Prospective trial of combined hyperfractionated radiotherapy and bronchial arterial infusion of chemotherapy for locally advanced nonsmall cell lung cancer

Int. J. Radiation

Oncology

Biol.

Phys.. Vol. 34, No. 2. pp. 309-313. 1996 Copyright 10 IYYh Elsevier Science Inc. Printed in the USA. All rights reserved 0360-3016196 $15.00 + .oO

ELSEVIER

0360-3016(95)02111-6

0 Clinical Original Contribution PROSPECTIVE TRIAL OF COMBINED HYPERFRACTIONATED RADIOTHERAPY AND BRONCHIAL ARTERIAL INFUSION OF CHEMOTHERAPY FOR LOCALLY ADVANCED NONSMALL CELL LUNG CANCER GUOMIN

WANG,

M.D.,*

MEIFANG

SONG, M.D.,*

HUAIYU

Xv,

M.D.+

AND YI FANG,

PHD*

*Department of Radiotherapy, ‘Department of Medicine, East China Hospital, 221 Yan An Road West, Shanghai, China, 2ooO40, and $Industrial Membrane Research Institute, University of Ottawa, Ottawa, ON, Canada, KIN 6N5 Purpose: This article is a prospective trial of hyperfractional radiotherapy with bronchial arterial infusion ofncer drugs to treat locally advanced bronchogenic cancer. The treatment results, the complications of bronchial arterial infusion, the failure patterns, the relationship of technical aspects of delivery of radiotherapy, and the protocol of anticancer drugs are presented. Methods and Materials: One hundred and twenty-six patients with locally advanced bronchogenic cancer, treated from January 1988 to January 1990, were divided randomly into four groups in our hospital. Group 1: combination of hyperfractional radiotherapy with bronchial arterial infusion of anticancer drugs (30 cases); Group 2: combination of conventional radiotherapy with bronchial arterial infusion of anticancer (33 cases); Group 3: combination of systemic chemotherapy and split-course radiotherapy (33 cases); Group 4: conventional radiotherapy only (30 cases). Results: AU the patients were followed for 3 years. The l-year survival rates for Groups 1, 2,3, and 4 are 80, 63.6, 48.5, and 30%, respectively. The 2-year survival rates for Groups 1, 2, 3, and 4 are 23.3, 15.15, 9.1, and 6.6%, respectively. The 3-year survival rates for Groups 1, 2, 3, and 4 are 10, 3.3, 0, and 0%, respectively. Conclusion: This study demonstrated that the combination of hyperfractioual radiotherapy with bronchial arterial infusion anticancer drugs can be performed safely and effectively for locally advanced bronchogenic carcinoma. Hyperfractionated therapy.

radiotherapy,

Bronchial arterial infusion, Bronchogenic

INTRODUCTION

cancer, Split-course,

Chemo-

when used prior to definitive local treatment (9). Moreover, there is in vitro evidence that certain agents in treating NSCLC, including cisplatinum (DDP), sensitize tumor cells to radiation (7). Weitburg and Posner have demonstrated an 86% response rate, including 14% clinical remissions, in 44 patients receiving concurrent TRT (51.0-54.0 Gy), infusion cisplatinum (25 mg/m’ days l-4), and bolus etoposide (Vp16-213) (100 mg/m’ days 2 and 4), with chemotherapy administered weeks 1 and 4 of TRT (16). Of the 44 patients enrolled on the study, 21 were successfully resected, and in eight resected specimens no tumor cells were seen. Median survival of this group was 15.7 months. Although fractionation is one of the most important determinants of tumor response and normal tissue tolerance in radiation therapy, single fraction per day schedules, accepted as “standard,” evolved empirically (5).

