Pergamon

l Clinical Original Contribution

Int. J. Radiation Oncology Biol. Phys., Vol. 31. No. 2, pp. 267-272, 1995 Copyright 0 1994 Ekevier Science Ltd Printed in the USA. All rights reserved

0360-3016/95 69.5Ot.00

0360-3016(94)E0021-B

A PHASE III STUDY OF ACCELERATED RADIOTHERAPY WITH AND WITHOUT CARBOPLATIN IN NONSMALL CELL LUNG CANCER: AN INTERIM TOXICITY

ANALYSIS OF THE FIRST 100 PATIENTS

DAVID BALL, F.R.A.C.R.,* JAMES BISHOP, M.D., F.R.A.C.P., F.R.C.P.A.,* JENNIFER SMITH, PH.D,* ELIZABETH CRENNAN, F.R.A.C.R.,* PETER O’BRIEN, F.R.A.C.R.,’

SIDNEY DAVIS, F.R.A.C.R.,* GAIL RYAN, D.R.A.C.R.,* DAVID JOSEPH, F.R.A.C.R.’ AND QUENTEN WALKER, F.R.A.C.P., F.R.A.C.R., F.R.C.P.A.§

*Peter MacCallum Cancer Institute, 48 1 Little Lonsdale Street, Melbourne, Victoria 3000, Australia +Royal Adelaide Hospital, Adelaide, South Australia *Newcastle Mater Misericordiae Hospital, Newcastle, New South Wales

$QueensIand Radium Institute, Brisbane, Queensland

Purpose: In 1989 we initiated a multicenter randomized trial to determine if accelerated radiotherapy with or withoutconcurrent carboplatin improves local control and survival in patients with limited nonsmall cell lung cancer. This interim analysis was performed on the first 100 patients to determine whether the toxicity of the four treatment arms is accentable. Methods and Materials: One hundred patients with limited nonsmall cell lung cancer have been randomized to receive one of four treatments: arm I, radiotherapy 60 Gray (Gy) in 30 fractions in 6 weeks: arm II. accelerated __ _ _. radiotherapy 60 Gy in 30 fractions in 3 weeks; arm III, radiotherapy as in arm I plus carboplatin 350 mg/m* during weeks 1 and 5 of radiotherapy, arm IV, radiotherapy as in arm II plus carboplatin 350 mg/m’ during week 1. Survival was measured for the group as a whole and treatment-related toxicities in the four arms were compared. Results: The estimated median survival for all 100 patients was 17.1 months with 33% estimated survival at 2 years. The major toxicities were hematologic and esophageal. Patients receiving carboplatin had more neutropenia (p < 0.0001) and thrombocytopenia (p = 0.002) than patients receiving radiotherapy alone, and this was most marked in patients on arm III. Both carboplatin and accelerated radiotherapy separately caused more severe esophagitis when compared to conventional radiotherapy alone (p = 0.011 andp = 0.0017, respectively). Esophagitis was more prolonged in patients having accelerated radiotherapy (p < 0.0001, median duration 3.2 months compared with 1.4 months for patients receiving conventional fractionation). Six patients (23%) treated on arm II have required dilatation of esophageal stricture, one dying with a laryngo-esophageal fistula. Conclusion: In patients receiving radiotherapy for unresectable lung cancer, overall treatment time can be halved and carboplatin administered concurrently with increased but acceptable esophageal and hematologic toxicity.

Lung cancer, Nonsmall cell, Radiotherapy, Accelerated fractionation, Carboplatin.

INTRODUCIION rience suggests that high doses are associated with im-

Uncontrolled disease at the primary site is an important cause of death in patients with nonsmall cell lung cancer (NSCLC) and explains why surgery is the most effective treatment for patients with resectable disease. If local control can be improved in patients with unresectable disease, survival may also improve. Higher doses of ra- diotherapy to the primary site and draining lymph nodes have produced higher response rates (8), and our expe-

proved survival (2). We reasoned that further improve- ments in local control (and survival) may be possible by counteracting two possible causes of treatment failure; namely, accelerated repopulation during treatment, and the cancer cells’ capacity to repair radiation injury. We have previously reported a pilot study ( 1) in which patients receiving radiotherapy were given carboplatin (to inhibit repair) and were treated over a shorter overall time (to counteract accelerated repopulation). We had chosen car-

