Retreatment tolerance of normal tissues

19.1 INTRODUCTION

Improvements in cancer therapy, particularly advances in medical radiation physics and radiation biology, have resulted in prolonged survival times and increased survival rates for a variety of malignancies over the past two decades. Surviving cancer patients are, however, at an increased risk of developing secondary neoplasms (see Chapter 25). The most important reason for this is that patients cured of one cancer still retain more risk (e.g. molecular predisposition) to develop a (second) tumour than any other person of similar age, gender, lifestyle, etc., who had not previously experienced the disease. Second, the aetiological factors associated with the first tumour, such as smoking for lung and head and neck tumours, or alcohol consumption for tumours of the head and neck or the oesophagus, or exposure to other carcinogens, can continue and hence promote the manifestation of a second malignancy. Of 30 000 irradiated patients with a primary head and neck tumour, more than 20 per cent developed a second neoplasm (Hashibe et al., 2005), out of which 80 per cent were found in the head and neck region, the oesophagus and the lung. Third, the therapy itself, radiation exposure as well as chemotherapy, is

associated with an increased risk for second tumours. This is of particular importance for children and younger adults; childhood cancer survivors are at an up to 19-fold increased risk for developing another malignancy (Dickerman, 2007).

Such second primary tumours are observed within, or, more frequently, close to the initial high-dose treatment volume (Dörr and Herrmann, 2002). Moreover, recurrent tumours can develop within or close to the original gross tumour volume. Both second primary tumours and recurrences must be treated adequately, which frequently involves radiotherapy. Decisions regarding safe retreatment are very complex; for example, surgical options are frequently compromised by local responses (e.g. fibrosis) to the first treatment. Hence, for the development of curative or even palliative re-irradiation strategies, a number of parameters must be considered:

●initial radiotherapy: dose (EQD2 – see below), volume, relationship to the required reirradiation fields

●additional treatments for the first tumour (e.g. chemotherapy, ‘biologicals’)

●time interval between therapy courses

●organs and tissues involved

●alternative treatment options.

Obviously, if the radiation tolerance within a given volume of an organ has already been exceeded during the first treatment and function is lost (or loss is to be expected), then no further treatment can be administered to this volume regardless of the first dose. Therefore, this chapter focuses on scenarios where the initial radiation treatment was in the range of subtolerance doses, with the induction of only subclinical or minimal damage, and with possible long-term recovery or potential residual damage after longer periods. Based on the risk factors mentioned above, the potential tissue-specific morbidity caused by the second treatment, and its impact on the patient’s quality of life, must be weighed against the expected benefits in terms of tumour response and survival.

This chapter summarizes the main findings from experimental and clinical studies on the re-irradiation tolerance of various normal tissues. Only clinical studies that provide information on one specific side-effect are included in the organspecific sections. More general descriptions for entire tumour entities are reviewed in the section on clinical studies.

In order to compare data from studies with different fractionation regimes, we have recalculated the doses administered in these studies to obtain the equivalent dose in 2-Gy fractions (EQD2) using the linear-quadratic (LQ) approach with α/β values of 10 Gy for early reactions and 3 Gy for late reactions (see Chapters 8 and 9). Tolerance doses (i.e. threshold doses above which defined grades of toxicity are observed) are referred to as

the EQD2tol. The intensity of both the initial treatment and the retreatment can be specified as a

percentage of EQD2tol.

19.2 EARLY TISSUE REACTIONS

Early tissue reactions are usually found in proliferating, turnover tissues (see Chapter 13, Section 13.2). Based on surviving stem cells within the irradiated volume or area, or on stem cells migrating into the irradiated tissue from non-irradiated sites, regeneration and restitution of tissue architecture and cellularity occurs, which should result in complete or partial restoration of the radiation tolerance.

Time before retreatment (months)

Figure 19.1 Retreatment tolerance of mouse skin at different times after initial treatments with 15–37.5 Gy. The vertical scale gives the retreatment dose required for a specified level of skin damage (ED50 for desquamation). The shaded area shows the range of ED50 doses for the same level of skin damage for previously untreated mice. Adapted from Terry et al. (1989), with permission.

