Clinical Oncology (1997) 9:96-99 © 1997 The Royal College of Radiologists Clinical

Oncology

Original Article

Immediate Side Effects of Large Fraction Radiotherapy

S. Devereux, M. Q. F. Hatton and F. R. Macbeth Beatson Oncology Centre, Western Infirmary, Glasgow, UK

Abstract. The use of hypofractionated radiotherapy regimens is becoming more widely recognized in the palliation of non-small cell lung carcinoma (NSCLC). Anecdotal reports of chest pain, rigors and fevers in the hours that follow radiotherapy led us to perform a survey estimating the frequency and severity of these symptoms following treatment to the thorax.

One hundred and eighteen patients completed questionnaires 24 hours after palliative radiotherapy treatment; 84 were male. The median age was 67 years. One hundred and seven had histologically confirmed NSCLC. A parallel opposed technique was used in 113 patients. Doses ranged from 8 Gy in a single fraction to 60 Gy in 30 fractions.

Chest pain was reported by 54 (45.8%) patients after the first radiotherapy fraction; in 42 it com- menced within 12 hours of treatment. The pain varied in site, nature and duration; on 23 occasions, it lasted under 2 hours. Systemic symptoms (rigors, sweating, fevers) were documented on 43 question- naires, starting within 12 hours of treatment in 33 patients and on 30 occasions lasting less than 2 hours. Chest pain and systemic symptoms occurred together in 28 patients. Only 49 (41.5%) patients reported no immediate side effects.

We conclude that patients receiving palliative radiotherapy for bronchial carcinoma often develop significant symptoms in the hours following treat- ment. The timing and duration suggest a relationship with the radiotherapy, and we feel that patients should be warned of the possible occurrence of these symptoms.

Keywords: Acute side effects; Bronchial carcinoma; Radiotherapy

INTRODUCTION

A recent UK survey estimated that treatment of carcinoma of the bronchus is 10%-25% of the clinical oncologist's work-load, with over 90% of the treat- ments being given with palliative intent [1]. British

Correspondence and offprint requests to: Dr M. Q. F. Hatton, Senior Registrar, Beatson Oncology Centre, Western Infirmary, Glasgow G l l 6NT, UK.

practice is increasingly using large fraction sizes for this palliative radiotherapy [1], following trials co- ordinated by the Medical Research Council Lung Cancer Working Party (MRC LCWP) [2,3], which demonstrated equivalent palliative to more con- ventionally fractionated regimens.

At the Beatson Oncology Centre, observations of chest pain, fevers and rigors during the first 24 hours following radiotherapy [4] raised concern about the immediate adverse effects from large fraction radio- therapy treatment. The MRC LCWP trials [2,3] used diary cards to assess the quality of life and document the frequency and severity of acute radiation side effects. Unfortunately, the immediate side effects, such as chest pain sweating and shivering, were not formally monitored, and, although such complaints were recorded, no formal analysis could be made. Other studies on the use of radiotherapy treatment for the palliation of non-small cell lung cancer (NSCLC) report acute and late radiation side effects [5,6], but the occurrence of immediate adverse effects is only occasionally documented [6].

Treatment-related morbidity is a major consider- ation for any palliative treatment and we felt it was important to assess the incidence and severity of the immediate side effects of palliative radiotherapy for bronchial carcinoma. This paper reports the results of a survey performed to assess the side effects occurring within 24 hours of such treatment.

METHODS

A questionnaire was designed to obtain details of symptoms occurring during the 24 hours following radiotherapy to the thorax. The questionnaire asked specifically about the occurrence of chest pain and symptoms suggesting a systemic response to treat- ment, namely rigors, fevers and sweating episodes. If chest pain was reported, the questionnaire asked specifically for details of its site, nature, speed of onset and duration. The speed of onset and duration of any systemic symptoms were also recorded. Details were also obtained of similar symptoms occurring prior to treatment, and medication used in the hours following the radiotherapy.

We requested that the questionnaire should be completed and returned 24 hours after treatment.

Immediate Side Effects of Large Fraction Radiotherapy 97

Symptoms that started after this time have been excluded from further analysis. The Pearson Chi- square test was used to determine the influence of fraction size o n the occurrence of immediate symptoms.

Between April 1993 and October 1995, patients with advanced Stage III and IV bronchial carcinoma, who were not suitable for curative treatment and who were attending for thoracic radiotherapy, were asked to complete this questionnaire. It was explained that the purpose was to assess the incidence of immediate side effects following treatment to the chest.

The dose of radiotherapy given was largely based on the patient's performance status following the results of recent MRC studies [2,3]. In the first phase of the study, patients attending for treatment received large fraction sizes (>8 Gy) and completed the questionnaire 24 hours after radiotherapy. Some patients were given treatment with two large fractions one week apart, and were asked to com- plete questionnaires after both treatments to assess the reproducibility of the symptoms. To determine if these symptoms were confined to treatment with large fraction sizes, a second phase of the study included patients receiving smaller fraction sizes of up to 4 Gy.