Locally advanced nonsmall cell lung carcinoma (NSCLC) is a major public health risk in the US, accounting for nearly 40,000 patient deaths annually. Standard therapy for inoperable patients with Stage IIIB and bulky IIIA disease has remained thoracic radiotherapy (TRT), at a dose of 60.0 Gy, administered in daily fractions weekdays for 6 weeks (12). Unfortunately, median survival time with this approach is 8- 12 months in most cases, with a 2-year survival rate of lo-20% (10). The 5-year overall survival rate does not exceed 5-7% (4). Attempts to improve outcome have included altered radiotherapy (RT) fractionation schedules and the introduction of chemotherapy on a neoadjuvant or concurrent basis. Although generally ineffective in Stage IV or recurrent disease, studies using various combinations of drugs in Stage III disease have generated response rates as high as 73%

Reprint requests to: Yi Fang, Industrial Membrane Research Institute, University of Ottawa, Ottawa, ON, Canada KIN 6N5.

Accepted for publication 23 August 1995. 309

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Large dose per fraction schedules, usually with fewer total fractions and/or shortened overall treatment times, were often associated with decreased tumor control and increased late normal tissue sequelae (2, 6). Treatment with multiple daily fractions (MDF), using smaller than conventional doses per fraction, was a theoretically appealing approach that offered the promise of an increased total dose to the tumor, recoverable, mild to moderately increased acute normal tissue effects, and no increased late normal tissue effects. By administering fractions twice daily at 6 h intervals (hyperfractionation), normal cells will repair sublethal damage, while tumor cells will be less likely to because they are less capable of sublethal damage repair (8). Multiple daily fraction schemes typically use two or three fractions daily, with a 4-6-h interval between fractions, which takes advantage of several radiobiology principles. The “S” phase of the cell cycle is relatively radioresistant (17). In rapidly dividing tumors with large growth fractions and short cell cycle times, tumor cells in relatively radioresistant phases during the first daily fraction may redistribute into a more sensitive phase, such as G2 or Ml, before the next daily fraction. Although the time interval between fractions may also allow time for repair of sublethal damage, normal tissues are more efficient at such repair than tumor (1). To some extent, MDF may also prevent repopulation of tumor cells between fractions. With increased cell loss and tumor shrinkage, residual tumor cells may become better oxygenated and, thus, more sensitive to irradiation. In China, the l-year survival rate of advanced bronchogenie carcinoma is less than 40%, and the mean survival period is only 11.2-17 months (14, 18). The main reason is that when the diagnosis is made, most patients have advanced disease and are unresectable. This manuscript describes the use of hyperfractionated radiation therapy combined with bronchial arterial infusion, as a means to increase the concentration of chemotherapy drugs in the tumor, tested in a form as prospective comparison trial. It describes the side effects and outcome of this approach. The rationale for bronchial arterial infusion of cisplatinum and adriamycin was based on obtaining a greater antitumor effect by delivering a higher concentration of drugs to the tumor. Administration of chemotherapy in this way may result in a prolonged exposure of the tumor to higher concentrations of drug, while reducing systemic side effects. METHODS

AND MATERIALS

Eligibility criteria Eligibility criteria for this study were as follows: (a) cytologic diagnosis of locally advanced, unresectable, NSCLC without evidence of distant spread amenable to a single TRT field; (b) Eastern Cooperative Oncology Group (ECOG) performance status O-2, adequate hematologic (white blood cell count (WBC) 2 3000/mtr3; absolute neutrophil count (ANC) > 1500/mm”; platelet > 6OOOO/mm’), hepatic (bilirubin I 1.5 mg%), and renal

