It has been established that lobectomy offers the best chance of cure for early-stage non-small cell lung cancer. According to the 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 forced expiratory volume in 1 second (FEV₁) of 0.8–1.2 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. Emerging 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. These new procedures have been reported to reduce local disease recurrence and improve palliation of symptoms. Additionally, they provide new treatment options for patients who are not physically capable of undergoing lobectomy or pneumonectomy or who are considered high-risk surgical candidates consequent to other comorbidities.

PLANAR SEED IMPLANT TECHNIQUE

There are several reports of wedge resection procedures for stage I tumors that have been performed in conjunction with planar ¹²⁵I seed implants. This new procedure has been reported to reduce local disease recurrence and improve palliative 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. 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 x 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. 75-1). 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. 75-2). The custom mesh then is placed over the area of interest and sutured into place, using extreme care not to puncture the seeds (Fig. 75-3). 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.

Planar Implant Experience

Santos and colleagues from Allegheny General Hospital published a large series using this new technique.² 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 100–120 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.³ The strands of seed in this series were implanted directly on the suture line without mesh. The planned dose was 125–140 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%.

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 the only 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.⁴ A more recent study from the Norris Cancer Center describes the volume implant technique used in 14 patients.⁵ 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.

LOCALLY ADVANCED DISEASE

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 0.5–1 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

Our institutional data consist of 44 patients with a total of 48 implants.⁶ 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 3–4 toxicity, one with a transesophageal 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.⁷

A retrospective series from the Memorial Sloan-Kettering Cancer Center demonstrated that stage III patients with mediastinal involvement exhibited similar median (16 versus 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.⁸ 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.⁹ This was compared with a 17-month median survival for complete resection. New York Hospital looked at this technique in a prospective study.¹⁰ 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 ¹⁰³Pd 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 45–60 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.¹¹

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 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 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.¹²

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.¹³ 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 10–15 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 75-1.

Abbreviations. OS is overall survival; EBRT is endobronchial radiotherapy

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.⁷ 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.¹⁴

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 LESIONS

Endobronchial Primary

Some data exist regarding the use of endobronchial therapy as a boost to external beam therapy for definitive treatment. Although, theoretically, the addition of endobronchial therapy should escalate the dose, there are no data showing that this therapy prolongs survival or increases local control. The only effect of endobronchial radiation demonstrated by these studies is the reduction of symptoms.

Palliation

One of the most common uses of brachytherapy is endobronchial brachytherapy 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

We have compared external beam radiation with endobronchial brachytherapy plus endobronchial radiation.⁶ This study was carried out in randomized fashion with 95 patients. The results showed added benefit with endobronchial therapy by increasing the incidence of reexpansion and decreasing the incidence of dyspnea. The toxicity was the same in both arms of the study.

The M. D. Anderson Cancer Center published its 10-year experience with endobronchial brachytherapy for palliation in a series of 175 patients, 160 of whom received previous external beam therapy. The treatment regimen was 15 Gy x 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 75-2 summarizes the published series on endobronchial brachytherapy.

Complications

The major complications from endobronchial brachytherapy, 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 and colleagues showed that treatment doses of 7.5 or 10 Gy yielded 11% mortality from hemoptysis, similar to controls,^15,16 whereas 15 Gy at 1 cm was associated with almost 50% mortality from hemoptysis. Similar results were reported by Muto and colleagues from Italy. They found that fractionating the dose from 10 Gy x 1, 7 Gy x 2, and 5 Gy x 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.¹⁷

SUMMARY

The goal of these innovative 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.

EDITOR'S COMMENT

Although this technique is well accepted for endobronchial disease in high risk individuals, it has only recently been used as a routine for unresectable or marginal patients. The current American College of Surgeons' Oncology Study Group (ACOSOG) Z40 study seeks to evaluate the role of brachytherapy seeds used after wedge resection in high-risk individuals. This study will show the safety and efficacy of this technique. Other high-dose techniques, including intraoperative radiation, are also discussed.

–MJK

REFERENCES