RESULTS

One hundred and eighty questionnaires were issued; 140 were returned by 118 patients. Eighty-four patients were male; the median age was 67 years (range 44-91). Histological confirmation of NSCLC was obtained in 107 patients. Eight were treated for small cell lung cancer (SCLC) and in three no histological diagnosis was reached. Only six patients

Table 1. The different radiotherapy fractionations and immediate

(all with SCLC) had received previous chemother- apy; none had had prior radiotherapy treatment.

All patients received palliative radiotherapy treat- ment to the mediastinum, 113 using a parallel opposed technique, with the dose prescribed to the midplane and a modal field size of 10 x 12 cm (range 8 x 8 cm to 13 x 15 cm). The remaining five patients were treated isocentricaUy with three or four fields. The dose and fractionation are summarized in Table 1, with the total dose for the 19 patients treated with the smaller fraction sizes ranging from 20 Gy in five daily fractions to 60 Gy given in 30 fractions over 6 weeks.

When the 118 questionnaires completed after the first fraction of radiotherapy were analysed (Table 2), 54 reported chest pain. The pain varied in site and nature. Twenty-five reported similar pain occurring at various times prior to radiotherapy; four compared it to previously experienced angina pain. Chest pain started within 12 hours of treatment in 42 of the 54 reports and was present for up to 24 hours. However, in 23 (42.6%) questionnaires, the pain was short- lived, lasting less than 2 hours. The pain was severe enough for analgesics to be used in half the patients.

In the 22 patients who completed questionnaires after the two fractions of their palliative radiother- apy, 13 reported chest pain; six experienced pain after both treatments, three after the first treatment only and four after the second. Systemic symptoms were documented by 11 of the 22 patients, with five experiencing these after both treatments. These results suggest that immediate symptoms are not confined to the first fraction, but we have not per- formed any further statistical analysis on these questionnaires in view of the small numbers involved.

Forty-three patients reported 'systemic' symptoms after the first treatment; 18 rigors, 24 feeling feverish and 30 sweating episodes. Clearly, a number of

symptoms experienced by the patients following treatment

Fraction size (Gy) Schedule No. patients

Phase 1 Phase 2 Total

No. with chest pain No. with systemic symptoms

Phase 1 Phase 2 Total Phase 1 Phase 2 Total

8-10 Single 49 10 59 25 8 33 18 5 23 8.5 (1st fraction) Weekly 22 18 40 9 5 14 8 4 12 2-4 Daily - 19 19 - 7 7 - 8 8 Total 71 47 118 34 20 54 26 17 43

Phase 1 = first 71 patients completing questionnaires. Phase 2 = second 47 patients completing questionnaires, including those treated with small fraction sizes.

Table 2. Incidence, speed of onset and duration of symptoms following the first fraction of radiotherapy

Symptom No. patients (n=118)

Onset <12 h (% with symptoms) Duration <2 h (% with symptoms)

Chest pain 54 42 (77.8) Chest pain alone 26 20 (76.9) Systemic symptoms 43 33 (76.7) Systemic symptoms alone 15 8 (53.3) Chest pain + systemic symptoms 28 22 (78.6) No immediate symptoms 49

23 (42.6) 8 (30.8)

30 (69.8) 14 (93.3) 15 (53.6)

98 S. Devereux et al.

questionnaires recorded more than one of these symptoms, with eight reporting all three. Symptoms started within 12 hours in 33 (76.7%) but tended to be short-lived, lasting less than 2 hours in 30 (69.7%) of patients. In 28 of the questionnaires reporting systemic symptoms, chest pain was also mentioned.

After 71 patients had returned 93 questionnaires, the study was widened to include patients receiving smaller fractions of radiotherapy for palliative treat- ment. Nineteen of the further 47 patients recording immediate symptoms received treatment with a fraction size of up to 4 Gy and completed their questionnaires 24 hours after their first treatment. Chest pain was reported by seven and systemic symptoms by eight patients. For the other 28 patients, fraction sizes of 8 Gy or greater were used; 13 reported chest pain and nine systemic symptoms. In these 47 patients, the Chi-square test detected no statistically significant effect of fraction size on immediate symptoms following radiotherapy.

In summary, 118 patients returned questionnaires after their first fraction of radiotherapy, with 54 reporting chest pain and 43 reporting 'systemic' symptoms (28 experiencing both) in the 24 hours following radiotherapy treatment. Only 49 question- naires (41.5%) documented no immediate side effects.

DISCUSSION

In this survey, 58.5% of the questionnaires docu- mented symptoms in the 24 hours after radiotherapy. We believe that the timing and duration of the symptoms suggest a relationship with the radiother- apy. These immediate side effects of radiotherapy are not widely recognized and their aetiology is unknown.

Rapid changes are known to occur within cells in response to irradiation, which can lead to the release of mediators, such as soluble cytokines, arachidonic acid derivatives and histamine. This can trigger local inflammatory and systemic reactions to treatment [7]. It is possible that these reactions may be respon- sible for the changes we have observed.