Reprint requests to: Dr. David Ball. the Newcastle Mater Misericordiae Hospital, Christine Thorpe Acknowledgements-We wish to thank the data managers who at the Queensland Radium Institute and Janey Stone at the Trial have collected the data and helped in the organization of the Centre, Peter MacCallum Cancer Institute. This trial has been trial at each institution, namely Jill Dipell and Ann-Maree Hayes supported by a research grant from the National Health and at the Peter MacCallum Cancer Institute, Nancy Olszewski and Medical Research Council of Australia. Jan Goulding at the Royal Adelaide Hospital, Vicky Clarke at Accepted for publication 5 January 1994.

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268 I. J. Radiation Oncology 0 Biology 0 Physics Volume 3 I. Number 2. 1995

boplatin not only because it is less likely to cause nausea and vomiting than cisplatin, but also because it has been shown to have a mild radiosensitizing effect on RIFl cells in vitro, and is a powerful inhibitor of repair of sublethal damage in the same system (3). Although the toxicity of the carboplatin and accelerated treatment was increased, it was acceptable, and we felt justified in proceeding with a randomized trial of 200 patients to test the value of adding carboplatin and shortening the treatment time in patients with nonsmall cell lung cancer.

A review of the acute and longer term toxicity in the first 100 eligible randomized patients forms the subject of this report.

METHODS AND MATERIALS

Between April 3, 1989, and November 5, 1992, 102 patients with histologically or cytologically proven non- small cell lung cancer were randomized to one of four treatment arms, provided they met the following eligibility criteria:

1. Performance status 0 or 1 [Eastern Co-operative On- cology Group grades (6)].

2. Disease confined to primary site and regional lymph nodes. Patients were ineligible if they had cervical lymph node involvement or pleural effusion and all patients had a radioisotope bone scan and computed tomographic (CT) scans of chest and upper abdomen to exclude metastatic disease. Patients with adenocar- cinema or large cell carcinoma had a CT scan of brain as well to exclude cerebral metastases.

3. Pretreatment neutrophil count 2 1.5 X log/L and platelet count 2 100 X 109/L.

4. No prior radiotherapy or chemotherapy. 5. Weight loss less than 10%. 6. Written informed consent.

Two patients with pleural effusions were randomized in error, but, because of their ineligibility, they have been excluded, leaving 100 patients in this analysis.

The treatment arms are as follows: Arm I-Conventional radiotherapy, 60 Gy in 30 frac-

tions, five fractions per week for 6 weeks. Arm II-Accelerated radiotherapy, 60 Gy in 30 frac-

tions, 10 fractions per week for 3 weeks. Arm III-Conventional radiotherapy as in Arm I, plus

carboplatin 70 mg/m2/day intravenously on days l-5 and 29-33 of radiotherapy.

Arm IV-Accelerated radiotherapy as in Arm II, plus carboplatin 70 mg/m2/day intravenously on days l-5 of radiotherapy.

Radiotherapy All patients were planned to receive radiotherapy to

the primary site and regional nodes plus a 2 cm margin, using a 6 MV linear accelerator. Planning was CT assisted, and corrections were made for tissue inhomogeneities.

Prescribed doses were specified so that variation in the target volume was no greater than + 5% of the prescribed dose. Two-thirds of the dose was given with anterior and posterior parallel opposed fields, including the spinal cord, and one-third was given using parallel opposed oblique or lateral fields, angled so as to exclude the spinal cord from the treated volume. The total dose to the spinal cord was not permitted to exceed 45 Gy. In those patients re- ceiving carboplatin, radiotherapy was given 30 to 60 min after completion of the carboplatin infusion. On the days carboplatin was administered, the treatment immediately following was given by obliques or laterals to avoid any potential sensitization of the spinal cord. In those patients randomized to two treatments per day (accelerated radio- therapy arms) the minimum interval between treatments was set at 6 hr. For two weeks of the treatment, oblique or lateral fields were used once per day so that the spinal cord was included in the treated volume for only one fraction per day; for the third week the spinal cord was treated twice a day.

