Limited resection followed by intraoperative seed implantation is comparable to stereotactic body radiotherapy for solitary lung cancer

Authors


Abstract

BACKGROUND:

The objective of this study was to compare the outcomes of patients who underwent wedge resection plus intraoperative brachytherapy versus patients who received stereotactic body radiotherapy (SBRT) for single malignant lung nodules.

METHODS:

A retrospective chart review included 55 patients who were treated for single lung nodules, and 47 of those patients who had adequate information were chosen for the current analysis. Twenty-five patients with single malignant lung nodules received SBRT. Twenty-two patients underwent limited surgical resection plus radioactive seed implantation for solitary malignant lung nodules.

RESULTS:

Univariate statistical analysis demonstrated a significance difference only for age in the 2 groups: The mean age in the radioactive seed group (66.6 years) was statistically significantly different from the mean of the age in the SBRT group (75.9 years; 2-sided P = .04). No significant differences were observed between the 2 groups in terms of local control, distant metastasis, survival, or toxicity.

CONCLUSIONS:

The current results demonstrated comparable efficacy in outcome and toxicity between surgical resection with radioactive seed implantation and SBRT for the treatment of single malignant lung nodules in patients who were not candidates for lobectomy/pneumonectomy. Cancer 2010. © 2010 American Cancer Society.

Surgery remains the standard of care for patients with early stage (stage I and II) nonsmall cell lung cancer. However, the treatment remains wasteful: A significant amount of normal lung parenchyma also is removed,1 because the procedure may involve a lobectomy, bilobectomy, or pneumonectomy with mediastinal lymph node sampling/dissection. A lobectomy has been the preferred surgery for patients with early stage lung cancer because of higher local control rates and survival compared with wedge resection.2-6 Patients who have compromised pulmonary function—because of either previous lobectomy/pneumonectomy or medical comorbidities—often are not considered candidates for lobectomy. In such patients, alternative local treatments include stereotactic body radiotherapy (SBRT), wedge resection, limited resection with the addition of intraoperative radioactive seed (IOS) implantation, or radiofrequency ablation.

It has been demonstrated that brachytherapy (IOS implantation) after limited resection reduces the incidence of local recurrence compared with wedge resection alone.7-9 IOS implantation resulted in a 2% local recurrence rate compared with 19% in patients who underwent wedge resection alone7 for early stage nonsmall cell lung cancer. Radiofrequency ablation is a relatively new procedure that allows local treatment without parenchymal damage.10 Clinical experience with SBRT has been reported since 1995,11 and several studies have produced impressive outcomes using this technique for early stage lung cancer.12 SBRT generally delivers doses ≥10 grays (Gy) per fraction in ≤5 fractions. Only small targets (<5 cm) usually are treated, and accuracy and reproducibility are essential.

The choice of the type of curative radiation treatment in patients who are not candidates for lobectomy or more extensive surgery is not clear. To our knowledge, this is the first study to compare IOS implantation and SBRT in this group of patients.

MATERIALS AND METHODS

A retrospective chart review of patients who were treated at our institute for malignant solitary lung nodules between 1999 and 2009 was performed. Patients who were ineligible for a lobectomy or more extensive surgery received SBRT or IOS implantation. In total, 55 charts were reviewed, and 47 patients were identified as eligible for the current study because they had adequate follow-up and documentation. Patient characteristics are listed in Table 1. Patients were required to have a Zubrod performance status of 0 to 3. Our study was performed in accordance with the guidelines of the institutional review board, which approved the study. Informed consent was not required because of the retrospective nature of the review.

Table 1. Patient Characteristics for All Patients
CharacteristicTreatment
Radioactive SeedsSBRT
  1. SBRT indicates stereotactic radiotherapy; NSCLC, nonsmall cell lung cancer; NA, not available.

No. of patients22 (23 Lesions)25 (26 Lesions)
Sex  
 Men914
 Women1311
Median age, y71.577.5
Histology  
 NSCLC2023
 Small cell1 
 Other12
Tumor size, cm1.71.5
Total no. of seeds used26NA
Follow-up, mo921

Standard patient characteristics that were used to select patients for either IOS implantation or SBRT were any 1 of the following (Radiation Therapy Oncology Group [RTOG] criteria): a predicted baseline forced expiratory fraction in 1 minute (FEV1) <40%; a predicted postoperative FEV1 <30%; severely reduced diffusion capacity, baseline hypoxemia, and/or hypercapnia; predicted exercise oxygen consumption <50%; severe pulmonary hypertension, Diabetes mellitus with severe end-organ damage (selected for SBRT); severe cerebral, cardiac, or peripheral vascular disease (selected for SBRT); or severe chronic heart disease. If a patient has resectable disease but declined surgery after consulting with a thoracic surgeon, then that patient was considered eligible for SBRT. Regarding the lymph node assessment, patients who had hilar or mediastinal lymph nodes that measured ≤1 cm and no abnormal hilar or mediastinal uptake on positron emission tomography (PET) studies were classified with N0 lymph node status. Patients who had >1 cm hilar or mediastinal lymph nodes on computed tomography (CT) or abnormal PET studies (including suspicious but nondiagnostic uptake) were eligible if directed tissue biopsies of all abnormally identified areas were negative for cancer.

