Elsevier

Radiotherapy and Oncology

Volume 61, Issue 3, December 2001, Pages 233-246
Radiotherapy and Oncology

Quantification of late complications after radiation therapy

https://doi.org/10.1016/S0167-8140(01)00457-1Get rights and content

Abstract

Background: An increasing number of patients survive cancer after having received radiation therapy. Therefore, the occurrence of late normal tissue complications among long-term survivors is of particular concern.

Methods: Sixty-three patients treated by radical surgery and irradiation for rectal carcinoma were subjected to an unconventional sandwich therapy. Preoperative irradiation was given in four fractions of 5 Gy each applied within 2 or 3 days; postoperative irradiation consisted mostly of 15×2 Gy (range, 20–40 Gy). A considerable proportion of these patients developed severe late complications (Radiother Oncol 53 (1999) 177). The data allowed a detailed analysis of complication kinetics, leading to a new model which was tested using data from the literature.

Results: Data on late complications were obtained for eight different organs with a follow-up of up to 10 years. For the various organs, the percentage of patients being free from late complications, plotted as a function of time after start of radiation therapy, was adequately described by exponential regression. From the fit, the parameter pa was obtained, which is the percentage of patients at risk in a given year of developing a complication in a given organ during that year. The rate pa remained about constant with time. Following sandwich therapy, the annual incidence of complications in the bladder, ileum, lymphatic and soft tissue, and ureters was about the same (pa=10–14%/year), whereas complications in bone or dermis occurred at lower rates (4.7 or 7.5%/year, respectively).

Discussion: Numerous data sets collected from published reports were analyzed in the same way. Many of the data sets studied were from patients in a series where there was a high incidence of late effects. Three types of kinetics for the occurrence of late effects after radiotherapy were identified: Type 1, purely exponential kinetics; Type 2, exponential kinetics, the slope of which decreased exponentially with time; Type 3, curves composed of two components, a fast initial decline followed by an exponential decrease. For each kind of kinetics, provided that the dose distribution is not too heterogeneous, the incidence of late effects appears to occur at exponential or approximately exponential kinetics, even many years after treatment. This implies that a random process might be involved in the occurrence of late radiation sequelae.

Conclusions: There might be a lifelong risk of developing late complications, of which patients and clinicians should be aware. It appears worthwhile to try to identify, in follow-up examinations of patients after radiation therapy, what kind of processes might be involved in triggering subclinical residual injury to develop into a clinically manifest late effect.

Introduction

At the Department of Radiotherapy of the University of Hamburg, a subgroup of patients with rectal carcinoma was subjected to an unconventional treatment schedule from 1986 to 1990. High total doses were applied pre- and postoperatively to large volumes using high doses/fraction, and short time intervals between fractions. A considerable proportion of these patients developed severe late complications. This led to litigation, which has not yet been finally resolved. The authors of this study were not involved in the radiation treatments, but evaluated the data for scientific purposes [39]. The high rate of late morbidity observed in this group of patients made it possible to analyze in detail the time course of the incidence of late complications occurring after irradiation. For comparison, a large number of data sets was collected from the literature and analyzed in the same way.

Section snippets

Treatment

Treatment of rectal carcinoma consisted of preoperative irradiation, radical surgery of tumor, and postoperative irradiation using photons (16 MV) or electrons (42 MeV). Preoperative treatment was given by an opposed AP and PA pair of fields in four sessions of 5 Gy each. Most patients received two fractions of 5 Gy/day on 2 successive days. The median irradiated volume was 5.8 l (range, 4–14 l). Most patients underwent surgery the day after the last preoperative irradiation. Twenty-five

Complications after sandwich therapy for rectal cancer

Fig. 1 shows complications following sandwich therapy for rectal cancer. The percentage of patients without late complications in the corresponding organ is plotted in a semilogarithmic scale as a function of time after the start of radiation therapy. The data were taken from the actuarial incidence curves published previously (Fig. 1 in Ref. [39]). The straight lines drawn were calculated by fitting the data to Eq. (1); each point was weighed in inverse proportion to its standard error

Data from the literature

Due to the far-reaching conclusions that might be drawn from our results, numerous data sets from the literature were reanalyzed to address the question of whether the exponential kinetics reported here might be a peculiarity of the unconventional sandwich treatment applied. In particular, papers reporting on relatively large numbers of late effects were analyzed, since time kinetics may not be derived with sufficient accuracy, when late morbidity occurred in very few of the patients treated.