Epidermis

Reports on the re-irradiation tolerance for early, epidermal skin reactions in rodents are consistent in demonstrating very good recovery from the initial damage with restoration of the radiation tolerance (Fig. 19.1). Recovery is faster after lower initial doses and is inversely proportional to the extent of

(stem) cell kill (see Chapter 13, Fig. 13.3). After single radiation doses that induce clinical desquamation of the epidermis, complete restitution of the initial tolerance has been observed after 2 months (Terry et al., 1989). In another study with fractionated irradiation, high initial doses, causing severe acute damage, resulted in some residual damage even after 6 months, with the consequence of

reduced tolerance (c. 80 per cent EQD2tol after 10 5 Gy pretreatment), as demonstrated by

increased early responses, particularly to high retreatment doses (Brown and Probert, 1975).

Oral and oesophageal mucosa

No preclinical animal data are available on re-irradiation effects in oral and oesophageal

Mucositis score (RTOG/EORTC)

mucosa. However, oral mucositis has been quantified after repeated radiotherapy courses with treatment breaks. If these breaks are in the range of 2 weeks, then mucositis developed with an identical time-course and severity after each of three treatment cycles (van der Schueren et al., 1990). If the breaks are shorter, around 10 days, then the severity of oral mucositis can even be lower after a second cycle (Maciejewski et al., 1991), as repopulation is still maximally active and can effectively counteract the cell kill right from the onset of re-irradiation.

However, early reactions after short treatment breaks do not necessarily reflect the responses to re-irradiation. Patients subject to re-irradiation in the head and neck region after longer intervals of

2–3 years may present with mucosal erythema (mucositis grade 1 according to RTOG/EORTC), or even focal lesions, even before the start of the second radiotherapy. More severe reactions (confluent: grade 3) are frequently observed earlier after re-irradiation than in the first radiation series (Fig. 19.2). This indicates mucosal atrophy, resulting in increased vulnerability and a reduction in the time required for cell depletion (see Chapter 13, Section 13.2).

Bone marrow

The potential and extent of long-term recovery in bone marrow is clearly dependent on the toxicity

Haematopoietic system

Figure 19.3 Changes in peripheral blood cell counts (dashed line) versus number of haematopoietic stem cell numbers in bone marrow (solid line). Earlier recovery of the peripheral cell number is based on stimulated transitproliferation, and does not reflect recovery of the stem cell population (i.e. restoration of radiation tolerance).

of the initial treatment. At high doses, in the range used for total body irradiation as a conditioning regimen for bone marrow/stem cell/progenitor cell transplantation, the stem cell pool is irreversibly damaged and no recovery is possible without an external supply of stem cells. At more moderate doses, the first response of the bone marrow is the stimulation of transit divisions (see Chapter 13, Section 13.2), resulting in an increased output of differentiated cells per stem cell division. This counteracts cell depletion in the peripheral blood at early time-points (Fig. 19.3), but regeneration at the stem cell level may take much longer (Hendry and Yang, 1995). The toxicity of the initial treatment must therefore be considered carefully for re-irradiation, independently of blood cell counts that may be critically misleading.

Restitution of stromal elements, which closely interact with the stem–progenitor cell system in the bone marrow, may take even longer than for the haematopoietic system itself. At higher doses, no regeneration occurs and the marrow is irreversibly converted into fatty tissue. Thus in mice, irradiation with 6.5 Gy resulted in persistent damage in the stromal and the progenitor compartment after 1 year; the effect was even more pronounced when the initial exposure was fractionated over 15 days. It has also been demonstrated in

Time after onset of first treatment (days)

Figure 19.4 Retreatment tolerance of mouse urinary bladder (early damage) at different times after irradiation with 5 5.3 Gy over 1 week. The ordinate indicates the retreatment ED50 required for a 50 per cent reduction in bladder storage capacity (at 1–3 weeks after re-irradiation). The shaded area shows the ED50 for the effect in previously untreated mice. From Satthoff and Dörr, unpublished data.

mice and dogs that this residual injury is more pronounced in neonates and younger animals than in adults (Hendry and Yang, 1995).

