88: Innovative Radiation Techniques: Role of Brachytherapy and Intraoperative Radiotherapy in Treatment of Lung Cancer

Brachytherapy, the use of radioactive isotopes placed directly on the desired target tissues during surgery or placed endoluminally, can be used for treatment of lung cancer. It offers several theoretic advantages when compared with traditional radiotherapy. Direct surgical placement of the radiation source allows for specific targeting and uniform delivery of the radiation minimizing the amount of normal lung in the radiation field. This potentially limits radiation side effects and ensures patient compliance which has been a major disadvantage of external beam radiation therapy.

It has been established that lobectomy offers the best chance of cure for early-stage non–small-cell lung cancer. According to the Lung Cancer Study Group, sublobar or wedge resection is not as effective as lobectomy or pneumonectomy because it is associated with a high incidence of local recurrence.¹ However, a large resection requires the patient to have a reasonable residual forced expiratory volume in 1 second (FEV₁) of 0.8 to 1.2 L and a ventilation–perfusion scan corresponding to adequate breathing in other lung segments. Patients who have long histories of smoking commonly fail to have these advantageous characteristics. Techniques that combine sublobar resection with radiotherapy delivered intraoperatively or through the implantation of radioactive ¹²⁵I seeds at the lung resection margin have shown promising results (see section “planar seed experience”). This procedure has been reported to reduce local disease recurrence and improve palliation of symptoms. Additionally, it provides a treatment option for patients who are not physically capable of undergoing lobectomy or pneumonectomy or who are considered high-risk surgical candidates consequent to other comorbidities.

Varying systems for radiation delivery are presently used in clinical practice. Three techniques have been described for use following sublobar resection all of which are compatible with thoracoscopy.

There are several reports of wedge resection procedures for stage I tumors that have been performed in conjunction with planar ¹²⁵I seed implants. This procedure has been reported to reduce local disease recurrence and improve local control.

After the wedge resection, the surgeon must measure the area at risk for length and width to determine the dimension of the implant. The implant is made of two components. The source material, called the Seed-in-Carrier, available through the Oncura Company (Plymouth Meeting, PA), consists of ¹²⁵I seeds that are embedded in strands of absorbable Vicryl suture. A second isotope recently became commercially available, using ¹³¹Cs, from Isoray Medical (Richland, WA). There are 10 seeds in each strand, and each seed and strand is spaced 1 cm apart center to center. The individual seed measures 0.7 × 4 mm in dimension. The source material is attached to an absorbable mesh material made of either Dacron or Vicryl that is custom trimmed to fit the area at risk. Before trimming, 1 cm is added to the overall dimension to ensure an adequate margin for suturing. Parallel lines spaced 1 cm apart are drawn longitudinally on the mesh patch. The radioactive strands then are stitched to the mesh along these lines. The radioactive strands and suture should be handled with care using forceps only (Fig. 88-1). The source material is anchored on each side of the implant with a small staple, and any excess source material should be cut and disposed of properly in accordance with radiation disposal guidelines (Fig. 88-2). The custom mesh then is placed over the area of interest and sutured into place, using extreme care not to puncture the seeds (Fig. 88-3). Previously the mesh was prepared in the operating room; however, a prefabricated mesh construct is now available, in either ¹²⁵I or ¹³¹Cs, which simplifies this step (Fig. 88-4). After the operation is concluded and the patient is stable (or at some future date), a postoperative CT scan is obtained over the area of interest to verify and document the final dose.

A novel technique of delivering radiation has also been developed at Brown University, where a ¹⁶⁹Yb brachytherapy source delivery system has been developed which can be used in conjunction with commercially available surgical stapling instruments (Fig. 88-5). This includes a radioactive ¹⁶⁹Yb seed sealed within titanium tube 0.28 mm in diameter and then capped and resealed by titanium wires laser welded to the tube to serve as legs of a tissue-fastening system. The use of these in patients is subject of future study.²

Planar Implant Experience

Santos et al.³ from Allegheny General Hospital published a large series using this technique. Their retrospective study of 101 patients with sublobar resection and planar seed implants at the suture line was compared with 102 similar patients with sublobar resection alone. Patients were surgically resected using video-assisted thoracic surgery (VATS) technique. The implants were made using Vicryl mesh. A planned dose of 100 to 120 Gy was delivered to a depth of 0.5 cm. The mesh then was sutured to the staple line. The local relapse rate was 2% for seeds (at 18 months) versus 18.6% for sublobar resection alone (at 24 months, p = 0.0001). Age and FEV1 were similar in each group, but the group with the implants had more stage IB patients (n = 23) than the group undergoing surgery alone (n = 0). Overall 4-year survival was 60% for surgery alone and 67% for surgery plus seed implants. The results were not statistically significant.

