- Research
- Open Access
The evolution of rectal and urinary toxicity and immune response in prostate cancer patients treated with two three-dimensional conformal radiotherapy techniques
https://doi.org/10.1186/1748-717X-6-87
© Vranova et al; licensee BioMed Central Ltd. 2011
Received: 1 April 2011
Accepted: 27 July 2011
Published: 27 July 2011
Abstract
Background
Our research compared whole pelvic (WP) and prostate-only (PO) 3-dimensional conformal radiotherapy (3DCRT) techniques in terms of the incidence and evolution of acute and late toxicity of the rectum and urinary bladder, and identified the PTV-parameters influencing these damages and changes in antitumor immune response.
Methods
We analyzed 197 prostate cancer patients undergoing 3DCRT for gastrointestinal (GI) and genitourinary (GU) toxicities, and conducted a pilot immunological study including flow cytometry and an NK cell cytotoxicity assay. Acute and late toxicities were recorded according to the RTOG and the LENT-SOMA scales, respectively. Univariate and multivariate analyses were conducted for factors associated with toxicity.
Results
In the WP group, an increase of acute rectal toxicity was observed. A higher incidence of late GI/GU toxicity appeared in the PO group. Only 18 patients (WP-7.76% and PO-11.11%) suffered severe late GI toxicity, and 26 patients (WP-11.21% and PO-16.05%) severe late GU toxicity. In the majority of acute toxicity suffering patients, the diminution of late GI/GU toxicity to grade 1 or to no toxicity after radiotherapy was observed. The 3DCRT technique itself, patient age, T stage of TNM classification, surgical intervention, and some dose-volume parameters emerged as important factors in the probability of developing acute and late GI/GU toxicity. The proportion and differentiation of NK cells positively correlated during 3DCRT and negatively so after its completion with dose-volumes of the rectum and urinary bladder. T and NKT cells were down-regulated throughout the whole period. We found a negative correlation between leukocyte numbers and bone marrow irradiated by 44-54 Gy and a positive one for NK cell proportion and doses of 5-25 Gy. The acute GU, late GU, and GI toxicities up-regulated the T cell (CTL) numbers and NK cytotoxicity.
Conclusion
Our study demonstrates the association of acute and late damage of the urinary bladder and rectum, with clinical and treatment related factors. The 3DCRT itself does not induce the late GI or GU toxicity and rather reduces the risk of transition from acute to late toxicity. We have described for the first time the correlation between organs at risk, dose-volume parameters, and the immunological profile.
Keywords
Background
Quality of life is becoming one of the most significant issues in treatment decision-making, in general, and more so in prostate cancer [1]. Thus late rectal and urinary damage became a major concern in prostate cancer; and many studies have been dedicated to the search for correlations between dose-volume, treatment-related factors, and late GI and GU toxicities [2–7]. Three-dimensional conformal radiotherapy (3DCRT) represents one of the standard treatments of prostate cancer allowing the delivery of highly "conformed" (focused) radiation to the cancer cells, while significantly reducing the amount of radiation received by surrounding healthy tissue. 3DCRT should increase the rate of tumor control, while also decreasing side effects. In spite of this focus, a higher dose to the prostate implies that the surrounding organs at risk (OARs) may also receive higher doses.
In addition, local radiation therapy (RT) alters the balance of circulating immune cells by the depletion of radiosensitive cell subsets [8]. Recently, radiation-induced functional changes in immune cells raised interest, suggesting the possible use of radiation as an antitumor immune response enhancer. Irradiation can induce leukopenia due to apoptosis of various leukocyte subpopulations. The acute exposure to low- and high-dose irradiation in mouse models changes the quantitative and functional parameters of immune cells, due to different sensitivity of splenocyte subsets to radiation doses [9]. Similar effect was described in vitro for cervical cancer patients [10]. Tabi et al. reported a prevalent loss of naive and early memory cells vs. more differentiated T cells in peripheral blood of patients during RT to the pelvis [11]. The release of the heat shock protein 72 (HSP72) during RT increased the cytotoxic CTL and NK cells [12]. Some pathological changes can be caused by the apoptosis of bone marrow (BM) stem cells and BM stromal damage [13]. Radiation-induced BM injury depends on both the radiation dose and the volume of BM irradiated [14].
We performed a prospective 4-year study, enrolling prostate cancer patients to elucidate whether the risk level of acute and particularly late rectal and urinary toxicities caused by 3DCRT techniques (whole pelvic (WP) and prostate-only (PO)), are at an acceptable level. This study reports our 42-month follow-up results, and evaluates the relationships between pretreatment, acute and late rectal and urinary syndromes and tumor-, patient- and treatment-related factors. In the last 3 years of the study, we investigated the influence of 3DCRT techniques, as well as the GI and GU toxicity on selected patient immune parameters, with special regard to the cells involved in antitumor immunity (natural killer-NK, NKT, and T).
