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F.(. Kong

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    MS19 - New Health Technology for Lung Cancer; Assessment and Implementation (ID 36)

    • Event: WCLC 2013
    • Type: Mini Symposia
    • Track: Radiation Oncology + Radiotherapy
    • Presentations: 4
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      MS19.1 - Assessing New Technology in Lung Cancer Radiotherapy (ID 546)

      14:05 - 14:25  |  Author(s): F. Macbeth

      • Abstract
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      Abstract
      The past 15 years has seen dramatic developments in radiotherapy (RT) technology and techniques many of which are being applied to patients with lung cancer. The most important of these are PET imaging for RT planning, 3D conformal RT, Intensity Modulated RT, stereotactic body RT (SBR), Image Guided RT and techniques to compensate for respiratory movement such as gating. These are now in widespread use and becoming the ‘standard of care’ in developed countries. But significant questions remain about how fully they have been evaluated and whether or not they have actually led to improvements in clinical outcomes, let alone whether they are in fact cost effective innovations. In this presentation I will address the following questions: · Why are new RT technologies difficult to evaluate for anything beyond efficacy and safety? · Should they be subjected to the same rigorous evaluations as new pharmaceuticals through randomised controlled trials (RCTs) before entering wide clinical practice? · What strategies could be used to assess ‘value for money’ in the absence of high quality evidence? The model for assessing new technologies is derived from pharmaceutics where the new drug is first evaluated for safety and dosage (Phase I), then for efficacy (Phase II) and finally for clinical effectiveness compared to standard therapy (Phase III) before (in some health systems) being assessed for cost effectiveness. New non-pharmacological technologies are not subject to the same regulatory regime and, other than meeting routine requirements for radiation safety, RT technologies can be introduced into routine practice without evidence of clinical effectiveness – improving outcomes. Novel RT technologies are difficult to evaluate formally because: · They often develop incrementally over time with new refinements, especially in associated computer software. · There may be competing manufacturers with slightly different products. · There is often a ‘learning curve’ before they are used most effectively. · There are demonstrable improvements in planned dose distributions, imaging and accurate dose delivery which lead to a reasonable belief that clinical outcomes will be better. · There is always a need for capital investment, sometimes substantial, which means that only centres that already have the technology can participate in comparative clinical trials and those clinicians may be reluctant because they may already be convinced that their new technology is better. · The important clinical outcomes, local control, survival, late radiation toxicity take years to evaluate. · Funding for such research may be hard to find. Does this really matter? It can be argued that demonstration of better-looking computerised plans and apparently more accurate and consistent delivery of radiation dose is a good in itself and one should always try to use the best tools available. That is true – up to a point. But there are two important considerations. First does this apparent improved ‘accuracy’ give false reassurance and result in in unsafe margins and poorer local control? This problem can be partly addressed by careful and well planned prospective follow up studies. Secondly these innovations come with a real cost in capital investment, staff time and, often, longer individual treatment times and lower throughput. How much is that cost and could that money be used in another area to deliver more health benefit? In other words are these innovations cost effective? There are increasing concerns everywhere about the escalating costs of healthcare and whether the payer is the state, an insurance system, a health maintenance organisation or an individual, health professionals have a responsibility to deliver cost effective care. Given the difficulty of carrying out RCTs in this area, what can be done to help those deciding on the best use of resources? One option is to undertake modelling studies not only of dosimetric and clinical consequences but also of costs and consequences. It may then be possible to make to some high level decisions about whether the benefits are likely to large enough and the costs low enough to justify introduction into routine clinical practice, whether comparative research (ideally an RCT) is needed or whether further evaluation of efficacy and safety is needed in institutions experienced in such research. I would therefore argue for better coordinated efforts, preferably at an international level, to address this difficult problem and provide more information about how best to use these new and important resources.

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      MS19.2 - Cost Effectiveness of Prevention of Lung Cancer (Developed and Developing World) (ID 547)

      14:25 - 14:45  |  Author(s): C. Dresler, R. Herbst, A. Hutson

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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      MS19.3 - Resource Constraints as a Barrier to Lung Cancer Management: Developing Nations (ID 548)

      14:45 - 15:05  |  Author(s): S. Thongprasert, U. Premsuwan

      • Abstract
      • Presentation
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      Abstract
      Resource Constraints is an important barrier to Lung Cancer Management. In order to understand this issue in Developing Nations, the questionnaires was set up and send to an experts in Asian countries to find out the fact about this issues. Data gather from the questionnaires will be present at the meeting. Specific information in the questionnaires are Drug lagging period, time to get new cancer drug approval, the important of economic analysis during the approval of new anticancer drug. The other information related to man power including specialist in all related subspecialties and the availability and accessibilty to diagnostic and treatment will be captured by questionnaires. Pattern of Health Insurance and other cost was also the information gathered at the same time.

