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Lung Cancer in Australia

      Population

      Australia’s population of 25 million lives in eight states and territories covering 7.6 million km2. There is a strong history of migration and cultural diversity with 29.7% of the population born overseas. The population is aging, with the proportion aged 65 years and over increasing from 12.3% to 15.9% between 1999 and 2019, and this is projected to increase further.
      First Nations Australians represent 3.3% of the population, comprising hundreds of distinct groups of indigenous Aboriginal and Torres Strait Islander people. They experience worse health outcomes than non-indigenous Australians. In 2015 to 2017, life expectancy at birth was 71.6 years and 75.6 years for the indigenous male and female population, respectively (8.6 y and 7.8 y less than non-indigenous people, respectively).
      Australian Government
      Closing the gap report 2020.
      Compared with non-indigenous Australians, indigenous people are 70% more likely to be diagnosed with lung cancer and only partly because of smoking differences. Smoking is the leading cause of cancer death in indigenous people; survival is lower owing to higher smoking-related comorbidities, late-stage diagnosis, and lower likelihood of receiving and completing treatment
      • Valery P.C.
      • Coory M.
      • Stirling J.
      • Green A.C.
      Cancer diagnosis, treatment, and survival in Indigenous and non-indigenous Australians: a matched cohort study.
      ; these disparities are deeply rooted in sociopoliticoeconomic inequality.
      • Bond C.J.
      • Singh D.
      More than a refresh required for closing the gap of Indigenous health inequality.
      About 29% of Australians live in rural and remote areas and have poorer health outcomes than their metropolitan counterparts with higher rates of smoking, alcohol consumption, physical inactivity, and obesity. Geographic isolation poses many challenges for health care. Some rural locations have visiting specialists or outreach services, but many subspecialty services are located only in major cities. Telemedicine has helped improve access, but even so, health service delivery to rural and remote areas remains a challenge.
      • Tracey E.
      • McCaughan B.C.
      • Young J.M.
      • Armstrong B.K.
      How can we ensure that people with lung cancer living in rural and remote areas are treated surgically when appropriate?.

      Health Care Delivery

      Health care delivery in Australia is based on the principle of universal access, provided through a complex model of public and private health services which are funded by local, State, and Territory and Commonwealth (national) government, nongovernment organizations, private health insurers, and individuals for some products and services that are not reimbursed or only partially reimbursed.
      The taxpayer-funded Australian Medicare public health insurance scheme underpins the health system and guarantees fee-free treatment in public hospitals. Hospital treatment, as a private patient, is partially covered by Medicare and partially by private health insurance. In 2017, 11.3 million Australians (46% of the population) had some form of private patient hospital cover. Episodes of care may be delivered by public, private, or a combination of providers.
      Australian Government, Australian Institute of Health and Welfare
      Australia’s health 2018.
      Over 900 medications, including systemic therapies (chemotherapeutic, immunotherapy, targeted agents) and smoking cessation pharmacotherapy, in addition to associated adjunct medicines (antiemetics, cytokine support, opiates, and other palliative medicines), are subsidized through the Commonwealth Government Pharmaceutical Benefits Scheme (PBS), in which patients copay for the cost of each PBS medicine. Health expenditure in Australia has gradually increased as a proportion of gross domestic product (GDP), consuming 8.7% of GDP in 2006 to 2007 to 10.3% in 2015 to 2016.
      Australian Government, Australian Institute of Health and Welfare
      Australia’s health 2018.
      Other organizations that contribute to lung cancer care recognize the central role of the consumer in the delivery of quality patient-centered care, for example, Cancer Australia, a national body established by the Australian Government in 2006.

      Tobacco Control

      Australia has a strong history of tobacco control. For example: legislation for smoke-free motor vehicles (2007) and plain tobacco packaging (2012), which have been subsequently introduced by many other nations, and annual increases in tobacco excise rates (2013–2020), which have pushed the price of cigarettes to 30 USD per pack by 2020.
      These measures have led to a steady decline in cigarette consumption since the 1980s (Fig. 1). However, if smoking prevalence could be reduced to 10%, 5%, or 0% by 2025, an estimated additional 97,432, 208,714, or 360,557 lung cancer deaths could be averted from the year 2016 to 2100, respectively.
      • Luo Q.
      • Steinberg J.
      • O’Connell D.L.
      • et al.
      Lung cancer mortality in Australia in the twenty-first century: how many lives can be saved with effective tobacco control?.
      Figure thumbnail gr1
      Figure 1Timeline for tobacco control and annual number of cigarettes smoked per capita from 1920 to 2016 in Australia (with permission from Luo et al.
      • Luo Q.
      • Steinberg J.
      • O’Connell D.L.
      • et al.
      Lung cancer mortality in Australia in the twenty-first century: how many lives can be saved with effective tobacco control?.
      ). TV, television.

