Helical Tomotherapy for Simultaneous Multitarget Radiotherapy for Pulmonary Metastasis
Ji Yoon Kim, IJROP 2009;75:703
 

To retrospectively evaluate our experience with tomotherapy for simultaneous multitarget radiotherapy in patients with pulmonary metastases.

Methods and Materials

Thirty-one patients were treated with tomotherapy for pulmonary metastases. We defined gross tumor volume (GTV) in computed tomography scans, and the margin of the planning target volume was 1 to 1.5 cm from the GTV. The median doses prescribed were 50 Gy and 40 Gy delivered in 10 fractions over 2 weeks to the 95% isodose volume of the GTV and planning target volume, respectively. Prior to each treatment, online corrections were made in the three axes, and rotation was done after registration of the megavoltage and simulation computed tomography scans. Survival was calculated from the completion of tomotherapy, using the Kaplan-Meier method and log rank test.

Results

The overall survival rate at 12 months was 60.5%, and the median survival time was 16.0 months. A rating of 1 or below on the Eastern Cooperative Oncology Group scale, a breast or colon cancer as the primary cancer, primary lesions that were completely controlled, and a response maintained at 3 months after tomotherapy were shown by univariate analysis to be statistically significant favorable prognostic factors. Progression-free survival rates at 1 and 2 years were 39.6% and 27.7%, respectively. The posttreatment failure rate was 64.5%, the local failure rate was 9.7%, the regional failure rate was 51.6%, and the synchronous local and regional failure rate was 3.2%. Grades I and II radiation-related toxicity levels were observed in 41.9% and 16.0% of patients, respectively. There were no treatment-related deaths.

Introduction 

Pulmonary resection remains the standard of care for early stage lung tumors and is also an option for oligometastases to the lungs. However, resection may not be feasible in patients of extremely advanced age or with poor underlying cardiopulmonary function or multiple comorbidities because of the risk of significant morbidity and mortality in these settings. In such patients, external-beam radiation therapy is often the treatment of choice. However, this treatment also has its drawbacks, including the potential to damage adjacent lung and nearby normal structures and its association with a local failure rate that is higher than that seen for resection. To minimize collateral injury to normal tissues, adequate fractionation (e.g., 1.82.0 Gy/fraction) over 6 to 7 weeks is commonly used.

The use of stereotactic body radiotherapy (SBRT) to overcome problems with normal tissue injury in patients with primary and metastatic lung cancer has now been actively studied at many institutions. In SBRT, radiation is targeted almost exclusively to the tumor, while tissues not grossly involved with the tumor are spared. However, the unique radiobiology of SBRT that ensures maximal tumor control but minimal normal tissue complications is what really sets SBRT apart from other radiotherapy techniques. Additional defining characteristics of SBRT include the abilities to securely immobilize the patient for the typically long treatment sessions; to accurately duplicate patient position between simulation and treatment; to minimize normal tissue exposure through the use of multiple- or large-angle, arcing, small-aperture fields; to rigorously account for organ motion; to stereotactically register tumor target and normal tissue structures; and to deliver ablative dose fractions with subcentimeter accuracy to the patient. Many studies of SBRT in the treatment of primary and metastatic lung cancer have been done in the recent decade, and the findings from these studies are summarized. Overall, these studies have shown SBRT is associated with an 85% to 95% local control rate, with acceptable toxicity levels after higher-dose radiation delivered in a few fractions in patients with lung tumors. However, the dose of radiation that can be delivered by SBRT is still limited by potential problems with normal tissue toxicity stemming from lung tumor movement. One relatively new technology that may be able to minimize some of these problems is helical tomotherapy. It has the ability to acquire pretreatment megavoltage computed tomography (CT) images that can be fused with kilovoltage CT images, which can be used for treatment planning to determine the positional shifts that need to be made prior to delivery of radiation. A further advantage of the tomotherapy unit is that it is a dedicated intensity-modulated radiation therapy delivery system that can create a highly conformal dose distribution with a helical delivery pattern provided by a fan beam mounted on a slip ring gantry and a binary multileaf collimator. Radiation is then delivered over 360 of rotation with 51 projections per rotation. The image guidance and intensity modulation capabilities of tomotherapy can potentially translate into the delivery of an increased tumor dose with a dose to normal tissue that is decreased compared with that of other techniques. However, its use in patients with pulmonary metastases, whose health is compromised by factors that rule out surgical resection, has not been studied in depth.

Discussion 

The clinical existence of oligometastatic disease was first proposed in 1995 by Hellmann and Weichsellbaum, who hypothesized that a certain extent of disease exists in a transitional state between localized and widespread systemic disease in some patients with a limited number of clinically detectable metastatic tumors. They surmised from this that the local control of oligometastasis should lead to improved systemic control.

Metastatic disease to the lung is very common for most types of cancers and precludes a favorable outcome in most patients. Thus, it is important to identify more effective treatments for patients with such metastases. Currently, chemotherapy is the standard of treatment for patients with such pulmonary metastases, but long-term survivors are extremely rare. Local therapy such as surgical excision or radiotherapy can be expected to improve the treatment results, but this has not been established. In an effort to make this determination, the International Registry of Lung Metastasis was established to assess the long-term results of the resection of pulmonary metastases resulting from all tumor types. Multivariate analysis of over 5,000 cases revealed that a certain group of patients with germ cell tumors, a disease-free interval of 36 months or more, and a single metastasis had a better outcome.

SBRT is an alternative to resection for those patients who have unresectable lesions because of the proximity of the lesions to vessels or other critical structures, multilobar involvement, the patients are medically unfit, or the patients decline surgery. The total number of patients in these studies was 389, the total number of targets was 457, and the mean number of targets per patient ranged from 1 to 1.5. The crude local control rate ranged from 85% to 95%, and the median follow-up ranged from 8 to 60 months.