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function (serum creatinine zz 1.5 mgidl), a forced expiratory volume in 1 s (FEV,) 2 1.0 liter; and (c) absence of symptomatic pulmonary or cardiovascular disease and no prior history of malignancy, with the exception of nonmelanomatous skin cancer, cervical or breast carcinoma in situ. Patients had to be greater than 18 years of age and had clearly measurable disease. Pretreatment evaluation included completed history and physical examination, complete blood count, biochemical screen, posterior-anterior (PA) and lateral chest x-ray, pulmonary function tests, pre- and postbronchodilators, with diffusing capacity of carbon monoxide (DLCO) and arterial blood gas, in addition to complete metastatic staging, including bone scan and computerized tomography of thorax, abdomen, and brain. In equivocal instances, thoracotomy was used to confirm the unresectability. Informed consent in writing was obtained after the nature of the procedures was fully explained. Patient characteristics One hundred and twenty-six patients with pathologically documented advanced bronchogenic cancer including squamous cell carcinoma, adenocarcinoma, large cell carcinoma, divided randomly into four groups, were treated between January 1988 and January 1990, prospectively (Table 1). Group 1 received infusion of bronchial artery combined with hyperfractionated radiation. Group 2 received infusion of bronchial artery using DDP with radiation. Group 3 received chemotherapy with splitcourse radiation. Group 4 received radiation only. The numbers of the males were 28,29, 27, and 29 for Groups I, 2, 3, and 4, respectively. The numbers of the females were 2,4,6, and 1 for Groups I, 2, 3, and 4, respectively. The numbers of the patients in each age group for Groups Table 1. Characteristics of patients with advanced bronchogenic cancer treated by four methods Characteristics Gender Male Female Age

30-39 40-49 50-59 260

Cell type Squamous cell Adenocarcinoma Large cell Stage* I II III

Group 1 Group 2 Group 3 Group 4 30 cases 33 cases 33 cases 30 cases 28 2

29 4

27 6

29

0 5

0

2

7

6 19

8 12 13

9 15

3 4 12

11

20 7 3

21 7 5

18 9 6

21 6 3

0

0 13 20

0 10

0

9 21

23

1

8 22

* UICC Stages are defined as follows: Stage I, Tl -2 NO MO; Stage II, Tl-2 Nl MO; Stage III, Tl-4 N2 MO.

Combined

hyperfractionated

radiotherapy

1, 2, 3, and 4 are: between age 30-39, 0, 0, 2, and 3, respectively; between age 40-49, 5, 8, 7, and 4, respectively; between age 50-59,6, 12,9, and 12, respectively; more than 60 years old, 19, 13, 15, and 11, respectively. For Groups 1, 2, 3, and 4, the cell types were, squamous cell, 20, 21, 18, and 21 cases, respectively; adenocarcinoma, 7, 7, 9, and 6, respectively; large cell, 3, 5, 6, and 3, respectively. Patient numbers in different groups were: Stage I, zero for all groups; Stage II, 9, 13, 10, and 8 for Groups 1, 2, 3, and 4, respectively; Stage III, 2 1, 20, 23, and 22 for Groups 1, 2, 3, and 4, respectively. Intemational Union Against Cancer Corporation (UICC) Stages are defined as follows: Stage I, Tl-2 NO MO; Stage II, Tl-2 Nl MO; Stage III, Tl-4 N2 MO. The following examinations were mandatory: chest x-ray, bronchoscopy, computed tomography (CT) of the chest, and ultrasonography. Abdominal computed tomography and bone scan were conducted if distant metastasis was suspected. Computed tomography of brain was done if signs suggestive for metastasis were presented. Therapy A linear accelerator unit was used with a source-axis distance of 100 cm. All of the patients were treated with 15 MV photons. Group 1. Using the Seldinger technique (15), the catheter was introduced percutaneously into the femoral artery, and placed into the bronchial artery. After infusion 3-5 ml of ultrast or omnipaque, an x-ray chest film was taken and bronchial artery was developed, so we were sure that the tip of the catheter had been placed in the bronchial artery. Then the chemotherapy agents were administered into the bronchial artery through the catheter. For squamous cell, DDP 60 mg + 0.9% normal saline solution (NS) 80 ml first, then adriamycin 40 mg + 0.9% NS 20 ml; for adenocarcinoma, DDP 60 mg + 0.9% NS 80 ml first, then adriamycin 40 mg + 0.9% NS 20 ml, and last, mitomycin 10 mg + 0.9% NS 20 ml or Etoposide (Vp16213) 100 mg + 0.9% NS 30 ml. For large cell, the same as the squamous cell (Table 2). The sequence was: DDP adriamycin mitomycin or Vp16-213. Cisplatinum 60 mg was diluted by 0.9% salt solution 80 ml. Adriamycin was diluted by 0.9% salt solution 20 ml. Mitomycin was diluted by 0.9% salt solution 20 ml. Etoposide was diluted by 0.9% salt solution 60 ml. Two weeks after the first