Stereotactic Body Radiotherapy

In our department, we used extracranial stereotactic targeting techniques in conjunction with an Elekta Stereotactic Body Frame (SBF) by (Elekta, Stockholm, Sweden). The SBF is an effective immobilization system that uses 2 He-Ne lasers pointed at the patient's sternum and tibia to position the patient very reproducibly. It also serves as an accurate localization system. There are fiducial marks in the frame that are visible on CT images. From the relative position of these marks and the patient's anatomy, the precise stereotactic coordinates of the center of the lesion (anteroposterior, lateral, and vertical) are obtained relative to the rigid frame. We obtain a CT study before each fraction. Each CT image yields updated stereotactic coordinates for the center of the lesion that are used to target the lesion most accurately. The third use of the SBF is to facilitate precise targeting of the lesion. Instead of setting up the patient using skin marks—a rather imprecise method—the 3 stereotactic scales of the frame, in conjunction with the lasers in the linear accelerator room, allow us to set up the frame so that the center of the lesion is located precisely at the machine isocenter. Multiple narrow beams then converge on the isocenter, maximizing the dose to the lesion and maintaining low dose levels to the surrounding, normal anatomy. The shaping of these multiple beams is done by a computerized multileaf collimator (MLC). With lung nodules in close proximity to critical structures, like the spinal cord, further dose shaping is possible through the use of inverse planning optimization techniques and the dynamic mode of the MLC (intensity-modulated RT).

Because of effective immobilization, exact localization, and targeting with the SBF, margins around the target can be kept at a minimum, and large doses of radiation can be delivered safely. The planning target volume (PTV), which is based on the clinical target volume (CTV) plus a margin to allow for target movement, is obtained through a 1-cm uniform expansion of the CTV. More recently, we have been using 4-dimensional (4D) CT scans, in which multiple CT datasets are obtained and correlated with the patient's breathing cycle. Typically, 5 coplanar beams are used, all of which converge on center of the CTV. The MLC allows shaping the fields, and the fields measure <4 × 4 cm. The Pinnacle planning system (Philips Healthcare, Andover, Mass) is used to perform the planning and dose calculations. The critical structures (organs at risk) that are outlined are the lungs, spinal cord, esophagus, heart, and rib cage (especially if the lesion is close to it). The beams are positioned approximately equidistant from each other; and, through the use of digitally reconstructed radiography, we try to avoid beam angles that enter or exit through an organ at risk. The prescription is based on a percentage isodose line that encompasses the PTV with 100% set at the isocenter. Dose volume histograms and dose distributions in the axial, sagittal, and coronal planes are used to evaluate the merit of the plan.

Twenty-five patients with single malignant lung nodules who received SBRT were identified. These patients were referred to our department after a surgical assessment because they were identified as ineligible for lobectomy or more extensive surgery. One patient had 2 separate primary tumors identified, 1 patient had a solitary metastasis from a head and neck primary tumor (high-grade parotid cancer), and another patient had a solitary metastasis from an endometrial primary tumor. Patients who had a single metastatic lung nodule were categorized with stable systemic disease. The median dose to the tumor was 30 Gy. Fourteen patients received 30 Gy (13 patients received 10 Gy in 3 fractions, and 1 patient received 15 Gy in 2 fractions), 4 patients received 40 Gy in 4 fractions, 3 patients received 48 Gy in 4 fractions, and 4 patients received 60 Gy in 4 fractions. After treatment, patients were followed with CT or PET/CT scans every 3 to 6 months in addition to clinical examinations in the Departments of Cardiothoracic Surgery, Medical Oncology, and Radiation Oncology.

