Inr J. Radialron Oncology BIO/ Phys Vol. 23. PP. 127-132 Printed in the U.S.A. All rights reserved.

0360-3016/92 fS.OO + .OO Copyright 0 1992 Pergamon Press Ltd.

0 Phase I/II Clinical Trials TREATMENT OF NON-SMALL CELL LUNG CANCER WITH EXTERNAL RADIOTHERAPY AND HIGH DOSE RATE BRACHYTHERAPY

BEAM

CENGIZAYGUN, M.D., SEYMOURWEINER,M.D.,ALBERTSCARIATO,M.D., DAVID~PEARMAN, M.E. ANDLINDA STARK,PA-C Radiation Oncology Affiliates of Maryland and Radamerica, Inc., Baltimore, MD Between August 1985 and September 1989,62 patients with medically inoperable or surgically unresectable, nonsmall cell lung cancer were treated with both external beam radiotherapy and high dose rate bronchial brachytherapy. Treatment consisted of external beam radiotherapy (5000-6000 cCy in 5-6 f weeks) and weekly high dose rate bronchial braehytherapy (three to five fractions, 500 cGy at 1 cm from the source) delivered either concurrently or sequentially. Median survival for all patients was 13 months (m). Stage I and Stage IDA-B patients had median survivals of 20 m and 10 m, respectively. Patients without nodal disease (No) had a significantly longer median survival compared to patients with regional node metastases (Nl-3), 17 m versus 9 m. A total of 54 patients were evaluable for local tumor control analysis. Local tumor control was achieved in six of eight patients who had a normal pre-treatment radiograph. Patients with measurable tumor on the pre-treatment radiograph and negative regional nodes had local tumor control in eight of twenty-two (36%) cases. In patients with regional lymphadenopathy, loco-regional tumor control was achieved in four of eight cases. Additionally, there were sixteen patients with nonmeasurable tumor due to associated effusion, atelectasis and/or infiltrate. Four of these (25%) were considered to have local tumor control. Of 60 evaluable patients, there were nine occurrences of fatal hemorrhage, one of whom was disease-free (NED) at autopsy. The remaining eight patients had either clinical or pathological evidence of recurrent or persistent tumor. Patients who had follow up bronchoscopies were found to have varying degrees of concentric narrowing in the treated areas. One such patient had total lung collapse with no evidence of tumor. While this form of treatment may yield high local control rates in earlier stages, this study suggests the potential risk of fatal complication. Additional studies are warranted to further investigate the use of this modality in the treatment of lung cancer. High dose rate brachytherapy,

Lung cancer, Endobronchial brachytherapy,

INTRODUCTION

Radiotherapy.

vival. Radiation Therapy Oncology Group (RTOG) studies showed significantly higher response rates with higher doses. Two year survival was also better, though not significantly, with higher doses ( 18). RTOG also tested dose levels above the standard dose using rapid fractionation and hyperfractionation. The former showed the highest response rate (72.7%) ever achieved by RTOG lung cancer studies. The later showed a survival benefit with increasing doses up to 6960 cGy, but with no further improvement in survival in the highest total dose arms (4,9). Similarly, Eisert et al. observed increased local tumor control and ultimately increased survival up to a dose of 1450 ret, but no further correlation at higher dose levels (8). Others have observed a positive correlation between tumor response and survival (17, 20, 22, 27). While anyone has yet to prove that loco-regional tumor control will ultimately result in a higher cure rate in locally

It is estimated that 16 1,000 persons will be diagnosed with, and 143,000 patients will die from, lung cancer in 199 1 (2). While surgery remains the only realistic hope for cure in non-small cell lung cancer (16) only about 25% of patients have resectable tumors at diagnosis. Radiation therapy has been the treatment of choice for those who are not candidates for surgery. Most patients referred for radiotherapy have a large tumor volume. Such large volumes would require approximately 8000 cGy for 90% tumor control probability if compared to dose-tumor volume relationships for squamous cell carcinomas of the upper digestive and respiratory tracts (10). In the radiotherapeutic management of non-small cell carcinoma of the lung, there appears to be a dose response for both local tumor control and sur-

Presented at the 6th International High Dose Rate Remote Afterloading Conference, 2-4 May 199 1, Budapest, Hungary. Reprint requests to: Cengiz Aygun, M.D., Suite 100, 9105 Franklin Square Drive, Baltimore, MD 2 1237.

