Background
Methods
Patients and ethics
Clinical response
PET scans
ROI analysis
Static PET quantification
Dynamic PET quantification
Statistical analysis
Results
Patients
Median (IQR) or number of patients (%) | |
---|---|
Group | RHYTHM B |
Number | 11 |
Age (IQR) | 67 (19) |
Male | 9 (82) |
Tumour stage (MRI) | |
T2 | 2 (18) |
T3 | 9 (82) |
T4 | - |
Nodal stage (MRI) | |
N0 | 4 (36) |
N1 | 6 (55) |
N2 | 1 (9) |
Metastasis stage (CT) | |
M0 | 11 (100) |
Differentiation | |
Well | 1 (9) |
Moderate | 6 (55) |
Poor | 1 (9) |
Not specified | 3 (27) |
Underwent TME | 8 (73) |
Response to CRTa
| |
Good | 5 (45) |
Poor | 6 (55) |
Clinical response
Statistics
Analysis of static [18F]FMISO PET scans at 4 h
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(a)T:M SUVmax: Tumour hypoxic volume was defined using a threshold of T:M SUVmax ratio > 1.3 and the corresponding percentage of tumour volume that is hypoxic are outlined in Table 2. In 3 patients, T:M SUVmax (Fig. 1) rose by up to 27% (range 0.17–27.05%), whereas it fell in 6 patients with a range of 25.43 to 58.96%. The median T:M SUVmax was 2.14 (IQR 0.58) at baseline and decreased by 33% to 1.30 (IQR 0.19) by week 2. The corresponding median tumour hypoxic volume was 1.08 (IQR 1.31) cm3 and decreased by 95% to 0 (IQR 0.15) cm3 by week 2. A hypoxic tumour volume was identified in all but one patient who underwent baseline [18F]FMISO PET, with a range of 0–13.16%. It increased in 3 patients and reduced in 5 by week 2 CRT.
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(b)T:B SUVmax: Tumour hypoxic volume was defined using a threshold of T:B SUVmax ratio > 1.3 and the corresponding percentage of tumour volume that is hypoxic are outlined in Table 3. T:B SUVmax (Fig. 1) rose in 2 of 9 patients, but by less than 2%. These patients also demonstrated an increase in T:M SUVmax at week 2 CRT. For those whose values fell, the range of % change was 10.94 to 71.01%. The median T:B SUVmax was 2.46 (IQR 1.50) at baseline and decreased by 29% to 1.61 (IQR 0.14) by week 2. The corresponding median tumour hypoxic volume was 5.68 (IQR 5.86) cm3 and decreased by 56% to 0.76 (IQR 0.78) cm3 by week 2. All patients scan demonstrated a hypoxic volume at baseline (range 0.48–36.25%), which fell in 6 patients (including the 5 with a reduction in T:M SUVmax -defined hypoxic volume) at week 2.
Baseline | After 8–10# CRT | % Change | |||||||||||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
Patient | pTRG | Stage | Clinical | Tumour | Muscle | T:M | Tumour | Tumour | % of | Tumour | Muscle | T:M | Tumour | Tumour | % of | Tumour | Muscle | T:M | Tumour | Tumour | % of |
Number | AJCC | Response | SUV | SUV | SUV | hypoxic | ROI | tumour | SUV | SUV | SUV | hypoxic | ROI | tumour | SUV | SUV | SUV | hypoxic | ROI | tumour | |
max | max | max | volume | volume | volume | max | max | max | volume | volume | volume | max | max | max | volume | volume | volume | ||||
cm3
| cm3
| i.e. hypoxic | cm3
| cm3
| i.e. hypoxic | i.e. hypoxic | |||||||||||||||
