3D CT-based high-dose-rate brachytherapy for cervical cancer: Clinical impact on late rectal bleeding and local control

Background and purpose

To identify the impact of 3D CT-based high-dose-rate intracavitary radiotherapy (ICR) on late rectal bleeding (LRB) and local control (LC) in patients with cervical cancer.

Material and methods

The outcomes of 97 consecutive patients treated with 3D CT-based ICR (3D-ICR) were compared with those of 133 consecutive historical patients with conventional 2D brachytherapy planning (2D-ICR). The median follow-up periods were 41 and 56 months for the 3D and 2D groups, respectively.

Results

The overall rectal bleeding rate was similar between the groups (42% for 3D-ICR vs. 44% for 2D-ICR); however, the incidence of severe LRB was higher in the 2D-ICR group than in the 3D-ICR group (13% vs. 2%, respectively; p = 0.02). In multivariate analysis, the factors associated with severe LRB were tumor >4 cm (12% vs. 3%) and 2D-ICR (10% vs. 2%). The LC rates were 97% and 91% for 3D-ICR and 2D-ICR, respectively (p = 0.14); the progression-free survival rate was 80% for both groups. A significant difference in the LC rates between the two groups was observed in patients with larger tumor sizes with the tumor diameter of over 4 cm (98% vs. 81% by 3D-ICR vs. 2D-ICR, respectively; p = 0.02).

Conclusions

The implementation of 3D-ICR in radiotherapy for cervical cancer can reduce the incidence of severe LRB and may improve the LC rate.     

Combination external beam radiotherapy and high-dose-rate intracavitary brachytherapy for uterine cervical cancer: analysis of dose and fractionation schedule

PURPOSE: To determine an appropriate dose and fractionation schedule for a combination of external beam radiotherapy (EBRT) and high-dose-rate intracavitary brachytherapy (HDR-ICBT) for uterine cervical cancer. METHODS: Eighty-eight patients with uterine cervical squamous cell carcinoma treated with EBRT and HDR-ICBT were analyzed. Twenty-five patients were classified as early disease (nonbulky Stage I/II, less than 4-cm diameter) and 63 patients as advanced disease (greater than 4 cm diameter or Stage IIIB) according to the American Brachytherapy Society definition. Tumor diameter was measured by MRI. Pelvic EBRT was delivered before applications of ICBT. HDR-ICBT was performed once a week, with a fraction point A dose of 6 Gy. Source loadings corresponded to the Manchester System for uterine cervical cancer. No planned optimization was done. A Henschke-type applicator was mostly used (86%). Median cumulative biologic effective dose (BED) at point A (EBRT + ICBT) was 64.8 Gy(10) (range: 48-76.8 Gy(10)) for early disease, and 76.8 Gy(10) (range: 38.4-86.4 Gy(10)) for advanced disease. Median cumulative BED at ICRU 38 reference points (EBRT + ICBT) was 97.7 Gy(3) (range: 59.1-134.4 Gy(3)) at the rectum, 97.8 Gy(3) (range: 54.6-130.4 Gy(3)) at the bladder, and 324 Gy(3) (range: 185.5-618 Gy(3)) at the vagina. Actuarial pelvic control rate and late complication rate were analyzed according to cumulative dose and calculated BED. RESULTS: The 3-year actuarial pelvic control rate was 82% for all 88 patients: 96% for those with early disease, and 76% for advanced disease. For pelvic control, no significant dose-response relationship was observed by treatment schedules and cumulative BED at point A for both early and advanced disease. The 3-year actuarial late complication rates (Grade > or =1) were 12% for proctitis, 11% for cystitis, and 14% for enterocolitis. There were significant differences on the incidence of proctitis (p < 0.0001) and enterocolitis (p < 0.0001), but not for cystitis by the treatment schedules and cumulative point A BED. All 4 patients treated with 86.4 Gy(10) at point A suffered both proctitis and enterocolitis. Patients with cumulative BED at rectal point of > or =100 Gy(3) had significantly higher incidence of proctitis (31% vs. 4%, p = 0.013). CONCLUSIONS: In view of the therapeutic ratio, cumulative BED 70-80 Gy(10) at point A is appropriate for uterine cervical cancer patients treated with a combination of EBRT and HDR-ICBT. Present results and data from other literatures suggested that cumulative BED at the rectal point should be kept below 100-120 Gy(3) to prevent late rectal complication.     