Urinary bladder

The early response of the urinary bladder, presenting as a reduction in storage capacity, is independent of urothelial cell depletion, which would not be expected during or shortly after radiotherapy, based on long turnover times of several months in this tissue (see Chapter 13). Re-irradiation tolerance of the urinary bladder with regard to early reactions, assessed as a 50 per cent reduction in compliance capacity during the first 4 weeks after treatment, has been studied in mice. After an initial treatment with 5 5.3 Gy (inducing reduced compliance in c. 30 per cent of the animals), the original tolerance was restored between 25 days and 50 days (Fig. 19.4). Longer intervals were required after higher initial doses. At late timepoints, reduced tolerance was found because of an overlap between the acute response to the re-irra- diation and the onset of late damage from the first treatment.

Figure 19.5 Retreatment tolerance for late hind-limb deformity in mice, as measured by fibrosis. Re-irradiation was with 10 fractions at the dose per fraction indicated on the abscissa, administered at 6 months after an initial treatment with 10 4 Gy or 10 5 Gy, or without previous irradiation. Redrawn from Brown and Probert (1975), with permission.

Time before retreatment (months)

Figure 19.6 Retreatment tolerance of the mouse lung. The ordinate indicates LD50 values caused by pneumonitis for retreatment at the indicated times after priming treatment with 6, 8 or 10 Gy. The shaded area shows the LD50 value for previously untreated animals. Adapted from Terry et al. (1988), with permission.

19.3 LATE EFFECTS

Skin

Using hind-limb deformation as an endpoint for late subcutaneous fibrosis (Brown and Probert, 1975), there is a clear reduction in tolerance for re-irradiation after 6 months (Fig. 19.5). The effect of re-irradiation was much more pronounced after more aggressive initial radiation protocols (10 5 Gy vs 10 4 Gy). Also, this effect was markedly more prominent than for early skin reactions in the same animals (cf. epidermis in Section 19.2). Further studies similarly suggest a significantly poorer retreatment tolerance than for early reactions. In general, a reduction to 50–70 per cent of the EQD2tol is found after re-irradiation. However, there are contradictory studies, where very good retreatment tolerance has been demonstrated for late deformity endpoints (e.g. in pig skin; Simmonds et al., 1989). In the mouse study, the reduced re-irradiation tolerance for late damage may have been influenced by the severity of early epidermal reactions in the first treatment, based on the development of consequential changes (see Chapter 13).

Lung

The response of the lung to irradiation occurs in two waves: pneumonitis as a delayed early effect, followed by late fibrosis. These effects, however, are not independent (see Chapter 13), indicating a strong consequential component. Moreover, the pathogenic processes appear to be connected, with continuous (subclinical) changes from the time of the initial radiation exposure.

In a mouse study using death from pneumonitis to evaluate lung re-irradiation tolerance (Terry et al., 1988), there was complete recovery from an initial dose of 6–8 Gy (approximately 30–50 per cent of a full tolerance dose). The time to restitution was, depending on the initial dose, in the range of 1–2 months (Fig. 19.6). After higher initial doses ( 70 per cent of the initial tolerance), re-irradiation tolerance increased from 1 day to 3 months, at which time tolerance was approximately 75 per cent of tolerance in previously untreated mice. Yet, at 6 months a decline in retreatment tolerance was then observed. No later time-points were studied, and hence it is unclear whether this trend continued or also occurred after lower initial doses. The basis for the later decreased tolerance may be the development of (subclinical) fibrosis.

The remarkably good re-irradiation tolerance of the lung demonstrated in experimental studies only applies for the pneumonitis phase. It is likely that retreatment tolerance for late lung fibrosis may be poorer, although no conclusive evidence is available.

