Joiner has a good chapter on retreatment tolerance of normal tissues, on which this information is based.
Remembered dose refers to the 'memory' tissues retain of dose they have been exposed to in the past. Remembered dose is an important concept when retreating patients. Retreatment may be necessary due to development of a second malignancy within the treatment field or in a nearby structure - for instance, rectal cancer following prostate radiotherapy. An important point is that for some reactions and in some tissues dose may be 'forgotten' over time, allowing a higher dose to be delivered safely.
Remembered dose in early responding tissues
Early reactions are mostly due to an inflammatory response and death of stem cells in rapidly dividing tissues (such as epithelial layers and the bone marrow). If the cells are able to recover, it is due to either:
- Survival and repopulation of stem cells
- Migration of unaffected stem cells into the affected region
Due to the nature of early reactions, it is likely that if full recovery from the effect has occured tissues should be able to tolerate a similar dose with nearly identical pre-treatment tolerance. This is mitigated somewhat by the late effects which can cause vascular insufficiency or fibrosis in the underlying submucosa.
Evidence for recovery of early responding tissues
Studies in animals and humans have shown that early tissues can show significant recovery.
- Mouse skin studies show that the time to full recovery is dependent on initial dose. Large doses that cause severe acute reactions may never fully recover.
- Oral mucosa shows less recovery than skin in human subjects, with grade 3 reactions occuring more rapidly. This suggests there is some mucosal atrophy (due to late effects in the submucosa) that causes reduced early tolerance.
- Human and mouse studies show that the haematopoietic marrow has two critical tissues - the haematopoietic marrow and the supporting stroma. Remembered dose is highly dependent on the initial treatment - if it is too toxic then there may be minimal recovery and minimal retreatment tolerance, whereas lower doses may allow significant repopulation of both tissue compartments
- Murine urinary bladder studies suggest full recovery of early tolerance within 1 - 2 months, although again it shows a dependence on initial dose.
Summary of early responding tissues
Early responding tissues are able to recover their normal tolerance if:
- Their stem cell compartment is not completely depleted by large initial doses
- The supporting stroma is capable of supporting the regenerating tissue
- Sufficient time is left between the treatments
Late responding tissues typically have more 'memory' than their early counterparts and provide more of a barrier for retreatment.
Remembered dose in late responding tissues
Deterministic late effects are due to a combination of:
- Stem cell loss in slowly proliferating tissue
- Damage to endothelial cells leading to vascular insufficiency
- Increased activity of fibrocytes leading to fibrosis
- Possible immune mediation of the above effects
These effects take months to years to develop and may be progressive in some tissues. Other tissues may undergo some repair of their damage over time, allowing them tolerate further dose in the future.
Evidence in specific late responding tissues
Skin
Unlike early effects, which show a complete restoration in tolerance after a few months, late effects in the skin show much less recovery. Although studies are not conclusive, there seems to be a 50% reduction in skin tolerance with retreatment due to remembered dose.
Lung
The lung has two phases of late reaction - an early pneumonitic phase and a later fibrotic phase. Retreatment tolerance is linked to these effects. In mice, there is a rapid restoration of tolerance to 75-100% of pre-treatment values by 3 months, depending on dose. This tolerance falls after 6 months due to progressive fibrotic reactions.
Kidney
Fibrosis and vasculopathy in the kidney as a chronic process that worsens over time. There is evidence that retreatment tolerance of the kidney worsens with time due to the progressive fibrosis of glomeruli.
Urinary bladder
The urinary bladder shows no recovery of tolerance with time. Further doses of radiation decrease the latent period until symptoms become apparent.
Spinal Cord
The spinal cord is a sensitive structure that is frequently irradiated in many different treatment regimens. There has been extensive investigation of the remembered dose within the spinal cord in mouse and primate studies. After delivering doses that caused 10% of monkeys to become paralysed (about 44 Gy), treatment was repeated at time intervals of 1, 2 or 3 years. This demonstrated loss of remembered dose, and allowed doses of 150-160% of the tolerance to be given (counting both treatments). Mouse studies are similar and it is believed that this data can be transferred to humans.
Summary of remembered dose in late responding tissues
Late responding tissues demonstrate differences in remembered dose. Some tissues, in which there is progressive changes (such as lung fibrosis and the kidney) show worsening retreatment tolerance over time. Others, such as spinal cord, show improved tolerance with time.