It is worth noting that the immediate symptoms were not confined to patients receiving large fraction radiotherapy. Both chest pain and systemic symptoms were reported by over one-third of those treated with fraction sizes of 4 Gy or less. The fraction sizes used in the two groups will have different radiobiological effects, which would lead one to expect more side effects with a larger dose per fraction. Our survey showed no statistically signifi- cant difference when fraction sizes were compared, although the number of patients analysed is small.

Some of the symptoms experienced by these

patients may not be caused by the radiotherapy treatment itself, but by the underlying tumour, or the presence of an undiagnosed infection. We have collected no data on the incidence of such symptoms in a similar group who have not undergone radiother- apy treatment and therefore cannot estimate the proportion whose symptoms were coincidental with the radiation treatment. Even in those patients in whom an alternative cause, such as cardiac ischae- mia, was suggested, the possibility that the reaction to radiation acted as a precipitating factor cannot be discounted [8].

This survey suggests that patients with bronchial carcinoma are often troubled by symptoms in the hours after radiotherapy. These symptom are some- times of sufficient severity to require treatment. Half of those experiencing chest pain, for instance, took extra analgesics to combat this. Reports suggest that the early cellular reactions to radiotherapy can be modified by corticosteroids or non-steroidal anti- inflammatory drugs [9]. We have started, therefore, to study the use of prophylactic corticosteroids in reducing the frequency and severity of these immedi- ate reactions to radiotherapy.

The occurrence of chest pain and other symptoms, especially rigors, may cause great anxiety. We feel it is important to warn patients that these symptoms could occur in the hours after radiotherapy, to suggest appropriate treatment, and to reassure them that the symptoms are likely to be of short duration.

References

1, Maher EJ, Timothy A, Squire CJ, et al. Audit: The use of radiotherapy for NSCLC in the UK. Clin Oncol 1993;5:72-9.

2. Medical Research Council Lung Cancer Working Party. Inoperable non-small cell lung cancer (NSCLC): A Medical Research Council randomised trial of palliative radiotherapy with two fractions or ten fractions. Br J Cancer 1991;63:265- 70.

3. Medical Research Council Lung Cancer Working Party. A Medical Research Council randomised trial of palliative radio- therapy with two fractions or a single fraction in patients with inoperable non-small cell lung cancer. Br J Cancer 1992;65:934-41.

4. OmandM, MeredithC. A study of acute side effects related to palliative radiotherapy treatment of lung cancer. Eur J Cancer Care 1994;3:149-52.

5. Slotman BJ, Njo KH, Dejonge A, et al. Palliative radiother- apy in advanced metastatic and non metastatic non-small cell lung cancer. Lung Cancer 1992;8:285-92.

6. Stevens MJ, Begbie SD. Hypofractionated irradiation for inoperable non-small cell lung cancer. Australas Radiol 1995;39:265-70.

7. Rubins P, Finkelstein J, Shapiro D. Molecular biology mec- hanisms in the radiation induction of pulmonary injury syn- dromes: Interrelationship between the alveolar macrophage and septal fibroblast. Int J Radiat Oncol Biol Phys 1992;24:93- 101.

8. Arsenian MA. Cardiovascular sequelae of therapeutic thora- cic radiation. Prog Cardiovasc Dis 1991;33:29%312.

9. Michalowski AS. On radiation damage to normal tissue and its treatment. II: Anti-inflammatory drugs. Acta Oncol 1994 ;33:139-57.

Received for publication June 1996 Accepted following revision October 1996

Immedia te Side Effects of Large Fraction Radiotherapy 99

APPENDIX

Chest Radiotherapy Questionnaire

Please complete 24 hours after your radiotherapy treatment .

1. Did you experience any chest pain after your radiotherapy t rea tment? Yes/No

2. Where was the chest pain? centre/left side/right side/all over

3. How soon after t rea tment did the pain start? . . . . . . . . . . . . . .

4. How long did the pain last? . . . . . . . . . . . . . .

5. Did you take medicine for the pain? Yes/No What? . . . . . .

6. Have you had a similar pain before?Yes/No When? . . . . . .

7. Have you had angina? Yes/No

8. Was the pain experienced over the past 24 hours like the angina? Yes/No

9. Did you experience a shaking fit (rigor) after radiotherapy? Yes/No

10. If so, how soon after t reatment? . . . . . . . . . . . . . . . . . . . . . . . . and how long did it last? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

11. Did you experience any feverish (flu-like) symptoms after radiotherapy? Yes/No

12. If so, how soon after t rea tment? . . . . . . . . . . . . and how long did they last? . . . . . . . . . . . . . . . . . . . . . . . . . . . .

13. Did you experience any sweating episodes after radiotherapy? Yes/No

14. If so, how soon after t reatment? . . . . . . . . . . . . . . . . . . . . . . . . and how long did it last? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

15. Did you take any medicine for the rigors/fevers/sweating? Yes/No What? . . . . . . . . . . . . . .

16. Please list all the medicines that you have taken over the past 24 hours . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

17. Have you any other comments to add? . . . . . . . . . . . . . . . . . .