Okunieff  reported that SBRT for multiple lung metastases could be curative in patients with five or fewer metastatic lesions. The crude local control rate in their study was 94%, and the median overall survival time from the time of treatment completion was 23.4 months. The progression-free survival rates were 25% and 16% at 12 and 24 months, respectively. Grade I toxicity occurred in 35% of all the patients, Grade II toxicity in 6.1%, and Grade III toxicity in 2%. Our study results were inferior to those of Okunieff et al. in terms of median survival, crude local control rate, and rate of radiation-related toxicity because of the larger number of patients with more advanced disease in our series of patients. For example, the mean numbers of pulmonary metastases were 4.32 (range, 110) in our study and 2.6 (range, 15) in the study by Okunieff et al.

Kavanagh have suggested selection criteria for SBRT for patients with oligometastases. These criteria require that patients with controlled or removed primary tumors should be capable of self care; that patients should ideally have four or fewer tumors of less than 4 cm in diameter that originate from colon, breast, sarcoma, or renal cell primary tumors; and that tumors should be identifiable on primary treatment planning images. Tumors located next to hollow viscous organs are cause for excluding patients from SBRT. Our results also showed that superior survival was achieved in patients showing a good performance status, patients with breast or colon cancer, and patients with a completely removed or controlled primary lesion.

There are a few drawbacks to our study that need to be acknowledged. For example, we should have separated the breast and colon cancer patients in our study because of the small number of patients. In addition, although it was not statistically significant, the overall median survival and 1-year survival rates were better in patients with five or fewer pulmonary metastases than the rates in patients with more than five metastases (17.0 months and 77.8% vs. 10.0 months and 37.5%, respectively). Milano also reported the SBRT results with 121 patients with five or fewer detectable metastases, who had been treated with curative intent. However, they found no evidence that the number of metastatic lesions was a significant predictor of outcome in patients with five or fewer oligometastatic lesions. We also found some indication that the response at 3 months after tomotherapy was another prognostic factor for overall survival but not for progression-free survival. We consider our results reasonable because the better survival rate was achieved in patients who had undergone complete resection.

The optimal dose and fractionation can be regarded as the lowest dose schedule that still controls the tumor but at the same time maximally limits normal tissue damage. In previous series, the higher local control rate of more than 95% and long-term survival were achieved at a biologically equivalent dose of more than 100 Gy, but our chosen dose was 50 Gy given in 10 fractions over 2 weeks (biologically equivalent dose, 75 Gy), which was lower than in those other series but the same as those used in the Phase II study by Okunieff  and the study by Milano. These investigators chose the dose as a tumor control dose of 85% because the integral dose received by the whole lung should be reduced for the number of pulmonary lesions that can be safely treated. It was also based on mathematical calculations from literature searches.

Fractionation is also important issue. For example, just two fractions can reduce the hypoxic effects, and the reoxygenation effect after seven fractions is minimal. It is also important to complete treatment before repopulation occurs, which can commence as early as 28 days after the initiation of radiotherapy given in a fractionated regimen (28). For these various reasons, we used 10 fractions to ensure maximal reoxygenation and minimal repopulation.

Normal physiologic motion is a major hurdle in the delivery of extracranial SBRT. Currently there are four techniques for overcoming this limitation: respiratory gating of the radiation beam, a tumor tracking method, a voluntary breath hold technique, and an abdominal pressure method. Respiratory gating involves tracking the respiratory cycle throughout inspiration and expiration during free breathing. The beam is then activated when the patient is in a specific phase of the respiratory cycle (typically, end-expiration phase) and turned off in other phases. Tumor tracking, or chasing, involves physically moving a beam of radiation to coincide with tumor motion in the beam's eye view. Generally, a surrogate for tumor motion, such as an implanted fiducial or chest wall marker, is used for tracking in this technique. The breath hold technique requires the participation of the radiation therapist, who either has been trained in the technique or is guided by computer-assisted biofeedback. The therapist activates the beam while watching the patient's respiration. Patients are allowed free or shallow breathing with abdominal compression. The diaphragm's excursion along the craniocaudal direction is limited in this technique, thereby limiting the motion of tumors, particularly those in the lower lungs and liver. Regardless, there was little obvious difference in tumor control rates or toxicities by technique. The possibility of differences must be studied in greater depth in future clinical trials, however.

There is no radiation dose that is absolutely safe for use in the lungs; there is bound to be some toxicity from treatment; but as many as 60% of patients receiving a mean lung dose of more than 30 Gy do not have significant pulmonary toxicity. Among a variety of pulmonary dosimetric parameters, the MLD, V20, or V30 and the normal tissue complication probability are widely accepted as predictors of radiation-induced lung injury. In this regard, Miller proposed an evaluation/care map as a practical approach based on pulmonary function, rather than on the use of strict guidelines for patients being considered for thoracic radiotherapy for inoperable lung cancer. In the map, they suggested an MLD of <25 Gy and a V25 of <35% in patients with FEV1 and DLCO of >50% to 60%, defined as favorable pulmonary function in our study, and a MLD of <15 Gy and a V25 of <20% in patients with FEV1 and DLCO of <50% to 60%, defined as unfavorable pulmonary function in our study. We used their map technique in the treatment of our patients and encountered no Grade III or greater radiation-related pulmonary toxicity.

Conclusions

Tomotherapy could be offered to patients as a safe and effective treatment in select patients with lung metastases. However, large-scale, prospective clinical trials should be done to confirm our results.