Evaluation and Definitive Management of Medically Inoperable Early Stage Non-Small-Cell Lung Cancer

Evaluation and Definitive Management of Medically Inoperable Early Stage Non-Small-Cell Lung Cancer

ABSTRACT: 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.

As noted in part 1 of this two-part article, surgical resection with pathologic nodal staging remains the standard of care in patients with early-stage non-small-cell lung cancer (NSCLC), but the high rate of comorbid medical illness in patients with this disease often raises concern about perioperative morbidity, postoperative pulmonary function, and long-term quality of life. In the absence of a curative surgical option, many patients and physicians appropriately opt for either a palliative or an observational approach, but there are a substantial number of patients for whom a definitive, nonsurgical, approach is appropriate. As described in part 1, which appeared in the June issue of ONCOLOGY, definitive radiotherapy has been the most commonly employed regimen, based on data suggesting a modest survival benefit. Emerging evidence suggests that new modalities, such as stereotactic radiosurgery and radiofrequency ablation (RFA), may offer curative treatment alternatives. These options will be discussed in part 2.

Stereotactic Body Radiotherapy

Stereotactic radiosurgery is well established as an appropriate definitive treatment modality for both primary and metastatic intracranial neoplasms. Highly conformal dose distributions delivering high single-fraction doses that spare nearby critical structures are possible because organ motion within the confines of the skull is limited, and the cranium therefore serves as an ideal medium to which a fiducial reference system may be attached. Extracranial stereotactic radiosurgery, or stereotactic body radiotherapy (SBRT), is emerging as a new treatment option for primary or metastatic targets in the liver, lung, retroperitoneum, and pelvis.[1] This strategy has become possible because of technical advances in treatment planning, immobilization, patient imaging, and tumor targeting. The safe use of SBRT to treat early, medically inoperable primary NSCLC with curative intent has been documented in numerous single-institution experiences[2-10] and is currently the subject of an ongoing multicenter phase II investigation (Radiation Therapy Oncology Group [RTOG] 0236).

Radiosurgery seeks to take advantage of basic radiobiologic principles of dose, fraction size, and treatment duration. By delivering a high dose in an abbreviated treatment course, the biologically effective dose is far larger than that achievable with a conventional dose escalation scheme. Because overall treatment time is not extended, this should result in an increased tumoricidal effect without increased tumor cell repopulation. Additionally, such a treatment may prove far more convenient for many patients. Typical treatment regimens incorporate doses of 20 to 60 Gy in three to six fractions; the ongoing RTOG 0236 specifies 60 Gy in three fractions over 8 to 14 days.

The high biologically effective dose of SBRT also exerts increased normal tissue effects, and thus, there is a theoretical risk of markedly increased acute and late toxicity. This is especially of concern in this population of patients who frequently have borderline pretreatment pulmonary function. For this reason, greater care is taken to limit both the volume of such tissue included and the dose that it receives. Multiple converging beams, often noncoplanar, are often used. Normal tissue margins, included in conventional radiotherapy regimens to account for setup variation, organ motion, and dose buildup, are significantly reduced. This follows the paradigm of intracranial stereotactic radiosurgery, in which meticulous pretreatment imaging evaluation, effective immobilization, and highly conformal treatment planning results in rapid dose falloff between a well-defined target and surrounding normal tissue.

Minimizing Setup Variability and Tumor Motion

The high dose per fraction, small number of fractions, and minimal normal tissue margin treated during SBRT necessitates specialized methods to account for reproducible patient setup. When SBRT is delivered by linear accelerators, patient immobilization frames—either custom-designed or commercially produced— minimize intertreatment setup variability by decreasing patient translational and rotational motion. They may also provide the fiducial markers in reference to which the treatment is delivered. Stereotactic treatment implies that treatment beams are delivered in reference to such markers, placed either on the patient, in the tumor, or on the immobilization frame.

In the case of primary lung tumors, minimizing treatment margins also requires accounting for tumor motion associated with breathing. Diaphragmatic movement with breathing can alter the craniocaudal position of lung targets by up to 2-5 cm,[11-13] an effect that is most prominent in cases of peripheral, lower lobe lesions. With linear accelerator-based treatment, reducing such movement can be accomplished in two distinct ways: either by reducing diaphragmatic excursion or by gating treatment to the respiratory cycle.[11,14] The former is implemented with immobilization devices that limit abdominal wall motion,[15] or via patient breathing control.[13,16] In the latter case, beam-on time can be controlled by chest wall excursion, or by real-time fluoroscopic imaging on the treatment table. Alternatively, emerging technology allows treatment beams to move and conform to targets that vary with the respiratory cycle.

Several authors have used linear accelerators linked with a diagnostic computed tomography (CT) scanner to obtain patient and target imaging immediately prior to treatment.[17,18] The patient remains on the treatment couch, appropriately immobilized, throughout the separate scan and treatment. In this way, normal tissue margins included to account for systematic variations in patient daily setup may be eliminated. New linear accelerators from multiple manufacturers now include onboard three-dimensional kilovoltage imaging acquisition that can reconstruct detailed axial images with soft-tissue discrimination. Such data may be used to make incremental daily adjustments in patient setup and can significantly increase the confidence of treatment design, allowing little variation in patient and tumor position.


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