P1 | 1 | ypT3N2 | Poor | 2.09 | 1.54 | 1.35 | 0.05 | 80.41 | 0.06 | 1.79 | 1.32 | 1.36 | 0.15 | 88.60 | 0.17 | −14.35 | −14.50 | 0.17 | 199.99 | 10.19 | 172.26 |
P2 | 1 | ypT3N1 | Good | 5.19 | 2.30 | 2.26 | 1.93 | 23.20 | 8.32 | 4.97 | 1.73 | 2.87 | 2.93 | 26.85 | 10.93 | −4.31 | −24.68 | 27.05 | 51.90 | 15.70 | 31.28 |
P3 | 3 | ypT3N0 | Poor | 3.39 | 1.95 | 1.74 | 0.98 | 179.77 | 0.54 | 2.24 | 1.93 | 1.16 | 0.00 | 86.53 | 0.00 | −33.86 | −1.00 | −33.19 | −100.00 | −51.87 | −100.00 |
P4 | 2 | ypT3N0 | Poor | 4.16 | 1.74 | 2.39 | 4.03 | 30.66 | 13.16 | 2.70 | 1.84 | 1.47 | 0.20 | 13.35 | 1.47 | −35.10 | 5.79 | −38.65 | −95.15 | −56.46 | −88.86 |
P5 | NR | N/A | Good | 4.98 | 1.93 | 2.58 | 3.18 | 62.59 | 5.08 | 1.78 | 1.68 | 1.06 | 0.00 | 55.79 | 0.00 | −64.17 | −12.69 | −58.96 | −100.00 | −10.86 | −100.00 |
P6 | NR | N/A | Poor | 3.38 | 2.03 | 1.66 | 0.81 | 18.80 | 4.29 | - | - | - | - | - | - | - | - | - | - | - | - |
P7 | NR | N/A | Good | 3.52 | 1.62 | 2.17 | 0.39 | 4.16 | 9.41 | 2.44 | 1.51 | 1.62 | 0.12 | 0.93 | 13.16 | −30.54 | −6.85 | −25.43 | −68.75 | −77.65 | 39.80 |
P8 | 2 | ypT3N2 | Poor | 5.31 | 2.35 | 2.27 | 1.17 | 28.43 | 4.13 | 2.49 | 1.95 | 1.27 | 0.00 | 28.61 | 0.00 | −53.22 | −16.71 | −43.84 | −100.00 | 0.60 | −100.00 |
P9 | 2 | ypT3N1 | Poor | 3.04 | 1.45 | 2.10 | 1.44 | 15.06 | 9.58 | 1.82 | 1.41 | 1.30 | 0.00 | 13.96 | 0.00 | −39.97 | −2.59 | −38.37 | −100.00 | −7.31 | −100.00 |
P10 | 0 | ypT0N1 | Good | - | - | - | - | - | - | - | - | - | - | - | - | - | - | - | - | - | - |
P11 | 2 | ypT3N0 | Good*
| 1.94 | 1.74 | 1.11 | 0.00 | 10.98 | 0.00 | 2.40 | 1.88 | 1.27 | 0.00 | 5.23 | 0.00 | 23.87 | 8.16 | 14.52 | 0.00 | −52.34 | 0.00 |
Median | 3.46 | 1.83 | 2.14 | 1.08 | 25.82 | 4.68 | 2.40 | 1.73 | 1.30 | 0.00 | 26.85 | 0.00 | −33.86 | −6.85 | −33.19 | −95.15 | −10.86 | −88.86 | |||
IQR | 1.65 | 0.36 | 0.58 | 1.31 | 38.61 | 7.70 | 0.66 | 0.37 | 0.19 | 0.15 | 42.44 | 1.47 | 25.62 | 13.49 | 38.81 | 100.00 | 52.94 | 131.28 |
Baseline | After 8–10# CRT | % Change | |||||||||||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
Patient | pTRG | Stage | Clinical | Tumour | Blood | T:B | Tumour | Tumour | % of | Tumour | Blood | T:B | Tumour | Tumour | % of | Tumour | Blood | T:B | Tumour | Tumour | % of |
Number | AJCC | Response | SUV | SUV | SUV | hypoxic | ROI | tumour | SUV | SUV | SUV | hypoxic | ROI | tumour | SUV | SUV | SUV | hypoxic | ROI | tumour | |
max | max | max | volume | volume | volume | max | max | max | volume | volume | volume | max | max | max | volume | volume | volume | ||||
cm3
| cm3
| i.e. hypoxic | cm3
| cm3
| i.e. hypoxic | i.e. hypoxic | |||||||||||||||
P1 | 1 | ypT3N2 | Poor | 2.09 | 1.32 | 1.58 | 0.39 | 80.41 | 0.48 | 1.79 | 1.13 | 1.58 | 1.27 | 88.60 | 1.43 | −14.35 | −14.65 | 0.34 | 225.99 | 10.19 | 195.85 |
P2 | 1 | ypT3N1 | Good | 5.19 | 1.45 | 3.57 | 8.41 | 23.20 | 36.25 | 4.97 | 1.56 | 3.18 | 3.99 | 26.85 | 14.85 | −4.31 | 7.44 | −10.94 | −52.62 | 15.70 | −59.05 |
P3 | 3 | ypT3N0 | Poor | 3.39 | 1.76 | 1.93 | 5.31 | 179.77 | 2.95 | 2.24 | 1.44 | 1.56 | 0.59 | 86.53 | 0.68 | −33.78 | −18.14 | −19.11 | −88.94 | −51.87 | −77.02 |
