****Secondary Cancer Induction

Question 1

What are the criteria for classifying secondary cancers?

Answer 1

1. the second tumour occurs in locations irradiated by primary or secondary* therapeutic beams,
2. the histology of the second tumour is different from that of the original disease so a metastasis is excluded,
3. the existence of a latency period, typically of several years,
4. the second tumour was not present at the time of radiation treatment and
5. the patient does not have a cancer-prone syndrome.

Question 2

What is the evidence for cancer induction caused by relatively low doses of radiation based on?

Answer 2

• Biological studies
• Atomic bomb survivors
• Patients exposed to diagnostic or therapy radiation doses
• Occupationally exposed workers

Question 3

What does the data collected from atomic bomb survivors say about cancer induction due to radiation exposure?

Answer 3

The Excess Relative Risk of secondary cancer induction depends on the age at exposure and decreases from:

• about 15% per Sv at under 10 years of age
• to about 1% per Sv for adults exposed at over 60 years age.

Question 4

Where can data collected about cancer induction caused by radiation be found?

Answer 4

It is collated in:

• ICRP 103 (Assumes linear response at low doses, the combined detriment due to excess cancer and heritable effects is around 5% / Sv )
• Biological Effects of Ionizing Radiation (BEIR) report VII (Uses linear no threshold model)
• UNSCEAR 2000 & 2006 Reports: united nations scientific committee on the effects of atomic radiation

Question 5

Which model is used for an expression of cancer induction risk for low doses?

Answer 5

Linear no threshold.

Question 6

Which model is used for an expression of cancer induction risk for high doses?

Answer 6

Non-linear model with fitted parameters fitted from epidemiological evidence.

Question 7

What is Excess Absolute Risk (EAR)?

Answer 7

It is expressed as per 10^4 person-years (PY) per Gy (or Sv).
EAR = (Fraction of RT patients contracting Ca) - (Fraction of non-RT patients contracting Ca)

Question 8

What is Relative Risk (RR)?

Answer 8

RR = (Fraction of RT patients contracting Ca) / (Fraction of non-RT patients contracting Ca)

Question 9

What is Excess Relative Risk (ERR)?

Answer 9

ERR = RR - 1
It is expressed as a fraction or percentage per Gy (or Sv).
where RR = Relative Risk = (Fraction of RT patients contracting Ca)/(Fraction of non-RT patients contracting Ca)

Question 10

How is the Linear No Threshold (LNT) hypothesis used in risk of secondary cancer induction calculations?

Answer 10

• Sum dose distributions from different sources of radiation dose
• Apply organ-specific risk coefficients (eg: ICRP, BEIR)
• Age and sex dependent
• Apply generalised risk coefficient (approx 5% per Sv)

Question 11

What is the Linear No Threshold hypothesis?

Answer 11

At low dose there is a linear no threshold relation between cancer induction and radiation dose

Question 12

What is the non-linear model for cancer induction?

Answer 12

At higher acute doses, cell sterilisation has been thought to reduce the response gradient and eventually reduce the chance of cancer induction as cell sterilisation rates overtake cell cancer induction effect – i.e. the linear-exponential dose response curve. However….

• this shape of curve implies that nearest the margins of radiotherapy treatment volumes, or in low dose bath volumes (IMRT) is where it is most likely that secondary cancers will occur
• it is likely that there is a plateau or slower fall off with large dose
• the A-bomb survivors data differs from radiotherapy patient data (A-bomb = carcinoma but not sarcoma, RT patient = significant fractions of sarcoma). This implies different response from fractionated treatment.

Question 13

What is Organ Equivalent Dose (OED)?

Answer 13

The uniform dose with the same risk of radiation-induced cancer as the patient’s actual DVH.
It takes into account the dose-response relationship for radiation-induced cancer in different organs:
- OED calculation ouses a linear-exponential dose-risk model (shape of curve: starts linear, becomes exponential fall off)

Question 14

What is the equation for the radiation induced cancer incidence rate at a low dose (linear <2Gy)?

Answer 14

I(org) = I(0) * D * exp ( - α(org) * D )

where:
- I(0) is the radiation induced cancer incidence at any dose
- D is the dose after k fractions
- α(org) is the organ specific cell sterilization parameter

Question 15

What is the equation for Organ Equivalent Dose?

Answer 15

OED(org) = 1 / N * Σ D(i) * exp ( - α(org) * D(i) )

where:
- N is N calculation points, which represent the same constant volume of the organ
- D(i) is the dose to bin i after k fractions
- α(org) is the organ specific cell sterilization parameter

Question 16

What is the downside of moving from 3DCRT to IMRT in terms of radiobiology?

Answer 16

There is a larger low dose bath, resulting in the risk of second malignant neoplasms (SMN) to increase.