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      MS19.4 - Resource Constraints as a Barrier to Lung Cancer Management: Developed Nations (ID 549)

      15:05 - 15:25  |  Author(s): W. Evans

      • Abstract
      • Presentation
      • Slides

      Abstract
      The chronic disease burden of developed countries is increasing as the postwar “baby boomers” enter their senior years. The cost of managing these chronic diseases is compounded by the increasing availability and use of expensive technologies. Cancer drug costs are a key driver of health care costs and the expenditure on cancer drugs is rising faster than spending in most other areas of healthcare. Because of this and the fiscal constraint most developed countries have put in place a rigorous drug review process. The United Kingdom’s National Institute for Health and Care Excellence (NICE), amongst others has led the way in establishing drug review processes. These reviews are generally viewed by the pharmaceutical industry, healthcare providers and the public itself as a barrier to access. The pan-Canadian Oncology Drug Review (pCODR) evaluates the clinical benefits and safety of new cancer drugs, as well as their cost-effectiveness and alignment with patient values using a standardized clinical and economic review process, an expert panel, a deliberative framework and broad public engagement (1). Commonly, recommendations are conditional on the drug price being lowered because the drug is not felt to be cost-effective. The determination of incremental cost-effectiveness or cost-utility is critical to drug funding approval in most jurisdictions except the United States. This is determined by assessing the incremental cost of the new drug or regimen over the standard treatment and dividing by the incremental benefit usually measured as years of life gained. In Canada, $50,000 per life year gained or less was generally accepted as cost-effective. As drug costs have increased, this "threshold" has crept higher and $100,000 per LYG is increasingly accepted as “reasonable”. To take account of morbidity from the disease and its treatment, the quantity of life gained is weighted by the quality of that life into a single multidimensional measure (i.e. the quantity adjusted life year or QALY). The availability of other resources, not related to the cost of drugs, can be a barrier to access. In 2008, Cancer Care Ontario began to measure concordance with guidelines developed through its Program in Evidence-based Care and to report this information through a Cancer System Quality Index (CSQI) (3). In 2010- 2011, it was noted that only 41% of resected stage II/IIIA patients received guideline recommended adjuvant chemotherapy (AC) at Ontario’s regional cancer centres. There was also substantial variation in guideline adherence between centers ranging from 42.9% to 72.1%. Men were significantly less likely to be treated with AC (38.2% compared to 52.7% for women) (p=0001), as were patients over age 65 (65% < 65 yrs. vs. 34% > 65 yrs.)(p=.0001). Patients from regions with the highest tercile of immigrants were significantly less likely to be treated: 14.3% for the highest, 46% for the middle and 51% for the lowest tercile. Similar variations were seen for the uptake of the guideline recommendation for the use of combined modality therapy in the treatment of stage III NSCLC. To better understand the reasons for these variances, a survey and key informant interviews were undertaken with clinicians and administrators. The perception of respondents was that the most common barriers to implementing practice guidelines were the slow referral process of patients to the treatment centers, lack of support from the organization’s leadership to implement the recommended regimens and the difficulties that patients had in getting to the treatment centers. These results suggested that greater efforts are required to communicate best practices to providers, (including primary care physicians), to improve the efficiency of clinic processes and to arrange patient transportation. For aboriginal and immigrant populations, culture and language are known barriers. Resources to lower language barriers, to assist patients in health system navigation and to educate health providers in the provision of culturally sensitive care may be necessary to ensure equitable access to appropriate care. Some developed countries have experienced resource constraints that have delayed access to cancer surgery and to radiation treatment. Excessive wait times result from inadequate capacity and/or inefficiencies in the health system. To resolve these issues first requires recognition of the problem, the development of a plan of action, appropriate funding to address capacity issues, process improvements to increase efficiency and incentives to providers to prioritize cancer treatments. In a recent review of access to cancer care services in Canada, Maddison et al. noted that inequity of access occurs across the continuum of care for different disease sites (4). The review suggested that access to cancer services is most inequitable at the beginning (i.e. screening) and at the end (i.e. end-of-life care). Income level appeared to have the most influence on screening while age and geography were most influential on access to end-of-life services. As the results of the NLST are implemented as population-based screening programs, low dose CT will compete for diagnostic service resources and other services. Smokers at risk from lower socioeconomic levels, in particular, may encounter barriers to access. At the other end of the cancer spectrum, access to palliative care resources varies widely in developed countries. Conclusions: Access to optimal lung cancer care across the continuum from screening and early detection through treatment and end-of-life care can encounter numerous resource barriers, which are not all monetary in nature. Although the cost of new drugs is the most significant potential resource barrier, numerous other barriers can exist in developed countries related to the resources available for screening or diagnosis, radiation and surgery, access to knowledge specialists, supportive care services and accessible end-of-life care in the home or community. References: 1. Pan-Canadian Oncology Drug Review (pCODR) (website). Toronto, Ontario. (Accessed August 1, 2013) Available at http://www.pCODR.org 2. Cancer System Quality Index (CSQI) (website). Toronto, Ontario: Cancer Quality Council of Ontario (accessed August 6, 2013). Available from: http://www.csqi.on.ca 3. Maddison AR, Asada Y, Urquhart R. Inequity in access to cancer care: a review of the Canadian literature. Cancer Causes Control 2011; 22:359-366