The New England Medical Hospital and Tufts University published a series of 33 patients who underwent a wedge resection (or segmental resection) with seed implants at the lung margins.⁴ The strands of seed in this series were implanted directly on the suture line without mesh. The planned dose was 125 to 140 Gy delivered to a depth of 1 cm. There was recurrence at the suture line in 2 of 33 (6%) patients (median follow-up 51 months), and the 5-year projected survival was 47%. The cancer-specific 5-year survival was 61%.

A multicenter retrospective study⁵ compared lobar and sublobar resection in stage I non–small-cell lung carcinoma and examined the use of adjuvant brachytherapy with sublobar resection. A total of 291 patients with T1N0 disease were evaluated, 124 treated with sublobar resection and 167 with lobectomy. Within the sublobar resection cohort, 60 out of 124 were treated with adjuvant Vicryl mesh brachytherapy with a significant decrease in local recurrence rate from 17.2% to 3.3% at a mean follow-up of 34.5 months in the mesh patient group. The American College of Surgeons Oncology Group (ACOSOG) has recently completed a phase III clinical trial ACOSOC Z4032 comparing sublobar resection alone and sublobar resection with adjuvant mesh brachytherapy. The early toxicity results for pulmonary function and dyspnea have been published.^6,7 These show no significant change from baseline on either PFT or dypnea scores. The outcome results of this trial will provide the first prospective data for the use of brachytherapy to augment sublobar resection.

Stereotactic Ablative Body Radiotherapy (SABR) or stereotactic body radiation therapy (SBRT) has also emerged as an option for treatment in medically inoperable patients with early-stage lung cancer. Another prospective ACOSOG study, ACOSOG Z4099/RTOG1021, is specifically for high-risk operable patients and randomly assigns patients to either sublobar resection with mesh implant brachytherapy or SABR.

Volume Tumor Implanting

For patients unable to tolerate surgery, the seeds can be implanted directly in the tumor using a variation of this technique called volume implanting. Although this technique yields an inferior result to surgery, for inoperable patients, this may be an option for increasing the radiation dose. The radioactive seeds, usually ¹²⁵I, are implanted in the tumor and any other area of gross disease. After the needle is inserted into the tumor, the seeds are deposited individually or in a line. The seeds are placed to cover a volume of disease, in contrast to the planar technique, which targets the resection cavity and margin. Clinicians at the Memorial Sloan Kettering Cancer Center of New York reported 65% locoregional control in their experience with volume implants.⁸ Another study from the Norris Cancer Center describes the volume implant technique used in 14 patients.⁹ All patients underwent surgical lymph node staging before the procedure. ¹²⁵I seeds were used to implant the tumor. The local control rate was 71% with a 15-month median follow-up. All the relapses occurred in patients with stage III cancers. A dose of 80 Gy was delivered at the periphery, with a high dose of 200 Gy in the center of the tumor. There was no incidence of radiation pneumonitis.

Surgical Limitations

For advanced disease, brachytherapy sometimes can be used to convert an unresectable or marginally resectable tumor into a lesion that is acceptable for oncologic resection. After maximal resection by the surgeon, the area at risk (close or positive margin) is noted by the radiation oncologist and surgeon. The area is measured, usually adding 0.5 to 1 cm to all dimensions for a radiation dosimetric margin. The area typically is a rectangle, but can be any shape. This area then is treated with brachytherapy. One way to clear this margin is to place a permanent planar implant.

Planar Seed Experience for Locally Advanced Disease

Dana-Farber Cancer Institute published their experience of patients with a total of 48 implants.¹⁰ The implant model we used consisted of ¹²⁵I seeds in suture that were then sutured to a mesh patch and implanted in high-risk surgical beds. The mean follow-up in our series was 21 months. Local control was maintained in 81%. There were three patients (6%) with grade 3 to 4 toxicity, one with a tracheoesophageal fistula, one with esophageal perforation, and one with persistent pneumothorax. Both patients with esophageal problems had partial-thickness resection of their esophagus with seeds placed on the surgical bed.¹¹

A retrospective series from the Memorial Sloan Kettering Cancer Center demonstrated that stage III patients with mediastinal involvement exhibited similar median (16 vs. 17 months) and 5-year survival (15%) for complete resection versus incomplete resection plus brachytherapy. These results were superior to brachytherapy alone without resection and neither resection nor brachytherapy.¹² The Memorial Sloan Kettering Cancer Center reported another series of patients with all lung cancer stages. This series had a 50% increase in median survival (8–12 months) with brachytherapy after incomplete resection compared with no surgery.¹³ This was compared with a 17-month median survival for complete resection. New York Hospital looked at this technique in a prospective study.¹⁴ Twelve patients with stage III non–small-cell lung cancer who had gross or microscopically positive margins after resection were implanted using the planar technique. The implants were composed of either ¹²⁵I or ¹⁰³ Pd embedded in a Gelfoam plaque. The dose prescribed was a 1-cm margin around the area of positive margins. All patients received either preoperative or postoperative external beam radiation at a dose range of 45 to 60 Gy. The results showed 82% local control with addition of brachytherapy for positive margins after surgery. The 2-year overall and cancer-specific survivals were 45% and 56%, respectively. In another series, the Memorial Sloan Kettering Cancer Center also reported 75% locoregional control with partial resection and implant compared with 86% locoregional control with full resection.¹⁵

