Objective To update its 2013 recommendation, the US Preventive Services Task Force (USPSTF) commissioned a systematic review on the accuracy of screening for lung cancer with low-dose computed tomography (LDCT) and on the benefits and harms of screening for lung cancer and commissioned a collaborative modeling study to provide information about the optimum age at which to begin and end screening, the optimal screening interval, and the relative benefits and harms of different screening strategies compared with modified versions of multivariate risk prediction models.
Handbook of Lung Cancer and Other Thoracic Malignancies pdf
Evidence Assessment The USPSTF concludes with moderate certainty that annual screening for lung cancer with LDCT has a moderate net benefit in persons at high risk of lung cancer based on age, total cumulative exposure to tobacco smoke, and years since quitting smoking.
Recommendation The USPSTF recommends annual screening for lung cancer with LDCT in adults aged 50 to 80 years who have a 20 pack-year smoking history and currently smoke or have quit within the past 15 years. Screening should be discontinued once a person has not smoked for 15 years or develops a health problem that substantially limits life expectancy or the ability or willingness to have curative lung surgery. (B recommendation) This recommendation replaces the 2013 USPSTF statement that recommended annual screening for lung cancer with LDCT in adults aged 55 to 80 years who have a 30 pack-year smoking history and currently smoke or have quit within the past 15 years.
The T lymphocyte, especially its capacity for antigen-directed cytotoxicity, has become a central focus for engaging the immune system in the fight against cancer. Basic science discoveries elucidating the molecular and cellular biology of the T cell have led to new strategies in this fight, including checkpoint blockade, adoptive cellular therapy and cancer vaccinology. This area of immunological research has been highly active for the past 50 years and is now enjoying unprecedented bench-to-bedside clinical success. Here, we provide a comprehensive historical and biological perspective regarding the advent and clinical implementation of cancer immunotherapeutics, with an emphasis on the fundamental importance of T lymphocyte regulation. We highlight clinical trials that demonstrate therapeutic efficacy and toxicities associated with each class of drug. Finally, we summarize emerging therapies and emphasize the yet to be elucidated questions and future promise within the field of cancer immunotherapy.
The recognition of CTLA4 as a negative regulator of T cell activation gave rise to the idea that blocking its actions could unleash a therapeutic response of T cells against cancer45 (Fig. 3). James Allison and colleagues first tested this idea and demonstrated that neutralizing anti-CTLA4 antibodies enhanced antitumoural immunity in mice against transplanted and established colon carcinoma and fibrosarcoma46. In addition, during rechallenge, animals treated with anti-CTLA4 were able to rapidly eliminate tumour cells through immune mechanisms, providing evidence that blocking of CTLA4 induces long-lasting immunological memory46,47. Although CTLA4-targeted monotherapy was shown to confer benefit in animal models of brain48, ovarian49, bladder50, colon46, prostate47 and soft tissue46 cancers, less immunogenic cancers, including SM1 mammary carcinoma51 and B16 melanoma52, did not respond as favourably. Furthermore, heterogeneity between cancer models yielded discordant tissue-specific results45,53. In addition, a greater tumour burden correlated with reduced tumour responses to anti-CTLA4 treatment because larger tumours foster a more robust anti-inflammatory tumour microenvironment45,49.
Despite the mixed success in preclinical studies, mAbs targeting CTLA4 proved effective in clinical trials of melanoma45. Ipilimumab, a human IgG1κ anti-CTLA4 mAb, gained FDA approval in 2011 for non-resectable stage III/IV melanoma following evidence that it elicited potent tumour necrosis54 and conferred a 3.6-month short-term survival benefit55. Long-term survival data demonstrated that 22% of patients with advanced melanoma treated with ipilimumab benefited from an additional 3 years or more of life56. Additional long-term studies have demonstrated the durability of this survival benefit, indicating the persistence of antitumoural immunity following CTLA4 blockade56,57. Unfortunately, trial results in renal cell carcinoma58, non-small-cell lung cancer59, small-cell lung cancer60 and prostate cancer61 have yielded less impressive effects than those seen in patients with melanoma. Tremelimumab, an IgG2 isotype form of a CTLA4-blocking antibody, has yet to receive FDA approval as it did not increase survival in advanced melanoma62. It is hypothesized that effectiveness varies between ipilimumab and tremelimumab owing to differences in binding kinetics and the capacity to mediate antibody-dependent cell-mediated cytotoxicity63,64.