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Author of

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    E02 - Radiation Toxicity (ID 2)

    • Event: WCLC 2013
    • Type: Educational Session
    • Track: Radiation Oncology + Radiotherapy
    • Presentations: 1
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      E02.3 - Functional Biophysical Model (FUNBIPM) to Predict Radiation Lung Toxicity (ID 379)

      14:45 - 15:05  |  Author(s): F.(. Kong

      • Abstract
      • Presentation
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      Abstract
      Treatment toxicity not only reduces quality of life, but also may be life threatening (and can be unidentified) when it is severe. Radiation induced lung toxicity (RILT) is among the most important dose limiting toxicity in the treatment of lung cancer, particularly locally advanced non-small cell lung cancer (NSCLC) or small cell lung cancer (SCLC). The current standard of RT techniques considers the whole lung as a uniform organ and uses the same dose limit for all patients with the assumption that all have a SAME sensitivity to radiation damage. However, patients with NSCLC frequently have a respiratory comorbidity such as chronic obstructive pulmonary disease (COPD) that results in heterogeneous function within different lung regions. Patients often respond remarkably differently to the same amount of radiation dose. Furthermore, the presence of the tumor itself often affects local vascular supply and ventilation, and changes function level. In this presentation, I will review the current functional imaging for lung and predictive biomarkers for RILT with an emphasis on recent advances regarding 1) ventilation/perfusion single photon emission tomography (V/Q SPECT) for treatment planning and RILT prediction, and 2) blood markers and its integration with physical and functional dosimetric factors for RILT prediction. Ultimately, we would like to generate Functional Imaging and Biophysical Model (FunBipM) to guide individualized treatment planning to minimize treatment toxicity V/Q SPECT is a commonly available technique in most hospitals to image the perfusion (Q) and ventilation (V) of the lung. It has been proposed that Q-SPECT images can be used to guide RT planning so that radiation is directed to the non-functional lung regions [1-4]. It was known to us that the Q-SPECT-guided plans produced more favorable functional dose volume histograms (DfVHs) compared to non-SPECT guided plans, with the fV20 and fV30 values reduced by an average of 13.6% ± 5.2% and 10.5% ± 5.8%, respectively [2]. We have further demonstrated that 1) NSCLC often presents with defect regions on V/Q SPECT, some of which are from tumor compression that improves with tumor shrinkage during- RT; 2) SPECT defect regions are more resistant to post-RT function reduction; 3) V/Q SPECT guided radiation therapy can reduce dose to functional lung without increasing doses to the total physical lung; 4) V/Q SPECT based DfVHs from during-RT may predict clinical significant RILT more accurately than anatomic CT lung based DVH. From treatment planning point of view, I will use example cases to demonstrate that we can avoid V/Q SPECT functional regions in pre- and during- RT to minimize damage to functional lung, particularly by the combined use of pre- and during-. V/Q SPECT adds lung ventilation mapping on top of the Q-SPECT, providing more information (including the mechanism for lung function defects and their potential for recovery). During-RT V/Q SPECT allows adaptive-RT because lung function changes globally and locally during RT, largely due to RT-induced tumor volume reduction improving the vascular supply and ventilation[5]. The combination of pre- and during- V/Q SPECT can classify the lung into different functional regions and strategize to differentially prioritize certain regions, a technique our group developed to minimize lung damage. Additionally, we can compute DfVHs from both pre- during- SPECT scans to predict post-treatment functional loss and clinically significant RILT. Patients with the same dosimetric parameters have shown very different levels of toxicity largely due to their biologically different intrinsic sensitivity to radiation damage [6]. Many studies have been conducted to understand the correlation between pro-inflammatory and pro-fibrogenic cytokines, including TGF-ß1, IL-1ß, IL-6, IL-8, and TNF-α and radiation-induced normal tissue injury [7]. TGFß1, a fibrogenic and