Question 17

What causes the larger dose bath in IMRT when compared with 3DCRT?

Answer 17

• IMRT requires many more fields from different angles than conformal therapy, and therefore a larger volume of normal tissue is exposed to radiation
• The exposure of out-of-field tissues from leakage X‑rays is also increased, because IMRT requires two to three times more monitor units to deliver a specified dose to the target compared with 3D‑CRT

Question 18

What is the method for quantifying dose baths? Describe it.

Answer 18

Integral dose:

• Important for comparing different radiotherapy modalities
• Defined as the mean energy deposited in the total irradiated volume of the patient (in kg x Gy): ID = m ∙D
• For an inhomogeneous dose distribution the total Integral Dose is the summated Integral dose across all dose beams. (n.b. Integrating the dose over the DVH gives the same result as multiplying the mean dose by the total DVH volume).

Question 19

What is a concomitant dose?

Answer 19

All exposures other than treatment exposures. They irradiate normal tissue outside the the target volume or the intended path of the primary treatment beam and therefore contributes to potential detriment to the patient.

Question 20

Give 2 examples of something that gives concomitant dose?

Answer 20

• Simulation
• Check simulation
• CT localisation
• Portal localisation
• Verification imaging

Question 21

What are the 2 issues that occur from incorrect delivery of fractionated?

Answer 21

• Incomplete repair between fractions

- Treatment gaps

Question 22

Describe the incomplete repair between fractions in radiobiology for accelerated radiotherapy, continuous low dose rate brachytherapy and pulsed brachytherapy.

Answer 22

Accelerated radiotherapy:

• Time intervals between fractions < 24 hours.
• Half time for repair of single strand breaks is about an hour, so most repairable damage will be repaired after about 6 hours.
• However there is some (debated) evidence for slow repair components in which case there may be some unrepaired damage and the BED calculation should be modified to take this into account

Pulsed Brachytherapy:
- Time between fractions is approximately one hour.

Continuous Low Dose Rate brachytherapy:
- Constant ongoing repair during irradiation. This leads to a different form of the BED formulae

Question 23

What are the equations for incomplete repair between fractions in radiobiology?

Answer 23

For fractionated radiotherapy:
This adjustment to the equations is derived from the principal that the βd2 term in the survival fraction is modified such that the relative effectiveness per unit dose is greater due to incomplete repair:
BED = n * d [ 1 + ( d * [ 1 + h] ) / ( α/β ) ]
where h: takes into account whether the repair is modelled according to the single exponential, multi-exponential or reciprocal repair models.

For continuous Low Dose Rate brachytherapy:
The inclusion of an exponential repair term in the β damage part of the survival fraction equation leads to the following equation, simplified for cases where overall treatment time is large (a few days):
BED = RT [ 1 + ( 2 * R ) / ( μ ( α/β ) ]

Question 24

Describe treatment gaps in radiobiology terms.

Answer 24

Causes of unintentional prolongation of treatment:

• Patient non attendance and insufficient catch up capacity (e.g. available weekends)
• TITA (Too Ill To Attend)
• Adverse weather
• Non-cooperation
• Machine breakdown and insufficient backup capacity

Possible loss of tumour control if no action taken but can increase in NTCP if action is taken. The only way to maintain both tumour and OAR orginal prescribed effects is to maintain original fractionation regime, total treatment time, and repair between fractions.
Features:
- Repair half time varies for different cells (and between tumour and normal tissue) and is approx 1.5hr for normal tissue and 0.5hr for tumour. Therefore after 6 hours repair of normal tissue = 1 - exp(-ln(2)*6/1.5) = 94%. After 8 hours = 97.5%. After 24 hours = 99.998%.
- Repair may be multiphasic. i.e. initial rapid repair period of 10 to 15 minutes and a longer slower repair over a few hours. Overall still need at least 6 hours between fractions, but if there is a long repair component for normal tissue then only 6 hours may still not be ideal.
Repopulation occurs if over T(delay), so need to change d and n to regain tumour BED.

Question 25

What is the equation for BED early?

Answer 25

BED(early) = D * [ 1 + ( d / (α/β) ) ] - [ ln(2) / α ] * [ ( T - T(delay) / T(p) ]

Question 26

What are the categories of patient tumour types?

Answer 26

Category 1: should not have their radical treatment prolonged (NSCLC, SCC Cervix, SCC H&N)
Category 2: Every effort should be made to keep any prolongation in the treatment of those in Category 2 to a minimum
Category 3: Patients being treated palliatively

Question 27

What methods are there to compensate for unscheduled gaps in treatment?

Answer 27

• Acceleration (>6hr)
• Weekend treatments
• Bank holiday treatments
• Adjust d,n to maintain T
• Add fractions if maintaining T impossible (usually sacrifice Therapeutic ratio more)