Out, out, brief candle!
Life's but a walking shadow, a poor player
That struts and frets his hour upon the stage
And then is heard no more; it is a tale
Told by an idiot, full of sound and fury,
Signifying nothing (Macbeth Act V, Scene V, William Shakespeare)
In this familiar quotation, Shakespeare has Macbeth express his disgust for life, and, in so doing, he eloquently articulates the perspective of the existential nihilist—that life itself is meaningless. The extension of this philosophy to medicinal therapy gave rise to the concept of therapeutic nihilism, namely the belief that the treatment of disease does more harm than good. This philosophy gained prominence in the mid-1800s and has continued to endure, so much so that the modern version of the Hippocratic oath (as written in 1964 by Louis Lasagna, Academic Dean of Tufts Medical School) specifically addresses therapeutic nihilism in the third stanza: “I will apply, for the benefit of the sick, all measures (that) are required, avoiding those twin traps of overtreatment and therapeutic nihilism.”
One could argue that no common oncologic disease has suffered more at the hands of therapeutic nihilism than lung cancer. A recent survey of 1,132 primary care clinicians assessing whether referral patterns and treatment differed between breast and lung cancer patients, revealed that physicians were significantly more likely to refer breast cancer patients for the treatment of their disease with lung cancer patients often being referred purely for symptom control.1 It is easy to understand why this disparity exists. The numbers tell a grim tale; 219,000 patients are diagnosed annually with nearly 160,000 deaths.2 Five-year survival for inoperable stage III disease is extremely poor at 5% to 40%. It is also difficult to blame radiation oncologists for being nihilistic because they are charged with the Sisyphean task of treating an unpredictably mobile, often unresponsive tumor that is embedded within an exquisitely sensitive, poorly functioning vital organ.
The pendulum is beginning to swing, however. The past decade has seen significant gains in the understanding of non–small-cell lung cancer (NSCLC) tumor biology, moving beyond simple histologic classification to the characterization of aberrant growth factor signaling pathways in these tumors and the development of targeted therapies that successfully achieved reversal of this activation. The past decade has also seen significant advances in radiation dosimetric planning, tumor imaging, and treatment-delivery techniques that allow the treating radiation oncologist to assess and account for uncertainties such as tumor motion and the volume of critical normal structures being irradiated. This issue of Seminars in Radiation Oncology deals with the radiotheraputic management of NSCLC and pleural malignancies and touches on many of the gains that have been achieved in thoracic radiation oncology over the past decade.
The issue opens with two articles that focus on tumor biology because it relates to radiation response. The article by Das et al introduces the emerging field of radiogenomics and discusses the application of genome-wide association studies in lung cancer cell lines to identify predictive and prognostic biosignatures of radiation response. In the second article, Graves et al discuss what is currently understood about the tumor microenvironment in NSCLC and its relevance for modulating the response to therapy. The article examines the utility of functional imaging to quantify tumor hypoxia and the vascular response to radiotherapy.
Moving from the bench to bedside, Robinson and Bradley discuss the management of early-stage NSCLC. This article includes a discussion of the emergence of stereotactic body radiotherapy and hypofractionation in the management of stage I disease. Cox and Chang examine the recent advances in treatment planning that have allowed for the refinement of conformal treatment delivery techniques such as intensity-modulated radiotherapy as it applies to NSCLC. Additionally, they briefly examine what may be the next step in the evolution of conformality of dose delivery, proton beam radiotherapy.
Another approach to improving the therapeutic ratio for radiotherapy in the treatment of NSCLC is through the use of image guidance to reduce the margins required to account for variations in patient positioning and tumor motion. Cho et al examine the use of volumetric imaging for target definition and also discuss the utility of incorporating in-treatment response assessment for adaptive treatment delivery. This widening of the therapeutic ratio has taken on increased importance because combined modality approaches have been increasingly incorporated in the treatment paradigm for the management of locally advanced disease. Anderson and Curran discuss the emergence of combined modality therapy for the management of stage III NSCLC and summarize the emerging data on the incorporation of targeted agents with concurrent chemoradiotherapy for locally advanced disease.
The past decade has also seen a significant evolution in the role of surgery in the management of NSCLC. In an article discussing the controversial role of postoperative radiotherapy in the management of completely resected NSCLC, Saynak et al note that although distant failures predominate, locoregional failure rates after surgical resection alone are as high as 28% for patients with N0 and 65% for patients with N2 disease. In the era after publication of the postoperative radiotherapy meta-analysis and where adjuvant chemotherapy is the standard of care for all surgically resected node-positive patients and certain high-risk subsets of node-negative patients, the additional benefit of adjuvant radiotherapy has been called into question. However, these authors argue that as systemic treatments are improved, “locoregional” control will be of increased importance and will likely translate directly into a survival benefit for our patients. They note that with modern radiotherapeutic techniques and fields that are tailored to deliver treatment only to the regions that are deemed to be at greatest risk for relapse based on the location of the primary tumor, one can deliver effective treatment while minimizing the dose to the normal lung.
The issue concludes with a review of the management of pleural malignancies by Friedberg and Cengel. Pleural malignancies, whether primary or metastatic, present a significant challenge to the thoracic surgeon, medical oncologist, and radiation oncologist alike. The article discusses the current standard as well as experimental approaches, such as photodynamic therapy, for both the palliative and definitive treatment of pleural disease including mesothelioma and the difficult problem of pleural spread of NSCLC.
In summary, the past decade has seen a significant explosion in our understanding of NSCLC and a concomitant evolution in the field of thoracic radiation oncology. As we enter the new decade armed with these advances in biology and physics, one can hope that we will move from an era of therapeutic nihilism to that of therapeutic optimism in the management of NSCLC.
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