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. 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, 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.
The authors have no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.
1. Timmerman RD, Forster KM, Chinsoo CL: Extracranial stereotactic radiation delivery. Semin Radiat Oncol 15:202-207, 2005.
2. Uematsu M, Shioda A, Suda A, et al: Computed tomography-guided frameless stereotactic radiotherapy for stage I non-small cell lung cancer: A 5-year experience. Int J Radiat Oncol Biol Phys 51:666-670, 2001.
3. Nagata Y, Negoro Y, Aoki T, et al: Clinical outcomes of 3D conformal hypofractionated single high-dose radiotherapy for one or two lung tumors using a stereotactic body frame. Int J Radiat Oncol Biol Phys 52:1041-1046, 2002.
4. McGarry RC, Papiez L, Williams M, et al: Stereotactic body radiation therapy of early-stage non-small-cell lung carcinoma: Phase I study. Int J Radiat Oncol Biol Phys 63:1010-1015, 2005.
5. Fukumoto S, Shirato H, Shimzu S, et al: Small-volume image-guided radiotherapy using hypofractionated, coplanar, and noncoplanar multiple fields for patients with inoperable stage I nonsmall cell lung carcinomas. Cancer 95:1546-1553, 2002.
6. Zimmermann FB, Geinitz H, Schill S, et al: Stereotactic hypofractionated radiation therapy for stage I non-small cell lung cancer. Lung Cancer 48:107-114, 2005.
7. Hiraoka M, Nagata Y: Stereotactic body radiation therapy for early-stage non-small-cell lung cancer: The Japanese experience. Int J Clin Oncol 9:352-355, 2004.
8. Wulf J, Haedinger U, Oppitz U, et al: Stereotactic radiotherapy for primary lung cancer and pulmonary metastases: A noninvasive treatment approach in medically inoperable patients. Int J Radiat Oncol Biol Phys 60:186-196, 2004.
9. Hof H, Herfarth KK, Munter M, et al: Stereotactic single-dose radiotherapy of stage I non-small-cell lung cancer (NSCLC). Int J Radiat Oncol Biol Phys 56:335-341, 2003.
10. Onishi H, Araki T, Shirato H, et al: Stereotactic hypofractionated high-dose irradiation for stage I nonsmall cell lung carcinoma: Clinical outcomes in 245 subjects in a Japanese multiinstitutional study. Cancer 101:1623-1631, 2004.
11. Giraud P, Yorke E, Ford EC, et al: Reduction of organ motion in lung tumors with respiratory gating. Lung Cancer 51:41-51, 2006.
12. Yorke E, Rosenzweig KE, Wagman R, et al: Interfractional anatomic variation in patients treated with respiration-gated radiotherapy. J Appl Clin Med Phys 6:19-32, 2005.
13. Shirato H, Seppenwoolde Y, Kitamura K, et al: Intrafractional tumor motion: lung and liver. Semin Radiat Oncol 14:10-18, 2004.
14. Ford EC, Mageras GS, Yorke E, et al: Respiration-correlated spiral CT: A method of measuring respiratory-induced anatomic motion for radiation treatment planning. Med Phys 30:88-97, 2003.
15. Lax I, Blomgren H, Naslund I, et al: Stereotactic radiotherapy of malignancies in the abdomen. Methodological aspects. Acta Oncol 33:677-683, 1994.
16. Balter JM, Dawson LA, Kazanjian S, et al: Determination of ventilatory liver movement via radiographic evaluation of diaphragm position. Int J Radiat Oncol Biol Phys 51:267-270, 2001.
17. Onishi H, Kuriyama K, Komiyama T, et al: A new irradiation system for lung cancer combining linear accelerator, computed tomography, patient self-breath-holding, and patient-directed beam-control without respiratory monitoring devices. Int J Radiat Oncol Biol Phys 56:14-20, 2003.
18. Shiu AS, Chang EL, Ye JS, et al: Near simultaneous computed tomography image-guided stereotactic spinal radiotherapy: An emerging paradigm for achieving true stereotaxy. Int J Radiat Oncol Biol Phys 57:605-613, 2003.
19. 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.
20. Ohashi T, Takeda A, Shigematsu N, et al: Differences in pulmonary function before vs. 1 year after hypofractionated stereotactic radiotherapy for small peripheral lung tumors. Int J Radiat Oncol Biol Phys 62:1003-1008, 2005.
21. Uno T, Aruga T, Isobe K, et al: Radiation bronchitis in lung cancer patient treated with stereotactic radiation therapy. Radiat Med 21:228-231, 2003.
22. Miller KL, Shafman TD, Anscher MS, et al: Bronchial stenosis: An underreported complication of high-dose external beam radiotherapy for lung cancer? Int J Radiat Oncol Biol Phys 61:64-69, 2005.