radiation-inducible cytokine, has been known to play a key role in this process. Animal studies demonstrated significantly elevated TGFß1 mRNA and protein expression within type II pneumocytes and fibroblasts in radiation-sensitive mice after thorax radiation [8-11], which subsequently contributed to increased TGFß1 levels in circulation. The Duke University group reported that plasma TGFß1 levels at the end of radiation are correlated with the later onset of symptomatic RILT in patients treated with definitive radiation therapy [9][,][12][,][13]. Though the result was not consistently reproduced by others [14], possibly due to technique issues [15], end-of-treatment TGFβ1 correlation nevertheless has limited value. We have demonstrated that TGFß1 elevation in the middle of treatment (2-4 weeks during-treatment) relative to pre-treatment is highly correlated with late-onset grade >2 RILT in NSCLC patients [16][,][17] . Most recently, we have demonstrated that combining baseline IL-8, during-treatment TGF-ß1, and mean lung dose into a single model yielded an improved predictive ability (P<.001) for RILT compared to either variable alone [16]. The findings on baseline and during-treatment markers are more important than end-treatment markers, as they provide us an opportunity to adjust treatment accordingly. More importantly, an individual’s susceptibility to radiation normal tissue toxicity may be genetically determined, which can be measured pre-RT. Germ-line genetic variations, most often single nucleotide polymorphisms (SNPs), may play an important role in radiation damage pathogenesis. SNPs associated with molecules involved in radiation damage pathways, such as DNA double-strand break repair (ATM, XRCC1) and inflammation (TGF β1 and cytokines) have been studied for their association with clinical toxicity [18][,][19]. It was reported that SNPs in TGFβ1 and NOS3 were associated with a lower risk for radiation pneumonitis [20][,][21] whereas SNPs in ATM, IL1A, IL8, TNFa, TNFRSF1B and MIF were associated with an increased risk of radiation pneumonitis [20][,][22]. TGFβ1 rs1800470 was positively associated with RILT [21]. We also demonstrated that SNPs of TGFβ1 genes may be associated with overall risk of other organs’ toxicity, including esophagus or heart/pericardium [23]. This finding is also very important because after limiting lung toxicity to less than certain level (such as 15-17%), increased dose to the most resistant tumors may increase toxicity of other organs. This is complicated but should be taken into consideration. In summary, we may generate a FunBipM through the combination of pre- and during-RT V/Q functional dosimetric parameters and blood biomarker data to predict the risk of lung toxicity for each individual patient: i.e. using a FunBipM that integrates biologic markers into the existing dosimetry-based model. By identifying high-risk patients, adjusting lung dose limit according to the threshold of tolerance, and applying the FunBipM to optimize radiation planning for dose and dose arrangement, we may anticipate a significant reduction of the incidence of toxicity without compromised tumor control.1. Seppenwoolde Y, Engelsman M, De Jaeger K, et al. Optimizing radiation treatment plans for lung cancer using lung perfusion information. Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology. May 2002;63(2):165-177.2. McGuire SM, Zhou S, Marks LB, Dewhirst M, Yin FF, Das SK. A methodology for using SPECT to reduce intensity-modulated radiation therapy (IMRT) dose to functioning lung. International journal of radiation oncology, biology, physics. Dec 1 2006;66(5):1543-1552.3. Lavrenkov K, Christian JA, Partridge M, et al. A potential to reduce pulmonary toxicity: the use of perfusion SPECT with IMRT for functional lung avoidance in radiotherapy of non-small cell lung cancer. Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology. May 2007;83(2):156-162.4. Lavrenkov K, Singh S, Christian JA, et al. Effective avoidance of a functional spect-perfused lung using intensity modulated radiotherapy (IMRT) for non-small cell lung cancer (NSCLC): an update of a planning study. Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology. Jun 2009;91(3):349-352.5. Yuan S, Frey KA, Gross M, Hayman J, Arenberg D, Cai X. Changes in global function and regional ventilation and perfusion on SPECT during the course of radiotherapy in patients with non-small-cell lung cancer. International journal of radiation oncology, biology, physics. 