Kidney

The kidneys are among the most radiosensitive of organs, although the latent period before expression of clinically manifest radiation effects may be very long, particularly after low doses. Progressive, dose-dependent development of functional damage, without apparent recovery, has been clearly demonstrated in rodents (Stewart et al., 1989, 1994). This is consistent with clinical observations of slowly progressive renal damage, which develops many years after irradiation. Based on the known dose-dependence of renal radiation injury, large initial doses ( 14 Gy) result in complete loss of function and hence re-irradiation cannot cause any further damage.

After subtolerance doses, the absence of any clinically measurable renal dysfunction at the time of retreatment certainly cannot be interpreted as a sign that the tissue has regained full tolerance, because of progression of the subclinical effects. Experimental studies demonstrate that doses of radiation too low to produce overt renal damage nevertheless significantly reduce the tolerance to retreatment (Stewart et al., 1989); none of these studies has demonstrated any long-term functional recovery of the kidney. After an initial dose of only

6 Gy (25 per cent of the EQD2tol) the tolerance for retreatment actually decreases with time between

2 weeks and 26 weeks (Fig. 19.7). This is consistent with continuous progression of occult damage in the interval between treatments and implies that re-irradiation of the kidneys after any previous irradiation should be approached with extreme caution, if preservation of function is required.

Urinary bladder

Studies on the re-irradiation tolerance of mouse bladder have also not demonstrated any recovery

0

Retreatment dose (Gy)

Figure 19.7 Dose–response curves for renal damage in mice at 35 weeks after re-irradiation. Retreatment was administered either 2 weeks (open circles) or 26 weeks (closed circles) after the initial treatment with 6 Gy. The response of age-matched control animals without previous irradiation (open squares) is also shown. Renal damage was worse for retreatment with the longer 26-week interval than for a shorter interval, indicating progression of subthreshold damage rather than recovery. From Stewart et al. (1989), with permission.

from late functional damage (as measured by increased urination frequency or reduced bladder compliance) for retreatment intervals of 12 or 40 weeks compared with short (1 day) intervals (Fig. 19.8). The latent period before expression of permanent functional damage was also much shorter in animals that were re-irradiated than in those after a single course of treatment, even after low, subtolerance initial doses (Stewart et al., 1990; Dörr and Satthoff, unpublished data).

Spinal cord

Spinal cord has been studied most extensively with regard to retreatment, in various rodent species and in non-human primates. Moreover, clinical data are available. There is evidence for substantial long-term recovery, indicating that retreatment is feasible.

Analyses of data obtained on re-irradiation of rodent spinal cord, using paralysis as an endpoint, are illustrated in Fig. 19.9. In juvenile animals,

Urination frequency

Figure 19.8 Dose–response curves for late urinary bladder damage in mice after irradiation with two doses separated by 1 day (closed circles), 3 months (open circles) or 9 months (open triangles). The total dose for a given effect did not increase with increasing time from first treatment. From Stewart et al. (1990), with permission.

Time after first treatment (months)

Figure 19.9 Long-term recovery after irradiation of rodent cervical cord. The total cumulative isoeffective dose (for 50 per cent paresis) is expressed as a percentage of EQD2tol (equivalent tolerance dose at

2 Gy) and as a function of the interval between initial and re-irradiation dose. Data are for 3-week-old (open circles) and adult (closed circles) rats. Data from Ruifrok et al. (1992), White and Hornsey (1980), van der Kogel et al. (1982), with permission.

long-term recovery started early and maximum retreatment tolerance was observed after 1–2 months; the maximum total dose (initial plus re-irradiation) was 120 per cent of the tolerance for previously untreated animals (Ruifrok et al., 1992). The higher the initial dose was, the lower

Figure 19.10 Total tolerance (initial plus retreatment) of monkey spinal cord. Retreatment was performed after 1–3 years after an initial dose of 44 Gy (i.e. 60 per cent of tolerance dose at 2 Gy, EQD2tol). All treatments were given with 2.2 Gy per fraction. Data from Ang

et al. (2001), with permission.

was the tolerance to re-irradiation. In adult animals, restitution started with a delay of several months and reached a maximum of c. 140 per cent of the original tolerance after 5–6 months (White and Hornsey, 1980; van der Kogel et al., 1982). These data were confirmed in an extensive study in rats for different levels of initial damage (Wong and Hao, 1997).