Methods
Patients and clinical protocol
Patient characteristics
Characteristics | WP (n = 116) | PO (n = 81) |
|---|---|---|
Age | ||
Median | 73 | 74 |
Range | 57-100 | 57-92 |
Mean ± SD | 72.93 ± 8.55 | 74.88 ± 7.79 |
TNM Stage | ||
T0 | 1 (0.86%) | - |
T1 | 6 (5.17%) | 22 (27.16%) |
T2 | 34 (29.31%) | 30 (37.04%) |
T3 | 62 (53.44%) | 15 (18.52%) |
T4 | 4 (3.45%) | 1 (1.24%) |
Metastases | 2 (1.72%) | - |
Gleason score | ||
Median | 7 | 5 |
Range | 2-9 | 3-10 |
Initial PSA [ng/mL] | ||
Median | 19 | 10 |
Range | 2-133 | 1-97 |
Mean ± SD | 31.00 ± 8.67 | 12.46 ± 2.34 |
ADT | 93 (80.07%) | 33 (40.74%) |
Previous surgery | ||
RP | 23 (19.83%) | 22 (27.16%) |
TURP | 7 (6.03%) | 5 (6.17%) |
Therapy duration (m) | ||
Median | 57 | 54 |
Range | 33-81 | 22-80 |
Mean ± SD | 57.50 ± 5.56 | 54.04 ± 7.03 |
Recurrence Risk* | ||
Low | 1 (0.86%) | 19 (23.46%) |
Intermediate | 20 (17.24%) | 38 (46.91%) |
High | 94 (81.03%) | 23 (28.40%) |
Prescription dose (Gy) | ||
≤ 71 | 60 (51.72%) | 6 (7.41%) |
72, 73 | 53 (45.69%) | 72 (88.89%) |
≥ 74 | 3 (2.59%) | 3 (3.70%) |
Disorders | ||
Without complications | 49 (42.24%) | 37 (45.86%) |
Cystoureteritis | 16 (13.79%) | 15 (18.52%) |
Cystoureteritis + diarrhea | 15 (12.93%) | 1 (1.23%) |
Proctocolitis + diarrhea | 28 (24.14%) | 14 (17.28%) |
Unknown | 8 (6.69%) | 14 (17.28%) |
Acute and late GI and GU toxicities were studied in order to identify the treatment-related, clinical and patient characteristics that correlated with the severity of complications and disorders. Acute reactions included those arising during treatment or within 90 days after RT completion. Late complications were defined as those developing more than 90 days after the last treatment. Acute and late toxicities were scored according to RTOG and LENT-SOMA morbidity scale (grades 1-5). Into the category of low toxicities were encompassed the patients without the need of pharmacological intervention (grade 1), while the serious toxicity (grade ≥ 2) was under medication. In 37 cases (WP: n = 16; PO: n = 21) the immune response before treatment, during 3DCRT (day 14), and 15-20 days after treatment completion was evaluated. The protocol was approved by the local board ethics committee; and written informed consent was obtained from all patients.
Irradiation technique, target volume and critical normal structure definition
Treatment planning and irradiation were performed with the patients in supine position (using knee and ankle supports) with an emptied rectum and "comfortably full" bladder filling. 3D conformal treatment planning based on CT images with 5 mm thickness, involved delineation of CTVs, PTVs and organs at risk, according to ICRU 50 and 62 recommendations. The plans, using MLC to shape beams, were calculated on Eclipse treatment planning system. Box technique or four wedged field technique (two lateral and two oblique fields at angles of 90°, 270°, 30° and 330°) was used. The dose was normalized to the ICRU reference point, located in the central part of the PTV or near the central axis of the beam intersection, according to ICRU 50. Dose homogeneity was between 95% and 107% of the ICRU reference dose. Dose-volume histograms were used for evaluation of doses to target volumes and organs at risk. DRRs were generated for all treatment beams and for two extra setup beams from the anteroposterior (AP) and the lateral directions (LAT).
Before the radiotherapy, the treatment plans were simulated on a conventional simulator (Ximatron and Acuity®, Varian Medical Systems). The isocenter was marked on the patient's skin. Patients were irradiated on a Clinac 2100 C/D (Varian) equipped with Millenium MLC-120 with beams of 18 MV or 6 MV. The dose was delivered in daily fractions of 1.8 Gy to the pelvis and of 2 Gy to the prostate and seminal vesicles, in given period five sessions per week. In the treatment room, the patients were aligned on a carbon-fiber couch panel within their immobilization device using the skin marks. Before the therapy, patient set-up was checked using electronic portal imaging (PortalVision PV-aS500®). Simulator images of setup fields were used as reference images for matching with portal images. Planning target volume (PTV) of the prostate (PTV3) was the entire organ (clinical target volume of prostate-CTV3), and PTV2 was the entire prostate and seminal vesicles (CTV2). Both PTVs were enlarged by 1.5 cm margin, except for the prostate-rectum interface where a 1 cm margin was again used to decrease the risk of rectal toxicity. PTV1 in the WP Group was only the CTV of lymph nodes (LNs). LNs were defined according to RTOG recommendations (treatment of only subaortic presacral LNs, contours of common iliac vessels starting at the L5/S1 interspace, external iliac contours stopping at the top of femoral heads, and contours of obturator LNs stopping at the top of the symphysis pubis) plus a 1 cm margin.
Patients from the PO group received a dose of 60 Gy in 30 fractions to the PTV2. Then the PTV3 received the prescribed dose of 10-18 Gy in 5-9 fractions. Patients from the WP group received a dose of 45 Gy in 25 fractions to the PTV1, then a dose of 20 Gy in 10 fractions to the PTV2. Finally the PTV3 received the prescribed dose 6-10 Gy in 3-5 fractions. Dose volume histograms (DVH) were generated for all PTVs and OARs. The OARs included the bladder, rectum, bone marrow, and femoral head.