P4 | 2 | ypT3N0 | Poor | 4.16 | 1.57 | 2.66 | 6.58 | 30.66 | 21.45 | 2.70 | 1.56 | 1.73 | 0.76 | 13.35 | 5.68 | −35.10 | −0.11 | −35.02 | −88.48 | −56.46 | −73.53 |
P5 | NR | N/A | Good | 4.98 | 1.31 | 3.79 | 14.38 | 62.59 | 22.97 | 1.78 | 1.62 | 1.10 | 0.00 | 55.79 | 0.00 | −64.17 | 23.60 | −71.01 | −100.00 | −10.86 | −100.00 |
P6 | NR | N/A | Poor | 3.38 | 1.50 | 2.26 | 6.06 | 18.80 | 32.25 | - | - | - | - | - | - | - | - | - | - | - | - |
P7 | NR | N/A | Good | 3.52 | 1.06 | 3.33 | 1.17 | 4.16 | 28.24 | 2.44 | 1.14 | 2.14 | 0.51 | 0.93 | 55.26 | −30.54 | 7.81 | −35.58 | −56.25 | −77.65 | 95.72 |
P8 | 2 | ypT3N2 | Poor | 5.31 | 1.19 | 4.45 | 10.66 | 28.43 | 37.49 | 2.49 | 1.46 | 1.71 | 1.91 | 28.61 | 6.68 | −53.14 | 22.10 | −61.62 | −82.08 | 0.60 | −82.19 |
P9 | 2 | ypT3N1 | Poor | 3.04 | 1.35 | 2.25 | 2.08 | 15.06 | 13.80 | 1.82 | 1.14 | 1.60 | 1.30 | 13.96 | 9.28 | −39.97 | −15.35 | −29.09 | −37.64 | −7.31 | −32.73 |
P10 | 0 | ypT0N1 | Good | – | – | – | – | – | - | – | – | – | – | – | - | – | – | – | – | – | – |
P11 | 2 | ypT3N0 | Good* | 1.94 | 1.22 | 1.58 | 2.15 | 10.98 | 19.61 | 2.40 | 1.49 | 1.61 | 0.15 | 5.23 | 2.80 | 23.87 | 21.73 | 1.76 | 0.00 | −52.34 | 0.00 |
Median | 3.45 | 1.34 | 2.46 | 5.68 | 25.82 | 22.21 | 2.40 | 1.46 | 1.61 | 0.76 | 26.85 | 5.68 | −33.78 | 7.44 | −29.09 | −56.25 | −10.86 | −59.05 | |||
IQR | 1.65 | 0.24 | 1.50 | 5.86 | 38.61 | 16.00 | 0.67 | 0.42 | 0.14 | 0.78 | 42.44 | 7.85 | 25.62 | 36.37 | 24.64 | 50.83 | 52.94 | 77.02 |
Analysis of 0–45 min dynamic [18F]FMISO PET scans
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(a) Tumour: The most meaningful parameters, hypoxia (K a ) and perfusion (F), from the Casciari model are presented in Fig. 2 (Table 4 for details). For tumour data, the median K a was 0.92 (IQR 0.41) min-1 at baseline and decreased by 24% to 0.70 (0.10) min-1 by week 2. The median F was 4.10 (IQR 1.71) millilitres/gram/minute ( ml g−1 min−1) at baseline and decreased by 29% to 2.48 (IQR 3.62) ml g−1 min−1 by week 2 (which is in concordance with earlier studies in solid tumours of rectal cancer (17)). In 9/11 patients that were scanned twice, the tumour perfusion decreased in non-responders and increased in responders except in one patient. None of the other changes in PET parameters between baseline and week 2 showed any clear trend with clinical outcome.
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(b) Muscle: The K a and F from Casciari model in muscle are reported in Fig. 2 (Table 4 for details). The median F was 0.12 (IQR 0.04) ml g−1 min−1 at baseline and increased by 376% to 0.60 (0.12) ml g−1 min−1 by week 2. The median K a was 0.02 (IQR 0.03) min-1 at baseline and increased by 3073% to 0.86 (0.76) min-1 by week 2. These values were higher than those reported by Schwartz et al. [36] perhaps due to differences in model or muscle region used. None of these changes in PET parameters between baseline and week 2 showed any clear trend with clinical outcome.