Intraoperative Radiation Therapy (IORT) and Afterloading Catheters

Radiation delivered intraoperatively also can be used for treating close and positive resection margins. Two methods can be used: afterloading and IORT. Afterloading is delivered by placing hollow blind-ended plastic catheters along the area at risk, after which the radiation is loaded into the catheters. The catheters are spaced 1 cm apart in parallel lines. The open end of the catheter is directed out of the skin. Care must be taken to prevent kinking or sharp angles, which would prevent loading. The patient is permitted to stabilize for a period and then sent to the radiation department for loading. IORT is delivered more conventionally using a mobile accelerator in a specially equipped operating room (OR).

Afterloading

Afterloading can be delivered by a low-dose-rate (LDR) or high-dose-rate (HDR) method. With the LDR method, radioactive sources on a string are loaded into the catheters, where they remain for several days. During the interval, the patient must remain isolated in a radiation-safe room with full radiation precautions. After an appropriate interval, the catheters are removed and radiation precautions are withdrawn. A newer version of this technique, HDR afterloading, uses a remote-control device. Catheters are placed, as with the LDR method. However, the radiation is delivered using a single computer-controlled source that can be placed at various positions and dwell times. This flexibility permits greater dose conformation, termed dose optimization. All treatments are delivered in a shielded room, which reduces incidental dose exposure to the technical staff. Both techniques are considered radiobiologically equivalent. The Memorial Sloan Kettering Cancer Center has used the afterloading technique (LDR) in the mediastinum with good local control and 2-year actuarial survivals of 76% and 51%, respectively, for N2 disease. Another group from Seattle also demonstrated good local control with the addition of brachytherapy.¹⁶

Intraoperative Radiation Therapy

Specialized equipment is needed for IORT. The radiation can be delivered using a mobile accelerator in a shielded OR or in the radiation department, where the radiation vault is also a functional OR. After surgical resection, the area at risk must be demarcated by the surgeon. The normal tissue can be moved out of the field or shielded with thin strips of lead. The cone from the linear accelerator is inserted into the patient, or applicators for HDR brachytherapy are placed. All personnel must leave the room when the radiation is delivered, which usually takes several minutes.

IORT Experience

Several series have used this technique. The largest series in the literature is from the University Clinic of Navarra, Pamplona, Spain.¹⁷ Calvo and colleagues retrospectively reported findings in 104 patients treated between 1984 and 1993, all of whom had stage IIIA or IIIB cancers. Between 1984 and 1989, 22 patients had surgery and IORT followed by endobronchial brachytherapy (EBRT). Between 1989 and 1993, 82 patients had neoadjuvant chemotherapy. Responders (46 patients) had surgery, IORT, and EBRT; nonresponders had chemoradiation, surgery, with IORT as a final boost. Their technique used a dose of 10 to 15 Gy (18–20 Gy unresectable). The series reported local control rates for patients with microscopic residual disease of 66% (33 of 50) and 35% (15 of 42) for patients with macroscopic residual disease. The best results were observed with Pancoast tumors, which demonstrated a local control rate of 92% (11 of 12) and 100% (5 of 5) for microscopic and macroscopic disease, respectively. The most common toxic event was grade III–IV esophagitis in 25%. Other reported toxicities were symptomatic pneumonitis, transient neuropathy, and lung fibrosis. Other series are listed in Table 88-1.

Complications

Complications from any of these techniques are similar and minimal compared with the surgery itself. Poor wound healing or abscess formation can occur but is very rare. The most concerning toxicity is fistula formation. Care must be used to avoid placing the seeds directly on any injured organ, such as the esophagus or blood vessels.¹¹ Intact tissue can tolerate very-low-dose-rate (VLDR) radiation well; however, any injury to the organ, whether caused by the tumor or as a consequence of the surgery, can predispose to a fistula. This complication can be avoided when implantation is necessary by adding another layer of luminal protection for the blood vessels of the esophagus using biologic or artificial technique. However, if there has been extensive dissection in the subcarinal space or partial esophageal wall resection, we do not recommend permanent seed implantation because of the predisposition to fistula formation, necessitating further surgery. We have reported two cases of mediastinal carcinoid tumors in patients who had been treated previously with chemoradiation. In both instances, the tumor was adherent to the esophageal muscularis, and an esophageal fistula developed, necessitating additional surgical repair.²²