Pelvic bone marrow definition
For each patient, the pelvic bone marrow (PBM) volume was first defined according to the method described by Mell et al. [16]. The external contour of the PBM was delineated on the planning CT using bone windows. Three sub sites were defined: 1) iliac BM (IBM), extending from the iliac crests to the superior border of the femoral head; 2) lower pelvis (LP), consisting of the pubes, ischia, acetabula, and proximal femora, extending from the superior border of the femoral heads to the inferior border of the ischial tuberosities; and 3) lumbosacral spine (LS), extending from the superior border of the L5 vertebral body to the coccyx, but not extending below the superior border of the femoral head. To find the association of local radiation doses and changes in the number of leukocytes among patients with different body sizes, the percentage of BM irradiated volume at different doses was used as a first approximation.
Cell separation for immunological evaluations
Citrated blood samples from patients were separated by Ficoll-Hypaque 1,077 (Sigma-Aldrich, St. Louis, MO, USA) density centrifugation for 40 min to obtain the peripheral blood mononuclear cell (PBMC) fraction.
Flow cytometry
The fluorochrome-conjugated antibodies CD3-Pacific Blue (UCHT1), CD4-APC-Alexa Fluor 750 (S3.5), CD8-Pacific Orange (3B5) CD19-Pacific Blue (HD37), CD20-PE-Cy7 (2H7), CD38-PerCP-Cy5.5 (HIT2), and CD56-APC (MEM-188), were obtained from Dako (Glostrup, Denmark), Exbio (Prague, Czech Republic), BD Biosciences (Franklin Lakes, NJ, USA), and e-Bioscience (San Diego, CA, USA). PBMCs (5 × 105 cells/well) were stained with the antibody mixture for 30 min on ice, washed, and measured with a Becton Dickinson LSRII instrument (BD Biosciences). We included single-stain controls for further offline compensation. Measurement and subsequent analysis was performed using FACSDiva (BD Biosciences) and TreeStar FlowJo 8 (Ashland, OR, USA) software, respectively.
NK cell-mediated cytotoxicity
The standard 51Cr-release assay was performed with PBMCs from patients as effectors and the NK cell-sensitive K562 erythroleukemia cell line as targets. PBMC (1.6 × 105 cells/well) were incubated with 104 Na251CrO4-labeled target cells in round-bottomed 96-well microtitre plates (NUNC) at 37°C, in a humidified atmosphere containing 5% CO2. NK cell activity was evaluated after 4 hr of incubation, and calculated as described previously [17].
Statistical analysis
We investigated all GI and GU toxicities (late and acute) separately. There were only 3 cases of grade 3 acute GI toxicity, only 5 cases of grade 3 acute GU toxicity, and none of grade 4 or 5. Similar observation was made for late GI toxicity (only 5 cases of grade 3, 1 of grade 4, and no instances of grade 5) and for late GU toxicity (only 13 patients of grade 3 and none of grade 4 or 5). As a consequence, we grouped the toxicity levels of all diagnosed toxicities (acute GI, acute GU, late GI, and late GU) in two categories and analyzed the binary response. The grouping of responses considered was: high toxicity (grade 2-3) vs. low or no toxicity (grades 1 or 0).
The grouped data were analyzed using multivariate logistic regression models. The list of predictive factors was the same for acute and late toxicities; except for the addition of acute toxicity, as the next predictive factor of late OAR damage. The patient-, tumor-, and treatment-related factors were as follows: 3DCRT technique used (WP vs. PO); volumes of rectum and urinary bladder; minimum, maximum, and mean dose received by the rectum and urinary bladder (Dmin, Dmax, Dmean); percentage of rectum and urinary bladder volume receiving 40 Gy, 50 Gy, 60 Gy, and 70 Gy, respectively; patient age; stage T of TNM classification; initial PSA; Gleason score; androgen deprivation therapy (ADT) added to RT (yes/no); surgical intervention (None/Transurethral resection/Radical prostatectomy) of the prostate (NONE/TURP/RP); occurrence of hemorrhoids (yes/no); and duration of RT (weeks). A Pearson's χ2 test or, in the case of small sample size, Fisher's exact test was used to examine whether there was a statistically significant difference in the occurrence and evolution of acute and particularly late GU and GI toxicity between the two observed 3DCRT techniques.
To evaluate the association of immune response and toxicity level, the patients were divided in the group T (patients with any toxicity level-grades 1-3) and group 0, those with no toxicity (grade 0). To compare the immune parameters between these groups of patients the t-test was performed. To find the relationship between immune response in prostate cancer patients and treatment related factors, Pearson's correlation coefficients were calculated.
For statistical analysis Statsoft's STATISTICA version 9 and SPSS Statistics version 18 were used. All tests were considered to be statistically significant at the level of p < 0.05. The required sample size for all performed statistical tests was calculated using IBM SPSS SamplePower software version 3.
