High Dose Rate Intraluminal Irradiation in Recurrent Endobronchial Carcinoma

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High Dose Rate Intraluminal Irradiation in Recurrent Endobronchial Carcinoma* Stephen L. Seagren, M.D.;t James H. Harrell, M.D., Richard A Horn, Ph.D.§

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Palliative therapy for previously irradiated patients with symptomatic recurrent endobronchial malignancy is a difficult problem. We have had the opportunity to treat 20 such patients with high dose rate (SO-loo rad/min) endobronchial brachytherapy. Eligible patients had received previous high dose thoracic irradiation (TDF ~90), a performance status and symptoms caused by a bronchoscopically of ~50, de8ned and implantable lesion. The radiation is produced by a small cobalt-60 source (0.7 Ci) remotely afterloaded by cable control. The source is fed into a 4 mm diameter catheter which is placed with bronchoscopic guidance; it may oscillate if necessary to cover the lesion. A dose of 1,000 rad at 1 em from the source is delivered. We have performed !! procedures in 20 patients, four following YAG laser

debu1ldng. Most had cough, some with hemoptysis. Eight had dyspnea secondary to obstruction and three had obstructive pneumonitis. In 12, symptoms recurred with a mean time to recurrence of 4.3 months (range 1-9 months), Eighteen patients were followed-up and reexamined via bronchoscope 1-2.5 months following the procedure; two were lost to follow-up. All had at least 50 percent clearance of tumor, and six had complete clearance; most regressions were documented on 81m or videotape. In six, the palliation was durable. The procedure has been well tolerated with no toxicity. We conclude that palliative endobronchial high dose rate brachytherapy is a useful palliative modality in patients with recurrent endobronchial symptomatic carcinoma.

carcinoma has become the most lethal

4. Suitable endobronchial location for afterloading catheter placement. 5. Karnofsky performance status ~50. 6. Consent to the procedure. The high dose rate unit we used is called the Brachytron (AECL). It is a remote afterloading device in which a 3 mm diameter cobalt-60 source (average strength 0.7 Ci during this use) is cable driven from a lead pig into an afterloading catheter (Fig 1). The source may oscillate any desired distance up to 16 em. This particular unit is no longer in production, but two other high dose rate brachytherapy irradiators currently are (Selectron HDB Co"', [AECL] and Gamma Med II, [Isotopen Technik]). The endobronchial extent of the tumor was determined bronchoscopica1lyand an appropriate oscillation distance chosen. Under bronchoscopic guidance, a flexible aftel'-loading catheter (4 mm diameter, 46 em length) was placed adjacent to the lesion and secured (Fig 2, 3). We chose to .give a dose of 1,000 rads in one fraction 1 em from the edge of the source to all patients. Totaltime for delivery of this dose varied from 12-27 minutes depending on source strength and length of oscillation. All patients were admitted to the hospital overnight following the procedure for observation. Between February 1982and October 1983 we treated 20 patients; two were still eligible for the study at recurrence and retreated, but not to the same volume. Four were treated after debulking by endobronchial Nd-YAG laser therapy. Eighteen had the primary site in the lung; two had symptomatic endobronchial metastatic disease. Thirteen lung cancer patients had squamous histology, two adenocarcinoma, two large cell undifferentiated, and one adenoidcystic. The median interval from completion of external radiation to symptomatic recurrence was nine months; the range was 3-21 months, except for one patient with an adenoidcystic primary who

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human malignancy in both men and women. Patients with locally advanced disease without evidence of blood-borne metastases are often treated by radiation. Recurrence followingirradiation therapy is a common problem; 40 percent of lung cancer deaths are attributable to loco-regional disease at autopsy. 1 Thirty-three to 50 percent of patients irradiated for local control will have had disease progression within the irradiated field by 15 months.P" When they are symptomatic, we have elected to treat many of these patients with high-dose rate intraluminal radiation. SUBJECTS AND METHODS

To be selected for this therapy, patients had to meet the following criteria: 1. History of endobronchial carcinoma, bronchogenic or metastatic. 2. Received at least the equivalent of 5,000 rad external beam irradiation to the lesion. 3. Bronchoscopically documented endobronchial recurrence producing local symptoms-cough, hemoptysis, dyspnea or obstructive pneumonitis. *From the University of California, San Diego. t Associate Adjunct Professor of Radiology and Medicine. *Clinical Professor of Medicine. 'Associate Clinical Professor of Radiology. Manuscript received February 18; revision accepted June 7. Reprint requests: Dr. Seagren, 225~ Dickinson(H-757), San Diego 92103

810

Intraluminal Irradiation In Recurrent Endobronchial Carcinoma (Seagren, Harrell, Hom)