23. Fernando HC, De HA, Landreneau RJ, et al: Radiofrequency ablation for the treatment of non-small cell lung cancer in marginal surgical candidates. J Thorac Cardiovasc Surg 129:639-644, 2005.
24. Gadaleta C, Catino A, Ranieri G, et al: Radiofrequency thermal ablation of 69 lung neoplasms. J Chemother 16(suppl 5):86-89, 2004.
25. Akeboshi M, Yamakado K, Nakatsuka A, et al: Percutaneous radiofrequency ablation of lung neoplasms: Initial therapeutic response. J Vasc Interv Radiol 15:463-470, 2004.
26. Lee JM, Jin GY, Goldberg SN, et al: Percutaneous radiofrequency ablation for inoperable non-small cell lung cancer and metastases: Preliminary report. Radiology 230:125-134, 2004.
27. Suh RD, Wallace AB, Sheehan RE, et al: Unresectable pulmonary malignancies: CT-guided percutaneous radiofrequency ablation-preliminary results. Radiology 229:821-829, 2003.
28. vanSonnenberg E, Shankar S, Morrison PR, et al: Radiofrequency ablation of thoracic lesions: Part 2, initial clinical experience-technical and multidisciplinary considerations in 30 patients. AJR Am J Roentgenol 184:381-390, 2005.
29. Erdi YE, Macapinlac H, Rosenzweig KE, et al: Use of PET to monitor the response of lung cancer to radiation treatment. Eur J Nucl Med 27:861-866, 2000.
30. Bojarski JD, Dupuy DE, Mayo-Smith WW: CT imaging findings of pulmonary neoplasms after treatment with radiofrequency ablation: Results in 32 tumors. AJR Am J Roentgenol 185:466-471, 2005.
31. Belfiore G, Moggio G, Tedeschi E, et al: CT-guided radiofrequency ablation: A potential complementary therapy for patients with unresectable primary lung cancer-a preliminary report of 33 patients. AJR Am J Roentgenol 183:1003-1011, 2004.
32. Fernando HC, Hoyos AD, Litle V, et al: Radiofrequency ablation: Identification of the ideal patient. Clin Lung Cancer 6:149-153, 2004.
33. Jain SK, Dupuy DE, Cardarelli GA, et al: Percutaneous radiofrequency ablation of pulmonary malignancies: Combined treatment with brachytherapy. AJR Am J Roentgenol 181:711-715, 2003.
34. Mathur PN, Edell E, Sutedja T, et al: Treatment of early stage non-small cell lung cancer. Chest 123:176S-180S, 2003.
35. Sutedja TG, van Boxem AJ, Postmus PE: The curative potential of intraluminal bronchoscopic treatment for early-stage non-small-cell lung cancer. Clin Lung Cancer 2:264-270, 2001.
36. Okunaka T, Kato H, Tsutsui H, et al: Photodynamic therapy for peripheral lung cancer. Lung Cancer 43:77-82, 2004.
37. Deygas N, Froudarakis M, Ozenne G, et al: Cryotherapy in early superficial bronchogenic carcinoma. Chest 120:26-31, 2001.
38. Freitag L, Ernst A, Thomas M, et al: Sequential photodynamic therapy (PDT) and high dose brachytherapy for endobronchial tumour control in patients with limited bronchogenic carcinoma. Thorax 59:790-793, 2004.
39. Sanfilippo NJ, Hsi A, DeNittis AS, et al: Toxicity of photodynamic therapy after combined external beam radiotherapy and intraluminal brachytherapy for carcinoma of the upper aerodigestive tract. Lasers Surg Med 28:278-281, 2001.
40. Arriagada R, Bergman B, Dunant A, et al: Cisplatin-based adjuvant chemotherapy in patients with completely resected non-small-cell lung cancer. N Engl J Med 350:351-360, 2004.
41. Strauss GM, Herndon J, Maddaus MA: Randomized clinical trial of adjuvant chemotherapy with paclitaxel and carboplatin following resection in stage IB non-small cell lung cancer (NSCLC): Report of Cancer and Leukemia Group B (CALGB) protocol 9633 (abstract 7019). J Clin Oncol 22(14S):621s, 2004.
42. Winston TL, Livingston R, Johnson D: A prospective randomized trial of adjuvant vinorelbine and cisplatin in completely resected stage IB and II non small cell lung cancer (NSCLC): Intergroup JBR.10 (abstract 7018). J Clin Oncol 22(14S):621s, 2004.
43. Sedrakyan A, Van Der MJ, O'Byrne K, et al: Postoperative chemotherapy for non-small cell lung cancer: A systematic review and meta-analysis. J Thorac Cardiovasc Surg 128:414-419, 2004.
44. Fry WA, Phillips JL, Menck HR: Ten-year survey of lung cancer treatment and survival in hospitals in the United States: A national cancer data base report. Cancer 86:1867-1876, 1999.