Rectal bleeding after high-dose-rate brachytherapy combined with hypofractionated external-beam radiotherapy for localized prostate cancer: impact of rectal dose in high-dose-rate brachytherapy on occurrence of grade 2 or worse rectal bleeding

PURPOSE: To evaluate the incidence of Grade 2 or worse rectal bleeding after high-dose-rate (HDR) brachytherapy combined with hypofractionated external-beam radiotherapy (EBRT), with special emphasis on the relationship between the incidence of rectal bleeding and the rectal dose from HDR brachytherapy. METHODS AND MATERIALS: The records of 100 patients who were treated by HDR brachytherapy combined with EBRT for > or =12 months were analyzed. The fractionation schema for HDR brachytherapy was prospectively changed, and the total radiation dose for EBRT was fixed at 51 Gy. The distribution of the fractionation schema used in the patients was as follows: 5 Gy x 5 in 13 patients; 7 Gy x 3 in 19 patients; and 9 Gy x 2 in 68 patients. RESULTS: Ten patients (10%) developed Grade 2 or worse rectal bleeding. Regarding the correlation with dosimetric factors, no significant differences were found in the average percentage of the entire rectal volume receiving 30%, 50%, 80%, and 90% of the prescribed radiation dose from EBRT between those with bleeding and those without. The average percentage of the entire rectal volume receiving 10%, 30%, 50%, 80%, and 90% of the prescribed radiation dose from HDR brachytherapy in those who developed rectal bleeding was 77.9%, 28.6%, 9.0%, 1.5%, and 0.3%, respectively, and was 69.2%, 22.2%, 6.6%, 0.9%, and 0.4%, respectively, in those without bleeding. The differences in the percentages of the entire rectal volume receiving 10%, 30%, and 50% between those with and without bleeding were statistically significant. CONCLUSIONS: The rectal dose from HDR brachytherapy for patients with prostate cancer may have a significant impact on the incidence of Grade 2 or worse rectal bleeding.     

Analysis of prognostic factors in stage IIB–IVA cervical carcinoma treated with radiation therapy: Value of computed tomography

: Androgen ablation is often combined with radiation in the treatment of patients with prostate cancer, yet, the optimal sequencing and the mechanisms governing the interaction are not understood. The objectives were to determine if cell killing via apoptosis is enhanced when the combined treatment is administered and to defined the relationship of changes in this form of cell killing to tumor volume growth delay.

: Dunning R3327-G rat prostate tumors, grown inthe flanks of Copenhagen rats, were used at a volume of approximately 1 cc. Androgen ablation was initiated by castration, and androgen restoration was achived with 0.5 cm silastic tube implants containing testosterone. ⁶⁰Co was used for irradiation. The terminal deoxynucleotidyl transferase (TUNEL) histochemical assay was used to quantify apoptosis.

: Tumors from intact and castrate unirradiated control rats had average apoptotic indices (percent of apoptotic cells) of 0.4 and 1.0%, respectively. The apoptotic index varied only slightly over time (3 h to 28 days) after castration (range 0.75-1.43%). Irradiation of intact rats to 7 Gy resulted in a peak apoptotic response at 6 h of 2.3%. A supradditive apoptotic response was seen when castration was initiated 3 days prior to 7 Gy radiation, with peak levels of about 10.1%. When the radiation was administered at increasing times beyond 3 dats after castration, the apoptotic response gradually diminished and was back to levels seenin intact rats by 28 days after castration. Tumor volume growth delay studies were consistent with, but not conclusive proof of, a supraadditive effect when the combination was used.

: A supraaddtive apoptotic response was seen when androgen ablation and radiation were used to treat androgen sensitive R3327-G rat prostate tumors. This supraadditive effect was dependent on the timing of the two treatments. Further studies are required to more fully define the optimal timing and administration of androgen ablation and radiation.     