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FIGURE 1. The radiation device, called the Brachytron. These cobalt-60 sources of different intensities are connected to wire cables (A, left) and housed in a lead container (B, right).

had recurrence with the same histology five years later. Fifteen had cough, nine hemoptys is, six dyspnea and four had obstructive pneumonitis and/or atelectasis. Eighteen of 20 patients were seen at least once 1-2.5 months following the procedures . They were asked about their symptoms and quality oflife and were re-examined by bronchoscope. No formal

and codi6ed symptomatic assessment was done . Complete relief was defined as complete freedom ofpresenting symptom at any follow-up visit. Partial relief required at least 50 percent reduction in quantity of symptom. Progression of symptoms after complete or partial relief was judged non-durable palliation. Impressions of symptom relief and objective response were recorded in the clinic progress notes. Two who lived a long distance away were followed-up by their referring physicians and were not reexamined in San Diego; they are not considered evaluable. RESULTS

Seventeen (94 percent) had at least partial palliation of the symptom(s) treated; eight enjoyed complete relief In six, the palliation was durable with no recurrence of symptoms; in 12, the symptoms recurred or progressed with a mean time to recurrence of 4.3 months (range 1-9). Cough and hemoptysis were more responsive than dyspnea and pneumonia/atelectasis (Table 1). Although no quality of life assessment was done prospectively, it is our impression that most

FIGURE 2A (left). A motor drives a selected source out of the container through a tube connected to the afterloading cathete r which has been placed during bronchoscopy 2B (right) .

FIGURE 3. A patient with the source in place. No patient had a problem with catheter placement. CHEST I 88 I 8 I DECEMBER. 1985

811

Table l-COfTelation if Symptom and Palliation No. Patients Cough-IS Hemoptysis-9 Dyspnea-6 Pneumonitis, fever-4 (atelectasis)

Complete

8 6

1

1

Palliation

Table 2-COfTeWtion if Bronchoscopic Reaponae and Palliation

Partial

None

6 3

1

5

3

o o

o

patients enjoyed an improved quality oflife as a result of the procedure. Several moribund patients returned to work or full-time leisure activity. All 18 patients were reexamined by bronchoscope at least once between 1 and 2.5 months following endobronchial radiation . All had at least 50 percent regression of the irradiated lesion, and six had complete clearance. Most of these responses were documented either photographically or on videotape (Fig 4). There was a general correlation between an objective and subjective complete response (Table2), as well as between an objective complete response and durability of symptom relief (Table 3). Pre-irradiation laser therapy was associated with good palliation, but the number of patients is too small to generalize (Table 4). Survival was also measured, although not a major end-point of this trial. Of the 20 patients, 17 are dead, two are alive (ten and 29 months), and one is lost to follow-up. Medial survival is nine months from implant, range foul'-29 months . Five patients died of massive hemoptysis, all of whom were known to have persistent or recurrent endobronchial tumor. The

Symptomatic Response Complete Partial

Bronchoscopy Complete

o

2

4 4

Partial

None

1

7

Table 3-CorTelation if Bronchoscopic Reaponae and Durability if Palliation Recurrence (or Progression) of Symptoms No Yes

Bronchoscopy Complete

2

4

2

Partial

10

other patients' deaths were attributed to progressive systemic disease . Toxicity has been minimal. There has been no complication from bronchoscopy and afterloading catheter placement. There has been no radiation tracheitis, bronchitis, pneumonitis or esophagitis. One patient developed clinical evidence of transient pericarditis three weeks following the procedure. There has been no fistula or other manifestation oflate radiation effects. DISCUSSION

Aggressive high dose external beam radiation is commonly used to treat locally advanced, nonresectable, nonmetastatic bronchogenic carcinoma (T3No.2, T 2NJ, although some controversy about its utility remains ." The prognosis for good performance status patients (Karnofsky ;;::80) whose intrathoracic disease is controlled is less bleak than commonly assumed; 20-25 percent of these patients may live five years.6 Nonetheless, one-third to one-half of these patients will relapse in the chest followingaggressive radiation . These patients often become symptomatic with cough, hemoptysis, dyspnea or symptoms of obstructive pneumonitis. These recurrences often occur in the absence of widespread metastases, and a patients projected survival may be more than a few months . Palliative management thus is an important issue for this subset of lung cancer patients. Palliation was the most important end-point of our study. We recognize that quantification of symptom relief is difficult, but has been reported for bronchogenic carcinoma in both single institution7 and cooperative group trtals ." Cough, hemoptysis, fever and dyspnea are more easily measured than, say, pain. Pneumonitis and atel~ctasis j•

Table 4-Outcome if Four Patienta Receiving La8er before Endobronchial Irradiation 4. Serial bronchoscopic photographs of a typical lesion A, top: before, B, center: during, and C, bottom: one month after endobronchial radiation. FIGURE