Tumour | Muscle | ||||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|
Patient | Clinical | Baseline | After 8–10# CRT | % Changes | Baseline | After 8–10# CRT | % changes | ||||||
Number | Response | F | Ka
| F | Ka
| F | Ka
| F | Ka
| F | Ka
| F | Ka
|
P1 | Poor | 0.588 | 1.380 | 0.294 | 1.188 | −50 | −14 | 0.144 | 0.018 | 0.570 | 0.864 | 296 | 4700 |
P2 | Good | 1.428 | 1.578 | 2.472 | 0.702 | 73 | −56 | 0.102 | 0.042 | 0.672 | 1.434 | 559 | 3314 |
P3 | Poor | 3.198 | 0.912 | 2.484 | 0.696 | −22 | −24 | 0.120 | 0.018 | 0.600 | 0.360 | 400 | 1900 |
P4 | Poor | 4.410 | 0.630 | 3.132 | 0.702 | −29 | 11 | 0.126 | 0.024 | 0.600 | 0.360 | 376 | 1400 |
P5 | Good | 6.702 | 0.924 | 4.380 | 0.720 | −35 | −22 | 0.138 | 0.006 | 0.600 | 0.360 | 335 | 5900 |
P6 | Poor | 6.702 | 0.924 | – | – | – | – | 0.600 | 0.444 | – | – | – | – |
P7 | Good | 3.942 | 0.924 | 4.656 | 0.618 | 18 | −33 | 0.174 | 0 | 0.054 | 1.116 | −69 | n.d. |
P8 | Poor | 4.368 | 0.870 | 0.750 | 0.312 | −83 | −64 | 0.078 | 4.806 | 0.348 | 2.058 | 346 | −57 |
P9 | Poor | 4.248 | 0.714 | 0.756 | 0.096 | −82 | −87 | 0.084 | 0.036 | 0.480 | 1.056 | 471 | 2833 |
P10 | Good | – | – | – | – | – | – | – | – | – | – | – | – |
P11 | Good | 2.526 | 0.762 | 6.192 | 0.720 | 145 | −6 | 0.114 | 0.006 | 0.600 | 0.366 | 426 | 6000 |
Median | 4.100 | 0.920 | 2.480 | 0.700 | −28.980 | −23.680 | 0.120 | 0.020 | 0.600 | 0.860 | 376.190 | 3073.810 | |
IQR | 1.710 | 0.140 | 3.620 | 0.100 | 68.110 | 41.600 | 0.040 | 0.030 | 0.120 | 0.760 | 91.530 | 3225.000 |
Impact of bladder activity accumulation
Impact of rectal activity accumulation and the effect of enema
Discussion
Analysis of static [18F]FMISO PET scans at 4 h
Analysis of 0–45 min dynamic [18F]FMISO PET scans
Selection of 0–45 min data
Arterial input function
Selection of Casciari model
Parameter initialisation
Parameter fixing
Parameter interpretation
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(a) Tumour showed a median 29% and 24% decrease in F and K a respectively after 2 weeks of CRT. However, a reduction in K a post treatment can be indicative of reduced tracer delivery due to damaged capillary bed rather than a reduction in tumour hypoxia [57]. Tumour K a did not show any relationship with F. This suggests that the changes in median K a in tumour during treatment were not due to the direct consequence of changes in perfusion and may suggest a radiotherapy-induced reoxygenation [50, 58] as it starts early during CRT and has been previously shown to correlate with outcome in H&N tumours [59, 60]. In our study, the alterations in tumour perfusion trend with response highlighted the importance of changes in vasculature-related functional parameters during radiotherapy, its important role in understanding hypoxia [61] and its relation with outcome [59, 62, 63].
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At baseline, tumour F showed a weak relationship with T:M SUVmax and T:B SUVmax at 4 h and none after 2 weeks of CRT, suggesting that these parameters from static PET may primarily exhibit chronic hypoxia. The K a showed poor relationship with T:M SUVmax and T:B SUVmax at baseline and after 2 weeks of CRT suggesting that the semi-quantitative and quantitative method of measuring hypoxia from static and dynamic PET, respectively, are not equivalent [16].
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(b) At baseline, the muscle showed low F values and negligible K a levels as expected. Despite a median increase of 376% in F at week 2 CRT, the median F in muscle was 4 times lower compared to that in tumour. The K a in muscle increased by a median value of 3076% at week 2, but the median K a in muscle was of the order obtained in the tumour. Acute effects of radiotherapy include reversible inflammation occurring in actively proliferating cells [64]. It is therefore likely that the muscle underwent radiation response causing inflammation in this region [64, 65]. The mechanism between inflammation and hypoxia is not well understood [66, 67], but increased perfusion due to inflammatory changes secondary to radiotherapy have been reported in rectal cancer [68]. It is also known that the [18F]FMISO reduction to nitro radical is reversible in the presence of oxygen. It is possible that the prolonged duration of increased blood perfusion beyond 45 min increased the accumulation of tracer in muscle during the first 2 h post tracer injection which then reversed between 2 and 4 h when we observed a large washout of tracer suggesting that the trapping mechanism is rather time dependent and fluctuating. The pattern of blood perfusion in acute hypoxia can alter on a 20 min time scale [69], which is less than our experiment time of 45 min for dynamic analysis. In our study, muscle K a and F showed weak relationship suggesting that the muscle [18F]FMISO uptake was not affected by the changes in muscle perfusion [66].