Chemotherapy Patients randomized to arms III or IV were given car-

boplatin approximately 1.5 to 2 hr before the first radia- tion dose. The dose of carboplatin was 70 mg/m2 in 500 mL normal saline infused over a period of 1 hr on days l-5. In those patients receiving conventional fraction- ation, a second course of carboplatin was given on days 29-33, at the same dose and timing as for the first course, provided the neutrophil count was 2 1.5 X 1 Og/L and the platelet count was 2 100 X 109/L. If myelosuppression below these levels was present on day 29, the second course was to be deferred for a week. If grade 4 toxicity was encountered following the first course of carbopiatin, the dose for the second course was to be reduced by 50%. Doses were also to be modified if patients had renal im- pairment as indicated by low creatinine clearance or high serum creatinine.

Toxicity Most toxicities were graded according to the World

Health Organization (WHO) guidelines (6). Esophageal toxicity was graded as follows: 0, no symptoms; 1, mild pain, normal diet, no medication; 2, pain, requires med- ication to eat solids; 3, liquid diet only possible; 4, severe pain, alimentation not possible. Patients were seen and had toxicity assessed weekly while having treatment and thereafter every 4 weeks for at least 4 months. Late tox- icities were defined as those occurring more than 4 months after commencing radiotherapy. Acute and late toxicities occurred in continuity in some patients with esophagitis. An esophageal stricture was said to have occurred if the patient required at least one mechanical dilatation to im- prove swallowing.

Statistical analysis Survival and duration of esophagitis curves were cal-

culated using the Kaplan-Meier product limit method

Accelerated radiotherapy plus carboplatin in nonsmall cell lung cancer 0 D. BALL et al. 269

Table 1. Patient characteristics ( 100 patients)

Characteristics at randomization Number

Sex Male 80 Female 20

ECOG performance status 0 32 1 68

Histology Squamous 72 Nonsquamous 28

Stage* I 23 II 4 III 72 Unknown 1

Weight loss in last 3 months None 63 2 10% 37

* UICC TNM (4th edition, 1987) staging criteria were used (7).

and confidence intervals for estimated median survival or duration were calculated using the Brookmeyer-Crow- ley method (5).

Survival was measured from the date of randomization to the date of last contact or death, and all deaths were counted regardless of cause. All patients were followed up to between December 1992 and April 1993 inclusive, giving a median follow-up for living patients of 13 months (range 3 to 32 months). No close-out date was used in the analysis because it was considered desirable to include the latest information available for all patients in this interim report.

Duration of esophagitis was measured from the date esophagitis was first noted at a routine assessment until the date it was resolved. Patients who were treated but who did not develop esophagitis were included in the curve with a duration of 0. For patients whose esophagitis was still present at their last assessment, the duration was cen- sored at that date. The Mantel-Cox log rank test was used to test differences between curves for different treatment groups.

Comparisons between treatment arms of the worst grades of toxicities reached were tested using the Mann-

Whitney U-test. Fourteen specific toxicities were exam- ined, and for eight of them six formal statistical compar- isons were carried out between arms or combinations of arms. Reported p values have not been adjusted for mul- tiple comparisons, but, if the 48 comparisons were in- dependent, then a conservative statistical significance level for each comparison would be 0.05/48, that is 0.001, to preserve an overall significance level of 0.05.

RESULTS

Table 1 shows the characteristics of the first 100 eligible patients randomized. The median age of patients was 66 years, range 40-79 years. Twenty-five patients have been randomized to conventional radiotherapy (arm I), 26 to accelerated radiotherapy (arm II), 25 to conventional ra- diotherapy plus carboplatin (arm III), and 24 to acceler- ated radiotherapy plus carboplatin (arm IV).

Three patients received no treatment. One decided to have surgery, one developed metastases before the com- mencement of treatment, and the third patient withdrew consent. One patient received a total of 6 Gy only when metastases were discovered and he had no further radio- therapy. These four patients were excluded from the tox- icity analysis. In addition, one patient received only 32 Gy because of early death and one received 58 Gy and none of his planned carboplatin because he withdrew consent. The remainder received 60 Gy. Three patients had short breaks in their radiotherapy treatment.

Hematologic toxicity Patients randomized to receive carboplatin (arms III

or IV) had significantly more neutropenia than patients randomized to receive radiotherapy alone (arms I or II) (p < 0.0001). Similarly, carboplatin patients had more thrombocytopenia, although this was not quite statistically significant (‘J = 0.002). Four patients on arm III were unable to have the second course of carboplatin because of neutropenia and/or thrombocytopenia. No other dose modifications for carboplatin were required. There were no deaths from sepsis while neutropenic and no neutro- penia-related infections.

