Clinical investigation
Prostate
Acute and late gastrointestinal toxicity after radiotherapy in prostate cancer patients: Consequential late damage

https://doi.org/10.1016/j.ijrobp.2006.03.055Get rights and content

Purpose: Late gastrointestinal (GI) toxicity after radiotherapy can be partly explained by late effects of acute toxicity (consequential late damage). We studied whether there is a direct relationship between acute and late GI toxicity.

Patients and Methods: A total of 553 evaluable patients from the Dutch dose escalation trial (68 Gy vs. 78 Gy) were included. We defined three outcomes for acute reactions: 1) maximum Radiation Therapy Oncology Group acute toxicity, 2) maximum acute mucous discharge (AMD), and 3) maximum acute proctitis. Within a multivariable model, late endpoints (overall toxicity and five toxicity indicators) were studied as a function of acute toxicity, pretreatment symptoms, and relevant dose parameters.

Results: At multivariable analysis, AMD and acute proctitis were strong predictors for overall toxicity, “intermittent bleeding,” and “incontinence pads” (p ≤ 0.01). For “stools ≥6/day” all three were strong predictors. No significant associations were found for “severe bleeding” and “use of steroids.” The predictive power of the dose parameters remained at the same level or became weaker for most late endpoints.

Conclusions: Acute GI toxicity is an independent significant predictor of late GI toxicity. This suggests a significant consequential component in the development of late GI toxicity.

Introduction

Acute and late gastrointestinal (GI) toxicity rates after radiotherapy for prostate cancer are considerable and have been the subject of many studies. Dose–volume effect relationships have been described extensively in the past decades. More recently, several authors have mentioned that there might be a direct relationship between acute and late GI toxicity independent of dose (1, 2). This phenomenon, known as consequential late effect (CLE), is defined as a direct consequence of acute radiation response causing tissue damage, which eventually leads to late effects after a latent symptom-free interval. This mechanism is schematically depicted in Fig. 1. It has been described for several organs at risk such as skin, mucosa, and the GI tract (1, 3).

Previous studies with rats described CLE in the GI tract: acute epithelial damage after irradiation of the rectum induced late toxicities after a latent period (2, 4). Dubray and Thames (5) describe late stenosis in rats as a result of both early and late responding rectal wall components after irradiation. In clinical studies concerning prostate cancer patients, little has been published however about CLE. Several authors described the correlation between acute and late toxicity, but in most studies individual dose data were not included in the models (3, 6, 7). Dose–volume parameters of the organs at risk are known to be related to acute toxicity as well as late toxicity, so a straightforward comparison of late toxicity risks in patients with and without acute toxicity is not sufficient because the interfering relation with the dose parameters will obscure the measurement of the possible consequential effects (Fig. 1). Some authors have reported that acute toxicity scores remain significant in multivariable (MV) models predicting late GI toxicity, even when dose parameters are included (8, 9). These results strongly suggest that acute toxicity plays a role in the development of late GI toxicities after radiotherapy for prostate cancer. Some authors reported, however, that acute toxicity did not remain significant in MV models (10).

We have previously reported on acute and late toxicity in a randomized trial (68 Gy vs. 78 Gy) for prostate cancer patients (11, 12). In that earlier study we identified dose parameters that correlated with different late GI complications. We also found relationships between pretreatment complaints and the incidence of several late endpoints. We used this extensive dataset from our randomized trial to investigate whether there is a direct link between acute and late effects, which could not be explained by the dose–volume effects or pretreatment GI symptoms.

Section snippets

Patient group

We selected prostate cancer patients from the Dutch randomized Phase III trial (68 Gy vs. 78 Gy), known as the CKVO 96-10 study (Commissie Klinische Vergelijkend Ondoerzock [Committee Clinical Comparative Research]). These patients were all treated with external radiotherapy for localized prostate carcinoma between June 1997 and February 2003 at the Erasmus Medical Center in Rotterdam and The Netherlands Cancer Institute–Antoni van Leeuwenhoek Hospital in Amsterdam, the Netherlands. The total

General statistics

Characteristics of the analyzed patient group are summarized in Table 1. Median follow-up time was 44 months. The mean age was 69 years (6.4 1 SD). The mean volume of the delineated anorectal wall was 34.3 cm3, and the mean length was 16.8 cm. Pre–radiation therapy (pre-RT) symptoms were present in 19% of the patient population. Most frequently reported was “urgency” (8%) and “abdominal cramps” (7%). The distributions of the maximum acute proctitis score, the maximum acute RTOG score, and the

Discussion

The presented analyses strongly suggest that acute tissue reactions have a major impact on the development of late GI toxicity, apart from dose–volume effects. The acute “maximum score of acute proctitis” and “maximum score of acute mucous discharge” were strongly related with the majority of the investigated late GI toxicity endpoints. The acute RTOG score showed much weaker associations with the late endpoints. Patients who reported strong acute reactions (acute proctitis) had a higher risk

Conclusions

Acute tissue damage plays a significant role in the development of late GI toxicity apart from dose–volume effects and the impact of pretreatment symptoms. This suggests the presence of a consequential component in the development of late rectal toxicity.

Acknowledgments

We want to thank M. van Herk, B. Mijnheer, and H. Bartelink for their comments on the manuscript.

References (19)

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This project was supported by the Dutch Cancer Society (NKB Grant NKI 98-1830 and CKTO 96-10).

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