Results
Logistic regression models for GI and GU toxicities
Four logistic regression models for acute GI, acute GU, late GI, and late GU toxicity were created. All models were statistically significant and adequately interpolated the data; however in both models for late toxicities, GI and GU, a large disparity between the number of patients in groups with high toxicity vs. low or no toxicity was observed. The classification ability of all four models was very good-80.0% for acute GI toxicity, 78.9% for acute GU toxicity, 76.3% for late GI toxicity, and 76.0% for late GU toxicity. The area under the ROC curve (AUC) which determines the discrimination power of the logistic model reached the following values: 0.836 for acute GI toxicity-discrimination quality according to Tape [18], "Good"; 0.810 for acute GU toxicity-"Good"; 0.784 for late GI-"Fair"; and 0.761 for late GU toxicity-"Fair".
Logistic regression models for acute and late GI and GU toxicities.
Acute GI toxicity | Late GI toxicity | ||||||
|---|---|---|---|---|---|---|---|
Variable | OR | 95% CI | p | Variable | OR | 95% CI | p |
Age | 1.097 | 1.03-1.17 | 0.006 | Volume of rectum | 1.028 | 1.00-1.06 | 0.036 |
Percentage of rectum receiving 70 Gy | 1.134 | 1.03-1.25 | 0.009 | T stage of TNM classification | 4.630 | 1.09-20.00 | 0.037 |
3DCRT technique WP vs PO | 26.163 | 5.10 -134.2 | 0.000 | Acute GI Low vs High | 0.115 | 0.01-0.92 | 0.042 |
Acute GU toxicity | Late GU toxicity | ||||||
Variable | OR | 95% CI | p | Variable | OR | 95% CI | p |
Age | 1.108* | 1.02-1.20 | 0.015 | Volume of urinary bladder | 1.016 | 1.00-1.03 | 0.018 |
Percentage of urinary bladder receiving 50 Gy | 1.127 | 1.01-1.25 | 0.026 | Percentage of urinary bladder receiving 40 Gy | 1.144 | 1.00-1.30 | 0.045 |
Surgical intervention None vs RP | 0.161 | 0.04-0.68 | 0.013 | Surgical intervention None vs RP | 0.089 | 0.01-0.85 | 0.035 |
3DCRT technique WP vs PO | 0.580 | 0.10-1.74 | 0.029 | ||||
GI and GU toxicity evolution after WP and PO 3DCRT techniques
Scoring of GI and GU disorders for WP and PO 3DCRT techniques.
Incidence and development of acute GI/GU toxicity from pretreatment symptoms | |||||||||
|---|---|---|---|---|---|---|---|---|---|
Acute GI toxicity | Acute GU toxicity | ||||||||
WP | PO | WP | PO | ||||||
Pretreatment Symptoms | Acute toxicity | n | % | n | % | n | % | n | % |
0 → 0 | 33 | 28.45% | 40 | 49.38% | 43 | 37.07% | 36 | 44.44% | |
0 → 1 | 14 | 12.07% | 17 | 20.99% | 18 | 15.52% | 12 | 14.81% | |
0 → 2 | 58 | 50.00% | 20 | 24.69% | 25 | 21.55% | 17 | 20.99% | |
0 → 3 | 1 | 0.86% | 1 | 0.86% | |||||
1 → 0 | 1 | 1.23% | 13 | 11.21% | 7 | 8.64% | |||
1 → 1 | 2 | 2.47% | 6 | 5.17% | 3 | 3.70% | |||
1 → 2 | 5 | 4.31% | 1 | 1.23% | 4 | 3.45% | 3 | 3.70% | |
1 → 3 | 2 | 1.72% | |||||||
2 → 0 | 1 | 0.86% | 1 | 0.86% | 1 | 1.23% | |||
2 → 1 | 1 | 1.23% | |||||||
2 → 2 | 1 | 0.86% | 1 | 0.86% | |||||
2 → 3 | 2 | 1.72% | 1 | 1.23% | |||||
3 → 0 | 1 | 0.86% | |||||||
3 → 1 | |||||||||
3 → 2 | 1 | 0.72% | |||||||
3 → 3 | 1 | 0.86% | |||||||
Development of late GI/GU toxicity from acute GI/GU toxicity | |||||||||
GI toxicity | GU toxicity | ||||||||
WP | PO | WP | PO | ||||||
Acute toxicity | Late toxicity | n | % | n | % | n | % | n | % |
0 → 0 | 29 | 25.00% | 34 | 41.98% | 41 | 35.34% | 31 | 38.27% | |
0 → 1 | 5 | 4.31% | 5 | 6.17% | 13 | 11.21% | 8 | 9.88% | |
0 → 2 | 2 | 2.47% | 1 | 0.86% | 3 | 3.70% | |||
0 → 3 | 1 | 0.86% | 3 | 2.59% | 2 | 2.47% | |||
1 → 0 | 10 | 8.62% | 11 | 13.58% | 17 | 14.66% | 9 | 11.11% | |
1 → 1 | 4 | 3.45% | 7 | 8.64% | 4 | 3.45% | 2 | 2.47% | |