812

Symptomatic CR PR

3

1

Objective CR PR

1

3

Yes

1

Relapse

No

3

Intraluminal IrrBdaIIon In Recurrent Endoblonchlal Caldnoma (Seagfflll. HatTfIII. Hom)

are not symptoms per Be, but correlate with dyspnea and fever when present and therefore useful. Quality of life is the most difficult and most subjective; we did not attempt to measure it, but only comment on our impressions. At least three alternative fonns of management are available; some may be combined. External beam radiation usually palliates cough, hemoptysis and dyspnea in the previously unirradiated patient. 7 Concern with radiation overdose and toxicity has caused reluctance to retreat these patients with external beam therapy. However, this concern may be unwarranted based on the retrospective analysis of Green and Melbye" who reviewed retreatment results in 29 patients. Only two experienced significant complications while 14 (48 percent) received palliative benefit, compared with our 94 percent. 'Iransbronchoscopic laser therapy is another management alternative, one with growing popularity and applicability," We have found the Nd-YAG laser to be most useful in conjunction with the rigid bronchoscope under general anesthesia, rendering the procedure quite expensive. There is no potential of enhanced radiation toxicity in previously radiated patients, although increased bleeding and anatomic deformity may render the treatments more hazardous. Laser therapy is limited to mucosal lesions, which are exophytic in the trachea or mainstem bronchus. Submucosal compressing lesions cannot be managed with laser obliteration. Because only the intraluminal extent of the tumor can be treated, rapid recurrence can OCCUI:

Endobronchial reradiation is a third alternative. By placing a radioactive source near the tumor (brachytherapy), a relatively high dose is given to the tumor, but the dose falls off rapidly because of the inverse square law. Since only a small volume of tissue receives a therapeutic dose of radiation, the chance of severe normal tissue damage is reduced. Brachytherapy has been used for re-irradiation in other sites with an acceptable complication rate. 10.11 Several alternative approaches are available for endobronchial radiation. The variables include the technique of bronchoscopy, source placement, and radiation dose rate.

Bronchoscopic Technique Use of the rigid bronchoscope requires hospitalization, general anesthesia and access to only the most proximal lesions. The fiberoptic bronchoscope can be used as an out-patient procedure employing local anesthesia, and more distal lesions as well as upper lobe lesions are approachable.

Source Placement The sources may be placed interstitially or in-

traluminally," Interstitial sources are embedded into

the bronchial submucosa and remain permanently. Intraluminal sources are removed after the desired dose has been given. Interstitial placement can be associated with bleeding," radioactive seed displacement," difficulty with seed insertion," and uncertain radiation dose." Intraluminal therapy has none of these problems, although, because of the linear source, falloff of radiation dose is quite rapid. Accurate and reproducible control of radiation dose is possible with intraluminal sources, but not with interstitial applications.

Dose Rate Dose rate is the third variable. External beam radiation is high dose rate therapy (50-500 rad/min), conventional brachytherapy is low dose rate (40-100 rad/hour), iodine-125 brachytherapy is very low dose rate (50-150 rad/day and less). High dose rate therapy is biologically more efficient, but potentially more injurious to normal and tumor tissue for any given dose. The dose is given in a relatively short time min), and therefore, hospitalization is unnecessary. Low dose rate techniques require hospitalization. Because of iodine-125s very low energy, hospitalization for radioprotection is not necessary, but is required for seed placement. High dose rate delivers the dose rapidly and palliation is likely to be prompt. Prompt palliation is less likely for iodine-125 seed placement. For this trial we chose an intraluminal high dose rate system and placement by flexible bronchoscope. These choices represent the optimal alternatives. This approach was made possible by the availability of a high dose rate brachytherapy radiator: We thus have avoided the expense of hospitalization and anesthesia, and the complications of airway bleeding and seed displacement. Palliation is rapid. The procedure has been free of any toxicity, and can be delivered at reasonable cost. Our choice of dose, 1,()()() rad at 1 cm can be critized. Since we desired to minimize late radiation effects in these previously irradiated patients, perhaps we should have fractionated the dose or performed a dose escalation study. However, since we saw no evidence of late radiation complication and both subjective and objective evidence of response, we have continued to use the same dose. Since the afterloading catheter must be placed bronchoscopically, a single fraction has the advantage of lower cost and greater patient comfort. Therefore, we have chosen not to fractionate or modify the dose. Palliation is also likely to be more rapid when the entire dose is given in one fraction. It is possible that higher fractionated doses may produce higher subjective and objective complete response rates. The fact that five of 18 patients died from massive

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CHEST I 88 I 6 I DECEMBER, 1985

