This section describes the recently published Quantec data which attempts to more precisely identify normal tissue radiation tolerances. Earlier, Emami compiled a list of commonly recognized normal tissue dose tolerances. The Normal tissue complication probability model. NTCP has been used early in the development of modern 3D conformal radiation therapy treatment planning systems through the generation of Dose-Volume histograms. These histograms permit a more detailed analysis of the likelihood a given radiation does will result in either acute or chronic/permanent radiation sequalase. The toxicity of treatment must be balanced against the desired outcome of treatment (i.e. cure, local/regional control, palliation, prophylaxis). Toxicity is a function of type of tissue treated, volume of tissue treated (which in and of itself is a function of the tissue organization), the dose per fraction and the overall dose delivered. Radiobiologists commonly associate higher dose/fraction and higher overall doses with the risk of late injury.
LThe original roots of the current QUANTEC toxicity data are in the Emami paper, which in essence was a survey of doses and was a first step at addressing a clear clinical need: What dose is a "safe" dose?
Prior to the Emami paper, the "safe dose" was a clinical judgement call, which in the days prior to the work of the 3d Conformal teams at UNC (Sherouse), NCI (Fraass), Michigan (Fraass, TenHaken, myself and others), were largely fluoroscopically derived large fields based more on bony anatomy than on soft tissue (organ descrimination). With the ability to visualize normal tissues involved in the field, we quickly came to realize that avoiding or limiting doses to these organs was a good idea.
This became abundantly clear when a traditional Total lymphatic irradiation field was contemplated on a child, which was the standard of care at that time. The conventional simulator was down, and due to a protocol requirement for starting treatment, the new CT scanner was substituted. A DRR was obtained and conventional TLI fields were drawn. The dosimetrist contoured the kidneys and at case review, we realized we were treating an inordinate amount of kidney, and far more than was necessary and the field was subequently modified to avoid the kidneys, while covering the para-aortic lymphatics. The gist of the discussion that followed was: This is the way we have treated lymphomas with no ability to visualize the kidneys. Now we can avoid them and use 3D conformal imaging and radiotherapy techniques to avoid normal tissue toxicity, and thus produce better outcomes.
Dose, fraction size, and volume irradiated are well known to be interrelated. Modern treatment planning systems (3D-conformal, imaging based and now IMRT), all produce dose-volume histograms as a function of dose delivery. DVHs graph volume (either percent total dose or absolute dose) as a function of dose.
DVH data, while useful have several key limitations:
The Emami paper, while pivotal in setting normal tissue dose tolerances did not account for volume of tissue, nature of tissue radiosensitivities, or tissue structural radiobiological information. Emami built on an earlier method of dose constraints known as the TD5/5 and TD50/5 which are the doses that statistically will cause a 5% normal tissue complication rate at 5 years or a 50% NTCP at 5 years. He created data sets based on 100% organ irradiation, 2/3 coverage and 1/3 coverage, all delivered at 2 Gy/fraction 5 fractions per week at 1.8 - 2.0 Gy/fraction.
