Adaptive cone-beam CT planning improves long-term biochemical disease-free survival for 125I prostate brachytherapy.

PURPOSE: Determining the independent effect of additional intraoperative adaptive C-arm cone-beam CT (CBCT) planning vs. transrectal ultrasound (TRUS)-guided interactive planning alone in 125I brachytherapy for prostate cancer (PCa) on biochemical disease-free survival (BDFS). METHODS AND MATERIALS: T1/T2-stage PCa patients receiving TRUS-guided brachytherapy from 2000 to 2014 were analyzed. From October 2006, patients received additional intraoperative adaptive CBCT planning for dosimetric evaluation and subsequent remedial seed placement in underdosed areas. Patients were stratified according to the National Comprehensive Cancer Network (NCCN) risk classification. Kaplan-Meier analysis was used to estimate BDFS (primary outcome), overall survival, and PCa-specific survival (secondary outcomes). Cox regression was used to assess the relation between CBCT use and biochemical failure (BF) and overall mortality. RESULTS: In all, 1623 patients were included. Median followup was 99 months (interquartile range 70-115) for TRUS patients (n = 613) and 51 months (interquartile range 29-70) for CBCT patients (n = 1010). BF occurred 203 times and 206 patients died, 26 from PCa. For TRUS and CBCT patients, 7-year BDFS was 87.2% vs. 93.5% (log rank: p = 0.04) for low, 75.9% vs. 88.5% (p < 0.001) for intermediate, and 57.1% vs. 85.0% for high-risk patients (p < 0.001). For TRUS and CBCT patients, 7-year PCa-specific survival was 96.0% vs. 100% (p < 0.0001). After Cox regression, CBCT patients had lower hazard of BF: hazard ratio (HR) 0.25 (95% confidence interval [CI]: 0.18-0.33; p < 0.0001). Corrected for confounders, CBCT remained a predictor of BF: HR 0.51 (95% CI: 0.31-0.86; p = 0.01) but not for overall mortality: HR 0.66 (95% CI: 0.40-1.07; p = 0.09). CONCLUSIONS: Additional intraoperative adaptive CBCT planning in 125I prostate brachytherapy leads to a significant increase in BDFS in all NCCN risk groups.

Value of 18F-FDG PET/CT in diagnosing chronic Q fever in patients with central vascular disease.

BACKGROUND: The aim of this study is to describe the value of 2-deoxy-2-[18F]fluoro-D-glucose positron emission tomography/computed tomography (18F-FDG PET/CT) in diagnosing chronic Q fever in patients with central vascular disease and the added value of 18F-FDG PET/CT in the diagnostic combination strategy as described in the Dutch consensus guideline for diagnosing chronic Q fever. METHODS: 18F-FDG PET/CT was performed in patients with an abdominal aortic aneurysm or aorto-iliac reconstruction and chronic Q fever, diagnosed by serology and positive PCR for Coxiella burnetii DNA in blood and/or tissue (PCR-positive study group). Patients with an abdominal aortic aneurysm or aorto-iliac reconstruction without clinical and serological findings indicating Q fever infection served as a control group. Patients with a serological profile of chronic Q fever and a negative PCR in blood were included in additional analyses (PCR-negative study group). RESULTS: Thirteen patients were evaluated in the PCR-positive study group and 22 patients in the control group. 18F-FDG PET/CT indicated vascular infection in 6/13 patients in the PCR-positive study group and 2/22 patients in the control group. 18F-FDG PET/CT demonstrated a sensitivity of 46% (95% CI: 23-71%), specificity of 91% (95% CI: 71-99%), positive predictive value of 75% (95% CI:41-93%) and negative predictive value of 74% (95% CI: 55-87%). In the PCR-negative study group, 18F-FDG PET/CT was positive in 10/20 patients (50%). CONCLUSION: The combination of 18F-FDG PET/CT, as an imaging tool for identifying a focus of infection, and Q fever serology is a valid diagnostic strategy for diagnosing chronic Q fever in patients with central vascular disease.

Development and internal validation of a multivariable prediction model for biochemical failure after whole-gland salvage iodine-125 prostate brachytherapy for recurrent prostate cancer.