1 → 2 | 1 | 0.86% | 2 | 2.47% | |||||
1 → 3 | 1 | 1.23% | 2 | 1.72% | 3 | 3.70% | |||
2 → 0 | 47 | 40.52% | 9 | 11.11% | 18 | 15.52% | 10 | 12.35% | |
2 → 1 | 9 | 7.76% | 6 | 7.41% | 8 | 6.90% | 8 | 9.88% | |
2 → 2 | 5 | 4.31% | 5 | 6.17% | 3 | 2.59% | 2 | 2.47% | |
2 → 3 | 2 | 1.72% | 1 | 1.23% | 1 | 0.86% | |||
2 → 4 | 1 | 0.86% | |||||||
3 → 0 | 2 | 1.72% | |||||||
3 → 1 | 1 | 0.86% | 2 | 1.72% | |||||
3 → 2 | 1 | 0.86% | |||||||
3 → 3 | 1 | 0.86% | 1 | 1.23% | |||||
Summary of last late GI/GU toxicities dynamics | |||||||||
WP | PO | ||||||||
Last late GI toxicity | n | % | n | % | |||||
Patients without toxicity | 29 | 25.00% | 34 | 41.98% | |||||
Decrease of toxicity (G1,2,3→G0) | 59 | 50.86% | 20 | 24.69% | |||||
Patients with moderate toxicity-G1 | |||||||||
Development G0 → G1 | 5 | 4.31% | 5 | 6.17% | |||||
Unchanged grade of toxicity G1 | 4 | 3.45% | 7 | 8.64% | |||||
Decrease of toxicity from G2, 3→ G1 | 10 | 8.62% | 6 | 7.41% | |||||
Patients with high level toxicity G2, 3, 4 | 9 | 7.76% | 9 | 11.11% | |||||
WP | PO | ||||||||
Last late GU toxicity | n | % | n | % | |||||
Patients without toxicity | 41 | 35.34% | 31 | 38.27% | |||||
Decrease of toxicity (G1,2,3 → G0) | 35 | 30.17% | 19 | 23.46% | |||||
Patients with moderate toxicity-G1 | |||||||||
Development G0 → G1 | 13 | 11.21% | 8 | 9.88% | |||||
Unchanged grade of toxicity G1 | 4 | 3.45% | 2 | 2.47% | |||||
Decrease of toxicity from G2, 3→G1 | 10 | 8.62% | 8 | 9.88% | |||||
Patients with high level toxicity G2, 3, 4 | 13 | 11.21% | 13 | 16.05% | |||||
In the cohort of patients included in the WP group, pretreatment GI toxicity of grade 2 was found in the history of 2 patients (1.72%), and only 1 patient (0.86%) showed grade 3. During treatment or within the first 90 days after treatment, acute grade 2 GI toxicity occurred in 65 (56.03%) and grade 3 GI toxicity in 3 patients (2.59%). The severe late GI toxicity of grade 2 occurred in 5 (4.31%), grade 3 in 3 patients (2.59%), and grade 4 in 1 patient (0.86%). There were no late grade 5 GI toxicity-suffering patients in this group. Pretreatment GU damage of grade 2 was found in the history of 4 patients (3.44%) and grade 3 in the history of 2 patients (1.72%). WP 3DCRT evoked acute grade 2 GU toxicity in 30 (37.04%) and acute grade 3 GU toxicity in 4 patients (3.45%). Severe late GU toxicity of grade 2 occurred in 8 patients (5.76%) and grade 3 in 6 patients (7.41%). There were no late grade 4 or 5 GU toxicities observed.
Summary of GI and GU symptoms scoring before and after 3DCRT. Comparison of GI (A) and GU (B) toxicity between the PO (n = 106) and the WP (n = 139) patient groups. Patients were scored according to the modification of RTOG morbidity scale. Percentage of occurrence of grades G0, G1, G2, and G3 of pretreatment pathology, acute, and late GU and GI toxicities are demonstrated.
Correlation between the 3DCRT parameters, GI/GU toxicity and immune response
We screened the immunological parameters, number of leukocytes, distribution of lymphocyte populations (T, B, NK, and NKT cells) and their subsets in the peripheral blood of patients before, throughout and after the finishing of 3DCRT, and correlated them to dose volume parameters, as well as to the volume of irradiated bone marrow.
Relationship between the percentage of irradiated volume of bone marrow and the dose applied.
Scatter plot showing the correlation between the percentage of irradiated volume of bone marrow and the decrease of number of leukocytes.
Pearson's correlation coefficients between bone marrow irradiation and immune parameters.
