Lung cancer is estimated to be the second most commonly diagnosed cancer in both men and women in 2006, and the leading cause of cancer mortality. Non-small-cell lung cancer represents the majority of such cases. Most of these patients have locally advanced disease at presentation and are not eligible for curative resection. For the minority of patients who are technically resectable at presentation, lobectomy or pneumonectomy and pathologic mediastinal nodal staging offer the best overall survival. The high rate of comorbid medical illness and poor baseline pulmonary function in this population, however, make many such early-stage patients medically inoperable. For these patients, conventional single-modality radiotherapy has been the primary definitive treatment option, as discussed in part 1 of this article, which appeared in last month's issue. Numerous retrospective reports demonstrate long-term disease-free and overall survival data that are modestly superior to that expected after observation, but both local and distant failure continue to be significant risks. Investigation of radiotherapy dose escalation is ongoing, in an effort to improve local control while maintaining minimal toxicity. Additionally, emerging evidence suggests that new modalities, such as stereotactic radiosurgery and radiofrequency ablation, may also be potentially curative treatment alternatives. These modalities are addressed in part 2.
In their overview of the management of medically inoperable but localized early-stage non-small-cell lung cancer (NSCLC), Decker and colleagues provide an excellent evaluation of the nonsurgical options for radical treatment, focusing particularly on radiotherapy as the current standard of care.
As becomes clear from the data cited by Decker et al, in the radical treatment of such patients, local control remains a major challenge. Indeed, among patients whose treatment fails-even though this may occur in the context of regional and distant metastasis-the majority will have evidence of local failure at the time of death. One intuitive response suggests that more effective radical treatment to the local primary site may have a significant impact on morbidity and mortality from the disease. Accepting that radical radiotherapy (potentially augmented by other treatment modalities) is likely to remain the standard of care, the question remains: How can the results of radical radiotherapy be improved for early-stage small volume NSCLC?
Conceptually there are a number of explanations for radiotherapy failure. These may be broadly divided into factors relating to geographic miss of the target and biologic factors resulting in radiation resistance within the tumor, which may be due to hypoxia, repopulation of tumor cells, or intrinsic cell resistance.
The first issue in determining a radiation treatment volume is to be confident of the distribution of the disease. As these authors state, staging of NSCLC has improved remarkably since the advent of three-dimensional cross-sectional imaging and functional imaging-in particular, 18F-fluorode-oxyglucose positron-emission tomography (FDG-PET) scanning. The latter has excluded a significant proportion of patients (around one in five) who previously would have undergone radical treatment but were already incurable by virtue of regional or distant metastasis undetected by conventional nonfunctional imaging techniques. Thus, the population of patients now treated is more favorable than in the past. Clearly, all patients in the group being considered in this review should undergo full computed tomography (CT) and PET staging prior to selection for treatment.
Similarly, advances in three-dimensional conformal and intensity-modulated radiotherapy planning have greatly improved our understanding of target definition and movement as well as normal tissue volumes within an irradiated area and their likely tolerance. The radiotherapy planning department can now define elegant radiation distributions to cover a defined tumor volume and minimize the dose to organs at risk.
In the lung, however, the major challenge is to transfer that sophisticated high-resolution mathematical exercise to a patient who is likely to be frail, anxious, and actively breathing while on the linear accelerator couch receiving radiation exposure. Internal organ movement presents a particular challenge in lung cancer. The simple, routine response to this problem is to allow wider margins around the defined microscopic and macroscopic tumor. The clinical target volume (CTV)-to-planning target volume (PTV) margin conventionally allows for 3- to 5-mm variations in patient setup even in the most rigorous radiation therapy facilities.
In a modern radiotherapy setting, it is unacceptable to omit some method of respiratory control when undertaking the radical treatment of lung cancer using either active breathing control (in which the patient controls respiration with positive physiologic feedback during radiation exposure) or respiratory gating (in which the treatment beam is pulsed with the respiratory cycle). Such considerations become increasingly critical for patients with small tumors and when techniques such as stereotactic radiotherapy and radiofrequency ablation-involving very high-dose treatment in a short time-are considered.
In many tumor sites, hypoxia has been identified as a major limiting factor in the efficacy of radiotherapy. Indeed, the condition is now recognized as conferring resistance to other important modalities of cancer therapy including chemotherapy and biologic therapies. The hypoxic cell is adapted to survive in low oxygen tension conditions, a consequence of which is relative resistance to radiation damage, probably through less efficient production of free radicals, thereby causing less DNA damage.