BACKGROUND: Localized recurrent prostate cancer after primary radiotherapy can be curatively treated using salvage iodine-125 ((125)I) brachytherapy. Selection is hampered by a lack of predictive factors for cancer control. This study aims to develop and internally validate a prognostic model for biochemical failure (BF) after salvage (125)I brachytherapy. METHODS AND MATERIALS: Whole-gland salvage (125)I brachytherapy patients were treated between 1993 and 2010 in two radiotherapy centers in the Netherlands. Multivariable Cox regression was performed to assess the predictive value of clinical parameters related to BF (Phoenix-definition [prostate-specific antigen [PSA]-nadir + 2.0 ng/mL]). Missing data were handled by multiple imputation. The model's discriminatory ability was assessed with Harrell's C-statistic. Internal validation was performed using bootstrap resampling (2000 data sets). Goodness-of-fit was evaluated with calibration plots. All analyses were performed using the recently published TRIPOD (Transparent reporting of a multivariable prediction model for individual prognosis or diagnosis) statement. RESULTS: After median followup of 74 months (range 5-138), 43 of a total 62 patients developed BF. In multivariable analysis, disease-free survival interval (DFSI) after primary therapy and pre-salvage prostate-specific antigen doubling time (PSADT) were predictors of BF: corrected hazard ratio (HR) 0.99 (95% confidence interval 0.97-0.999; p = 0.04) and 0.94 (95% confidence interval 0.89-0.99; p = 0.03), both for a 1-month increase (optimism-adjusted C-statistic 0.70). Calibration was accurate up to 36 months. Of patients with PSADT >30 months and DFSI >60 months, 36-month biochemical disease-free survival was >75%. Every 12-month increase in DFSI will allow 3-month decrease in PSADT while maintaining the same biochemical recurrence-free rates. CONCLUSIONS: We have presented results from a cohort of patients undergoing salvage (125)I-brachytherapy. Our data show that better selection of patients is possible with the DFSI and PSADT.

FDG-PET has no definite role in preoperative imaging in gastric cancer.

BACKGROUND: Gastric cancer is fourth on the incidence list of cancers worldwide with a high disease-related mortality rate. Curation can only be achieved by a radical resection including an adequate lymphadenectomy. However, prognosis remains poor and cancer recurrence rates are high, also due to lymph node metastases. To improve outcome, (neo)adjuvant treatment strategies with chemo- and/or radiotherapy regimes are employed. AIMS: Accurate staging of gastric cancer at primary diagnosis is essential for adequate treatment. In this non-systematic review the role 18-F-Fluoro-2-deoxyglucose (FDG) positron emission tomography (PET) in preoperative staging is investigated. Furthermore, the results of neoadjuvant chemotherapy-induced tumour response monitoring by FDG-PET are discussed. RESULTS AND CONCLUSION: It is concluded that currently FDG-PET has no role in the primary detection of gastric cancer due to its low sensitivity. FDG-PET shows, however, slightly better results in the evaluation of lymph node metastases in gastric cancer compared to CT and could have therefore a role in the preoperative staging. Improvement in accuracy could be achieved by using PET/CT or other PET tracers than FDG, but these modalities need further investigation. FDG-PET, however, adequately detects therapy responders at an early stage following neoadjuvant chemotherapy.

Long-term prognosis of patients with local recurrence after conservative surgery and radiotherapy for early breast cancer.

We have studied the long-term prognosis of 266 patients considered to have isolated local recurrence in the breast following conservative surgery and radiotherapy for early breast cancer. The median follow-up of the patients still alive after diagnosis of local relapse was 11.2 years. At 10 years from the date of salvage treatment, the overall survival rate for the 226 patients with invasive local recurrence was 39% (95% CI, 32-46), the distant recurrence-free survival rate was 36% (95% CI, 29-42), and the local control rate (i.e., survival without subsequent local recurrence or local progression) was 68% (95% CI, 62-75). Among patients with a local recurrence at or near the original tumour site a better distant disease-free survival was observed for patients with recurrences measuring 1cm or less, compared to those with larger recurrences. This suggests, though does not prove, that early detection of local recurrence can improve the treatment outcome but might as well point towards a different biologic behaviour, facilitating early detection.

The value of [18F]fluoro-2-deoxy-D-glucose positron emission tomography in the selection of patients with stage IIIA-N2 non-small cell lung cancer for combined modality treatment.