Surgery and Radioactive Seed Implantation

Twenty-two patients underwent limited surgical resection and radioactive seed implantation for solitary malignant lung nodules. Sixteen patients underwent wedge resection, 1 patient underwent segmentectomy, 4 patients underwent limited lung surgery had seeds implanted for suspicious margins, and 2 patients underwent limited excision of the chest wall area and had seeds implanted for positive/close margins. Twenty patients received iodine-125 (I125) implants, and 2 patients received cesium-131 (Cs131) implants. The median seed activity for I125 was 0.52 mCi, and the median seed activity for Cs131 was 2.3 U. One patient had 2 solitary nodules resected and had seeds implanted at the same time. Radiation seed implantation was done using either the Vicryl mesh technique or a double-suture seed technique. The choice of technique was based on the ease of performing the implantation. The prescription dose was 120 Gy at 0.5 cm from the wedge line for I125 and 100 Gy at 0.5 cm from the wedge line for Cs131 (as determined based on the nomogram developed at out institute). Suture seed placement and, thus, dose prescriptions were determined intraoperatively and depended on the length of the resection margin. A written dose prescription included the number of seeds, the number of strands, the activity of each seed, the total activity of the implant, and strand separation. Final dosimetry was obtained after complete reinflation of the lung with CT-based 3-dimensional planning a few days after the surgical procedure. Contrast enhancement was not required. The CTV was considered the resection suture line. PTV-1 was defined as the CTV plus 5 mm, and PTV-2 was defined as the CTV plus 7 mm. Dosimetry of the Cs131 seeds was based on Report TG 43 from the American Association of Physicists in Medicine.13 The average length of stay in the hospital was 4 days.

Dosimetric calculations were based on the postimplantation CT scan obtained within 1 week after implantation. Patients were followed with CT scans or PET-CT scans every 3 to 6 months after treatment for 3 to 5 years.

Local Failure

Local failure was defined as both 1) a 20% increase in tumor size (according to RTOG criteria) and 2) measurable local tumor enlargement apparent on a PET image with uptake intensity similar to that on the pretreatment staging PET image. When feasible, the measurable tumor was biopsied to confirm the presence of viable carcinoma. Marginal failures also were considered as local failures.

Statistical Analysis

Univariate statistical analyses were performed to compare the 2 groups. Age, tumor size, toxicity, and sex were analyzed using the Wilcoxon rank-sum test, the Student t test, and the Fisher exact test, as appropriate.

Survival analyses were performed for the entire cohort of patients and for a subset of patients who had follow-up ≥12 months. Kaplan-Meier curves were estimated for both treatment groups using local failure, distant failure, and disease as events for both cohorts. Equality of the Kaplan-Meier curves for the treatment groups was tested with the Mantel-Haenszel test and could not be rejected (2-sided P ≥ .34).

RESULTS

Of all 49 lesions (47 patients) that were treated, 26 of 49 lesions (53%) were treated with SBRT, and 23 of 49 lesions (47%) were surgically resected and had radioactive seeds implanted. The mean age for all patients was 71.8 years. There were 24 women (51%) and 23 men (49%). The overall local control rate was 96% (47 of 49 lesions), and the overall distant failure rate was 18% (7 of 49 lesions). The mean follow-up was 17.5 months (range, 1-72 months). At the last follow-up, with follow-up information available for 41 patients, 32 of 41 patients (78%) were alive with no evidence of disease, 7 of 41 patients (17%) were alive with disease, and 2 of 41 patients (5%) had died of disease. Tumor size was available for 45 lesions, and the mean tumor size was 1.9 cm (range, 0.25-6 cm).

In the IOS implantation group, the mean patient age was 66.9 years (range, 36-80 years). In this group of 22 patients, there were 12 women (59%) and 9 men (41%). The mean follow-up was 10.5 months (range, 1-28 months). The mean tumor size was 2.1 cm (range, 0.25-6 cm). There was 1 local failure (4%). Among 18 patients who had distant failure information available, 2 patients had distant failures (11%). Of 20 patients who had survival information available, 17 of 20 patients (85%) were alive with no evidence of disease at the last follow-up, and 3 of 20 patients (15%) were alive with disease. Toxicity information was available for 20 patients. Approximately 95% of patients reported no toxicity that could be ascribed to implantation. One patient reported mild fatigue at 1 month that was documented as caused by IOS implantation. No complications were noted during or after implantation that could be ascribed to the procedure.

In the SBRT group, the mean age was 76.1 years (range, 60-90 years). Approximately 44% of patients were women, and 56% (14 of 25) were men. The mean follow-up was 24.2 months (range, 1-72 months), and the mean tumor size was 1.75 cm (range, 0.3-4.8 cm). One patient (4%) had local failure. Of the 21 patients who had distant failure information available, 5 of 21 patients (24%) had distant metastasis, 15 of 21 (71%) were alive with no evidence of disease at the last follow-up, 2 of 21 patients (10%) had died of disease, and 4 of 21 patients (19%) were alive with disease. Five percent of patients developed RTOG grade 2 pneumonitis, which was managed conservatively using steroids.

Univariate statistical analysis indicate a significance difference only for age: Statistically the mean patient age in the radioactive seed group, 66.6 years, differed significantly from the mean patient age in the SBRT group, 75.9 years (2-sided P = .04).