An extensive re-irradiation study was performed in non-human primates (Ang et al., 1993, 2001). In these experiments, an 8-cm length of the cervical cord was initially irradiated with 20 fractions of 2.2 Gy, which is equivalent to about 60 per cent of the ED50 for a 50 per cent incidence of paralysis (76 Gy in 2.2-Gy fractions). After 1, 2 or 3 years the non-symptomatic monkeys were re-irradiated with graded doses in fractions of 2.2 Gy. Only a few animals developed paralysis with the retreatment doses administered; therefore, the data must be compared at a 10 per cent incidence level of paralysis rather than at 50 per cent. The reirradiation ED10 increased from 55 Gy after 1 year, to 59 Gy after 2 years to 66 Gy after 3 years. The total EQD2tol for initial and retreatment doses amounted to 150 per cent, 156 per cent and 167 per cent for retreatment after 1, 2, or 3 years, respectively

(Fig. 19.10). Hence, despite a different time-course in rodents and primates, the extent of long-term

recovery in spinal cord, using paralysis as an endpoint, is similar, and may be adopted for re-irradia- tion of patients.

Some clinical analyses of radiation myelopathy after re-irradiation of spinal cord are available. Nieder et al. (2006) summarized data from a total of 78 patients re-irradiated to the spinal cord with various regimens. Their conclusion was that, if the interval between the two radiotherapy courses was longer than 6 months, and the EQD2 in each course was 48 Gy, the risk for myelopathy was small after a total EQD2 of 68 Gy. In a smaller series, no myelopathies were seen after a cumulative EQD2tol of 125 per cent to 172 per cent, with intervals between the series of 4 months to 13 years.

For calculation of the re-irradiation tolerance for spinal cord, the initial tolerance must be defined. Both human and primate data (Baumann et al., 1994) demonstrate that, at an EQD2 of 55 Gy, the incidence of myelopathy is clearly 3 per cent. At a dose of 60 Gy, the incidence of myelopathy is about 5 per cent for doses per fraction 2.5 Gy and for one fraction per day. This level of risk may be acceptable in a re-irradiation situation, which is frequently the last curative option for the patient. Assuming, for example, that a patient received an initial dose to the spinal cord of EQD2 40 Gy, this leaves a 20-Gy tolerance from the first irradiation. Restitution of 40 per cent of the initial dose amounts to EQD2 16 Gy; hence re-irradiation with a dose of 36 Gy can probably be administered to the spinal cord in 2- Gy fractions. However, the dose to the spinal cord is usually less than the dose to the PTV, which must be included in the calculation of the initial dose. Moreover, the pronounced fractionation effect of the spinal cord can be exploited by administering hyperfractionated re-irradiation. Based on these considerations, re-irradiation with a curative intent is often possible.

In an analysis of clinical cases of myelopathy (Wong et al., 1994), the mean latent time before clinical symptoms became manifest after a single course of radiotherapy (EQD2 60.5 Gy) was 18.5 months (n 24). After re-irradiation to a total dose of EQD2 74 Gy (n 11), myelopathies were observed after a significantly shorter mean latent time of 11.4 months. These data are in line with results from the preclinical studies.

Summary of experimental data

Figure 19.11 summarizes results from experimental studies for re-irradiation tolerance in tissues where recovery following a range of initial treatments has been evaluated. Both the initial and the retreatment radiation exposures are shown as a percentage of the tolerance dose for a defined level of damage, calculated in terms of EQD2tol using the appropriate α/β ratio for each tissue. The dashed lines indicate the relationship that would be expected if no long-term reconstitution of tolerance would occur. Data points for retreatment above the dashed line (in skin, lung and cord) indicate some long-term recovery in the tissue. Where the data points fall below the dashed line (kidney), this indicates a progressive reduction of tissue tolerance with time after the initial irradiation rather than recovery. The general conclusion is that, on the basis of studies in experimental animals, several normal tissues are able to tolerate considerable retreatment with radiation. The phenomenon is not, however, universal.