Dose [Gy] | Volume [%] | Number of leukocytes | Proportion of NK cells | |||
|---|---|---|---|---|---|---|
Median | Range | Correlation coefficient | p | Correlation coefficient | p | |
5 | 44.54 | 30.31-98 | -0.3177 | 0.140 | 0,5185 | 0,019 |
6 | 43.92 | 29.57-98 | -0.3161 | 0.142 | 0,5197 | 0,019 |
7 | 43.38 | 28.95-98 | -0.3161 | 0.142 | 0,5225 | 0,018 |
8 | 42.77 | 28.42-98 | -0.3162 | 0.142 | 0,5239 | 0,018 |
9 | 42.31 | 27.95-97 | -0.3170 | 0.141 | 0,5236 | 0,018 |
10 | 41.86 | 27.53-97 | -0.3188 | 0.138 | 0,5224 | 0,018 |
11 | 41.34 | 27.12-97 | -0.3213 | 0.135 | 0,5261 | 0,018 |
12 | 40.74 | 26.74-96 | -0.3256 | 0.129 | 0,5196 | 0,019 |
13 | 40.13 | 26.36-96 | -0.3314 | 0.122 | 0,516 | 0,020 |
14 | 39.63 | 26.00-96 | -0.3361 | 0.117 | 0,5147 | 0,020 |
15 | 39.13 | 25.66-95 | -0.3390 | 0.114 | 0,5133 | 0,021 |
16 | 38.66 | 25.34-95 | -0.3402 | 0.112 | 0,5124 | 0,021 |
17 | 38.20 | 25.03-95 | -0.3411 | 0.111 | 0,5117 | 0,021 |
18 | 37.77 | 24.72-94 | -0.3423 | 0.110 | 0,5107 | 0,021 |
19 | 37.19 | 24.40-94 | -0.3446 | 0.107 | 0,5096 | 0,022 |
20 | 36.35 | 24.05-94 | -0.3463 | 0.105 | 0,5083 | 0,022 |
21 | 35.70 | 23.70-93 | -0.3481 | 0.104 | 0,5065 | 0,023 |
22 | 35.20 | 23.33-93 | -0.3496 | 0.102 | 0,5036 | 0,024 |
23 | 34.66 | 22.91-92 | -0.3517 | 0.100 | 0,4984 | 0,025 |
24 | 34.13 | 22.37-91 | -0.3675 | 0.084 | 0,4771 | 0,033 |
25 | 33.53 | 21.61-83 | -0.3713 | 0.081 | 0,4579 | 0,042 |
44 | 10.97† | 4.38-38.66 | -0.4619 | 0.027 | 0,4270 | 0,060 |
45 | 9.97 | 4.22-35.05 | -0.4645 | 0.026 | 0,3986 | 0,082 |
46 | 9.08 | 4.07-28.04 | -0.4827 | 0.020 | 0,4153 | 0,069 |
47 | 8.39 | 3.93-23.31 | -0.4769 | 0.021 | 0,3906 | 0,089 |
48 | 7.70 | 3.81-21.61 | -0.4731 | 0.023 | 0,3935 | 0,086 |
49 | 7.07 | 3.50-20.48 | -0.4701 | 0.024 | 0,4023 | 0,079 |
50 | 6.54 | 3.15-19.58 | -0.4710 | 0.023 | 0,4130 | 0,070 |
51 | 6.00 | 2.83-18.84 | -0.4751 | 0.022 | 0,4178 | 0,067 |
52 | 5.55 | 2.55-18.16 | -0.4747 | 0.022 | 0,4187 | 0,066 |
53 | 5.21 | 2.30-17.50 | -0.4709 | 0.023 | 0,4201 | 0,065 |
54 | 4.98 | 1.95-16.82 | -0.4655 | 0.025 | 0,4208 | 0,065 |
Pearson's correlation coefficients of immune cells proportions with dosimetric parameters
14th date of 3D CRT | 15-20 days after completion of 3D CRT | ||||||
|---|---|---|---|---|---|---|---|
Variable vs. | Variable | Pearson's correlation | p | Variable vs. | Variable | Pearson's correlation | p |
T cells (CD3+CD56-) | Dmin | -0.5869 (20)* | 0.012 | NK cells (CD3-CD56low) | Percentage of rectum receiving 70 Gy | -0.5436 (23) | 0.024 |
Dmean | -0.5068 (27) | 0.032 | |||||
Dmax of rectum | -0.4918 (29) | 0.038 | |||||
Dmax of urinary bladder | -0.6089 (18) | 0.007 | |||||
Percentage of urinary bladder receiving 70 Gy | -0.4906 (29) | 0.007 | |||||
NKT cells (CD3+CD56+) | Dmin of rectum | -0.5776 (20) | 0.012 | NKT cells (CD3+CD56+) | Dmax of rectum | -0.6755 (14) | 0.000 |
Dmean of rectum | -0.7243 (12) | 0.001 | Percentage of rectum receiving 70 Gy | -0.4148 (42) | 0.031 | ||
Percentage of rectum receiving 40 Gy | -0.7363 (11) | 0.000 | Dmax of urinary bladder | -0.6210 (17) | 0.001 | ||
Percentage of rectum receiving 50 Gy | -0.5613 (22) | 0.015 | |||||
NK cells (CD3-D56low) | Dmin of rectum | 0.3963 (47) | 0.033 | Activated B cells (CD19+CD20+ CD38+) | Dmin of rectum | 0.4582 (34) | 0.016 |
Dmean of rectum | 0.3724 (53) | 0.047 | Dmean of rectum | 0.4342 (38) | 0.024 | ||
Percentage of urinary bladder receiving 70 Gy | 0.5152 (26) | 0.004 | Percentage of rectum receiving 50 Gy | 0.4011 (46) | 0.038 | ||
Percentage of rectum receiving 60 Gy | 0.5800 (20) | 0.002 | |||||
Terminally differentiated NK cells (CD3-CD56+) | Dmin | 0.4887 (30) | 0.040 | Terminally differentiated NK cells (CD3-CD56+) | Dmax of rectum | -0.5549 (22) | 0.000 |
Percentage of rectum receiving 70 Gy | 0.4835 (30) | 0.042 | Dmax of urinary bladder | -0.4608 (34) | 0.016 | ||
Percentage of urinary bladder receiving 70 Gy | 0.5226 (26) | 0.026 | |||||
GI, GU toxicity | 0.5166 (26) | 0.028 | |||||
Influence of GI/GU toxicity on antitumor immune response.
