Commentary (Sause): Evaluation and Definitive Management of Medically Inoperable Early Stage Non-Small-Cell Lung Cancer
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.
It was a pleasure to read the manuscript written by Dr. Decker and colleagues regarding the role of radiation therapy in unresectable lung cancer. However, the reader should be advised that a great deal of this manuscript, as it pertains to radiation dose, confuses the issue by including stage I through stage III lung cancer. The most common clinical situation in radiation oncology concerns the management of patients with stage III disease. Most of the literature regarding radiation dose escalation comes from patients with regionally advanced, nonmetastatic, non-small-cell lung cancer (NSCLC). It is unclear whether data abstracted from the management of stage III patients is relevant to the management of those with relatively small peripheral lesions and no clinical evidence of metastatic disease.
Does biology trump anatomy? Radiation oncologists have long maintained that dose escalation to the tumor volume in patients with stage III disease will impart an improvement in local control that will result in an improvement in survival.[1] Theoretically this represents an attractive hypothesis, but there is little level 1 evidence to support this conclusion. The exception to this statement is the Saunders paper[2] referenced in Dr. Decker's review. The reader should also be aware that the data from Great Britain includes patients with stage I and II disease and may not necessarily be representative of stage III lung cancer patients treated in the United States.
Improved Survival in Stage III Lung Cancer
The median survival for regionally advanced NSCLC has improved steadily since 1973, when the Radiation Therapy Oncology Group (RTOG) conducted its first dose-escalation trial. However, it is unclear that radiation dose escalation has contributed to the improvement in median survival. Median survival has improved from approximately 10 to 18 months, but the cause for this improvement is multifactorial.[3]
The routine inclusion of systemic therapy into initial treatment in the management of stage III disease has undoubtedly contributed to an improvement in median survival. The inclusion of concurrent chemoradiation therapy into the management of patients with stage III disease has resulted in an increase in acute toxicity. As the toxicity of initial treatment increases, patient selection for these aggressive treatment regimens narrows. The resulting "Will Rogers effect" has also contributed to the observed improvement in median survival seen in recent cooperative group trials.
Clearly, in regionally advanced NSCLC, we have improved the median survival and decreased radiation toxicity with sophisticated treatment planning. Whether this supports the theoretical benefits of dose escalation, however, remains unclear.
Radioablation in Stage I NSCLC
The management of potentially operable lung cancer with external-beam radiation therapy represents an interesting chapter in the evolution of radiation oncology. Scientific developments related to equipment hardware, imaging, and treatment delivery software have contributed substantially to our ability to deliver finely directed radiation. Peripheral lung lesions represent a unique technical challenge that potentially lends itself to the adaptation of this new technology. Small peripheral lung lesions represent a moving target surrounded by relatively easily damaged tissue. Patients with smoking-induced cancer are functionally challenged at diagnosis and can suffer substantially from radiation injury.
As outlined in the review, the incorporation of these technologic advances in the management of lung cancer has resulted in clinical research into frequently administered, finely focused radiation therapy delivered to peripheral lesions. The biologic doses of radiation in most series are more correctly termed "radioablation," representing doses that far exceed what is normally delivered with standard technology.[4] Although theoretically attractive and preliminarily encouraging, one must be aware that no level 1 evidence suggests that dose escalation is either required or represents an improvement over surgical techniques.
When considering such technology to treat small peripheral lesions, one should be aware of a previously published phase III Lung Cancer Study Group trial[5] that randomized patients to segmental resection vs anatomic lobectomy for limited-stage NSCLC. The trial concluded that anatomic lobectomy improved disease-free survival. While this technologic approach is developing, computed tomography screening is being investigated in high-risk populations.[6] Would radioablation represent an attractive lung-sparing strategy for patients with lung cancer detected through such screening technologies, which are designed to detect malignancies at an early, more effectively treated stage?
Conclusions
In summary, the authors have presented an excellent discussion of the role of external-beam radiation therapy in the management of bronchogenic carcinoma. However, the reader should be aware that much of our data come from the management of stage III disease, and this may or may not be applicable to earlier-stage disease. New technology that allows finely focused high-dose irradiation to peripheral nodules is exciting and deserves the support of the clinical research community.
-William T. Sause, MD
Disclosures:
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.
References:
1. Cox JD, Le Chevalier T, Arriagada R, et al: Management of unresectable non-small cell carcinoma of the lung (NSCLC). Lung Cancer 42(suppl 1):S15-S16, 2003.
2. Bentzen SM, Saunders MI, Dische S: From CHART to CHARTWEL in non-small cell lung cancer: clinical radiobiological modelling of the expected change in outcome. Clin Oncol (R Coll Radiol) 14:372-381, 2002.
3. Curran WJ Jr: Treatment of locally advanced non-small cell lung cancer: What we have and have not learned over the past decade. Semin Oncol 32(2 suppl 3):S2-S5, 2005.
4. Timmerman R, Papiez L, McGarry R, et al: Extracranial stereotactic radioablation: Results of a phase I study in medically inoperable stage I non-small cell lung cancer. Chest 124:1946-1955, 2003.
5. Ginsberg RJ, Rubinstein LV: Randomized trial of lobectomy versus limited resection for T1 N0 non-small cell lung cancer. Lung Cancer Study Group. Ann Thorac Surg 60:615-622 (incl discussion), 1995.
6. Black C, Bagust A, Boland A, et al: The clinical effectiveness and cost-effectiveness of computed tomography screening for lung cancer: Systematic reviews. Health Technol Assess 10:1-106, 2006.