Accepted for publication

127

1 October 199 1.

128

1. J. Radiation Oncology ??Biology0 Physics Table 1. Patient distribution

Volume 23, Number 1, 1992

Table 2. Patient distribution per stage

per histology

Number

Number

Stage I Stage II Stage III-A Stage III-B

45 12 2 2 1

Squamous cell carcinoma Adenocarcinoma Large cell (undifferentiated) Poorly differentiated Adeno-squamous

19 2 36 5

The TNM System 1986. advanced lung cancers, there is potential for increased survival time with better tumor control. The use of endobronchial brachytherapy has generally been reserved for palliation in previously radiated patients with local recurrence. Few have used high dose rate brachytherapy combined with external beam radiotherapy with curative intent (14,26). This paper summarizes our experience in combining standard dose external beam radiotherapy with high dose rate endobronchial brachytherapy. MATERIALS

AND METHODS

From August 1985 to September 1989 a total of 79 patients with newly diagnosed localized non-small cell carcinoma of the lung were treated with both high dose rate bronchial brachytherapy and external beam radiotherapy. Of these 79 patients, 17 were excluded from this analysis. Twelve patients had incomplete treatment due to: deteriorated general condition (three patients), refused further treatment (four patients), or existing metastases prior or during treatment (five patients). Four patients who received only one or two fractions of brachytherapy are within the 12 excluded patients. Five other patients who completed the treatments were excluded from the analysis due to: bilateral lung cancer (one patient), metastases occurring under treatment (one patient), malignant pleural effusion (one patient), or adjunctive surgery (two patients). The study group for this retrospective analysis included 62 patients who had proven non-small cell carcinoma of the lung in one of the following categories: a) medically inoperable (n = 14), b) unresectable tumor, clinically (n = 36) or at thoracotomy (n = 5), or c) refused surgery (n = 7). All patients had endobronchial tumor and 21 patients (34%) had involvement of the main stem bronchus and/or trachea. Distributions per histology and stage are illustrated in Tables 1 and 2. In the study group, 18 patients (29%) had 25% weight loss. Four other patients had similar weight loss attributed to dieting. Another 26 (42%) patients had no available information from charts regarding weight loss. Metastatic work up (CT of chest including upper abdomen, bone

* Gamma Med III, manufactured Sauerwein GmbH.

by Isotopen-Technik

Dr.

scan, liver function tests) was extensive in 20 (32%) patients. Fifty-nine of sixty-two patients (95%) had a Karnofsky performance status of 50% or greater. The presence of endobronchial tumor and a performance status enabling bronchoscopy (usually Karnofsky 250%) were the only selection criteria. Patients received both external beam radiotherapy and three to five fractions of bronchial brachytherapy; 56 patients (90%) received four treatments. Brachytherapy usually started during the fourth week of external beam treatments. Under local anesthesia, the location and extent of endobronchial disease were determined using a bronchoscope. The brachytherapy catheter was then inserted and its position was verified with fluoroscopy and radiographs. Four-hundred to 600 cGy was delivered at 1 cm from the source along the involved segment of the bronchus. Fifty-nine patients (95%) received 500 cGy at each application. A typical example of dose distribution is illustrated in Figure 1. Where it was necessary, the dose distribution was modified to conform to the special geometry of the bronchial lumen by changing the source dwell times. A Gamma Med Iii *machine with a nominal 10 Ci Ir- 192 source was used for all patients. Dose rates at 1 cm depth ranged from 200-750 cGy/min depending on the age of the source, consistent with a “high dose rate” application as defined by the ICRU ( 13). All patients signed special consent forms for brachytherapy. Endobronchial radiation was given weekly and combined with external beam using Cobalt 60 or 6- 15 MV Linear Accelerator. External beam dosage ranged from 5000 cGy to 6 160 cGy given in 5-6 4 weeks. Fifty-seven of 62 patients (92%) received over 5900 cGy. External beam treatments were given through AP:PA ports until the spinal cord dose reached 4000 cGy. Then, oblique or occasionally lateral fields were used until the completion of treatments. An inhomogenity correction for lung tissue was made for the oblique and lateral techniques, but not for the AP:PA opposed technique. During the earlier part of the study, 19 patients were treated with both external beam and brachytherapy on the same day. This was later changed so that on days brachytherapy was given, external beam treatments were omitted (43 patients). This change in policy was not due