Combined modality treatment (CMT) for patients with stage IIIA-N2 non-small cell lung cancer (NSCLC) is at present studied extensively. To select patients with truly stage IIIA-N2 disease, however, proves to be difficult with current diagnostic tests. Distant metastases may become clinically overt during induction chemotherapy (IC) or shortly after, revealing the inaccuracies of current staging algorithms. A prospective study with [18F]fluoro-2-deoxy-D-glucose positron emission tomography (FDG PET) in IIIA-N2 NSCLC patients was performed to assess its value in the selection of this patient group. Fifty-seven patients received a whole body FDG PET scan as part of an ongoing response monitoring trial. Results were compared with conventional staging. In 32/57 (56%) PET suggested upstaging, which was confirmed in 17/57 (30%) with a median follow-up of 16 (range 2-49) months. These results show that using the conventional staging algorithm a substantial group of patients was understaged. FDG PET improves the selection of patients suitable for CMT.

Failure patterns of combined modality treatment in lung cancer: the impact of staging.

BACKGROUND: Patients with locally advanced non-small cell lung cancer (NSCLC) may be treated with induction chemotherapy (IC) followed by surgery with curative intent. The impact of staging inaccuracies on the failure rate of this intensive combined modality treatment approach, i.e. non-curative chemotherapy and thoracotomy, requires further investigation. METHODS: The records of a cohort of 38 consecutive NSCLC IIIA-N2 patients treated with IC followed by surgery were reviewed. RESULTS: The clinical course strongly suggested that the standard diagnostic algorithm failed to demonstrate stage IV disease in 34% of the cases. Surgery instigated by CT-based response criteria at restaging after chemotherapy proved to be irradical in 70% of cases. CONCLUSION: Our data confirm the limitations of the current work-up of patients with apparently locally advanced NSCLC. This applies to the selection of patients to be assigned to combined modality treatment as well as to the post-chemotherapy assessment of resectability. Improved (re)staging of these patients will enhance the efficiency of intervention trials and prevent patients from being exposed to intensive and toxic therapy from which they derive no benefit.

HDR brachytherapy applied to cervical carcinoma with moderate lateral expansion: modified principles of treatment.

BACKGROUND AND PURPOSE: In order to meet the deficiencies of endocavitary applications, a combined technique was introduced with the aim of achieving better target coverage for improvement of loco-regional tumour control. In high dose rate (HDR) endocavitary applications with tandem and ovoids, enlargement of the distance between the ovoids, shifting of dwell times and also optimization often fail to achieve sufficient expansion of the cervical parametrial area encompassed by the reference isodose. MATERIALS AND METHODS: The Deventer method, whereby HDR endocavitary and HDR interstitial brachytherapy are applied in the same session, was applied for tumours with a lateral expansion of 25 mm or more from the axis of the cervical canal. For the addition of HDR interstitial brachytherapy, each ovoid was provided with a channel which allowed insertion of an afterloading needle into the cervix up to a fixed depth. The dose specifications and dosimetry in neighbouring organs are presented in detail. RESULTS: Seventy-six combined applications were given to 41 patients. The follow-up averaged at 23 months, with a maximum of 59 months. No severe early or persistent late complications were observed. In stage IIB tumours, the most important evaluation of the merits of this technique, the disease-free 3-year survival determined with the Kaplan-Meier method was 75% (n=20). CONCLUSIONS: The Deventer method of HDR endocavitary and HDR interstitial brachytherapy applied in the same session is a feasible method for enlargement of the reference isodose envelope in the cervical parametrial area. The 3-year disease-free survival in stage IIB patients and the low complication rates in all stages together, justify its continuation.

Monitoring response to therapy in cancer using [18F]-2-fluoro-2-deoxy-D-glucose and positron emission tomography: an overview of different analytical methods.

[18F]-2-fluoro-2-deoxy-D-glucose positron emission tomography (FDG PET) is considered a valuable tool in the diagnosis and staging of cancer. In addition, it seems promising as a technique to monitor response to therapy. Progress is hampered, however, by the fact that various methods for the analysis of uptake of FDG in tumours have been described and that it is by no means clear whether these methods have the same sensitivity for monitoring response to treatment. As interest in monitoring response using FDG PET is growing, the danger exists that non-optimal methods will be used for evaluation. Hence an overview of the various analytical methods is given, highlighting both advantages and shortcomings of each of the methods. The ideal analytical method for response monitoring should represent an optimal trade-off between accuracy and simplicity (clinical applicability). At present, that trade-off still needs to be defined. Studies relating response, as measured with any of the available analytical methods, to outcome are urgently needed. Until then response monitoring studies should be conducted in such a way that all analytical methods can be compared with the most quantitative one, which at present is full compartmental modelling of the data.

