Therapeutic ratio Flashcards
For tumors exhibiting central hypoxia, what strategy is most likely to improve the therapeutic ratio of treatment?
A. Stimulation of repair in hypoxic tumor cells
B. Inhibition of re-oxygenation in tumor cells
C. Use of a systemic radioprotector drug that reaches both tumor and normal cells
D. Inhibition of DNA repair in tumor and normal cells
E. Use of a systemic radioprotector drug that preferentially accumulates in normal tissues
E
Normal tissues are typically well-oxygenated, but some tumors may contain a fraction of radioresistant hypoxic cells. Larger tumors are more likely to harbor hypoxic regions. In order for a radioprotector to be efficacious and improve the therapeutic ratio, it must have a preferential effect on normal tissues either through increased selectivity for normal tissues or decreased selectivity for tumor cells. Amifostine is the prototypical radioprotector with Phase III data and meta-analyses demonstrating reduction in mucositis and xerostomia without affecting progression-free survival or overall survival. The disadvantages of amifostine include the need for IV infusion, moderate rates of nausea/vomiting, and risk of hypotension.
Answers A and B describe strategies that would protect tumor cells.
Answer C describes radioprotection of both normal tissues and tumor, which is next expected to change the therapeutic ratio.
Answer D describes inhibition of DNA repair in both normal and tumor cells and would be expected to sensitize both populations but not change the therapeutic ratio.
All of the following could affect the slope of a tumor control probability (TCP) curve, EXCEPT:
A. Tumor size
B. Tumor oxygenation
C. Intrinsic tumor cell radiosensitivity
D. Volume of normal tissue in the radiation field
E. Histopathological tumor type and grade
D
The slope of a tumor control probability (TCP) curve is determined by factors that introduce heterogeneity into the population of tumors under study. Tumor heterogeneity can be caused by variations in tumor size, oxygenation, tumor cell radiosensitivity, or histological type and grade of the tumor. While it may be important for toxicity and therefore for the therapeutic ratio, the volume of normal tissue in the radiation field does not affect the tumor control probability.
A new agent that can alter blood flow is being assessed for its potential clinical usefulness in combination with radiation therapy. Which of the following effects on blood flow would be expected to result in therapeutic gain and thus lead to a potentially useful agent in the clinic?
A. Unchanged in normal tissues and increased in tumors
B. Increased in normal tissues but decreased in tumors
C. Decreased in normal tissues and in tumors
D. Unchanged in normal tissue but decreased in tumors
E. Increased in normal tissues and unchanged in tumors
A
In order for there to be a therapeutic gain, the differential between the radiation response of tumor and normal tissue must be increased. Since blood flow is typically not compromised in normal tissues. However, since many tumors contain hypoxic cells, increasing blood flow to the tumor could result in radiosensitization. In contrast, decreasing blood flow to tumors would not be expected to be advantageous, since it could cause increased hypoxia and thus radiation resistance.
Which of the following statements is CORRECT? Normal tissue regeneration/repopulation:
A. Occurs in acutely responding normal tissues during the course of a standard course of radiotherapy
B. Interferes with reoxygenation
C. Is the reason that prolonging overall treatment time spares late responding normal tissues
D. Occurs at the same rate after irradiation in acutely and late responding tissues
E. Is the reason why accelerated fractionation protocols increase reactions in late responding normal tissues
A
Regeneration/repopulation can occur in early responding tissues such as skin during the course of a standard course of radiotherapy, increasing the tolerance of these tissues to radiation.
The apparent slower kinetics of late responding tissues suggests that no repopulation occurs in these tissues compared to acutely responding tissues. If repopulation were to take place, then this would reduce, not increase, late effects, irrespective of the fractionation schedule. Repopulation/regeneration plays no role in reoxygenation.
A prostate cancer patient is planned to go through a moderately hypofractionated IMRT treatment. Your clinic’s standard for planning has been to use 10 mm margins in every dimension except 7 mm posteriorly without daily image guidance. Which of the following strategies would NOT improve the therapeutic ratio of the treatment?
A. The addition of a hydrogel spacer between the rectum and prostate
B. The use of daily cone-beam CT for image guidance
C. The use of smaller PTV margins (i.e., 5 mm except 3 mm posteriorly) without daily cone-beam CT
D. The use of daily cone-beam CT plus smaller margins
E. The use of implanted gold fiducials and intrafraction stereoscopic x-ray monitoring and targeting adjustment
C
All of the proposed interventions would improve the therapeutic ratio except the use of smaller PTV margins without image guidance. Image guidance increases the fidelity of setup and reduces the risk of geometric miss, particularly in the setting of variability in bladder and rectal filling. The use of reduced PTV margins can improve the therapeutic ratio by limiting the volume of normal tissue treated, but only if the dose to tumor is not compromised. The margins proposed in answer C would not be sufficient to cover tumor without image guidance. Lastly, hydrogel spacers have been shown to displace the rectum posteriorly and reduce GI toxicity
Hypofractionation is being used to definitively treat many different malignancies including breast and prostate cancer. Which of the following is TRUE about its use in prostate cancer?
A. Treatment of the whole prostate using the same total dose but higher dose per fraction allows safe dose escalation while sparing normal tissues
B. Treatment of the whole prostate to the same biologically effective dose (BED) to tumor but higher dose per fraction allows shorter treatment time and little to no change in the therapeutic ratio
C. Treatment of the whole prostate to the same BED to tumor but higher dose per fraction allows a shorter treatment time and selective sparing of the adjacent normal tissues
D. The BED to normal tissues is significantly higher with hypofractionated regimens and therefore stereotactic methods must be used to treat the prostate
B
The goal of hypofractionation is to provide more convenient (shorter) treatments to patients while maintaining or improving the therapeutic ratio. Hypofractionation for low- and intermediate-risk prostate cancer typically involves treatment of the prostate cancer to an EQD2 of 74-78 Gy (assuming α/β of 1-3 for tumor). The most thoroughly tested regimens include 70 Gy in 28 fractions (RTOG 0415) and 60 Gy in 20 fractions (UK CHHIP and PROFIT). In general, these regimens were tested for non-inferiority against roughly biologically equivalent conventional regimens (73.8 Gy/41 fractions for RTOG 0415, 74 Gy/37 fractions for UK CHHIP, and 78 Gy/39 fractions for PROFIT. A major concern about hypofractionation was the possibility of significantly increased acute and late toxicity not predicted by linear quadratic modeling. The above trials have demonstrated this not to be the case, so long as appropriate dose constraints are achieved. There is some evidence, however, of a small increase in acute GI toxicity across trials. Answer A is incorrect, as maintaining the same total dose (e.g., 78 Gy) while hypofractionating (e.g., 20 fractions) would increase the BED to both tumor and normal tissues. While this would improve the likelihood of tumor control, it also would move rightward along the normal tissue probability curve with a disproportionate increase in NTCP, thereby decreasing the therapeutic ratio.
Answer C is incorrect, as hypofractionation regimens maintaining an equivalent BED compared to an effective conventional regimen are not expected to significantly spare normal tissues (although the BED to normal tissues may be marginally less depending on the alpha/beta used for tumor).
Answer D is incorrect, as the BED to normal tissues for the regimens mentioned above is not significantly different from conventional regimens. As a result, both predicted toxicity and measured toxicity are not significantly different. Daily image guidance was not mandatory on UK CHHIP (~30% treated with it) but was required on PROFIT and RTOG 0415; none of these trials used real-time tracking methods. However, daily image guidance is typically preferred, especially if treating according to the respective protocol.