Table

2. Drugs

(per DDP

Squamous cell* Adenocarcinoma* Large cell*

60 mg 60 mg 60 mg

infusion)

and schedule

Adriamycin 40 mg 40 mg 40 mg

for

Mitomycin

Group 1 Vp16-213

10 mg or 100 mg -

* The sequence was: DDP -+ Adriamycin + mitomycin + or Vp16. 213. DDP 60 mg was diluted by 0.9% salt solution 80 ml. Adriamycin was diluted by 0.9% salt solution 20 ml. Mitomycin was diluted by 0.9% salt solution 20 ml. Etoposide (Vpl6-213) was diluted by 0.9% salt solution 60 ml.

and bronchial

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infusion of bronchial artery, radiation began in aoses of 1.2 Gy, twice a day, 5 days a week, and 36.0 Gy tumor dose was delivered in 3 weeks. Then, infusion of bronchial artery followed. A second course of radiotherapy was given after 2 weeks rest. Infusion of bronchial was repeated two times 5 and 10 weeks later. A total dose of 7.2 Gy were given in 8 weeks. Group 2. Using the Seldinger technique, the catheter was introduced percutaneously into the femoral artery, and placed into the bronchial artery. After infusion 3-5 ml of ultrast or omnipaque, a chest film was taken and bronchial artery was developed. We were sure that the tip of the catheter had been placed in the bronchial artery. Then, DDP 60 mg + 0.9% NS 80 mg was administered, and 15 days later, this procedure was repeated. The patients (15 cases) had three times infusion of bronchial artery if they had WBC > 3000/mm3 after two times infusion of bronchial artery. Otherwise, only two times infusion was given. Further, the radiation was given in doses of 2.0 Gy, once a day, 5 days a week, for a total dose of 60.0 Gy, delivered in 7 weeks. Group 3. Chemotherapy was combined with radiation according to different pathologic types. Different chemotherapy protocol was chosen. Protocol for squamous cell was: DDP 20 mg + 0.9% NS 250 ml, intravenous injection (iv.), days 1-4; VCR 1 mg + 0.9% NS 20 ml, day 1; cyclophosphamide (CTX) 400 mg + 0.9% NS 250 ml, i.v., days l-4. Protocol for adenocarcinoma was: DDP 20 mg + 0.9 NS 250 ml, i.v., days 1-4; VCR 1 mg + 0.9% NS 20 ml, day 1; Vp16-213 100 mg + 0.9 NS 250 ml, iv., days l-4. Protocol for large cell was the same as for squamous cell. After chemotherapy, the patients had a 2 week rest. Afterwards, radiation was given, 2.0 Gy a day, 5 days a week. The second chemotherapy was given when the dose reached 30.0 Gy, by following the same protocol. Then, again a 2-week rest was given and the second course radiation was given using the same prescribed dose. The total radiotherapy dose was 60.0 Gy. Group 4 was treated with conventional radiation. The protocol for squamous cell and large cell was 1.8 Gy, once a day, five times a week, for a total dose of 60.0 Gy; for adenocarcinoma, 2.0 Gy, once a day, five times a week, for a total dose of 70.0 Gy in 7 weeks.

RESULTS Tumor response was evaluated with CT, magnetic resonance imaging (MRI) or chest films 1 month after treatment. The results are summarized in Table 3. The definitions used in the table are as follows: complete response, disappearance of all the tumor; partial response, decreasing more than 50% of the tumor, but not completely; no response, no change of the tumor or decreasing less than 50% of all the tumor. The results show that complete response is 6 (20%), 4 ( 12.1%), 2 (6.6%), and 2 (6.6%) for Groups 1,2,3, and 4, respectively; that partial response is 22 (73.3%), 21 (63.6%), 19 (57.6%), and 17 (56.7%) for

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Table 3. Response to treatmentof 126patients* Response(%)

Group 1” cases(%)

Group 2bcases(%)