Once the PD1 axis was implicated in the negative regulation of T cells, preclinical work examined whether inhibitors of this pathway could be used for cancer treatment and biomarker discovery. First, overexpression of PDL1 or PDL2 in cancer cell lines was found to constrain the CD8+ T cell cytotoxic antitumour response, whereas tumours were rejected in mice without functional PD1 (refs89,90). Second, blockade of PD1 suppressed the growth of transplanted myeloma cells in syngeneic animals90. Conversely, transplanted cells overexpressing PDL1 or PDL2 in syngeneic mice allowed for increased tumour colonization, burden and invasiveness90. Neutralizing the PD1 axis using mAbs89,91 or secreted PD1 extracellular domains92 reversed these effects and enhanced T cell cytotoxicity towards tumour cells90 (Fig. 4). Rescuing CD8+ T cell cytotoxicity by PD1 blockade depends on the expression of CD28 as PD1-mediated immunomodulation is lost in the context of CTLA4Ig, B7 blockade or CD28 conditional-knockout mice92. In addition, reinvigorated T cells in the peripheral blood of patients with lung cancer following PD1 blockade were shown to express CD28 (ref.93). PD1 inhibition not only augments antitumoural immunity but also limits haematogenous seeding of B16 melanoma and CT26 colon carcinoma metastases in mouse models94. Thus, PD1/PDL1 blockade can both enhance tumour cytolysis and limit metastasis. Apart from a role of PD1 and its ligands in cancer treatment, multiple studies have also shown a negative correlation between human tumour expression of proteins involved in the PD1 axis and prognosis, indicating the utility of these proteins as potential biomarkers95,96,97.
Following preclinical success, mAbs designed to counteract negative immunoregulation by the PD1 axis were developed and efficacy was shown in clinical trials98. Development was initiated by Medarex (ultimately purchased by Bristol-Myers Squibb) in 2001 (ref.99). In 2010, a phase I trial demonstrated that PD1 blockade was well tolerated and could promote antitumoural responses100. In 2014, the humanized and fully human anti-PD1 mAbs pembrolizumab and nivolumab (both IgG4) became the first FDA-approved PD1-targeted therapeutics for refractory and unresectable melanoma101,102,103,104. In a head-to-head comparison, pembrolizumab showed better 6-month progression-free survival than ipilimumab and conferred an overall survival benefit105,106. Clinical trials of nivolumab demonstrated an overall survival of 72.9% at 1 year compared with 42.1% survival in the group of patients treated with the chemotherapeutic dacarbazine104. In 2015, pembrolizumab was approved for the treatment of PDL1-expressing non-small-cell lung carcinoma because it provided a 4.3-month increase in progression-free survival compared with platinum-based chemotherapeutics and was more effective than the chemotherapeutic paclitaxel107,108. Increased PDL1 expression on the target tumour was associated with improved responses to PD1 axis blockade109. Additional successful clinical trials expanded the use of pembrolizumab to head and neck squamous cell carcinoma110, Hodgkin lymphoma111, urothelial carcinoma112, gastric/gastro-oesophageal junction cancer113 and tissue-agnostic carcinoma with a high degree of microsatellite instability114. Following approval in tissue-agnostic cancers with microsatellite instability, pembrolizumab became the first drug to be approved based on a molecular biomarker rather than by cancer site. However, the immunosuppressive microenvironment of different tissues makes it hard to predict which patients will benefit115,116. Similar to prembrolizumab, the use of nivolumab has since been extended to renal cell carcinoma117, head and neck squamous cell carcinoma118, urothelial carcinoma119, hepatocellular carcinoma120, Hodgkin lymphoma121 and colorectal cancer with a high degree of microsatellite instability122. As was seen with anti-CTLA4 therapy, long-term survival analyses demonstrate a long-lasting immune-mediated survival benefit following PD1 blockade123. However, the reason why PD1 blockade has demonstrated broader clinical utility than anti-CTLA4 treatment has remained elusive. It is hypothesized that the difference may be because the PD1 axis is frequently co-opted by tumours via ligand expression, whereas CTLA4 represents a broader immunoregulatory circuit74,124.
PDL1 is also targetable by specific antibodies that have proven effective treatments in multiple forms of cancer. In 2016, the first PDL1-targeted humanized mAb, atezolizumab (an IgG4 antibody), was approved for treatment of urothelial carcinoma. An overall response rate of 15% was deemed statistically significant based on historical control data, although responses were dependent on tumour PDL1 expression status125. Unfortunately, additional trial data have not demonstrated that atezolizumab has clinical efficacy beyond the standard of care in urothelial carcinoma, although it is less toxic than traditional chemotherapy126. Indications have since expanded to include the treatment of non-small-cell lung carcinoma127, triple-negative breast cancer128 and small-cell lung cancer129. Additional anti-PDL1 human mAbs, avelumab and durvalumab, entered the market in 2017 (ref.98). Avelumab is used for the treatment of Merkel cell carcinoma130, urothelial carcinoma131 and advanced renal cell carcinoma132. Duvalumab is used for urothelial carcinoma133 and non-small-cell lung cancer134. Therefore, similar to PD1, blockade of PDL1 has been effective in difficult-to-treat forms of cancer. 2ff7e9595c
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