Drs. Kelsey, Marks, and Wilson open their excellent review article by asking “Where do we stand?” with respect to postoperative radiation therapy (PORT) for non–small-cell lung cancer (NSCLC). Frankly, PORT has not exactly been standing tall for the past decade-leaning, crouching, or perhaps squatting might be a better verb.
This article is a review of Postoperative Radiation Therapy for Lung Cancer: Where Do We Stand?
Drs. Kelsey, Marks, and Wilson open their excellent review article by asking "Where do we stand?" with respect to postoperative radiation therapy (PORT) for non–small-cell lung cancer (NSCLC). Frankly, PORT has not exactly been standing tall for the past decade-leaning, crouching, or perhaps squatting might be a better verb. Its use has dropped considerably in the past 10 years, since the publication of the well-known meta-analysis in 1998. Has the response to the PORT meta-analysis been exaggerated, and should PORT be reevaluated in 2008?
The rationale for using PORT to treat NSCLC is the same as that for radiotherapy in any other malignancy. It involves three hypotheses: (1) Patients at relatively high risk for local/regional recurrence can be identified; (2) radiotherapy is effective at improving local/regional control; and (3) the benefit in local/regional control outweighs the toxicity of radiotherapy, leading to improved major clinical outcomes. Since quality of life continues to be notoriously difficult to measure, the major clinical outcome of interest is quantity of life (survival).
The first and second hypotheses are supported in the setting of NSCLC. This is nicely shown in Table 6 of the article by Kelsey et al; nine studies are listed and every one showed at least a trend toward improved local/regional control with PORT. (How often does one see such a consistently beneficial distant control benefit with chemotherapy?) Clearly, radiotherapy is effective; NSCLC should not be considered radioresistant. The third hypothesis, however, is very much unproven. This differs from the situation for several other cancers, where radiotherapy-related improvements in local/regional control lead to improved survival.[4-6]
Toxicity and Comorbidity
As Kelsey et al note, the failure of PORT to improve survival may be due to the toxicity and comorbidity challenges faced by lung cancer patients. PORT universally causes fatigue and esophagitis, which can cause cardiopulmonary complications. Furthermore, in some patients thoracic radiotherapy leads to direct and serious radiation injury to the lung(s) and/or heart. Chemical or biologic radioprotectors have not been of demonstrated value. Physical radioprotection, using complex three-dimensional conformal (3D-CRT), intensity-modulated (IMRT), and/or proton-beam radiotherapy improves radiation dosimetric parameters to critical thoracic organs and may decrease certain complications.
The magnitude of the detrimental effects of radiotherapy seen in the Lancet meta-analysis probably reflects suboptimal techniques, as has been discussed elsewhere. However, the belief that modern radiotherapy is much safer than older techniques has not been proven by a randomized trial. Even "perfect" radiotherapy still has some toxicity. For patients at modest risk for local/regional failure (ie, all stage I and most stage II NSCLC patients), this toxicity probably still outweighs the benefits.
Clinical Research Questions
Since properly administered modern PORT is expensive and not risk-free, more insight into identifying patients at high risk for local/regional failure is needed. Perhaps future advances in surgery, pathology, and molecular biology can detect biomarkers for local/regional recurrence, allowing patients to be rationally selected for PORT, just like the ongoing research focus into the individualization of systemic therapies. Detailed patterns-of-failure results from several important studies conducted by the American College of Surgeons Oncology Group (ACOSOG) are anxiously awaited, including the Z0030 (mediastinal nodal dissection vs sampling) and Z0040 (significance of nodal micrometastases in resected NSCLC) trials. These and other new data should help to guide the next generation of clinical trials in local/regional therapy for NSCLC.
The major clinical research question for PORT, though, is the following: Should a new large randomized trial of PORT vs no PORT for resected N2/IIIA disease be developed and activated in North America? A French trial was activated last year. A prior attempt in the United States failed to accrue sufficiently-only 44 patients were enrolled over 2 years. A definitive study would require a large number of patients, perhaps more than 750, to detect a small but clinically meaningful survival improvement. This raises feasibility concerns.
Resected pN2 NSCLC is probably less common than previously, due to improvements in preoperative noninvasive and invasive staging with subsequent triage of patients toward preoperative and/or nonsurgical therapies. Furthermore, reports show a pitifully low rate (< 1%) of all lung cancer patients enrolling onto a clinical trial. Even if this number were to be considerably higher for N2 patients, it would probably require about 10 years of accrual time plus several years of follow-up and analysis to receive a valuable answer to the N2 PORT question. Is society willing to accept this long waiting period, with the risk that the answer might not be completely relevant in 2020? If the answer is yes, then this phase III study is needed-perhaps while allowing patients to concomitantly enroll in separate systemic drug trials.
Patient Selection Criteria
Despite the challenges associated with researching PORT for N2 NSCLC, this is not a rare disease, particularly if patients treated with induction chemotherapy are included. Thus, oncologists will continue to be faced with difficult management decisions for these patients in the absence of quality randomized data. Who should receive PORT after surgery and chemotherapy outside of a clinical trial? There is no consensus; these are the criteria we use at our University practice:
(1) N2 disease (or selected suboptimally resected, potentially understaged N1 disease).
(2) No evidence of distant metastases on restaging positron-emission tomography after adjuvant chemotherapy.
(3) Good performance status (Zubrod PS 0/1).
(4) Good cardiopulmonary reserve and pre-PORT organ function testing as defined in prospective trials.
(5) Treatment with 3D-CRT and careful attention to dose-volume histogram parameters (V10, V20, mean lung dose, etc), and a target dose ≤ 54 Gy.
(6) Patient ability/willingness to comply with careful intratreatment and posttreatment medical care and visits-both with radiation and medical oncologists and with internists (pulmonology, cardiology, etc).
PORT for NSCLC will remain a controversial topic in thoracic oncology for years to come. Despite its decreased use in 2008, it should not be relegated to the Onco-Museum of Historical Interest. Until surgery/chemotherapy can achieve convincingly and reliably high local/regional control rates for NSCLC, PORT should continue to be studied and, yes, even offered to selected patients.
-Mitchell Machtay, MD
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