Thoracic Brachytherapy

Keyur J. Mehta, Nitika Thawani, and Subhakar Mutyala 

LUNG CANCER

In 2015, there will be an estimated 221,200 new cases of lung cancer in the United States. With more than an estimated 158,000 deaths from this disease, it remains the leading cause of cancer deaths (1). Lung cancer has had a long history with brachytherapy, from Yankauer inserting radium-226 (²²⁶Ra) into lung tumors in 1922 (2) and Graham and Singer placing radon-222 (²²²Rn) needles into lung tumors in 1933 (3). Currently, brachytherapy is widely used for lung cancer and at several stages. Following are the uses of interstitial brachytherapy for early stage and locally advanced lung cancer, intraoperative radiation, and intraluminal brachytherapy for endobronchial lesions and palliation.

Early-Stage Disease

Surgery for early-stage lung cancer is the gold standard for definitive treatment. The recommended surgery has always been lobectomy or pneumonectomy. The Lung Cancer Study Group showed that a limited resection had decreased local control as compared to a lobectomy (4). However, a large resection requires the patient to have a reasonable FEV1 (0.8−1.2 L) and a ventilation-perfusion scan corresponding to adequate breathing in other segments. Patients who have long histories of smoking commonly fail to have this lung reserve to handle a large resection. An alternative technique is to perform a sublobar resection with the placement of radioactive seeds at the resection margin. There are several reports of wedge resection for Stage I tumors with placement of the iodine-125 (¹²⁵I) seed at the resection margin (5–7). This can be done to perform surgery on patients who cannot undergo a lobectomy or pneumonectomy.

Until more information from the ACOSOG and other studies are available we caution the practitioner in making a treatment decision and to tailor the treatment to each individual. A more extensive surgical resection may not warrant brachytherapy, whereas a more limited procedure may need additional therapy. Ideally patients treated with this technique should be studied in a clinical trial. Currently, there is an ACOSOG Z4099 ongoing trial comparing sublobar resection with or without brachytherapy versus stereotactic body radiation therapy for early-stage lung cancer.

In addition to the larger study group trials listed earlier, these studies showed promising results with planar implants. A large published series comes from Allegheny General Hospital (13). A retrospective series of 101 patients with sublobar resection and seeds placed at the suture line were compared with 102 similar patients with sublobar resection alone. Patients were surgically resected using the video-assisted thoracoscopic surgery (VATS) approach. The implants were made on a Vicryl mesh and planned with a dose of 100 to 120 Gy at a 0.5 cm distance from the plane. The mesh was then sutured to the staple line. The local relapse rates are 2% for seeds (at 18 months) versus 18.6% for sublobar resection alone (at 24 months) (P = .0001). Age and FEV1 were similar in both groups, but the group with the implants had more stage IB patients than the surgery-alone group. Overall, the 4-year survival rates were 60% and 67% for surgery alone and surgery plus implant, respectively, but not significantly different. Published data of longer follow-up (7,14,15) confirm the long-term disease-free and overall survival of these patients.

New England Medical Center and Tufts University has another series (16) of 33 patients who underwent a wedge resection (or segmental resection) and implant. The technique varied slightly, with implanting the strands of the seed directly on the suture line, without the mesh. The dose intended was 125 to 140 Gy at 1 cm depth. The results showed 2/33 (6%) recurrence at the suture line (median follow-up: 51 months) with a 5-year projected survival of 47%. The cancer-specific 5-year survival was 61%.

A newer technique employs the microprecision movement of the da Vinci robotic system. Pisch (17) describes the resection of small tumors with a wedge resection and implantation of the ¹²⁵I seeds using the da Vinci robot, to assist in fine movements and distances in the chest. In 2010, Blasberg et al reported their results on 11 patients with 12 primary tumors with robotic sublobar resection and ¹²⁵I seed placement (18). They showed excellent coverage of the tumor bed (V87 = 88.2%, V100 = 84.1%), and low perioperative morbidity, concluding that this technique is a feasible and minimally invasive approach to limited resections.

Planar Seed Implant Technique

Figure 7.1 Using a sterile technique, the suture seed carrier is stitched into the absorbable mesh along grid lines drawn to control the distance between the strands. Note the careful use of long instruments. This implant is 15 × 9 cm (160 seeds) to cover a target area of 13 × 7 cm with 1 cm margin. Ten seeds will cover 9 cm.

Figure 7.2 The completed implant can be trimmed to match the operative bed.

Figure 7.3 A smaller implant 9 × 6 cm (70 seeds) to cover a 7 × 4 target area with 1 cm margin. The sutures are passed through the mesh at least four times per strand and secured with small surgical clips.