19.4 CLINICAL STUDIES

In some clinical studies, overall incidences of sideeffects (without specification of the complications) after primary or re-irradiation are compared; these studies will be reviewed here. However, the vast majority of the increasing number of clinical reports on re-irradiation do not include data from simultaneous control groups with primary irradiation of the same site, and hence do not provide quantitative information. It must also be emphasized that most of the clinical studies have enrolled patients over long periods, and therefore provide only limited information because of changes, for example, in irradiation techniques and side-effect scoring. Moreover, many studies include highly variable radiotherapy (and chemotherapy) protocols and curative as well as palliative treatment intent.

Head and neck

Kasperts et al. (2005) reviewed 27 retreatment studies of head and neck cancer, where the second

Re-irradiation dose (% of EQD2tol)

80

60

40

20

Spinal cord

0

Initial dose (% of EQD2tol)

irradiation was performed as teletherapy or brachytherapy, in combination with chemotherapy or after surgery. Major late complications were fibrosis, mucosal ulceration/necrosis, and osteoradionecrosis. Despite the toxicity, they recommended high-dose re-irradiation. Similar sideeffects were reported by De Crevoisier et al. (1998) in a series of 169 patients re-irradiated to cumulative doses of 120 Gy (re-irradiation 60–65 Gy). After initial irradiation with 68 Gy, plus 67 Gy in the second series, Salama et al. (2006) found grade 4–5 late reactions (osteoradionecrosis, carotid haemorrhage, myelopathy and neuropathy) in a total of 18 per cent of the patients, with 16 per cent fatalities. Lee et al. (2007) re-irradiated 105 patients with head and neck tumours with 59.4 Gy after initial doses of 62 Gy. Severe early and late complications were found in 23 per cent and

15 per cent of the patients; the latter comprised mainly temporal lobe necrosis, hearing loss, dysphagia and trismus. Lee et al. (2000) compared late complications (excluding xerostomia) in more than 3600 patients given a single course of radiotherapy and 487 patients given a second course of radiotherapy for nasopharyngeal carcinoma. The observed incidence of normal tissue injury was clearly lower than expected in the retreatment series, indicating partial long-term recovery of the head and neck tissues, particularly with intervals 2 years.

General conclusions from these and other studies in head and neck tumours are that good local control rates of over 30 per cent can be achieved with total retreatment doses of at least

50–60 Gy, but that lower doses are ineffective.

Serious complications in up to 60 per cent of

long-term survivors are generally associated with higher total cumulative doses and short intervals before retreatment.

Breast

Re-irradiation for breast cancer, as partial breast irradiation, can be delivered either as conformal external-beam irradiation (e.g. with electrons) or as interstitial brachytherapy, with an acceptable incidence of side-effects, but less acceptable results with regard to cosmesis. After chest wall re-irradiation, severe grade 4 reactions are observed in 10 per cent of the patients (Harms et al., 2004).

Lung

In recurrent lung cancer, re-irradiation with doses of 10–70 Gy (median 50 Gy, 1.8–3.0 Gy per fraction) after initial treatment with 30–80 Gy (median 60 Gy, 1.5–2.0 Gy per fraction) was studied in 34 patients (Okamoto et al., 2002). No radiation myelopathy was observed; major toxicities were symptomatic pneumonitis (56 per cent) and oesophagitis (18 per cent). Palliative retreatment was associated with lower levels of oesophagitis than the initial treatment and no increase in pneumonitis. The retreatment doses are, of course, much lower than the initial doses and most patients will succumb to their disease before late damage (i.e. lung fibrosis) has time to be expressed.