Esophagitis Table 2 shows the worst level of esophagitis recorded

during the first 4 months after commencing treatment for

Table 2. Worst grade of esophagitis by treatment arm (96 patients)

Grade

Without carboplatin

Conventional RT Accelerated RT

No. % No. %

With carboplatin

Conventional RT Accelerated RT

No. % No. %

0 5 22% 0 0% 1 4% 1 4% 1 8 35% 5 19% 5 21% 4 17% 2 8 35% 12 46% 11 46% 9 39% 3 2 9% 8 31% 6 25% 9 39% 4 0 0% 1 4% 1 4% 0 0%

270 I. J. Radiation Oncology 0 Biology 0 Physics Volume 31. Number 2. 1995

Table 3. Duration of esophagitis (96 patients)*

Estimated duration Number of in months median

Treatment arm patients (95% CI)

I conventional RT 23 1.4 (0.7-2.0) II accelerated RT 26 3.2 (2.8-5.4)

III conventional RT + carbo. 24 1.6 (1.3-2.4) IV accelerated RT + carbo. 23 2.4 (1.6-4.3)

* RT = radiotherpay, carbo. = carboplatin, CI = confidence interval, SE = standard error.

Estimated % with esophagitis

at 4 months)

% (SE)

5% (5%) 48% (10%)

5% (5%) 32% (11%)

each treatment arm. Although more severe esophagitis was seen in patients randomized to accelerated radio- therapy (with or without carboplatin) or conventional fractionation with carboplatin, the differences were not quite statistically significant (p = 0.0041, p = 0.0017, p = 0.0 11, respectively).

Table 3 shows the duration of esophagitis by treatment arm. There is a highly significant difference between the arms with longer duration of esophagitis with accelerated radiotherapy (p < 0.000 1, log rank test). A multivariate analysis of factors influencing the duration of esophagitis was carried out using step-wise regression in the Cox pro- portional hazards model. The factors tested in the model were treatment (accelerated radiotherapy or conventional, carboplatin or no carboplatin) and length of treatment field (< 140 mm, 140-159 mm, > 160 mm). The only factor that affected duration of esophagitis was accelerated

radiotherapy. A comparison of the duration of esophagitis between conventional and accelerated radiotherapy groups is shown in Figure 1.

Seven patients developed dysphagia requiring mechan- ical dilatation (“stricture”). Six of the seven had acceler- ated radiotherapy (Table 4). Patient 4 subsequently de- veloped a malignant trachea-esophageal fistula after re- treatment. Patient 72 died with a laryngo-esophageal fistula. The fistula developed at the upper level of the radiation field and biopsies of the fistula were negative for malignancy. The computed dose at the site of the fis- tula was 62.8 Gy, given in 30 fractions over 3 weeks.

Pulmonary toxicity There were no significant differences in pulmonary

toxicity between the treatment arms. However, the only instances of WHO grade 4 toxicity were seen in two pa-

. . . . . . . Accelerated FIT 49 pts

- Conventional RT 47 pts

80

60

6 A 1; 1;; 2b 214 2; MONTHS OF ESOPHAGITIS

Number not yet resolved Accelerated 48 18 6 4 2 1 1 0

Conventional 41 2 0

Fig. 1. Duration of esophagitis in 96 patients randomized to conventional radiotherapy or accelerated radiotherapy (p < 0.000 I, Mantel-Cox log rank test). Four patients who received little or no radiotherapy were excluded.

Accelerated radiotherapy plus carboplatin in nonsmall cell lung cancer 0 D. BALL et a/. 271

Table 4. Patients requiring mechanical dilatation for dysphagia (“stricture”)

Patient Treatment Date commenced radiotherapy number arm* month/year

4 II 5/89 27 II 7190 49 II l/9 1 72 II 6192 77 II 7192 18 111 8192 83 II 9192

Date(s) of dilatation(s) Date of death month/year month/year

5/91f 819 1 l/91, 1 l/91 12/91

1 l/91, 3192, l/93 Alive l/92, l/93 4193

10192 Alive 4193 Alive 2193 Alive

* Arm II = accelerated radiotherapy alone, Arm III = conventional radiotherapy + carboplatin. + Patient had second course of thoracic radiotherapy, 30 Gy in 10 fractions, in October 1990.

tients treated with accelerated radiotherapy plus carbo- platin. One of these patients died of chronic pulmonary sepsis superimposed on lung fibrosis without evidence of active cancer.