External

and high dose rate brachytherapy 0 C. AYGUN et a/.

129

Dose Levels

(rods> # 1= 1500.

# # # # # # # c

2= 1000. 3=750.00 4=500.00 5=400.00 .__ 6=300.00 7=200.00 8=150.00 9=100.00

-.

Fig. 2. Actuarial survival of all patients chial and external beam radiotherapy.

Fig. 1. Representative isodose curves for a single Ir-192 source that has been stepped through twelve positions which are separated by 0.5 cm.

to observed increased complications, but to possibly reduce long-term complications. All patients were followed for a minimum of 18 months or until death. The Kaplan-Meir life table method was used for survival analysis calculated from the first day of treatment to death, regardless of the cause or last follow up. A total of 54 patients were evaluable for loco-regional tumor control analysis. The analysis was based upon tumor size and nodal status. Tumor size is defined as the maximum diameter determined from CT scans or plain x-rays. Patients with no measurable tumor were further subdivided into two groups. Those who had normal xrays at diagnosis were analyzed separately from others who had no measurable tumor due to associated atelectasis, infiltrate and/or effusion. Local tumor control is defined as normalized, sustained improvement or stable radiographic examination at last follow up. Local failure is defined as clinical, radiographic progression or positive cytopathologic specimen obtained at follow up bronchoscopies despite radiographic improvement. “Suspicious for failure” is defined as possible radiographic progression, but negative repeat cytopathologic specimens obtained at follow up bronchoscopies.

tastases occurred at a rate of 22% for squamous cell carcinoma and 35% for all other histologies combined. The median survival for all patients was 13 months. The range was 2-65 months (Figure 2). Median survival for 41 Stage IIIA-B patients and 19 Stage I patients was 10 months and 20 months, respectively (Fig. 3). Patients with Tl-4 primary tumors and negative nodes (No) had a median survival of 17 months, while patients with positive nodes (Nl-3) had a median survival of 9 months (p = .005, Wilcox) (Fig. 4). For all stages there was no significant survival difference between patients with squamous cell carcinoma versus other histologies combined. Local tumor control results are summarized in Table 3. Twenty-one symptomatic patients with abnormal chest x-rays had repeat bronchoscopies following treatment. Only five (24%) had confirmed recurrence by cytopathology, indicating limited reliability of a single criterion for evaluating local tumor control. There were no serious acute complications from the brachytherapy procedure. None of the patients experienced pneumothorax, fistula, bleeding, or cardiovascular problems. Usually at the second or third bronchoscopy, mucositis at the site of brachytherapy treatment was observed. At follow-up bronchoscopies, dry mucosa with varying degrees of stenosis, sometimes associated with a mucous plug, was observed. Typically the site of implant was shiny and white with concentric narrowing. One patient had a total collapse of the lung due to bronchial

RESULTS

P

, Pi

After a minimum follow up period of 18 months, 10 of 62 patients were still alive. Of the fifty-two patients that died, 48 had evidence of disease, including eight who died of hemorrhage. The remaining 4 patients died of intercurrent disease at 6, 13, 28 and 63 months while free of tumor, including one who died of hemorrhage. Sixteen patients (3 1%) had metastatic disease at the time of death. One patient is alive with metastatic disease. Me-

treated with endobron-

0

- 0.02

,~.

