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

Presented at the 41st annual meeting of the American Society of Therapeutic Radiology and Oncology, San Antonio, TX, November 1999.
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Abstract

Purpose: To evaluate the incidence and prevalence of various signs of late morbidity, their time of appearance and pattern of progression during an observation period up to 34 years in breast cancer patients treated with postoperative radiation therapy after radical mastectomy.

Methods and Materials: A group of 71 breast cancer patients received in 1963–1965 aggressive postoperative telecobalt therapy to the parasternal, axillary, and supraclavicular lymph node regions after total mastectomy and axillary clearance. None of the patients received chemotherapy either prior to, or after the irradiation as part of their primary treatment. The prescribed dose to the three lymph node regions was 44 Gy in 11 fractions. Only two of the three fields were treated per day. This total dose was given in 16–17 fractions over 3–4 weeks. Because of the overlap of the supraclavicular and axillary fields, the dose received by the brachial plexus was not the dose that was prescribed. A retrospective dose calculation showed that the total dose to the brachial plexus was 57 Gy, delivered as a complex combination of 1.8 Gy, 3.4 Gy, and 5.2 Gy fractions. This cohort of patients has now been followed to 34 years and the late side effects of the treatment evaluated and scored.

Results: This series is unique in the literature. There is no comparable report of a detailed long-term follow-up in a homogeneously treated group of patients with such a high survival, especially among the younger women, where it is almost 50% at 30 years. This is the reason that they were able to develop some of the very slowly evolving injuries. There was progression of many of the late effects in the period between 5 and 34 years. The more serious morbidities have increased progressively over the whole 34-year follow-up period. Ninety-two percent of the long-term survivors have paralysis of their arm. Other neurological findings included unilateral vocal cord paralysis among 5% of the patients, who developed the disease after a median time of 19 years. All of them were left-sided, indicating a mediastinal involvement of the recurrent nerve. Local recurrence or the appearance of a new primary tumor infiltrating or causing pressure on the recurrent nerve were vigorously investigated and excluded as possible causes of these symptoms.

Conclusion: The greatest risk for all cancer patients is the inadequate treatment of their disease, because this is inevitably lethal. The aggressiveness of the therapy and the acceptable risk of complications must therefore be balanced against the risk of recurrence. The neuropathy seems to be closely linked to the development of fibrosis around the nerve trunks. The use of large daily fractions, combined with hot spots from overlapping fields contributed to the severity of the complications.

Introduction

The gradual success of cancer treatment has led to longer patient survival. Unfortunately, this carries with it the penalty of providing a greater opportunity for late effects to appear, increase in severity, and impact on the quality of life of the patient. Cancer is a disease that requires a long follow-up to monitor any tumor recurrence and to fully understand the toxicity of any treatment.

The incidence of complications involving muscles and nerves increases with time after radiation 1, 2. Late damage becomes more severe, progresses with time, and usually cannot be halted or reversed. Several papers have been published in which radiation-induced brachial plexus neuropathy (BPN) has been described 3, 4, 5, 6, 7, 8, 9. Radiation using large doses per fraction is less well tolerated by the brachial plexus than small doses per fraction (10). A couple of case reports have also been published on BPN after mantle radiotherapy to a dose of 40 Gy in 20 fractions for Hodgkin’s disease 11, 12. Other nerves such as the phrenic nerve (11) and the recurrent nerve (13) can also be affected, leading to more subtle symptoms.

Most of the studies and conclusions about the evolution of BPN are based on follow-ups that do not extend more than 5 years, at which time it is often assumed that all the late effects will have been detected. It is important to test that assumption and to see whether more damage appears in late reacting tissues if the patients are studied for a longer period. If there is further progression beyond 5 years, either in incidence or in severity, it will obviously be important to pay particular attention to the follow-up interval when comparing morbidity reports from different trials that do not have the same overall time since treatment. Only long-term follow-up can determine the ultimate risks of radiotherapy.

In the early 1960s a University Hospital with an Oncology Department was first established in Umeå. This provided the only radiation resources for the northern geographic half of Sweden. Some patients received surgical treatment in their local hospital, but all were sent to Umeå University hospital for their radiotherapy.

The first case of BPN was observed in 1965 at the radiotherapy department in Umeå, 2 years after the start of a hypofractionated telecobalt treatment modality for postoperative treatment of breast cancer. A cohort of 71 patients treated with this technique from March 1963 to March 1965 was defined (14) and has been followed for 34 years. In the present paper we focus on the incidence and prevalence of fibrosis, vocal cord paresis, and Grade 3 and Grade 4 neuropathy. The time of appearance and pattern of progression of the damage has been analyzed.

Section snippets

Patients

These breast cancer patients were treated with postoperative radiation therapy after radical mastectomy by a standardized 60Co technique during the period March 1963–March 1965. The patient characteristics are presented in Table 1. All medical records of these 71 patients were still available and were reviewed. The patient files included details of the diagnosis and staging of the breast cancer and details of the surgery and the subsequent follow-up. No analyses existed for hormone receptor

Results

The median survival for the whole group was 12 years and there was a threefold increase in the median survival in patients who were below the median age at treatment, relative to the older group (28 years versus 9 years). The 5, 10, 20, 30, and 34-year actuarial overall survival rates for the whole group are 81%, 59%, 38%, 25%, and 17% respectively.

The time course of evolution of injury is illustrated in Table 3 for fibrosis, BPN, vocal cord paresis (VCP), and Grade 3 or Grade 4 neurological

Discussion

The present long-term follow-up of a homogeneously treated group of patients has provided some insight into the evolution of late effects after overtreatment with radiation. There is no comparable long-term follow-up in a group with such a high survival rate, especially among the younger women where it is almost 50% at 30 years. The delayed incidence of neuropathy among these patients could develop because there were so many long-term survivors and these late morbidities could be detected due

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