Figure 7.4 The suture strand is pulled through a mesh along the grid line. Clips are applied at each end to secure the strands in mesh.

Figure 7.5 An even smaller implant (40 seeds) 7 × 4.5 cm to cover a target area of 5 × 3 cm can be made by doubling back to the next grid line with the same strand. Once the seeds are removed from the steel shield, the implant can be placed in a steel basin at the back of the table to minimize the radiation exposure to the operating room staff.

Implanting Tumor

If the patient cannot undergo surgery, the tumor itself could be implanted. Although this technique has more inferior results compared to surgery, for patients who cannot undergo any surgical resection, this might be the only option to increase dose. The Norris Cancer Center (19) describes volume implants on 14 patients. All patients had lymphatics surgically staged. Iodine-125 was used to implant the tumor. There was a 71% local control rate with 15 months’ median follow-up. All the relapses were in patients who had a Stage III tumor. The dose delivered was 80 Gy at the periphery with a high dose of 200 Gy in the center of the tumor. There was no incidence of radiation pneumonitis.

The tumor and any gross disease should be implanted with radioactive seeds, usually ¹²⁵I. A needle must be inserted into the tumor and then seeds dropped, either individually or in a line. This technique is called a volume implant. The seeds must be placed to cover a volume of disease, as opposed to the prior technique, a planar implant. MSKCC described this technique (20) with 65% locoregional control.

Figure 7.6 The last implant being sewn in with absorbable sutures over the target area previously agreed on and measured out by the surgeon and the brachytherapist.

Figure 7.7 Nomogram from the University of Pittsburgh for permanent planar ¹²⁵I seed dosimetry.

Figure 7.8 Lowell Anderson Nomogram from Memorial Sloan-Kettering Cancer Center for ¹²⁵I permanent implants seed dosimetry.

More recently, Wang et al describe a volumetric implant using the technique of CT-guided placement of radioactive ¹²⁵I seeds (21). A preprocedural plan was constructed on three-dimensional (3D) imaging to estimate the number of seeds to be used and their optimal distribution. A total of 21 patients were treated in this manner, all under local anesthesia. They reported a pain response rate in 83.3%. A tumor response rate was considered as a partial or complete response on serial postimplant imaging and was calculated to be 71.4%. Local tumor control rate was 85.7%. The procedure was well tolerated and the implant was successful. Only six patients died of progression of the primary tumor. The CT-guided implant certainly has its advantages of obviating general anesthesia, and should be explored further.

Locally Advanced Disease

Surgical Limitations

Certain tumors are deemed unresectable or marginally resectable on the basis of anatomic locations, such as proximity to bones or great vessels or superior sulcus tumors. Brachytherapy can assist in converting an unresectable, or marginally resectable, tumor into an acceptable oncological resection. Retrospective series from MSKCC (22) showed that Stage III patients with mediastinal involvement had similar median survival (16 vs 17 months) and a 5-year survival (15%) for complete resection versus incomplete resection plus brachytherapy, which were both better than no resection and brachytherapy alone or no resection and no brachytherapy. In another series with all lung cancer stages, there was an increase of 50% (8 to 12 months) in medial survival with brachytherapy after incomplete resection compared with no surgery (23). This was compared with a 17 month median survival for complete resection.

Figure 7.9 Dosimetry of a planar seed implant for a superior sulcus tumor.

Planar Seed Placement

The group at Cedars-Sinai Medical Center reported its results of a wedge resection with high dose rate (HDR) remote afterloading brachytherapy (6). They treated patients twice daily with HDR brachytherapy for seven fractions before removing the catheters, to a median dose of 24.5 Gy. In the follow-up period up to 27 months there were only four recurrences. Complications included prolonged air leak, atrial fibrillation, pneumonia, trapped lung, empyema, bleeding, and recurrent laryngeal nerve injury. Given the aforementioned complication risk, and the risk of movement and kinking of the catheters, this technique is typically not recommended unless radioactive seed implantation or IORT is not available.

Afterloading involves placing hollow blind-ended plastic catheters along the area at risk. The catheters should be spaced out by 1 cm in parallel lines. The open end of the catheter should be directed out of the skin through the surgical wound or percutaneous sites adjacent to the surgical incision. Care must be taken to not kink the catheters in any sharp angles, as this would not allow proper loading of the catheters. After appropriate time is given for the patient to stabilize, the patient should have a CT-generated treatment plan in the radiation department. Afterloading can be treated with low dose rate (LDR), pulsed dose rate (PDR), or HDR. LDR, a less common form of treatment now, requires the patient to have active radioactive sources on a string to be placed into the catheters and remain for a few days. During the interim, the patient must be isolated in a radiation safe room, with full radiation precautions. The radiation and catheters are removed at the appropriate time and the patient can be removed from radiation precautions. MSKCC reported implanting the mediastinum with afterloading techniques (LDR) with a good local control and 2-year actuarial survival (76% and 51%, respectively) for N2 disease (20).