      Incidence and Mortality

      Lung cancer represents 9.1% of all new cancer diagnoses and is now the fourth most often diagnosed cancer for both men and women in Australia (Fig. 2). Furthermore, lung cancer has been the leading cause of cancer mortality for decades, predicted to account for an estimated 8641 deaths in 2020 (4991 men and 3650 women).
      Australian Government, Cancer Australia
      Lung cancer in Australia statistics.
      Figure thumbnail gr2
      Figure 2Age-standardized incidence rates for lung cancer, 1982 to 2016, by sex.

      Screening

      The consistent evidence from two high-quality randomized controlled trials, together with supportive observational studies, has highlighted the potential of lung cancer screening in the Australian setting. The 2015 Australian Standing Committee on Screening did not recommend a national screening program, but the Australian Health Minister recently launched a national enquiry, including special consideration of indigenous Australians and people living in rural and remote communities.
      There are limited Australian data on screening. The prospective observational study of the National Health and Medical Research Council National Center for Asbestos Related Disease/Queensland SmartState funded Queensland Lung Cancer Screening Study recruited healthy volunteers at risk of lung cancer (60–74 y; smoking history ≥30 pack years, current or quit ≤15 y) for a low-dose computed tomography chest scan at baseline, year 1, and year 2. It revealed the feasibility of detecting curable early stage lung cancer, effective implementation of smoking cessation during screening, and the ability to detect and treat incidental actionable comorbidities at modest cost.
      • Marshall H.M.
      • Bowman R.V.
      • Crossin J.
      • et al.
      Queensland Lung Cancer Screening Study: rationale, design and methods.

      Diagnosis, Pathology, and Staging

      Most cases of lung cancer in Australia are NSCLC (64% and 61% in the male and female population, respectively) with SCLC incidence decreasing in recent decades and making up 11% to 13% of new diagnoses. Of the NSCLC subtypes, adenocarcinomas are the most frequent, particularly in women (34% versus 26% in men), and this subtype has been increasing in incidence over the preceding few decades. Squamous cell carcinomas have been decreasing in frequency and are more common in men than women (20% versus 10%).
      Australian Government, Australian Institute of Health and Welfare
      Lung cancer in Australia: an overview.
      Biopsy approaches for diagnosis vary widely depending on disease presentation, local expertise, and resources. There is a strong interventional pulmonary and radiology skill base in Australia with special multidisciplinary interest groups such as from the Thoracic Society of Australia and New Zealand leading research, such as the first-in-person study of robotic bronchoscopy.
      In most cases, sufficient tissue is obtained to establish diagnosis and undertake molecular testing where appropriate. Most anatomical pathologists in Australia do not subspecialize and will cover all or most body systems, but in larger centers there are pathologists with subspecialty expertise in pulmonary pathology. Molecular testing for EGFR mutations, ALK, and ROS1 rearrangements and programmed death ligand 1 (PD-L1) expression is government funded, and results are required to access corresponding treatments. Most cases of advanced-stage lung adenocarcinoma (or nonsquamous NSCLC) will undergo EGFR mutation testing, and although this has been increasing over time, is not achieved for every patient (Table 1). Molecular testing is available either locally in some larger centers or as a send-away test and is usually performed on diagnosis of advanced disease. The methodology varies from single-gene assays to variably sized next-generation sequencing (NGS) panels depending on local availability or referral pathways. Immunohistochemistry to screen for ALK or ROS1 fusions and to assess PD-L1 expression is widely available. Confirmation of ALK or ROS1 gene rearrangements is usually undertaken by fluorescence in situ hybridization assays at major centers rather than by NGS fusion panels as the latter is less often available and is not currently funded. Access to larger NGS panels covering other potentially targetable mutations is less widely available and is not government funded. Plasma testing for circulating tumor DNA is also not funded, but is available through several laboratories; however, access to targeted therapies is only funded through demonstration of an oncogenic mutation from tumor tissue, not plasma, thereby limiting its use.
      Table 1Usage by State/Territory of Requested Medicare Item 73337 (a Test of Tumor Tissue From a Patient Diagnosed to Have NSCLC, Reported to Have Nonsquamous Histology or Histology Not Otherwise Specified, Requested by, or on Behalf of, a Specialist or Consultant Physician, to Determine Whether the Requirements Relating to EGFR Gene Status for Access to Erlotinib, Gefitinib, or Afatinib Under the PBS Are Fulfilled) Processed From January 2015 to December 2019
      StateTotal
      NSWVICQLDSAWATASACTNT
      ServicesServicesServicesServicesServicesServicesServicesServicesServices
      ItemCalendar year
      733372015156776151312321311757173368
      2016148482654714123210957233419
      2017170289762521124312151133863
      2018172210036882063121635124147
      2019222510007451693336654114603
      Total87004487311885013335762706619,400
      ACT, Australian Capital Territory; NSW, New South Wales; NT, Northern Territory; PBS, Pharmaceutical Benefits Scheme; QLD, Queensland; SA, South Australia; TAS, Tasmania; VIC, Victoria; WA, Western Australia.
      Strong efforts are being made in Australia to facilitate accurate tumor, node, and metastasis staging by multidisciplinary teams, recognizing its pivotal role in determining prognosis and treatment options, because of the recognized gap that previously existed (Fig. 3).
      Figure thumbnail gr3
      Figure 3Stage distribution for the top five incident cancers in Australia, 2011.