On the use of image-derived input functions in oncological fluorine-18 fluorodeoxyglucose positron emission tomography studies.

There is growing interest in monitoring response to therapy in oncology patients using positron emission tomography and fluorine-18 fluorodeoxyglucose (FDG). Quantification is required, and various methods have been described. Arterial sampling, which provides the most accurate input function, often is not feasible in patients undergoing chemotherapy. In the thorax an image-derived input function can be obtained from the large vascular structures. In many studies the left ventricle (LV) is used, but the obtained data are rarely validated. In this study a simple quality control procedure for the image-derived input function was developed and compared with a standard LV curve. Twenty dynamic FDG scans were obtained in nine patients with non-small cell lung cancer stage IIIA-N2. Three venous blood samples were taken as a quality control for the image-derived input function. Regions of interest (ROIs) were defined for aorta, LV and left atrium. Input curves were generated according the the standard use of the LV curve and by applying the quality control method to all vascular ROIs. Tumour ROIs were defined and both input functions were used to calculate tumour glucose metabolism (MRglu), using both standard non-linear regression and Patlak analyses. Mean differences in MRglu using "standard" LV and "quality control approved" input functions were 16.2% and 17.5% for non-linear regression and Patlak analyses, respectively, indicating that the use of "standard" LV curve might lead to significant errors. It is concluded that care should be taken in using image derived input functions without appropriate quality control. The proposed procedure is simple and results in significantly more accurate MRglu data.

Histological determinants for different types of local recurrence after breast-conserving therapy of invasive breast cancer. Dutch Study Group on local Recurrence after Breast Conservation (BORST)

The purpose of this study was to determine which histological factors are associated with an increased risk for local recurrence in the breast after breast-conserving therapy for early breast cancer (TNM stage I and II) and whether risk patterns vary according to menopausal status and type of local recurrence. Through complete follow-up of the patients of eight regional radiation oncology departments, two cancer institutes and one surgical clinic in The Netherlands, 360 patients were identified with local recurrence in the breast after having received breast-conserving therapy (local tumour excision, axillary dissection and irradiation of the whole breast and a boost to the tumour bed) during the 1980s. For each case, two controls with a follow-up of similar duration without local recurrence were randomly selected. Histological slides of the primary tumour were reviewed. Among premenopausal patients the risk of recurrence for those younger than 35 years was significantly higher than that for premenopausal patients of 45 years or older (relative risk (RR) 2.9; 95% confidence interval (95% CI) 1.3-6.6, P < 0.05). The risk of recurrence at or near the site of the primary tumour was most significantly increased for patients with high grade extensive intraductal component (EIC) adjacent to the primary tumour (RR 4.1; 95% CI 1.7-9.8, P < 0.01). Microscopic margin involvement was an important risk indicator for diffuse recurrence and recurrence in the skin of the breast, especially in the presence of vascular invasion (RR 25; 95% CI 4.0-150, P < 0.001). To prevent local recurrence at or near the site of the primary tumour, local excision with a 1-2 cm margin of healthy tissue and a 15 Gy boost seemed adequate local treatment for patients with well differentiated EIC. In contrast, a wider surgical margin, a higher boost dose or mastectomy should be considered for patients with poorly differentiated EIC. Microscopic margin involvement in the presence of vascular invasion significantly increases the risk of diffuse recurrence or recurrence in the skin.

Variation in prostate position relative to adjacent bony anatomy.

PURPOSE: In prostatic cancer, the prostate cannot be discerned from a portal image. Setup information is, therefore, obtained from bony anatomy. To perform high-precision conformal therapy, knowledge about the variation in distance between the prostate and adjacent bony anatomy during an external radiotherapy treatment is mandatory. This report is concerned with that variation. METHODS AND MATERIALS: Nine patients previously treated interstitially for prostatic cancer with implantation of 125I seeds, agreed to cooperate in a study. They underwent a number of simulations of external radiotherapy treatment. After the first patient setup, this setup was repeated five times for each patient as if the patient was treated by external radiotherapy. Simulator radiographs were made from each setup in the anterior-posterior and left-right lateral directions. The seeds were clearly visible in the simulator film images and reflect the position of the prostate. No bladder instructions were given and the filling of the rectum was not quantified. RESULTS: Variation in distance between the prostate and the bony anatomy was measured and is presented in one standard deviation of the normal distribution function: 0.8 mm lateral, 1.5 mm ventrodorsal, and 1.7 mm craniocaudal. CONCLUSIONS: The bone structure of the pelvis reflects fairly well the position of the prostate. The prostate is least mobile in a lateral direction and most mobile in the craniocaudal and ventrodorsal directions.