Toxicity | Variable | Mean ± SD (T) | Mean ± SD (0) | p-value | N (T) | N (0) |
|---|---|---|---|---|---|---|
Acute GU 14th day of 3D-CRT | % of T cells (CD3+D56-) | 68.41 ± 0.70 | 58.33 ± 8.99 | 0.047 | 26 | 11 (6)* |
Acute GU 14th day of 3D-CRT | Cytotoxicity | 13.71 ± 5,21 | 6.54 ± 3.12 | 0.038 | 26 | 11 (6) |
Late GU 15-20 days after 3D-CRT | % of CTL (CD3+CD8+) | 15.99 ± 6.52 | 8.55 ± 2.26 | 0.002 | 13 | 24 (7) |
Late GI 15-20 days after 3D-CRT | Cytotoxicity | 25.44 ± 4.96 | 13.82 ± 3.68 | 0.032 | 14 | 23 (2) |
Cumulative effect of radiation vs. toxicity on NKT cell proportions in the course of 3DCRT. CD4+ out of CD3+CD56+ NKT cells were evaluated in the PBMC of patients suffering GI, GU toxicities of grades 1-3 (T) or without any toxicity (0) undergoing WP (n = 16; A) or PO (n = 21; B) types of radiotherapy. Pooled data of patients in each treatment group, at all time points tested, are presented as mean values, where standard deviation does not exceed 10%.
Discussion
In this study two different 3DCRT techniques (WP and PO) were analyzed and the degree of association was determined between the occurrence and evolution of acute and late GI and GU toxicities and the treatment related characteristics in patients entering our hospital. Important findings include: (i) a higher proportion of acute GI toxicity in the WP 3DCRT technique group and conversely a slightly higher proportion of late GI and GU toxicity in the PO patient group; (ii) acute GI toxicity as a significant predictor of late GI toxicity; (iii) a strong dependence of the occurrence and evolution of acute GI toxicity and of late GU toxicity on which 3DCRT technique is used; (iv) the association of both acute and late GU toxicity and radical prostatectomy performed prior to radiotherapy; (v) the influence of age on both acute GI and GU toxicities; (vi) a correlation between the percentage of volume of irradiated bone marrow and a decreased number of leukocytes; and (vii) the influence of radiotherapy preferentially on NK, NKT and T cell subpopulations.
We found an increase of acute vs. pretreatment GI symptoms predominantly in the WP group, even if the patients were irradiated with lower doses compared with the PO 3DCRT group. We assume that the limiting factor in high-volume irradiation is not the dosimetric parameters, but the overall patient tolerance. In addition, the WP technique was undergone by patients with advanced stages of disease, lower overall health status, and suppressed immune functions. These observations are supported by data of Jereczek-Fossa [19] and Schultheiss et al. [20]; however, some investigators didn't demonstrate this correlation [21]. On the other hand, the diminution of late GI and GU toxicities to grade 1 or to no toxicity in the majority of acute toxicity (grade 1-3) suffering patients, was observed also in the WP 3DCRT group.
Our data regarding the frequency of severe toxicities are similar to those of other series, despite the fact that a direct comparison of toxicities is difficult due to the existence of many modified versions of the classification, and modifications of grading scales. Similarities were found between our results, the RTOG 9413 [22] analysis, and the GETUG-01 [23] prospective study. The diversity in the diagnostics could be created by individual physicians due to the subjectivity of the scoring system, when the same toxicity could be graded differently. Due to the findings of decreased late GI and GU toxicities after 3DCRT in the cohort of our patients, we compared these results with the studies using hypofractionated stereotactic body radiotherapy SBRT, which is a new modality of localized prostate cancer RT. The SBRT, together with innovations in image-guidance technology, is able to automatically correct the movement of the prostate during treatment, and deliver highly-conformal beam profiles, which have greatly enhanced the capability of delivering high dose fractions to a well-defined target, with sharp dose fall-off towards the bladder and rectum. Most of the studies concerning SBRT as a monotherapy or even as a boost following external beam radiotherapy presented only negligible incidence of severe late GI and GU toxicity. Katz et al. [24, 25], Freeman et al. [26] and other authors [27] reported milder toxicity profiles in comparison with our results, particularly in the case of late GI and GU impairments. On the contrary, Jabbari et al. [28] presented in their study similar results as our ones in the occurrence of severe late GU toxicity (grades 2-3), and even worse outcomes in evolution of acute GU toxicity.
The analysis of GU toxicity is difficult, due to interference with pre-existing dysfunction, age-related diseases, and previous urological surgery [21, 29]. We have to remember that some of these pre-existing symptoms could have been erroneously interpreted as acute or even late GU toxicity. On the other hand, late bladder damage can occur with a long latency time, potentially resulting in the underestimation of the real severity of late toxicity [30]. The difference in the time of clinical manifestation could be the reason why some researchers demonstrated the correlation of acute and late GI, but not GU toxicity [31]. These outcomes were proved in our study, as well.