      Thoracic Surgery

      All cardiothoracic surgery training in Australia is overseen by the Royal Australasian College of Surgeons. There are approximately 160 trained cardiothoracic surgeons in Australia, of whom 125 belong to the Australian and New Zealand Society of Cardiac and Thoracic Surgeons. However, only approximately 20 surgeons have an exclusive or majority practice in Thoracic Surgery, and they are mostly located in the heavily populated Eastern states. There are only six specialist thoracic surgical units in the country, three of them being in Melbourne, Victoria. There are also five general surgeons in the regional cities of Ballarat, Bendigo, and Darwin who perform lung cancer resections, with mentor links to specialist units in Melbourne.
      Lung cancer surgery is a relatively safe procedure in Australia, which enjoys a high, consistent standard for all surgeries. The real-world 30-day mortality for lung cancer resection from population-based registry data from Queensland and Victoria (two of the largest states) is between 0.4% and 1.7%.
      From the registry data, two-thirds of patients with stages I to II receive curative surgery, and two-thirds of those are performed within 14 days of diagnosis. Two-thirds of the resections have associated lymph node sampling or dissection. Clinical stage IIIA lung cancer is mostly treated with combined radiotherapy and chemotherapy, with selected cases treated with neoadjuvant chemotherapy and surgery or on clinical trials of neoadjuvant or adjuvant immunotherapy. Salvage surgery after radical radiotherapy is offered at a few thoracic surgery units. Other than for selected T4 disease, stage IIIB lung cancer is treated nonsurgically in Australia.
      Video-assisted thoracic surgery (VATS), or thoracoscopic surgery, had a slow uptake relative to other developed countries. Most lung cancer resections are now attempted by VATS with low conversion rates. However, a few specialized units have performed more than 90% of their cases by VATS for over 10 years.
      Robotic thoracic surgery is only offered at a few centers in Sydney and Melbourne. Even in robotic centers, the more established procedure of thymectomy is more common than lobectomy.

      Radiotherapy

      Radiotherapy provisioning in Australia faces geographic barriers owing to a low population density across the continent. According to the most recent audit of the distribution of Australian radiotherapy centers of the Australian Clinical Dosimetry Service in September 2020, there are 104 centers, distributed across seven states. There are 226 linear accelerators, indicating that the average number per department is 2.2, resulting in the availability of 1 linear accelerator per 110,000 capita. From the perspective of concurrent chemoradiation therapy for locally advanced NSCLC or for limited-stage SCLC, the availability of radiotherapy facilities in close proximity to chemotherapy day centers is a challenge, particularly in rural settings.
      The uptake of stereotactic ablative body radiotherapy (SABR) was relatively late in Australia, with the first lung SABR delivered in 2010.
      • Siva S.
      • Kirby K.
      • Caine H.
      • et al.
      Comparison of single-fraction and multi-fraction stereotactic radiotherapy for patients with 18F-fluorodeoxyglucose positron emission tomography-staged pulmonary oligometastases.
      Since then, for - early stage NSCLC, SABR has become firmly established after the Trans-Tasman Radiation Oncology Group study revealed an overall survival benefit over conventional radiotherapy.
      • Ball D.
      • Mai G.T.
      • Vinod S.
      • et al.
      Stereotactic ablative radiotherapy versus standard radiotherapy in stage 1 non-small-cell lung cancer (TROG 09.02 CHISEL): a phase 3, open-label, randomised controlled trial.