Verification of source position in interstitial and intralumenal brachytherapy.

In brachytherapy afterloading, the treatment is simulated using dummy sources. In this study, imaging during treatment was performed to see whether the radioactive sources accurately replaced the dummy sources. In low-dose rate afterloading (manually or remote controlled) X-ray radiography was applied for verification. In high dose rate afterloading, the radioactive source was visualised under remote controlled X-ray fluoroscopy. Differences between dummy and treatment source position were observed, justifying verification imaging in brachytherapy.

Dose, fractionation and overall treatment time in radiation therapy--the effects on local control for cancer of the larynx.

The effect of total tumor dose, split course treatment and overall treatment time on local control was analysed in a retrospective series of 997 patients with carcinoma of the larynx, treated with megavoltage radiotherapy only. Primary tumors were classified by site (glottis and supraglottis) and T-stage. Continuous course (CC, n = 594) treatment was given primarily to small tumors. Split course radiation (SC, n = 403) was generally given to patients with larger field sizes. Total doses of irradiation ranged from 50 to 79 Gy, with a mean of 64 Gy in CC and 66 Gy in SC. Most of the treatments were given with fraction sizes between 2.0 and 2.1 Gy (91%). Overall treatment times ranged between 25 and 60 days in the CC group (mean, 45 days) and between 45 and 120 in the SC group (mean, 76 days). A local recurrence was observed in 256 patients. T-stage was the only tumor characteristic strongly related to local failure. Corrected for T-stage, no difference in local relapse rate was observed between glottic and supraglottic tumors, or between node-negative (n = 886) and node-positive patients (n = 111). After correction for T-stage the local failure rate of SC-treated tumors was 2.1 (95% confidence limits: 1.4-3.1) times higher than of CC-treated tumors. However, this effect could not be explained as an effect of the overall treatment time (OTT) itself, as no effect of OTT was found within the SC and the CC group, even though the variation in OTT's was considerable in the SC group. A higher tumor dose was associated with a lower local failure rate in the CC group (p = 0.005), but not in the SC group (p = 0.56).

Recurrent endometrial adenocarcinoma after surgery alone: prognostic factors and treatment.

Twenty-six patients with a local and/or regional relapse of a previously surgically treated adenocarcinoma of the endometrium were referred to the Dr. Daniel den Hoed Cancer Center (DDHCC) in Rotterdam, The Netherlands between 1965 and 1985 for external radiotherapy (ERT) and/or brachytherapy (BT). The 5-year overall survival was 44%. Tumour volume seemed to be an important prognostic factor in locoregional control; 1 out of 17 patients with tumour sizes smaller than or equal to 4 cm relapsed locoregionally, while in 3 out of 9 patients with tumour sizes of more than 4 cm a locoregional recurrence developed. Another important finding is the impact of RT on treatment outcome: none of the 16 patients treated with a combination of ERT and BT failed locoregionally, while 4 out of 10 patients treated with either ERT or BT relapsed.

Evaluation of brachytherapy implants using the "natural" volume-dose histogram.

The "natural" volume-dose histogram as described by Anderson visualises graphically even small differences between source arrangements, making it a useful tool to compare planned and realised source configurations. In this study the histogram is applied to demonstrate that the introduction of an applicator in oral cavity implants or of iridium wire spacers used as templates in bladder implants improved the quality of the implants considerably, resulting in close agreement between the planned and the realised source configuration.

Ultrasonically guided transperineal seed implantation of the prostate: modification of the technique and qualitative assessment of implants.

During the period 1988-1991, 23 patients with prostatic carcinoma were treated by transperineal iodine seed implantation guided by transrectal ultrasound. We introduce a refinement of the implantation technique using a rigid column of seeds and spacers. The uniformity parameter based on the peak width of the natural volume-dose histogram demonstrated quantitatively that this refinement resulted in a more accurate seed arrangement.