Rectum

Re-irradiation for rectal cancer was carried out with doses of 15–49.2 Gy plus fluorouracil (5FU)- based chemotherapy after a median interval of 19 months (Mohiuddin et al., 2002). Cumulative doses were 70.6–108.0 Gy. Early toxicity comprised grade 3 diarrhoea, mucositis and skin desquamation, requiring treatment breaks or cessation (15 per cent); late sequelae were fistula (4 per cent) and colo-anal strictures (2 per cent). All toxicities were independent of radiation dose.

Valentini et al. (2006) studied retreatment (hyperfractionation, chemotherapy) after initial doses of

55 Gy (median interval 27 months). Re-irradiation doses were 30 Gy plus a boost of 10.8 Gy with 2 1.2 Gy per day. Late toxicities were skin fibrosis and urinary complications requiring nephrostomy at an acceptable incidence.

Cervix uteri

Early experience of retreatment for recurrent cervical cancer was not encouraging. Local control and survival rates were generally poor (10–20 per cent long-term survival) and complication rates were high (30–50 per cent). Several more recent studies, in which patients were carefully selected on the basis of volume and location of the cancer, have demonstrated much better results, particularly for retreatment using brachytherapy. In these studies, long-term survivals of 60 per cent with a severe complication rate below 15 per cent could be achieved after full-dose retreatment. Favourable conditions were small tumour volume, second primary malignancies and retreatment with brachytherapy; unfavourable conditions were recurrent cancer, large tumour volume and retreatment with external-beam therapy. Re-irradiation, mainly by brachytherapy, of vaginal recurrences of carcinomas of the cervix has been tried with 20–40 Gy in three to five fractions in 3–4 weeks (Xiang et al., 1998). Side-effects were severe, with rectal changes (14 per cent), haematuria (12 per cent) and fistula (12 per cent).

Summary of clinical data

These clinical data clearly indicate that reirradiation is an option for patients with recurrent or second tumours. However, the risk of normaltissue damage and impact on the quality of life, as well as possible alternative therapeutic approaches, must be taken into account. If a second course of radiotherapy has to be administered, this should be done with maximum care. Optimum conformation of the planning target volume is required. For radiobiological reasons, in order to reduce the risk of late effects, hyperfractionation protocols should be considered, at least for curative treatments.

Key points

1.If the tolerance within a given tissue volume has already been exceeded during the first treatment, and loss of function is present or expected soon, then re-irradiation is not possible without loss of function.

2.For early effects, restitution of the original tolerance may be complete after low to moderate doses, and after tissue-specific and dose-dependent time intervals. At high doses, residual damage may remain for longer intervals, particularly at the stem cell level, which is not necessarily reflected by the number of differentiated cells in the functional tissue compartments (e.g. blood cell counts for bone marrow).

3.For some late-responding tissues, partial (central nervous system, lung) or complete (skin) restoration of tolerance is observed after low and moderate initial doses ( 60 per cent of the initial tolerance). For example, spinal cord can safely be re-irradiated to a total of 140 per cent of the initial EQD2tol.

4.In some late responding tissues (kidney, urinary bladder), progression of damage at a subclinical level must be expected, thus precluding re-irradiation without exceeding tolerance.

5.Alternative treatment options must be considered before re-irradiation.

6.If (curative) re-irradiation is to be administered, optimum treatment planning (dose conformation) and a proper choice of fractionation protocol (hyperfractionation) are required.

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■ FURTHER READING

Morris DE (2000). Clinical experience with retreatment for palliation. Semin Radiat Oncol 10: 210–21.

Nieder C, Milas L, Ang KK (2000). Tissue tolerance to re-irradiation. Semin Radiat Oncol 10: 200–9.

Stewart FA (1999). Re-treatment after full-course radiotherapy: is it a viable option? Acta Oncol 38: 855–62.

Stewart FA, van der Kogel AJ (1994). Retreatment tolerance of normal tissues. Semin Radiat Oncol 4: 103–11.