813

hemoptysis requires comment. Since all were known to harbor active endobronchial tumor, we postulate a tumor-related termination. It is possible, however, that late radiation effect may be implicated. Unfortunately, no autopsy was performed in these particular patients. Endobronchial radiation is not a new idea. First employed in 1921, the modality was further developed by Kernan. L5 The largest experience is from Memorial Hospital where 62 patients were treated, nine ofwhom had recurrence after external beam radiation. The rigid bronchoscope and interstitial radon-222 and later iodine-I25 seeds were used. Three of these nine patients appeared to benefit from treatment." More recently, there have been a few scattered cases reported using interstitial seeds and flexible bronchoscopy.lJ.14.17 The majority of the patients reported seemed to benefit. Endobronchial laser resection of recurrent lung cancer is an alternative, but rapid recurrence can be observed. It is possible to use high dose rate endobronchial radiation after laser therapy to improve durability of palliation. Of the four patients we radiated following laser therapy, only one had symptomatic recurrence, while the other three remained free of significant cough or hemoptysis for the duration of their survival. In summary, we have found high dose rate endobronchial radiation to be a highly satisfactory way to palliate the symptoms of recurrent endobronchial carcinoma. Questions of optimal dose and fractionation, as well as integration with laser therapy remain to beworked out. The technique may also prove useful as a means to boost the total tumor dose following radical external beam radiation fur locally advanced primary disease. REFERENCES

1 Luomanen R, Watson W. Autopsy findings. In: Watson W ed. Lung cancer: a study of five thousand Memorial Hospital cases. St. Louis: C. v Mosby, 1968; 504-10 2 Eisert DR, Cox JD, Komake R. Irradiation for bronchogenic carcinoma: reasons for failure. Cancer 1976; 37:2665-70

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3 Perez CA, Stanley K, Rubin ~ Kramer S, Brady L, PerezTamayo R, et ale A prospective randomized study of various irradiation doses and fractionation schedules in the treatment of inoperable non-oat-eell carcinoma of the lung. Cancer 1980; 45: 2744-53 4 Salazar OM, Rubin ~ Brown JC, Feldstein ML, Keller BE. Predictors of radiation response in lung cancer. Cancer 1976;37: 333-36 5 Cohen MH. Is immediate radiation therapy indicated for patients with unresectable non-small cell lung cancer? Cancer '&eat Reps 1983; 67:333-36 6 COX JD, Komaki R, Byhurdt RW. Is immediate chest radiotherapy obligatory for any or all patients with limited-stage non-small cell carcinoma of the lung? Cancer Treat Reps 1983; 67:327-31 7 Slawson RG, Scott RM. Radiation therapy in bronchogenic carcinoma. Radiol 1979; 132:175-76 7A Simpson IR, Francis ME, Perez-TamayoR, Marks RD, Rao nv Palliative radiotherapy for inoperable carcinoma of the lung: Final report of a RTOG multi-institution trial. Int J Radiation Oncology BioI Phys 1985; 11:751-58 8 Green N, Melbye RW. Lung cancer retreatment of local recurrence after definitive radiation. Cancer 1982; 49:865-68 9 Hetzel MR. Current use of lasers in pulmonary disease. WorldJ Surg 1983; 7:725-31 10 Emami B, Marks JE. Retreatment of recurrent carcinoma of the head and neck by afterloading interstitial 192IR implant. Laryngoscope 1983; 93:1345-47 11 Pathawala AA, Syed AMN, Fleming PA, Disaia PJ. Re-irradiation with interstitial implant for recurrent pelvic malignancies. Cancer 1982; 50:2810-14 12 Mittal BB, Matuschak G, Culpepper J. Endobronchial interstitial brachytherapy using a bronchofiberscope with a flexible injector system. RadioI1984; 152:219-20 13 Seagren SL, Harrell JH, Utley JR. Endobronchial radiation: early experience with two modalities. Inti J Badia Mol BioIPhys 1982; 8:1826 14 Moylan D, Strubler K, Unal A, Mohiuddin M, Giampetro A, Boon R. Transbronchial brachytherapy of recurrent bronchogenic carcinoma: a new approach using the flexiblefiberoptic bronchoscope. Radioll983; 147:253-54 15 Kerman JD. Carcinoma of the lung and bronchus treated with radon implantation and diathermy. Arch Otolaryngol 1933; 17: 457-75 16 Hilaris BS, Martin N, Luomanen RK. Endobronchial interstitial implantation. Clio Bull 1979; 9:17-20 17 Mendiondo OA, Dillon M, Beach LJ. Endobronchial brachytherapy in the treatment of recurrent bronchogenic carcinoma. Inti J Badia Oncol BioI Phys 1983; 9:579-82

Intraluminal Irradiation In Recurrent Endobronchial Carcinoma (Seagten, Hanell, Hom)