Group 3’ cases(%)

Group 4* cases(%)

Completeresponse’ Partial responses No response”

6 (20.0) 22 (73.3) 2 (6.6)

4 (12.1) 21 (63.6) 8 (24.3)

2 (6.6) 19 (57.6) 12 (36.3)

2 (6.6) 17 (56.7)

30

33

33

30

Total

11 (36.7)

* For the 1, 2, and3-year survival rates,the resultsof Group 1 are statisticallydifferent from that of Groups3 and4 (p-value < 0.05). But the resultsof Group 1 arenot statisticallydifferent from that of Group 2 due to smallnumbersof patients. ’ Completeresponse:disappearance of all the tumor. t Partial response:decreasingmore than 50% of all the tumor, but not completely. I No response:no changeof the tumor or decreasinglessthan 50% of all the tumor. aGroup 1: combinationof hyperfractionalradiotherapywith bronchialarterial infusion of anticancerdrugs(30 cases). hGroup 2: combinationof conventionalradiotherapywith bronchial arterial infusion of anticancerdrugs(33 cases). ’ Group 3: combinationof systemicchemotherapyand split-courseradiotherapy(33 cases). * Group 4: conventionalradiotherapyonly (30 cases). Groups 1, 2, 3, and 4, respectively; that no response is 2

(6.6%), 8 (24.3%),

12 (36.3%), and 11 (36.7%) for

Groups 1,2,3, and 4, respectively. All the patients except

three were followed up for 3 years. These three patients were considered dead when the follow-up was lost. Table 4 shows the l-, 2-, and 3-year survival rates for

the four groups. The l-year survival rates for Groups 1, 2,3, and 4 are 80%, 63.6%, 48.5%, and 30%, respectively. The 2-year survival rates for Groups 1, 2, 3, and 4 are 23.3%, 15.15%, 9.1%, and 6.6%, respectively. The 3-year survival rates for Groups 1, 2, 3, and 4 are lo%, 3.3%, O%, and O%, respectively. For the l-, 2-, and 3-year survival rates, the results of Group 1 are statistically different from that of Group 3 and 4 (p < 0.05). But the results of Group 1 are not statistically different from that of Group 2. The problem is that the numbers of patients were small. Failure of treatment is local recurrence, which is 61%, 74%, and 84%, respectively for Groups 2, 3, and 4 (the mean is 73%), and brain metastasis(15%). Failure

of Group 1 is brain metastasis (42.8%) and local recurrence (14.5%). Table 4. 1, 2, and 3-year survival ratesof the four groups* Survival rates (%I

Group 1” case(%)

Group 2b

l-Year 2-Year 3-Year

24 (80.0) 7 (23.3) 3 (10.0)

Group 3” case(%)

Group 4* case(%)

21 (63.6) 5 (15.1)

16 (48.5)

3 (9.1)

9 (30) 2 (6.6)

1 (3.3)

0 (0)

0 (0)

case(%)

* For the 1, 2, and3-year survival rates,the resultsof Group 1 are statisticallydifferent from that of Groups3 and4 @-value < 0.05). But the resultsof Group 1 arenot statisticallydifferent from that of Group 2 due to smallnumbersof patients. aGroup 1: combinationof hyperfractionalradiotherapywith bronchialarterial infusion of anticancerdrugs(30 cases). hGroup 2: combinationof conventional radiotherapy with bronchialarterial infusion of anticancerdrugs(33 cases). ’ Group 3: combinationof systemicchemotherapyand splitcourseradiotherapy(33 cases). * Group 4: conventional

radiotherapy

only (30 cases).