| TD 5/5 | TD50/5 | ||||||
|---|---|---|---|---|---|---|---|
| Organ | 1/3 | 2/3 | 3/3 | 1/3 | 2/3 | 3/3 | Toxicity |
| Kidney | 50 | 30 | 23 | — | 40 | 28 | Clinical Nephritis |
| Brain | 60 | 53 | 45 | 75 | 65 | 60 | Radionecrosis |
| Brain Stem | 60 | 53 | 50 | 65 | Infarct/Radionecrosis | ||
| Esophagus | 60 | 58 | 55 | 72 | 70 | 68 | Clinical Stricture/Perforation |
| Heart | 60 | 45 | 40 | 70 | 55 | 50 | Pericarditis |
| Lung | 45 | 30 | 17.5 | 65 | 40 | 24.5 | Pneumonitis |
| Liver | 45 | 35 | 30 | 55 | 45 | 40 | RILD/Failure |
| Small Bowel | 50 | – | 40 | 60 | – | 55 | Obstruction/Perforation |
| Colon | 55 | – | 45 | 65 | – | 45 | Obstruction/perforation/ulceration/fistula |
| Spinal Cord | 5 cm
50 |
10 cm
50 |
20 cm
47 |
5 cm
70 |
10 cm
70 |
20 cm
– |
Myelitis/Necrosis |
| Skin | 10 cm2
70 |
30 cm2
60 |
100 cm2
55 |
10 cm2
– |
30 cm2
– |
100 cm2
70 |
Necrosis/ulceration |
| Bladder | – | 80 | 65 | – | 85 | 80 | Symptomatic contracture and volume loss |
| Larynx | 79 | 70 | 70 | 90 | 80 | 80 | Cartilage necrosis |
| Larynx | – | 45 | 45 | 80 | 80 | 80 | Laryngeal Edema |
| Mandible/TMJ | 65 | 60 | 60 | 77 | 72 | 72 | Trismus |
| Cauda Equina | – | – | 60 | – | – | 75 | Clinically apparent nerve damage |
| Brachial Plexus | 62 | 61 | 60 | 77 | 76 | 75 | Clinically apparent nerve damage |
| Femoral Head | – | – | 52 | – | – | 65 | necrosis |
| Rectum | – | – | 60 | – | – | 80 | necrosis,severe proctitis, stenosis, fistula |
| Parotid | – | 32 | 32 | – | 46 | 46 | Xerostomia |
| Stomach | 60 | 55 | 50 | 70 | 67 | 55 | Ulceration/perforation |
| Retina | – | – | 45 | – | – | 65 | Blindness |
| Optic Chiasm
Optic Nerve |
– | – | 50 | – | – | 65 | Blindness |
| Lens | – | – | 10 | – | – | 18 | Cataract formation |
| Ribs | 50 | 50 | 50 | 65 | 65 | 65 | Pathologic Fracture |
| Thyroid | – | – | 45 | – | – | 80 | Clinical Thyroiditis |
The Emami data were an important early step in developing dose data limitations to control normal tissue toxicities and normal tissue complication rates. As radiation therapy delivery techniques and imaging techniques grew in sophistication, so did the complexity of determination safe doses and safe dose-volume deliveries. Radiobiologist divided organs into several cytological structures which behave differently in radiation treatments. These data are now being considered in radiotherapy treatment planning and delivery. The shortcomings of the Emami paper are well recognized: Emami relied on consensus and expert opinion, in other words, what works and what doesn't. These shortcomings were updated by a plethora of data at the advent of widespread 3D conformal planning and the available dose-volume histogram treatment philosophies.
The Quantec group took a different approach to the problem of normal tissue complications/toxicity by reporting only data on well studied toxicities. Whereas Emamai tried to develop a data set of dose-volume parameters for all clinical situations, Quantec relied on well demonstrated endpoints to determine volume restrictions. Thus the QUANTEC data has been criticized for being less "complete."
The proper consideration of toxicity must include the likelihood of acute toxicities and late toxicities of treatment. This must be balanced with the benefit of the treatment to make a final recommendation. It does no good to induce toxicity worse than the condition we are trying to treat. Thus, neither of these models (Emami or Quantec) are completely self-standing, and a combination of the data and philosophies must, at present be used to guide clinical judgement. An additional source of dose-volume constraints is available in the form of standard (or control) arms of RTOG studies.
Radiation exposure disrupts DNA leading to cell death by a variety of mechanisms. It also disrupts mitochondrial function causing an increase in reactive oxygen species, which may exceed the cell's ability to repair. This causes further damage by disrupting cell function and signalling pathways leading to changes in vascular integrity, ongoing inflammatory response and abnormal vascular profliferation. Overproduction if reactive oxygens species is thought to be self-perpetuating potentially increasing the area and severity of radiation damage. The precise mechanisms of radiation induced reactive oxygen species is not clear. Some think that early changes lead to a process that progresses over time leading to chronic late radiation injury. Thus, it may be important (and then again it may not be important) to be more aware of early acute injury and its prevention to prevent late radiation side effects.
Finally, the vast majority of data reported is listed for standard fractionation (1.8 - 2 Gy / fraction) only. Fraction size does matter, the question is how much?
| Quantec Section |
|---|
| CNS |
| Head and Neck |
| Chest |