Spinal cord toxicity One patient treated with conventional radiotherapy plus

carboplatin developed transient 1’Hermitte’s sign.

Survival At last contact, 39 patients were still alive and 5 1 had

died of disease progression. Eight patients died of other causes, mostly disease related, and two deaths were at- tributed to the protocol treatment as described above (one laryngo-esophageal fistula, one pulmonary sepsis). The estimated median survival for the whole group is 17.1 months (95% confidence interval 13.2-22.0 months) with

80

60

an estimated 2-year survival of 33% (standard error 6%) (Fig. 2).

DISCUSSION

This analysis of treatment toxicity experienced by the first 100 patients with NSCLC treated in a randomized clinical trial has been performed to determine whether any major treatment-related complications have occurred in the innovative treatment arms using combined che- motherapy/radiotherapy or accelerated radiotherapy fractionation. Two reports of altered fractionation for NSCLC patients have been published, one with hyper- fractionation (4) and one with a mixture of hyperfrac- tionation and acceleration (9). In both instances, the dose per fraction was reduced empirically to compensate for any potential increase in toxicity due to an increase in

40 -

0 I I I I I I I 0 6 12 18 24 30 36 42

MONTHS FOLLOWING RANDOMIZATION

Number at risk 100 81 50 27 15 6 1 0

Fig. 2. Survival of all 100 patients.

272 I. J. Radiation Oncology 0 Biology 0 Physics

total dose (4) or shortening of overall treatment time (9). We have chosen to alter only one variable, namely overall treatment time, in this phase III study of three experi- mental arms, keeping fraction size the same throughout. We are, thus, able to test the effect of altered treatment time on acute and late toxicity and on disease control, unconfounded by factors such as variation in fraction size.

As might be expected, patients randomized to accel- erated radiotherapy experienced more severe and more prolonged esophagitis than patients randomized to con- ventional fractionation. Patients randomized to conven- tional fractionation plus carboplatin appeared to experi- ence more severe esophagitis than patients randomized to conventional fractionation alone, suggesting radiosen- sitization of the esophageal mucosa by carboplatin. How- ever, the difference fell just short of statistical significance and there was no prolongation of esophagitis in this group.

A large proportion of patients (6/26) randomized to accelerated radiotherapy without carboplatin required mechanical dilatation for relief of dysphagia, although one of these patients developed his stricture only after retreat- ment. One patient subsequently died with a biopsy-proven malignant trachea-esophageal hstula. Another patient treated with accelerated radiotherapy died of a radiation- induced laryngo-esophageal fistula. In spite of the need for mechanical dilatation, all other patients are able to swallow and maintain their nutritional status. While esophageal stricture is of some concern, future analysis

Volume 31, Number 2. 1995

of tumor control endpoints is needed to determine if this toxicity is acceptable. No instances of esophageal stricture as defined have been seen in patients randomized to ac- celerated radiotherapy and carboplatin (arm IV).

Other toxicities were as expected, with some patients in arm III unable to have their second course of carbo- platin because of cytopenia. This may have been avoided if patients had been given their carboplatin dose according to area under the curve calculated by glomerular filtration rate rather than using body surface area. There was no significant difference in pulmonary toxicity between the treatment arms, and no permanent spinal cord injury has been seen to date, presumably because of the technique used.

The median survival of the whole group, 17 months, is very encouraging and compares favorably with an his- torical group of patients with unresectable lung cancer planned for radical treatment at Peter MacCallum Cancer Institute between 1984 and 1989, for whom the median survival was 14.5 months (2). We believe the increased acute toxicity, particularly in the accelerated treatment group, is acceptable, and we are continuing to accrue pa- tients in the study up to the planned total of 200.

Should accelerated radiotherapy prove to be of thera- peutic benefit in patients with lung cancer, the challenge will then become one of counteracting esophageal symp- toms, perhaps by the use of locally acting radioprotectors or mucosa-protecting cytokines.

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