The development of acute 3DCRT- induced GI and/or GU damage was generally mild in both groups; and none of the patients had an interruption of radiotherapy due to toxicity side effects. The risk of both acute GI and GU reactions depended preferentially on the age of patients, in agreement with the results demonstrated by Jereczek-Fossa et al. [31]. The biological variables and different clinical decisions based on patient age could participate on the final outcome. The association of acute GU toxicity with the percentage of the urinary bladder receiving 50 Gy found in our study was in accordance with the results of Fiorino et al.[32] and other authors [21, 29], who reported a significant correlation between DVH parameters and incontinence. Similarly, the acute GI toxicity associates with the percentage of rectum receiving 70 Gy as demonstrated also by the Italian Association for Radiation Oncology (AIRO) Group on Prostate Cancer (AIROPROS) 0101 trial (previous retrospective investigation [5], who described that the dose of 70 Gy at rectum was predictive for late G2-G3 bleeding), AIROPROS 0102 [33], and by others [34, 30, 7, 35]. Both late GI and GU toxicities positively associated with the volume of the irradiated organ at risk, rectum and urinary bladder, respectively. Furthermore, the late GI toxicity is associated with stage T of TNM classification of the disease, and is strongly influenced by acute GI toxicity. These finding are in agreement with the published data of Heemsbergen et al. [36]. The risk of late GU reactions depended on the percentage of urinary bladder volume receiving 40 Gy, the 3DCRT technique used, and the previous urological surgery [21, 29].
Originally, the primary mechanism of RT in cancer reduction has been considered the neoplastic cell DNA damage. However, Takeshima et al. have found that tumor-specific CTL, which were induced in the draining lymph nodes and tumor tissue of mice by RT, are fundamental to the inhibition of cancer growth [37]. The immunological evaluation performed during 3DCRT showed a positive correlation of the number of activated NK cells and the proportion of terminally differentiated tumor targeted cytotoxic effectors with GI and GU toxicities. Both of these subpopulations returned to normal values or decreased after completing RT. In contrast, T lymphocytes were decreased during RT and normalized after its completion; while NKT cells were down-regulated in all time periods. The acute GU and late GI and GU toxicities significantly increased the T cell proportion, NK cell-mediated cytotoxicity, and cytotoxic T cell numbers. We assume that these changes are caused by stress conditions induced by RT-damaged and GI or GU toxicity-affected tissues, eliciting stimulation of cytotoxic cells (NK and CTLs). These RT effects could be due to inflammation following increased apoptotic/necrotic events in the involved tissues. The surface expression or extracellular release of stress proteins (e.g. MICs, Hsp70), following tumor cell damage by RT, can play a key role in immune system modulation [38]. These molecules are ligands of the NK cell activation receptor NKG2D [39], and can stimulate NK cell functional maturation. Particularly, Hsp72 can act as an immunological adjuvant [39, 40], participating in the non-self recognition of prostate cancer cells. Thus we can hypothesize, according to results of Hurwitz et al. [12] that the enhanced immune function, involving resting and terminally differentiated NK cells during 3DCRT, as well as the up-regulation of CTL number and the NK cell-mediated cytotoxicity in GI or GU suffering patients, could follow the release of HSPs either evoked by radiation or by GI or GU toxicity-induced cellular stress.
Conclusion
Our RT series included 197 patients who were treated in one center and may serve as a basis for comparison with other oncology centers, particularly in the Czech Republic. We found a strong dependence of the development of GI and GU disorders on the 3DCRT technique applied. Most important from a clinical point of view and the overall quality of life of prostate cancer patients after 3DCRT treatment was the diminution of late GI and GU toxicity to grades 0-1 in a majority of acute toxicities of patients suffering grades 1-3. The relevance of our study lies in the complex evaluation of clinical and radio-therapeutical variables describing the correlations between OARs parameters, GI and GU toxicity, phenotype, and the functional profile of immune cells. Our results brought a new insight into the 3DCRT impact on OARs and the antitumor immune response.
List of abbreviations
- 3DCRT:
-
three-dimensional conformal radiotherapy
- ADT:
-
androgen deprivation therapy
- AUC:
-
area under the curve
- BM:
-
bone marrow
- CD:
-
cluster of differentiation
- CT:
-
computer tomography
- CTL:
-
cytotoxic T lymphocyte
- CTV:
-
clinical target volume
- DVH:
-
dose volume histogram
- GI:
-
gastrointestinal
- GU:
-
genitourinary
- IBM:
-
iliac bone marrow
- ICRU:
-
International Commission on Radiation Units
- LENT-SOMA:
-
Late effects in Normal Tissues Subjective, Objective, Management and Analytical scales
- LN:
-
lymph nodes
- LP:
-
lower pelvis
- LS:
-
lumbosacral spine
- MLC:
-
multileaf collimator
- NK:
-
natural killer
- OAR:
-
organs at risk
- OR:
-
odds ratio
- PBM:
-
pelvic bone marrow
- PBMC:
-
peripheral blood mononuclear cells
- PO:
-
prostate-only
- PSA:
-
prostate-specific antigen
- PTV:
-
planning target volume
- ROC:
-
receiver operating characteristic
- RP/TURP:
-
radical prostatectomy/transurethral resection
- RT:
-
radiotherapy
- RTOG:
-
Radiation Therapy Oncology Group
- WP:
-
whole pelvic.
Declarations
Acknowledgements
We thank Drs. Bela Malinova, Anna Kindlova, Jana Prausova, and Michaela Matouskova for excellent cooperation and valuable comments. The work was supported by the Grant agency of the Charles University, GAUK 109908/2008 and the Grant agency of the Academy of Sciences of the Czech Republic, IAA500200620.
Authors’ Affiliations
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