2012;82(4):e631-638.6. Kong FM, Ao X, Wang L, Lawrence TS. The use of blood biomarkers to predict radiation lung toxicity: a potential strategy to individualize thoracic radiation therapy. Cancer control : journal of the Moffitt Cancer Center. Apr 2008;15(2):140-150.7. Kong FM, Ten Haken R, Eisbruch A, Lawrence TS. Non-small cell lung cancer therapy-related pulmonary toxicity: an update on radiation pneumonitis and fibrosis. Seminars in oncology. Apr 2005;32(2 Suppl 3):S42-54.8. Yi ES, Bedoya A, Lee H, et al. Radiation-induced lung injury in vivo: expression of transforming growth factor-beta precedes fibrosis. Inflammation. Aug 1996;20(4):339-352.9. Anscher MS, Kong FM, Marks LB, Bentel GC, Jirtle RL. Changes in plasma transforming growth factor beta during radiotherapy and the risk of symptomatic radiation-induced pneumonitis. International journal of radiation oncology, biology, physics. Jan 15 1997;37(2):253-258.10. Bai YH, Wang DW, Cui XM, et al. Expression of transforming growth factor beta in radiation interstitial pneumonitis. Journal of environmental pathology, toxicology and oncology : official organ of the International Society for Environmental Toxicology and Cancer. 1997;16(1):15-20.11. Rube CE, Uthe D, Schmid KW, et al. Dose-dependent induction of transforming growth factor beta (TGF-beta) in the lung tissue of fibrosis-prone mice after thoracic irradiation. International journal of radiation oncology, biology, physics. Jul 1 2000;47(4):1033-1042.12. Vujaskovic Z, Marks LB, Anscher MS. The physical parameters and molecular events associated with radiation-induced lung toxicity. Seminars in radiation oncology. Oct 2000;10(4):296-307.13. Kong FM, Anscher MS, Sporn TA, et al. Loss of heterozygosity at the mannose 6-phosphate insulin-like growth factor 2 receptor (M6P/IGF2R) locus predisposes patients to radiation-induced lung injury. International journal of radiation oncology, biology, physics. Jan 1 2001;49(1):35-41.14. De Jaeger K, Seppenwoolde Y, Kampinga HH, Boersma LJ, Belderbos JS, Lebesque JV. Significance of plasma transforming growth factor-beta levels in radiotherapy for non-small-cell lung cancer. International journal of radiation oncology, biology, physics. Apr 1 2004;58(5):1378-1387.15. Zhao L, Wang L, Ji W, Lei M, Yang W, Kong FM. The influence of the blood handling process on the measurement of circulating TGF-beta1. Eur Cytokine Netw. Mar 1 2012;23(1):1-6.16. Stenmark M, Cai X, Shedden K, et al. Combining Physical and Biologic Parameters to Predict Radiation-Induced Lung Toxicity in Patients With Non-Small-Cell Lung Cancer Treated With Definitive Radiotherapy. International journal of radiation oncology, biology, physics. In press.17. Zhao L, Wang L, Ji W, et al. Elevation of plasma TGF-beta1 during radiation therapy predicts radiation-induced lung toxicity in patients with non-small-cell lung cancer: a combined analysis from Beijing and Michigan. Int J Radiat Oncol Biol Phys. Aug 1 2009;74(5):1385-1390.18. Damaraju S, Murray D, Dufour J, et al. Association of DNA repair and steroid metabolism gene polymorphisms with clinical late toxicity in patients treated with conformal radiotherapy for prostate cancer. Clinical cancer research : an official journal of the American Association for Cancer Research. Apr 15 2006;12(8):2545-2554.19. Hart JP, Broadwater G, Rabbani Z, et al. Cytokine profiling for prediction of symptomatic radiation-induced lung injury. International journal of radiation oncology, biology, physics. Dec 1 2005;63(5):1448-1454.20. Hildebrandt MA, Komaki R, Liao Z, et al. Genetic variants in inflammation-related genes are associated with radiation-induced toxicity following treatment for non-small cell lung cancer. PLoS One. 2010;5(8):e12402.21. Yuan X, Liao Z, Liu Z, et al. Single nucleotide polymorphism at rs1982073:T869C of the TGFbeta 1 gene is associated with the risk of radiation pneumonitis in patients with non-small-cell lung cancer treated with definitive radiotherapy. J Clin Oncol. Jul 10 2009;27(20):3370-3378.22. Zhang L, Yang M, Bi N, et al. ATM polymorphisms are associated with risk of radiation-induced pneumonitis. Int J Radiat Oncol Biol Phys. Aug 1 2010;77(5):1360-1368.23. Xie C, Yuan S, Ellingrod V, Hayman J, Arenberg D, Curtis JL. The Value of Single Nucleotide Polymorphisms in TGFβ1, TPA and ACE in Survival Prediction in Patients with Non-small Cell Lung Cancer. International journal of radiation oncology, biology, physics. 2010;78(3 suppl):199S - 200S.

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