Unique role of proximal rectal dose in late rectal complications for patients with cervical cancer undergoing high-dose-rate intracavitary brachytherapy

PURPOSE: To investigate the correlation of the radiation dose to the upper rectum, proximal to the International Commission of Radiation Units and Measurements (ICRU) rectal point, with late rectal complications in patients treated with external beam radiotherapy (EBRT) and high-dose-rate (HDR) intracavitary brachytherapy (ICRT) for carcinoma of the uterine cervix. METHODS AND MATERIALS: Between June 1997 and February 2001, 75 patients with cervical carcinoma completed definitive or preoperative RT and were retrospectively reviewed. Of the 75 patients, 62 with complete dosimetric data and a minimal follow-up of at least 1 year were included in this analysis. Of the 62 patients, 36 (58%) also received concurrent chemotherapy, mainly with cisplatin during EBRT. EBRT consisted of a mean of 50.1 +/- 1.3 Gy of 18-MV photons to the pelvis. A parametrial boost was given to 55 patients. Central shielding was used after 40-45 Gy of pelvic RT. HDR ICRT followed EBRT, with a median dose of 5 Gy/fraction given twice weekly for a median of four fractions. The mean dose to point A from HDR ICRT was 23.9 +/- 3.0 Gy. In addition to the placement of a rectal tube with a lead wire during ICRT, 30-40 mL of contrast medium was instilled into the rectum to demonstrate the anterior rectal wall up to the rectosigmoid junction. Late rectal complications were recorded according to the Radiation Therapy Oncology Group grading system. The maximal rectal dose taken along the rectum from the anal verge to the rectosigmoid junction and the ICRU rectal dose were calculated. Statistical tests were used for the correlation of Grade 2 or greater rectal complications with patient-related variables and dosimetric factors. Correlations among the point A dose, ICRU rectal dose, and maximal proximal rectal dose were analyzed. RESULTS: Fourteen patients (23%) developed Grade 2 or greater rectal complications. Patient-related factors, definitive or preoperative RT, and the use of concurrent chemotherapy were not associated with the occurrence of rectal complications. The maximal rectal dose during ICRT was at the proximal rectum rather than at the ICRU rectal point in 55 (89%) of 62 patients. Patients with Grade 2 or greater rectal complications had received a significantly greater total maximal proximal rectal dose from ICRT (25.6 Gy vs. 19.2 Gy, p = 0.019) and had a greater maximal proximal rectal dose/point A dose ratio (1.025 vs. 0.813, p = 0.024). In contrast, patients with and without rectal complications had a similar dose at point A (25.0 Gy vs.23.6 Gy, p = 0.107). The differences in the ICRU rectal dose (17.8 Gy vs.15.4 Gy, p = 0.065) and the ICRU rectal dose/point A dose ratio (0.71 vs. 0.66, p = 0.210) did not reach statistical significance. Patients with >62 Gy of a direct dose sum from EBRT and ICRT to the proximal rectum (12 of 29 vs. 2 of 33, p = 0.001) and >110 Gy of a total maximal proximal rectal biologic effective dose (13 of 40 vs. 1 of 22, p = 0.012) presented with a significantly increased frequency of Grade 2 or greater rectal complications. The correlations between the maximal proximal rectal dose and the ICRU rectal dose were less satisfactory (Pearson coefficient 0.375). Moreover, 11 of the 14 patients with rectal complications had colonoscopic findings of radiation colitis at the proximal rectum, the area with the maximal rectal dose. CONCLUSION: Eighty-nine percent of our patients had a maximal rectal dose from ICRT at the proximal rectum instead of the ICRU rectal point. The difference between patients with and without late rectal complications was more prominent for the proximal rectal dose than for the ICRU rectal dose. It is important and useful to contrast the whole rectal wall up to the rectosigmoid junction and to calculate the dose at the proximal rectum for patients undergoing HDR ICRT.     