HDR and PDR treatments could be performed with an afterloader, such as Nucletron Co. (Veenendal, the Netherlands) microSelectron or a similar device. The patient is implanted with the same catheters as mentioned in the preceding text. The radiation is delivered with only one source, which is computer controlled and can be placed at various positions and dwell times. This flexibility allows for more dose conformality than LDR. Also, all treatment is delivered in a shielded room, eliminating the dose to staff.

Intraoperative Radiation Therapy

Several series have been published, describing this technique. The group from University Clinic of Navarra, Pamplona, Spain, reported early clinical results of a phase I to II trial of IORT for Stage III lung cancer (28). Eligible patients had unresectable hilar tumors, or developed residual hilar, mediastinal, and/or chest wall disease after resection. They treated 34 patients with resection, if feasible, IORT of electron beams of 10 to 15 Gy in a single fraction, followed by external radiotherapy from 46 to 50 Gy over 5 weeks. Freedom from thoracic recurrence was 30%, 65% in cases of tumor resection, in a median follow-up time of 12 months. One patient suffered from a bronchopleural fistula, and another patient developed severe hemoptysis. Other less severe toxicities included acute pneumonitis and esophagitis, and late lung fibrosis.

Another pilot study from the group at Universiy Medical School in Graz, Austria, reported its results with single-fraction IORT (10−20 Gy using 7 to 20 MeV electrons) followed by external radiation therapy (46 Gy in 23 fractions) for unresectable NSCLC (29). Thirty-one patients were treated, 23 being evaluable for the study. Thirteen patients had a complete response, eight had at least a 50% response, and two had less than 50% response. Two patients had a local recurrence, one had local and distant recurrence, and two had distant recurrence only. The recurrence-free survival rate was 53.2% at the time of analysis.

For IORT, more equipment is needed. The radiation can be delivered using a mobile accelerator into a shielded operating room or in the radiation department, where a radiation vault is also a functional operating room. The surgeon demarcates the area at risk. The normal tissue can be moved out of the field or shielded with thin strips of lead. Either the cone from the linear accelerator is inserted into the patient or an applicator for HDR brachytherapy is placed, such as the Harrison–Anderson–Mick applicator (HAM applicator; Mick Industries, Westchester, NY). All personnel must leave the room before the radiation is delivered, which usually lasts only a few minutes.

Complications

Complications from any of these techniques are similar and minimal compared to the surgery itself. There could be some instances of poor wound healing or abscess formation, although very rare. The most concerning toxicity would be fistula formation or hemorrhage of large vessels. Intact tissue can tolerate the very low dose rate (VLDR) radiation well (31); however, any injury, either by tumor or surgery, can predispose to a fistula or hemorrhage. Care must be used to avoid placement of the seeds or catheters directly on any injured critical organ at risk, such as the esophagus (27) or blood vessels. This can be avoided if an implant is necessary by adding another layer of luminal protection for the vessel of the esophagus, by biological or artificial technique.

ENDOBRONCHIAL LESIONS

Endobronchial Primary

Endobronchial brachytherapy (EBBT) has been used alone or as a boost in addition to external beam radiotherapy (EBRT) for definitive treatment. One pilot study showed results for small superficial lesions limited to the bronchus treated with HDR EBBT only (32). The treatment dose was five fractions of 7 Gy at 1.0 cm depth. The 2 year actuarial survival was 58%, but with two of 19 deaths from late toxicity (hemoptysis).

Marsiglia et al described their experience in treating 34 patients with non-small cell bronchial carcinoma with EBBT only, as the patients were ineligible for surgery or EBRT (33). The treatment prescription was 30 Gy in six fractions. Local failure occurred in five patients (15%). At a 2-year median follow-up, the local control rate was 85%, and the survival rate was 78%. There was one patient who suffered from a pneumothorax, but had no other severe treatment-related toxicities.

A more recent study reported results on 106 patients treated with HDR EBBT who were not eligible for surgery or EBRT either due to respiratory insufficiency, previous EBRT, or recurrence after surgery (34). Six fractions of 5 to 7 Gy were prescribed 1 cm from the source. At 3 months, there was a complete response rate of 59.4%. At 3 and 5 years, the local control, overall survival, and cause-specific survival rates were 60.3% and 51.6%, 47.4 and 24%, and 67.9 and 48.5%, respectively. Despite these promising results, five patient deaths (two from hemoptysis, three from bronchial necrosis) were attributed to EBBT.

Palliation