      Systemic Therapies

      Recent advances in the management of NSCLC have been rapidly assessed by the Pharmaceutical Benefits Advisory Committee, and in most cases, funding accorded toward set indications. Systemic chemotherapeutics are widely available in all settings from adjuvant, neoadjuvant, concurrent with radiation, and metastatic. Chemotherapy remains the current standard of care in the adjuvant setting as tyrosine kinase inhibitors are currently not approved. Treatments available are summarized in Table 2. No tyrosine kinase inhibitors are approved for NTRK rearranged, BRAF, HER2, RET, or MET mutant NSCLC.
      Table 2Approved Targeted and Immune Therapies for NSCLC
      TargetDrugIndication
      EGFR
      GefitinibFirst- or subsequent-line therapy in patients with EGFR mutations
      ErlotinibFirst- or subsequent-line therapy in patients with EGFR mutations
      AfatinibFirst- or subsequent-line therapy in patients with EGFR mutations
      OsimertinibFor patients progressing on EGFR TKIs with EGFR T790M mutation revealed in tissue. First-line use approved, but reimbursement pending
      ALK
      CrizotinibFirst or subsequent line in patients with ALK gene rearrangements revealed by FISH
      CeritinibFirst or subsequent line in patients with ALK gene rearrangements revealed by FISH
      AlectinibFirst or subsequent line in patients with ALK gene rearrangements revealed by FISH
      BrigatinibFirst or subsequent line in patients with ALK gene rearrangements revealed by FISH
      LorlatinibOn progression with prior ALK inhibitor other than crizotinib
      ROS1
      CrizotinibFirst or subsequent line in patients with ROS1 rearranged NSCLC revealed by FISH
      EntrectinibFirst or subsequent line in patients with ROS1 rearranged NSCLC revealed by FISH
      Immunotherapy
      PD-1PembrolizumabInitial treatment of NSCLC. Can be combined with chemotherapy or used as single agent. Maximum 35 cycles
      NivolumabSecond line after progression on platinum doublet chemotherapy
      PD-L1AtezolizumabInitial treatment nonsquamous NSCLC in combination with platinum doublet chemotherapy and bevacizumab

      Second line after progression on platinum doublet chemotherapy
      DurvalumabUnresectable stage III NSCLC, after platinum-based chemoradiation
      FISH, florescence in situ hybridization; PD-L1, programmed death ligand 1; TKI, tyrosine kinase inhibitor.
      Immunotherapy has been available in the second-line setting since 2016, and agents available are summarized in Table 2. All immunotherapy given in the first-line context is capped at 2 years of treatment, whereas in the second-line setting, no time limit is mandated.
      Durvalumab is reimbursed after chemoradiotherapy for stage III NSCLC regardless of PD-L1 or mutation status. Earlier this year, the PBS altered the wording of reimbursement for immunotherapy such that patients are only allowed to receive immunotherapy once in their treatment pathway for NSCLC. This means that a patient who relapses after consolidation durvalumab would not have access to chemoimmunotherapy. Subsequently, this has led to clinicians needing to make cautious choices about using immunotherapy.
      For SCLC, atezolizumab was recently reimbursed in combination with chemotherapy in the first-line setting.

      Future Directions

      Effective tobacco control and universal health care have reduced the burden of lung cancer in Australia. However, challenges lie ahead, including an aging population, providing equitable health care to rural and indigenous populations, and eradication of smoking. The rapid advances coupled with increasingly costly diagnostics and therapies highlight limitations in our current system of test and drug approvals. Data sharing among U.S. Food and Drug Administration, European Medicines Agency, and our Therapeutics Goods Association has facilitated more rapid approvals; however, approvals from the Pharmaceutical Benefits Advisory Committee ultimately enable patients to access therapies. A mechanism to improve global transparency of funding models may achieve timely access to therapies in countries with universal health care.

      Acknowledgments

      Dr. Siva was supported by the Colebatch Fellowship from Cancer Council Victoria . Dr. Solomon was supported by the National Health and Medical Research Council (NHMRC) investigator grant. Dr. Marshall was supported by the NHMRC , Queensland Government , and Metro North Hospital and Health Service . Orcid: 0000-0002-9626-8014. Dr. Fong was supported by the NHMRC , Medical Research Future Fund, and Australian Cancer Research Foundation .

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