In vivo assessment of the gastric mucosal tolerance dose after single fraction, small volume irradiation of liver malignancies by computed tomography-guided, high-dose-rate brachytherapy

PURPOSE: The aim of this study was to assess the tolerance dose of gastric mucosa for single-fraction computed tomography (CT)-guided, high-dose-rate (HDR) brachytherapy of liver malignancies. METHODS AND MATERIALS: A total of 33 patients treated by CT-guided HDR brachytherapy of liver malignancies in segments II and/or III were included. Dose planning was performed upon a three-dimensional CT data set acquired after percutaneous applicator positioning. All patients received gastric protection post-treatment. For further analysis, the contours of the gastric wall were defined in every CT slice using Brachyvision Software. Dose-volume histograms were calculated for each treatment and correlated with clinical data derived from questionnaires assessing Common Toxicity Criteria (CTC). All patients presenting symptoms of upper GI toxicity were examined endoscopically. RESULTS: Summarizing all patients the minimum dose applied to 1 ml of the gastric wall (D(1 ml)) ranged from 6.3 to 34.2 Gy; median, 14.3 Gy. Toxicity was present in 18 patients (55%). We found nausea in 16 (69%), emesis in 9 (27%), cramping in 13 (39%), weight loss in 12 (36%), gastritis in 4 (12%), and ulceration in 5 patients (15%). We found a threshold dose D(1 ml) of 11 Gy for general gastric toxicity and 15.5 Gy for gastric ulceration verified by an univariate analysis (p = 0.01). CONCLUSIONS: For a single fraction, small volume irradiation we found in the upper abdomen a threshold dose D(1 ml) of 15.5 Gy for the clinical endpoint ulceration of the gastric mucosa. This in vivo assessment is in accordance with previously published tolerance data.     

放疗后复发宫颈癌的高剂量率组织间插植治疗研究现状

放疗后盆腔中央型复发的宫颈癌患者,采用高剂量率组织间插植近距离治疗是一种可行的方式.患者损伤小,并保留了器官完整性.但适应证、治疗剂量和危及器官限量均无明确界定.目前研究样本量小,但给予我们一定的治疗提示.肿瘤大小、治疗剂量、放疗间隔时间、临床分期均会对患者预后产生一定的影响.合并危险因素越多,预后越差,治疗获益越低.     

Computed tomography-based high-dose-rate intracavitary brachytherapy for uterine cervical cancer: preliminary demonstration of correlation between dose-volume parameters and rectal mucosal changes observed by flexible sigmoidoscopy

PURPOSE: To compare the dose-volume histogram (DVH) parameters obtained by three-dimensional gynecologic brachytherapy planning with the rectosigmoid mucosal changes observed by flexible sigmoidoscopy. METHODS AND MATERIALS: Between January 2004 and July 2005, 71 patients with International Federation of Gynecology and Obstetrics Stage IB-IIIB uterine cervical cancer underwent computed tomography-based high-dose-rate intracavitary brachytherapy. The total dose (external beam radiotherapy [RT] plus intracavitary brachytherapy) to the International Commission of Radiation Units and Measurements rectal point (ICRU(RP)) and DVH parameters for rectosigmoid colon were calculated using the equivalent dose in 2-Gy fractions (alpha/beta = 3 Gy). Sigmoidoscopy was performed every 6 months after RT, with the 6-scale scoring system used to determine mucosal changes. RESULTS: The mean values of the DVH parameters and ICRU(RP) were significantly greater in patients with a score of > or =2 than in those with a score <2 at 12 months after RT (ICRU(RP), 71 Gy(alpha/beta3) vs. 66 Gy(alpha/beta3), p = 0.02; D(0.1cc), 93 Gy(alpha/beta3) vs. 85 Gy(alpha/beta3), p = 0.04; D(1cc), 80 Gy(alpha/beta3) vs. 73 Gy(alpha/beta3), p = 0.02; D(2cc), 75 Gy(alpha/beta3) vs. 69 Gy(alpha/beta3), p = 0.02). The probability of a score of > or =2 showed a significant relationship with the DVH parameters and ICRU(RP) (ICRU(RP), p = 0.03; D(0.1cc), p = 0.05; D(1cc), p = 0.02; D(2cc), p = 0.02). CONCLUSION: Our preliminary data have shown that DVH values of the rectosigmoid colon obtained by computed tomography-based three-dimensional brachytherapy planning are reliable and predictive of score > or =2 rectosigmoid mucosal changes.     

