 patients were included (baseline characteristics in Table 1). Overall, only 24% received chemotherapy while 72% received some palliative radiotherapy. Median time from diagnosis to chemotherapy was 43 days. Reasons for not receiving chemotherapy included poor performance status (PS) (72%), patient choice (9%), clinical deterioration (6%) or co-morbidities (4%). Factors associated with receiving chemotherapy were good PS (OR 11.11 [95% CI 5.56-25.00], p<0.001), no constitutional symptoms (OR 2.86 [95% CI 1.41-5.88], p=0.004), no leukocytosis (OR 2.38 [95% CI 1.23-4.55], p=0.01), fewer co-morbidities (OR 1.54 [95% CI 1.27-1.89], p<0.001) and younger age (OR 1.09 [95% CI 1.05-1.12], p<0.001). Median OS was shorter in those not receiving chemotherapy (1.7 v 7.1 months, HR 2.76 [95% CI 1.72-4.41], p-value<0.001). Figure 1 shows Kaplan-Meier survival curves. In multivariate analysis, in addition to not receiving chemotherapy, factors associated with shorter OS were PS 3-4, (HR 1.55 [CI 1.03-2.33, p=0.04]), leukocytosis (HR 2.23 [95% CI 1.51-3.28], p-value <0.001) and thrombocytosis (HR 1.52 [1.06-2.18], p=0.02).

      Conclusion:
      Patients whose first consultation with medical oncologists occurs while hospitalized are an inherently sick population and only a minority receive chemotherapy. The lung cancer community must advocate for earlier diagnosis and referral, so more patients have access to treatment options before a terminal functional decline.

      Table 1: Baseline Characteristics
      Demographic (N=223) %
      Age in years, median (range) 65 (23-89)
      Gender
      Male 48
      Female 52
      Charlson Comorbidity Index total score, median (range) 10 (6-18)
      Performance status
      0-2 24
      3-4 69
      Unknown 7
      Smoking status
      Current 49
      Ex 34
      Never 9
      Unknown 8
      Stage at diagnosis
      IIIB 10
      IV 89
      Unknown 1
      NSCLC subtype
      Adenocarcinoma 45
      Squamous cell 23
      Large cell 8
      Other 23
      Dominant presenting symptom
      Dyspnea 34
      Pain 23
      Constitutional symptoms 9
      Pneumonia 7
      Cough 5
      Hemoptysis 3
      Other 18
      Weight loss
      <5% 22
      >5% 52
      Unknown 25
      Figure 1



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