Recurrence or Metastasis

Tumor recurrence or metastasis can be treated with brachytherapy. Brachytherapy has the advantage that it can be used for patients and tumors that have already received radiation. Care must be taken in reirradiating the heart, spinal cord, or esophagus; the other organs can tolerate reirradiation with brachytherapy. Depending on the location and surgical resection, any of the previously described techniques can be used, from permanent seeds, to afterloading catheters, to IORT. Sometimes seed implants are preferred because of their slower rate of delivery. The slower the rate, the larger is the dose of reirradiation the patient can tolerate. LDR and VLDR techniques are better tolerated than HDR techniques in certain risky organs.

Endobronchial Primary

Some data exist regarding the use of endobronchial therapy as a boost or alternative to external beam therapy for definitive treatment. Although, theoretically, the addition of endobronchial therapy should escalate the dose, there are no prospective data showing that this therapy prolongs survival or increases local control. One retrospective study shows good control from definitive EBRT.²³ The majority of data of endobronchial radiation shows reduction of symptoms.

Palliation

One of the most common uses of brachytherapy is EBRT for palliation. Patients with lung disease commonly experience obstructive pneumonia, hemoptysis, or both. These symptoms can drastically affect quality of life or even be life threatening. Radiation can be administered for palliation, either with external beam or brachytherapy. Brachytherapy provides a benefit because higher doses can be delivered directly to the tumor, sparing the normal lung. The only disadvantage of brachytherapy is the necessity of putting the patient through another procedure, which some end-stage patients might not be able to tolerate.

Technique

The patient is bronchoscoped under conscious sedation or general anesthesia. After the tumor is visualized, a brachytherapy catheter is threaded through the bronchoscope. The proximal end remains outside the patient, and the distal end lies distal to the tumor. The proximal and distal extents of the tumor in relation to the catheter should be noted for treatment planning, usually under fluoroscopy. The radiation source then is placed in the catheter, usually with an HDR afterloader, but LDR also can be used. The catheter could be used for multiple fractions if it can be secured safely and the patient has been admitted to the hospital. Otherwise, the entire procedure should be repeated for two-to-three fractions for full palliation.

Experience

The M. D. Anderson Cancer Center published²⁴ its 10-year experience with EBRT for palliation in a series of 175 patients, 160 of whom received previous external beam therapy. The treatment regimen was 15 Gy × 2 at 6 mm from the catheter for a total dose of 30 Gy. The results showed a rate of 66% subjective improvement (34% slight improvement, 32% significant improvement) and 78% objective improvement on repeat bronchoscopy. The complication rate was 11%. The rate of major complications (e.g., massive hemoptysis) was 5%. Table 88-2 summarizes the published series on EBRT.

Complications

The major complications from EBRT, aside from procedural events relating to bronchoscopy, are massive hemoptysis and bronchial necrosis. Whether the etiology of hemoptysis is a consequence of the treatment or the tumor is a controversial issue. However, by fractionating the treatment, toxicity can be avoided. Langendijk et al. showed that treatment doses of 7.5 or 10 Gy yielded 11% mortality from hemoptysis, similar to controls,^29,30 whereas 15 Gy at 1 cm was associated with almost 50% mortality from hemoptysis. Similar results were reported by Muto et al. from Italy. They found that fractionating the dose from 10 Gy × 1, 7 Gy × 2, and 5 Gy × 3 (all prescribed to a depth of 1 cm) yielded a similar response, but there were fewer side effects with the greater number of fractions.³¹

The goal of these innovative radiation therapies is locoregional control because not all patients are suitable candidates for lobectomy or pneumonectomy, and sublobar resections are associated with an increased rate of local recurrence. Since virtually every study comparing the effectiveness of lobectomy or pneumonectomy versus wedge resection favors the lobectomy, and many patients cannot tolerate a full surgical resection, the combination of limited resection and brachytherapy may have widespread application in future clinical studies.¹⁴ Other circumstances that favor the use of a limited resection with targeted brachytherapy include advanced age, poor pulmonary function, presence of other high-risk comorbidities, unresectable tumor mass, need for palliation, tumor reduction to render a mass oncologically resectable, and so forth.

Although this technique is well accepted for endobronchial disease in high-risk individuals, it has only occasionally been used as a routine for unresectable tumors or suspicious margins. The recently completed American College of Surgeons' Oncology Study Group (ACOSOG) Z40 study and subsequent other trials, seek to evaluate the role of brachytherapy seeds used after wedge resection in high-risk individuals to improve local control and perhaps disease-free survival. This study will show the safety and efficacy of this technique. Other high-dose techniques, including intraoperative radiation, are also discussed comprehensively.