Including all patients or the only subset of patients who had follow-up ≥12 months produced the same results. Kaplan-Meier curves are represented with their 95% confidence intervals in Figures 1 through 4. There were no significant differences between the 2 groups in terms of local control, distant metastasis, survival, or toxicity.

Figure 1.

Kaplan-Meier curves depicting local control in all patients are shown. SBRT indicates stereotactic body radiotherapy.

Figure 2.

Kaplan-Meier curves depicting distant failure in all patients are shown. SBRT indicates stereotactic body radiotherapy.

Figure 3.

Kaplan-Meier curves depicting local control in patients who had >12 months of follow-up are shown. SBRT indicates stereotactic body radiotherapy.

Figure 4.

Kaplan-Meier curves depicting distant failure in patients who had >12 months of follow-up are shown. SBRT indicates stereotactic body radiotherapy.

DISCUSSION

In the current study, we demonstrated equivalence in outcomes and toxicity between patients who were not candidates for lobectomy/pneumonectomy who either underwent surgical resection with IOS implantation or received SBRT for the treatment of a single malignant lung nodule. There was a significant difference in the mean age of the 2 groups. This probably was because older patients have a higher incidence of other medical comorbidities, thereby making them ineligible for a surgical procedure. Such patients were selected for SBRT. Outcomes of patients with early stage lung cancer are encouraging, with 5-year survival rates of 68.5% for surgically treated patients who have stage IA disease and 59% for patients who have stage IB disease. Approximately 25% of patients are medically inoperable because of medical comorbidities and are not candidates for standard surgical treatment. This is because “more” surgery (ie, lobectomy) results in worse pulmonary function compared with “less” surgery.14-16 However, the risk of local recurrence is greater with surgeries that are less extensive than a lobectomy.3 There is substantial variation in the reported rate of local recurrence for patients with stage I disease (range, 6%-45%).17-23 According to the Lung Cancer Study Group, crude rates of local failure for stage IA disease were 6% after lobectomy and 17% after sublobar resections. In patients with a previous history of lobectomy/pneumonectomy or poor pulmonary function, “less” surgery (ie, wedge resection or segmentectomy) has been used, and radioactive seeds have been added to the resection site to increase the chances of achieving local control.7-9 Alternatively, extracranial SBRT is used instead of a surgical option. To our knowledge, no previous studies have compared these 2 therapeutic options (IOS implantation and SBRT).

SBRT uses hypofractionation to deliver highly conformal doses to the target. Typically, lesions that measure <5 cm are treated, and the accuracy and reproducibility of the techniques are essential. Clinical studies using SBRT for early stage lesions have produced promising results, including local control rates between 85% and >95% at 1 to 3 years. In addition, the toxicity is acceptable.12 Recent evidence suggests that this high local control rate is achieved at a biologically equivalent dose (BED) ≥100 Gy.24 After 2005, our patients usually received a BED >100 Gy. However, patients before 2005 and some patients who had lesions close to the tracheobronchial tree or close to the rib cage were received 3 fractions of 10 Gy (BED <100 Gy). A lower fraction size was used because of the concern about RT-induced toxicity. Recently, 4-dimensional RT planning has been used to monitor breathing patterns, and treatment is planned accordingly. In patients without 4-dimenisonal planning, if the patient's breathing is erratic, then abdominal compression is used for breath control.

With IOS implantation, radioactive seeds are applied directly to the wedge resection site, resulting in precise targeting of the at-risk area and reducing radiation to the remaining normal lung. Although general anesthesia is required for the procedure, patients with very poor pulmonary function also can be treated. Most of the published reports have used I125 as the radiation source.25-30 We recently reported the first use of Cs131 seeds. The half-life of Cs131 is of 9.7 days, and its energy is 29 Kev. The dose rate is 0.3 Gy per hour compared with a dose rate of 0.06 Gy per hour for I125. The prescription dose for I125 is 120 Gy at 0.5 cm from the wedge line. We used a prescription dose of 100 Gy for Cs131 based on a nomogram that was developed at our institute, and this dose is comparable to I125. Reported local control rates using intraoperative brachytherapy with wedge resection have been in the range of 90% to 98% and have produced local control rates equivalent to those produced with lobectomy.7-9

To our knowledge, this is the first report comparing the 2 treatment modalities. The data suggest that both treatment modalities offer efficacy in terms of local control. Depending on the availability of the technology and the expertise of the treating physicians, either treatment can be offered. However, a prospective, randomized, controlled trial ultimately will be needed to make a more ideal comparison.

CONFLICT OF INTEREST DISCLOSURES

The authors made no disclosures.

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