The annual incidence rate pa

The main innovation of the present paper appears to be the introduction of the parameter pa describing what percentage of the patients at risk in a given year after radiotherapy develop a late effect of a given grade in a specific organ or organ group. In this respect, pa is an objective measure for describing the occurrence of late morbidity in quantitative terms and — equally important — in a comprehensible way. Since pa contains information about frequency and time of occurrence of late

Conclusions

Three different types of kinetics for the occurrence of late morbidity following radiotherapy were identified. For each type of kinetics, provided that the dose distribution is not too heterogeneous, the incidence of late effects, even after many years, occurs at exponential or approximately exponential kinetics that may be quantified by pa, the percentage of patients at risk of developing late morbidity/year. That means that the annual rate of the incidence of complications/patient at risk

Acknowledgements

The authors thank the Erich and Gertrud Roggenbuck Foundation, Hamburg, for funding the present study.

References (44)

  • K.K. Fu et al.

    Late effects of hyperfractionated radiotherapy for advanced head and neck cancer: long-term follow-up results of RTOG 83-13

    Int J Radiat Oncol Biol Phys

    (1995)
  • D.Y. Gelblum et al.

    Rectal complications associated with transperineal interstitial brachytherapy for prostate cancer

    Int J Radiat Oncol Biol Phys

    (2000)
  • G. Gyenes et al.

    Long-term cardiac morbidity and mortality in a randomized trial of pre- and postoperative radiation therapy versus surgery alone in primary breast cancer

    Radiother Oncol

    (1998)
  • C. Haie-Meder et al.

    Analysis of complications in a prospective randomized trial comparing two brachytherapy low dose rates in cervical carcinoma

    Int J Radiat Oncol Biol Phys

    (1994)
  • G.E. Hanks et al.

    A ten year follow-up of 682 patients treated for prostate cancer with radiation therapy in the United States

    Int J Radiat Oncol Biol Phys

    (1987)
  • R. Hatlevoll et al.

    Myelopathy following radiotherapy of bronchial carcinoma with large single fractions: a retrospective study

    Int J Radiat Oncol Biol Phys

    (1983)
  • D.M. Herold et al.

    Diabetes mellitus: a predictor for late radiation morbidity

    Int J Radiat Oncol Biol Phys

    (1999)
  • J.C. Horiot et al.

    Hyperfractionation versus conventional fractionation in oropharyngeal carcinoma: final analysis of a randomized trial of the EORTC cooperative group of radiotherapy

    Radiother Oncol

    (1992)
  • J.C. Horiot et al.

    Accelerated fractionation (AF) compared to conventional fractionation (CF) improves loco-regional control in the radiotherapy of advanced head and neck cancers: results of the EORTC 22851 randomized trial

    Radiother Oncol

    (1997)
  • B. Jereczek-Fossa et al.

    Late complications after postoperative radiotherapy in endometrial cancer: analysis of 317 consecutive cases with application of linear–quadratic model

    Int J Radiat Oncol Biol Phys

    (1998)
  • S. Johansson et al.

    Timescale of evolution of late radiation injury after postoperative radiotherapy of breast cancer patients

    Int J Radiat Oncol Biol Phys

    (2000)
  • A.W.M. Lee et al.

    Effect of time, dose, and fractionation on temporal lobe necrosis following radiotherapy for nasopharyngeal carcinoma

    Int J Radiat Oncol Biol Phys

    (1998)
  • Cited by (115)

    • Swallowing Function After Treatment of Laryngeal Cancer

      2023, Otolaryngologic Clinics of North America
    • Basics of radiobiology

      2022, Nuclear Medicine and Molecular Imaging: Volume 1-4
    • Gamma-H2AX Foci Decay Ratio as a Stronger Predictive Factor of Late Radiation Toxicity Than Dose-Volume Parameters in a Prospective Cohort of Prostate Cancer Patients

      2022, International Journal of Radiation Oncology Biology Physics
      Citation Excerpt :

      With a median follow-up of 31 months (IQR 22-40), a relatively short follow-up period was also a limitation of our study. Toxicities can take up many years to develop; therefore, the rates may have been underestimated.36,37 Nevertheless, the median follow-up for the separate groups did not differ significantly; therefore, a higher incidence of toxicities cannot be attributed to follow-up duration.

    • Individual response to ionizing radiation

      2016, Mutation Research - Reviews in Mutation Research
    • Radiation pneumonitis

      2014, FMC Formacion Medica Continuada en Atencion Primaria
    View all citing articles on Scopus
    1

    Former affiliation: Department of Radiotherapy, Department of Clinical Oncology, St. Mary's Hospital, Portsmouth Oncology Centre, Portsmouth, UK.

    View full text