0

10

20

L

40

30

50

SO

70

Months ‘t

stage I

’ stage I,,

Fig. 3. Actuarial survival of Stage I and Stage IIIA-B patients treated with endobronchial and external beam radiotherapy.

130

I. J. Radiation Oncology 0 Biology 0 Physics

Volume 23, Number 1, 1992

modest improvements in survival can have a significant impact. Lung cancer is a disease in which many variables have important prognostic features. These include tumor size and extent, performance status, histology, history of weight loss, and the extent of metastatic work up (6, 11, 16, 19, 2 1). In addition, different criteria used in methodology and the small number of patients in individual studies make it difficult to compare results from different institutions, and may be misleading. Stage I patients (19 patients) in our study had a median survival of 20 months. Other published median survival rates in the literature range from 20 months to 28 months with five year survival ranging from 22.5% to 32% for early operable patients, treated with different selected criteria ( 12, 17,2 1,25,27). For later stage patients (Stage MA-B), we obtained a median survival of 10 months. A recent trial with induction chemotherapy followed by radiotherapy achieved a 13.8 months median survival (7). Other studies using a concurrent Cis-platinum containing chemotherapy regimen with radiotherapy obtained a median survival ranging from 7 months to 17 months (3). In our study, sixteen out of 2 1 (76%) patients with initially positive endobronchial tumor prior to treatment were found to have no cytopathologically confirmed residual disease on repeat bronchoscopies following treatment. This relatively high incidence of negative cytopathology is partially due to unconfirmed tumor beyond the lumen or inadequate specimens as a result of post treatment distorted anatomy. Local tumor control was highest in the group of patients who had a normal pretreatment radiograph (75%). This may be related to smaller tumor volume and/or better volume coverage with brachytherapy. In this group of patients, however, there was one fatal hemorrhage. In the moderate tumor volume group (tumor size less than or equal to 5 cm.), tumor control was achieved in four of eleven patients (36%). Similarly, in the larger volume group (tumor size greater than 5 cm), local tumor control was achieved in four of eleven patients (36%). The small numbers may explain this similarity. Tumor control was achieved in four of eight patients who had regional lymphadenopathy. All four patients with tumor control had primary tumors measuring 5 cm or less and nodes measuring 3 cm or less. There were nine occurrences of fatal hemorrhage from

---i20

30

40

50

SO

Months -

N (-)

-+

N (*I

Fig. 4. Comparison of actuarial survivals of node negative N (-) and N (+) patients.

without evidence of disease at follow up bronchoscopies. Sixty patients were evaluable for hemorrhagic events following therapy. Nine ( 15%) died from hemorrhage. Of these, one patient had no evidence of disease at autopsy. Eight patients had either pathologic (n = 3) or clinical (n = 5) evidence of persistent tumor. When upper lobe lesions were combined with main stem bronchus lesions and compared, the hemorrhage incidence was 25% and 10% for right and left sided lesions respectively. The higher incidence of hemorrhage for right sided lesions is believed to be related to the anatomical proximity of the pulmonary artery to these lesions. Additionally, none of the left sided lesions in the study group were observed to have complications that would indicate bronchial wall perforation such as mediastinitis, pneumo-mediastinum or bronchoesophageal fistula. The details concerning these nine patients are presented in Table 4. stenosis

DISCUSSION Extensive literature exists on the treatment of locally advanced lung cancer with external beam radiotherapy. Typical median survivals obtained with the radiotherapy alone arms of randomized studies range from 7 to 9.7 months. Treatment is limited by the sizes of the tumors and radiotherapeutic dosage constraints. Some recent trials have used alternative fractionation schemes or combined modality treatments in an effort to improve results. Given the large numbers of patients with this disease, even

Table 3. Local tumor control

Patient characteristics No. of pts. Controlled Failed Suspicious for failure

Normal pre-treatment radiograph

Unmeasurable Tumor

Ts5cm No.

