Do acute mucosal reactions lead to consequential late reactions in patients with head and neck cancer?

doi:10.1016/S0167-8140(99)00107-3

Radiotherapy and Oncology

Volume 52, Issue 2, 1 August 1999, Pages 157-164

https://doi.org/10.1016/S0167-8140(99)00107-3 Get rights and content

Abstract

Background and purpose: The relationship between acute and late mucosal reactions remains ill defined but is of considerable relevance to efforts to produce therapeutic gains through the use of altered fractionation schemes and concurrent chemotherapy. We therefore investigated whether acute mucosal reactions in patients treated with an accelerated and a conventionally fractionated radiotherapy regime predicted the severity of late mucosal reactions.

Patients and methods: The study population consisted of 191 patients randomised on a prospective trial comparing conventional fractionation at 2 Gy/fraction per day, 70 Gy over 47 days with an accelerated regimen of 59.4 Gy, 1.8 Gy BID over 24 days for Stage III–IV carcinoma of the head and neck. Acute and late mucosal reactions were scored according to RTOG/EORTC criteria and analyzed using multiple regression techniques.

Results: The duration of time spent by patients at the acute confluent mucositis grade 3 level was inversely related to the time to onset of the reaction for both fractionation schedules. Time to onset was more rapid for patients treated on the accelerated schedule but time spent at the reaction grade did not differ significantly between the schedules. After correction for treatment and patient related factors, anatomical site (oral cavity/oropharynx versus hypopharynx/larynx) and increasing duration of confluent mucositis emerged as independent predictors of the hazard of late mucosal reactions with the latter effect being more pronounced in the accelerated treatment arm. The expected reduction in late mucosal effects in the accelerated fractionation arm, predicted by the LQ model for late effects was identified only in patients whose acute confluent mucosal reactions lasted less than 20 days.

Conclusions: The presence of individual patient susceptibility factors that determine the severity of acute mucosal reactions is suggested. A link between severe and prolonged acute reactions and the risk of developing late mucosal reactions that is independent of biological dose, has also been found. Purpose designed prospective studies of these issues are necessary.

Introduction

Accelerated and hyperfractionated radiation schedules for head and neck cancer are now being widely employed in both standard and experimental radiotherapy situations. These regimens are generally devised to improve local tumour control while attaining an acceptable level of late normal tissue complications. However, these treatment strategies have been confirmed to produce more severe acute reactions than conventionally fractionated irradiation. While there is no strong clinical or experimental support for a general relationship between early and late normal tissue reactions [1], [9] there is good clinical evidence to support that late mucosal and skin changes occur, in part, as a consequence of acute denudation of squamous epithelium [2], [12], [13], [14], [15]. This raises concern that late normal tissue sparing from altered dose fractionation regimens may be off-set by increased consequential late tissue damage. If this turns out to be the case, then more attention should be devoted towards a better understanding of the mechanisms underlying acute mucosal reactions so that better preventative methods and management techniques can be developed.

It is unknown how much late mucosal morbidity can be accounted for by acute mucositis. In the present study we have examined the relationship between acute and late mucosal reactions in both arms of the randomised Trans-Tasman Radiation Oncology Group (TROG) trial comparing 70 Gy delivered using 35 daily fractions of 2 Gy over 47 days with 59.4 Gy delivered using 33 twice daily fractions of 1.8 Gy over 24 days [5], [11]. This trial, which met its accrual target of 352 patients last year provides an interesting study population for early and late mucosal reactions because the linear quadratic model predicts greater acute effects for the accelerated regime under test but substantially greater late effects for conventional regime (as described in Section 2). In the analysis presented in this report we have looked at the duration of acute mucosal reaction at the confluent mucositis grade because this measure has proved in previous studies to be a good quantitative surrogate for the acute cellular depletion in the human mucosa that is caused by courses of radiotherapy of identical length [4].

Section snippets

Patients and methods

The subjects of the present study are derived from 274 patients who were randomised between June 1991 and February 1997 in a phase III prospective multi-centre trial of accelerated versus conventional fractionated radiotherapy for stage III and IV squamous cell carcinoma of the oral cavity, oropharynx, larynx, and hypopharynx organised by the Trans-Tasman Radiation Oncology Group. Since the relationship between acute and late mucosal effects is being studied in the present report, only the 191

Patient details

In Table 2 the main characteristics of the patients studied in this analysis are listed according to the trial arm in which they were treated. Ninety patients were treated on the conventional fractionation arm to 70 Gy and 101 were treated to 59.4 Gy on the accelerated arm. It will be noted that distribution of the main explanatory variables studied: age, gender, site and size of the ‘cone down’ (high dose) volume are well balanced between the two treatment arms.

Acute reaction characteristics

The time course of acute

Discussion

Obviously caution is necessary in interpreting mucosal reaction data from a randomised clinical trial whose primary endpoints relate to tumour control rather than to mucosal damage per se. In addition it must also be acknowledged that although the data were collected prospectively, they were collected by different observers at different treatment centres. Inter-observer variation due to differences in interpretation of reaction severity and failure of patient compliance with prescribed follow

Conclusions

This study implicates the presence of individual patient susceptibility factors (which include individual patient radiosensitivity) in determining the severity of acute mucosal reactions that develop during a course of curative irradiation of head and neck cancer. It also indicates that there is a link between the severity of acute mucosal reactions and the risk of developing late mucosal reactions that is independent of biological dose in some patient subsets. The presence of a set of

Acknowledgements

Jorgen Johansen was supported by a grant from the Danish Medical Research Council and the Trans-Tasman Radiation Oncology Group has received support from the Queensland Cancer Fund. The contribution of Associate Professor Quenten Walker to the design, coordination and conduct of the trial is warmly acknowledged. Professor Kian Ang and Associate Professor Keith Dear's advice on the analytical methodology is highly appreciated and Miss Debbie Wright is once again thanked for her expert

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Citation Excerpt :
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¹: Present Address: Rigshospitalet, Copenhagen, Denmark.

²: Present Address: Royal Preston Hospital, England.

³: Formerly Royal Adelaide Hospital.

⁴: Formerly Townsville General Hospital.

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Do acute mucosal reactions lead to consequential late reactions in patients with head and neck cancer?

Abstract

Introduction

Section snippets

Patients and methods

Patient details

Acute reaction characteristics

Discussion

Conclusions

Acknowledgements

Semin. Radiat. Oncol.

Radiother. Oncol.

Radiother. Oncol.

Radiother. Oncol.

Radiother. Oncol.

Radiother. Oncol.

Preliminary work on acute toxicity. Radiother. Oncol.