Determining DVH parameters for combined external beam and brachytherapy treatment: 3D biological dose adding for patients with cervical cancer

Purpose

To compare two methods of DVH parameter determination for combined external beam and brachytherapy treatment of cervical cancer.

Materials and methods

Clinical treatment plans from five patients were used in this study. We simulated two applications given with PDR (32 × 60 cGy per application, given hourly) or HDR (4 × 7 Gy in two applications; each application of two fractions of 7 Gy, given within 17 h) standard and optimised treatment plans, all combined with IMRT (25 × 1.8 Gy). Additionally, we simulated an external beam (EBRT) boost to pathological lymph nodes or the parametrium (7 × 2 Gy).We determined D90 of the high-risk CTV (HR-CTV) and D_2cc of bladder and rectum in EQD2 in two ways. (1) ‘Parameter adding’: assuming a uniform contribution of the EBRT dose distribution and adding the values of DVH parameters for the two brachytherapy insertions, and (2) ‘distributions adding’: summing 3D biological dose distributions of IMRT and brachytherapy plans and subsequently determining the values of the DVH parameters. We took α/β = 10 Gy for HR-CTV, α/β = 3 Gy otherwise and half-time of repair 1.5 h.

Results

Without EBRT boost, ‘parameter adding’ yielded a good approximation. With an EBRT boost to lymph nodes, the total D90 HR-CTV was underestimated by 2.6 (SD 1.3)% for PDR and 2.8 (SD 1.4)% for HDR. This was even worse with a parametrium boost: 9.1 (SD 6.2)% for PDR and 9.9 (SD 6.2)% for HDR.

Conclusion

Without an EBRT boost ‘parameter adding’, as proposed by the GEC-ESTRO, yielded accurate results for the values for DVH parameters. If an EBRT boost is given ‘distributions adding’ should be considered.     

放射治疗83例宫颈癌预后的相关因素

目的 :探讨放射治疗宫颈癌预后的相关因素 ,着重从肿瘤大小、疗程、局部控制情况等方面分析其与生存率的关系。方法 :83例Ⅰ、Ⅱ、Ⅲ期的宫颈癌于 1993年 4月～ 2 0 0 1年 4月在本科行首次放射治疗 ,全部病例均用60 Co远距离治疗机行盆腔外照射加192 Ir高剂量率后装治疗机行腔内照射。外照射 :中平面剂量DT 2 5～ 2 6Gy/13次后中间挡铅加量至DT 4 8～ 5 0Gy。腔内治疗 :A点的剂量DT 5Gy/次 ,DT 35Gy/ 7次。生存率计算采用Kaplan Meier法 ,差异显著性采用Log rank检验。 结果 :①局部控制情况肿瘤消退的 :一年、二年、三年、五年的生存率分别为 95 87%、77 12 %、73 0 9%、73 0 9% ,肿瘤残留的 :一年、二年、三年、五年的生存率分别为 34 2 9%、0 %、0 %、0 % ,差异有显著性意义 (χ2 =111 75 36 ,P <0 0 0 0 1)。②疗程疗程 <5 6天 :一年、二年、三年、五年的生存率分别为 93 88%、82 86 %、80 19%、80 19% ;疗程≥ 5 6天 :一年、二年、三年、五年的生存率分别为 78 95 %、30 5 5 %、2 2 91%、2 2 91%。差异有显著性意义 (χ2 =2 2 4 115 ,P <0 0 0 1)③宫颈肿瘤最大直径 <4cm :一年、二年、三年、五年的生存率分别为 95 12 %、82 86 %、79 6 7%、79 6 7% ;肿瘤最大直     

The prediction of late rectal complications in patients treated with high dose-rate brachytherapy for carcinoma of the cervix

: The aim of this work is to invetigate an unusually high rate of late rectal complications in a group of 43 patients treated with concomitant irradiation and chemotherapy for carcinoma of the cervix between December 1988 and April 1991, with a view to identifying predictive factors.