The role of hypoxia in lung cancer has been poorly studied in the past, and much of our understanding is an extrapolation from other diseases such as head and neck cancer and primary carcinoma of the cervix. Both are squamous cell carcinomas with characteristics similar to lung cancer, including their high prevalence in cigarette smokers (where hypoxia has been shown to be a predictor of poor survival), high metastatic potential, and resistance to treatment. The hypoxia marker carbonic anhydrase IX has been shown to predict for poor prognosis in squamous cell lung cancers. One approach to improving radiotherapy results should be to incorporate methods of hypoxia modification or exploitation with the use of bioreductive drugs in radical treatment.
Lung cancer was one of the first tumors identified as having a short potential tumor-doubling time (on the order of 5 to 6 days). As a result, strategies such as accelerated radiotherapy and continuous hyperfractionated accelerated radiotherapy (CHART) have evolved. The hypothesis behind these regimens was that if the tumor cell population can double in number over such a short time, then any breaks in radiotherapy and prolongation of radiotherapy treatment would be deleterious. Therefore, continuous treatment without weekend breaks over as short a time as possible may be the most effective means of delivering treatment.
The extreme experiment was the CHART study, which compared conventional treatment (60 Gy in 30 fractions over 6 weeks) with the CHART schedule (54 Gy in 36 fractions over 12 days). The improvement in survival demonstrated in this study confirms the importance of proliferation as a limiting factor in NSCLC. As Decker and coauthors discuss, however, there are limits to how far this concept can be exploited given normal tissue tolerances, and in particular, dose-limiting esophageal mucosa recovery rates.
The relative impact of acceleration and other methods of treatment manipulation (eg, chemoradiation) remain unclear, as does the tolerance of normal tissues to chemotherapy with accelerated radiotherapy. These areas are being actively investigated at present. When radiotherapy alone is used, there is good evidence to justify acceleration, but controversy persists as to whether this should be conducted within a CHART-type schedule, a hypofractionated schedule (eg, 55 Gy in 20 fractions), or using a more complex concomitant boost approach.
Some cancer cells are undoubtedly more resistant than others to a given dose of radiation because of intrinsic factors relating to the way in which they handle radiation damage. Various methods to overcome this have been exploited, of which the simplest is dose escalation and perhaps the most common is addition of other cytotoxins, in particular, chemotherapy.
The role of dose escalation in NSCLC remains somewhat confused. As ably debated in this paper, a number of important studies (although limited true prospective randomized data) have looked at the dose-response relationship above 70 Gy, with conflicting results. Inevitably, as dose escalates, normal tissue reactions also escalate with the potential for greater toxicity. While a modest dose escalation beyond 70 Gy may be of value, my own interpretation of the data is that even for relatively small-volume tumors, dose escalation beyond 80 Gy is unlikely to be either feasible or effective in terms of improved survival.
Increasing evidence suggests that concomitant chemotherapy using cisplatin-based schedules will improve treatment results, albeit by relatively modest amounts. Increasingly, this is regarded by many as the standard of care, although much work needs to be done with regard to optimizing specific drug combinations and scheduling. In contrast, neoadjuvant chemotherapy-while theoretically attractive in terms of early control of microscopic disease and a reduction in primary tumor bulk enabling smaller-volume, higher-dose radiotherapy-has shown less promise and is probably best avoided in favor of concomitant treatment. This perhaps highlights the relative inefficacy of conventional chemotherapy in NSCLC, and the need to remain abreast of developments in systemic treatment and opportunities for new combined-modality scheduling.
There has been considerable excitement over the initial results of combining cetuximab (Erbitux) with radiation in head and neck cancer, and as an obvious corollary, similar advantages may be seen with such a combination in NSCLC. Other areas of active research include the use of vascular disrupting agents (VDAs), with the notable success of bevacizumab (Avastin) in colorectal cancer. Early data suggest that another VDA, combretastatin, is active in NSCLC, particularly in combination with radiotherapy. The role of antiangiogenic drugs is another fertile area of current research and should be considered in this group of patients. Coincidentally, for those with severe diabetes, these drugs may have important disease-modifying effects on their proliferative retinopathy as well.
Finally, it is important to recognize that for many of these patients the development of small-volume NSCLC is part of an ongoing chronic illness for which radical treatment may not be appropriate or desirable by the patient. The option of simple palliative procedures, therefore, should always be considered and discussed, and the small but significant long-term survival rate with palliative treatment must be acknowledged. For many, it is the comorbidity that will influence their lifestyle and produce limiting symptoms. Their management must be seen in this broader context.
-P.J. Hoskin, MD
The author has no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.
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