Tr5cm No.

8 6 -

11 4 6

11

8

4 6

4 3

16 4 8

2

1

1

1

4

T = Primary tumor; N+ = Regional lymphadenopathy.

N+

External and high dose rate brachytherapy 0 C. AYGUN et nl.

131

Table 4. Patients dead of hemorrhage Total dose ext. beamlbrachytherapy

Interval from last treatment

Pt.

Tumor location

1 2

Rt. MSB Rt. LL

8000 cGy 8000 cGy

8.5 mths 2 mths

3

Rt. BI

7940 cGy

21.5 mths

4

Rt. MSB

7460 cGy

1.8 mths

5 6

Rt. MSB Rt. MSB

7875 cGy 8000 cGy

5 mths 10 mths

Comments

Autopsy

(+) cytology 2 wks prior Persistent tumor, but improved at last branch 2 wks prior Laser surgery for recurrence 10 days prior, biopsy (+) Persistent tumor at branch, 1 wk prior Residual tumor per xray, 1 mth prior Vocal cord palsy 2.5 mth prior, xray

-

-

negative 7 8 9

Rt. UL Lt. UL Rt. UL BI = Bronchus intermedius,

8160 cGy 7760 cGy 7940 cGy

6 mths 65 mths 8.3 mths

NED Early signs of SVC syndrome 1 mth prior

No tumor Tumor in lung -

MSB = Main stem bronchus; LL = Lower lobe; UL = Upper lobe.

60 evaluable patients ( 15%). One appeared to be treatment related. The other eight cases had clinical or histologic evidence of persistent tumor. However, the presence of persistent tumor does not necessarily exclude the possibility of hemorrhage caused by treatment, since normal tissue tolerance can be exceeded before tumor control. The risk of hemorrhage was independent of dose or timing of brachytherapy with external beam radiotherapy. Since one-third of the patient population had central disease in close proximity to the large vessels, this incidence of hemorrhage was not unexpected. The incidence of fatal hemorrhage is not well documented and rarely mentioned in published studies. Cox et al. reported a VALG study of 300 consecutive autopsies that showed a fatal hemorrhage incidence from 2% to 8% depending on the histology (5). Bedwinek et al. observed a 32% incidence of fatal hemorrhage among recurrent, symptomatic lung cancer patients treated with high dose rate brachytherapy (1). Macha et al. reported death due to hemorrhage in 7% of 56 patients treated with high dose rate brachytherapy (15). Seagren et al. reported a 28% hemorrhage incidence (all with residual tumor) among patients treated with high dose rate brachytherapy after recurrence following external beam radiotherapy (24). Schray et al. reported an 11%

incidence of fistula and/or hemorrhage with low dose rate brachytherapy in patients who received prior or concurrent external beam radiotherapy (23). In our study, bronchial scarring was noted in some patients on repeat bronchoscopies after treatment. This was not usually of clinical significance since airway function had already been compromised prior to treatment. One patient had complete atelectasis of the lung secondary to scarring at 3 1 years after treatment and was dyspneic only on exertion. Our results suggests that the use of high dose rate endobronchial irradiation along with standard external beam radiotherapy is most effective in small volume disease. Since the study is a retrospective one without a comparison group treated with external beam only, it is unclear if similar results could have been achieved with external beam treatment alone. Nevertheless, while local tumor control in early stage patients is encouraging, there was one fatal complication that must be considered. We have narrowed the indications for the use of high dose rate brachytherapy combined with external beam radiotherapy to localized inoperable lung cancer, patients with small volume primary tumor and limited or negative nodal disease.

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I. J. Radiation Oncology 0 Biology 0 Physics

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