: The biologically effective dose received by each patient to the rectal reference point defined by the International Commission of Radiation Units and Measurements, Report 38, were calculated. Radiotherapy consisted of 46 Gy external beam irradiation plus three dose-rate intracavitary treatments of 10 Gy each prescribed to point A. Cisplatin 30 mg/m² was given weekly throughout the duration of the irradiation. The results have been compared to data from 119 patients treated with irradiation alone to assess the cofounding effect of the cisplatin.

: The relationship between the biologically effective dose delivered to the rectal reference point and the development of late complications shows a strong dose-response with a threshold for complications occurring at aproximately the same biologically effective dose threshold as that found for external beam irradiation in the head and neck region. The date from the group of patients treated wihout cisplatin is comparable to the date from the first group of patients in the lower dose ranges; the higher doses were not used and thus are not available for comparison.

: Using the linear quadratic model applied to our clinical results, we have established a threshold for late rectal complications for patients treated with external beam irradiation and high dose-rate brachytherapy for carcinoma of the cervix. This threshold is consistent with similar data for external irradiation in the head and neck region.     

Health-related quality of life and late morbidity in concurrent chemoradiation and radiotherapy alone in patients with locally advanced cervical carcinoma

Objective

Concurrent chemoradiation has improved survival of patients with cervical carcinoma. However, follow-up of randomized studies is relatively short and data on long term toxicity are scarce, as is information on their health-related quality of life. This study assesses and compares incidences of late side-effects among patients treated with radiotherapy or chemoradiation using two toxicity scoring systems, and investigates impact on health-related quality of life.

Methods

Between 1985 and 1993, 114 patients underwent radiotherapy (n=39) or chemoradiation (n=75) for stage IIA-IVB cervical carcinoma. Late side-effects were scored retrospectively by reviewing medical charts using standardised checklists, focusing on bladder- and intestinal side effects. Health-related quality of life was assessed once using the EORTC QLQ-C30.

Results

No significant differences in late treatment-related side-effects between radiotherapy and chemoradiation groups were found. Grade ≥ 2 toxicity was found in 33% (bladder), and in 6% (bowel). Only 1.8% had both grade 3-4 toxicity. Bladder syndrome with high urinary frequency, urine incontinence and small bowel toxicity had a significant impact on health-related quality of life.

Conclusion

Grade 2 are relatively frequent late side effects in curatively treated patients, but are not enhanced by the addition of chemotherapy. Their negative impact on health-related quality of life stresses the importance of new radiation techniques, aiming at reduction of these side effects.     

Early antiangiogenic activity of bevacizumab evaluated by computed tomography perfusion scan in patients with advanced hepatocellular carcinoma

BACKGROUND: Hepatocellular carcinoma (HCC) is a highly vascularized tumor with a poor prognosis. In a phase II study that combined bevacizumab with gemcitabine and oxaliplatin in advanced HCC, we examined computed tomography perfusion (CTp) scan parameters as surrogate markers of angiogenesis after bevacizumab administration. METHODS: HCC patients received bevacizumab alone i.v. at 10 mg/kg on day 1 during cycle 1. CTp scanning was performed at baseline and days 10-12 to assess changes in tissue blood flow (BF), blood volume (BV), mean transit time (MTT), and permeability surface area product (PS). RESULTS: Compared with baseline, a significant decrease in the estimated tumor perfusion parameters including BF, BV, and PS and an increase in MTT were seen on days 10-12 following bevacizumab administration alone. Patients with progressive disease had lower baseline MTT values and a higher percent increase following bevacizumab administration than those with stable disease or partial responses. CONCLUSIONS: Bevacizumab induced a significant decrease in tumor BF, BV, and PS and an increase in MTT by CTp scan in HCC. Baseline and percent change in MTT following bevacizumab administration correlated with clinical outcome, whereas BF, BV, and PS did not.