Side effects of bronchial infusion anticancer drugs were: (a) digestive tract: vomiting (44 out of 63); nausea (46 out of 63); no appetite (48 out of 63); (b) hemopoietic system: WBC decreasing to below 4000/n& (6 out of 63); (c) toxicity to heart: electrocardiogram (EKG) showed mild myocardiac injury (2 out of 30), after 1 week, and when examined EKG again, was no&, (d) functions of liver and kidney: normal; (e) others: tight feeling of chest (4 out of 63), and weakness (41 out of 63). Complications Bronchial infusion was performed 161 times without serious complications. One patient had a hematoma (> 5 cm) at the point of percutaneous puncture, which was absorbed 2 weeks later. No damage to the cord related to the arterial infusion was observed. DISCUSSION The reported complications of bronchial infusion are hematoma (> 5 cm) or bleeding at the point of percutaneous puncture, broken guide wire in small iliac artery, paraplegia caused by injury of the radicular artery, and so on (14, 18). In our series, only one patient had a hematoma > 5 cm. No other serious complications were observed. Our experience was that all the catheters and guide wires were examined carefully before the procedure. While the procedure was being performed, everything was carefully manipulated. If any resistance to the catheter passage was observed, fluoroscopy was used to determine the catheter location. We used nonionic contrast medium because it is safe for thf spinal cord. It was consideredsafer for the kidneys.

In this article, Group 1 (combined arterial chemotherapy and hyperfractionated RT) had a better response rate than the other three groups. Survival rates at 1, 2, and 3 years were also better for Group 1. Some authors believe that hyperfractionation increases radiosensitivity through redistribution and less dependence on oxygen effect. The greater the number of dose fractions in a treatment regimen, the greater is the opportunity for tumor cells to be sensitized

Combined

hyperfractionated

radiotherapy

and bronchial

by redistribution in the division cycle; that is to say, cells in a radioresistant phase at the time of any given fraction are more likely to be caught in a sensitive phase at the time of a subsequent fraction (3, 11, 13). Thus, hyperfractionated RT may improve local control. Adriamycin is one of the most potent anticancer agents. Unfortunately, clinical use of adriamycin has been associated with cardiomyopathy, which is dose dependent. Therefore, cumulative doses < 550 mg/m’ have been recommended for i.v. use. There were 10 patients over 60 years old in Group I. Only three of them developed detectable drug-related myocardial damage on EKG, which was transient and returned to normal after 1 week. It shows that advanced age is not a

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contraindication to bronchial arterial infusion of adriamycin, but adriamycin should not be used for patients who have preexisting myocardial damage on EKG. Our data showed that the local control rate of Group 1 was better than that of the other three groups, but three of seven cases who survived over 1 year developed brain metastasis. In summary, combined hyperfractionated RT and infusion of the bronchial artery chemotherapy for advanced lung cancer yield better results than conventional RT, but the relationships of dose time, fractionational times, and drug compatibility need further study.

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10. Mountain, C. A new international staging system for lung cancer. Chest Suppl. 89:2253-2338; 1986. 11. Perez, C. A.; Brady, L. W. Principles and practice of radiation oncology. Philadelphia, PA: J. B. Lippincott; 1991:103-104. 12. Perez, C. A.; Brady, L. W. Impact of irradiation technique and tumor extent in tumor control and survival of patients with unresectable nonoat cell carcinoma of the lung. Report by the Radiation Therapy Oncology Group. Cancer 50:1091-1099; 1982. 13. Prodos, M. D. Hyperfractionated craniospinal radiation therapy for primitive neuroectodermal tumor: Early reports of a pilot study. Int. J. Radiat. Oncol. Biol. Phys. 28:431438; 1981. 14. Qian, M. Complications of bronchial arterial infusion anticancer drugs. Chin. J. Radiol. 23:143; 1989. 15. Viamonte, M. J. Guided catheterization of the bronchial arteries. I. Technical considerations. Radiology 85:205; 1965. 16. Weitburg, A. Combined modality therapy for stage IIIA nonsmall cell carcinoma of the lung. Proc. Am. Sot. Clin. Oncol. 9:A 872; 1990. 17. Withers, H. R. Cell cycle redistribution as a factor in multifraction irradiation. Radiology 114: 199-202; 1975. 18. Zhang, H.; Qian, M. Preliminary report of combination of radiotherapy with bronchial arterial infusion cis-platin to treat advanced lung cancer. Chin. J. Radiat. Oncol. Biol. Phys. 1:8; 1987.