G. Bauman

Preoperative radiation with concurrent 5-fluorouracil continuous infusion for locally advanced unresectable rectal cancer

BACKGROUND AND PURPOSEnTo determine the percentage of complete responders and the resectability rate for patients with locally advanced carcinoma of the rectum treated by 5-fluorouracil (5-FU) infusional chemotherapy and pelvic radiation.nnnMATERIALS AND METHODSnBetween October 1992 and June 1996, 29 patients with a diagnosis of locally advanced unresectable rectal cancer received preoperative 5 FU by continuous intravenous infusion at a dose of 225 mg/m2/day concurrent with pelvic radiation (median 54 Gy/28 fractions). All patients were clinical stage T4 on the bases of organ invasion or tumor fixation. Median time for surgical resection was 6 weeks.nnnRESULTSnMedian follow-up for the group was 28 months (range 5-57 months). Six patients were felt to be persistently unresectable or developed distant metastases and did not undergo surgical resection. Of the 29 patients, 23 proceeded to surgery, 18 were resectable for cure, 13 by abdominoperineal resection, 3 by anterior resection and 2 by local excision. Of the 29 patients, 4 (13%) had a complete response, and 90% were clinically downstaged. Of the 18 resected patients, 1 has died of his disease, 17 are alive, and 15 disease-free. The regimen was well tolerated; there was only one treatment-related complication, a wound dehiscence.nnnCONCLUSIONnThe combination of 5 FU infusion and pelvic radiation in the management of locally advanced rectal cancer is well tolerated and provides a baseline for comparison purposes with future combinations of newer systemic agents and radiation.

Dosimetric impact of image-guided 3D conformal radiation therapy of prostate cancer

The goal of this work is to quantify the impact of image-guided conformal radiation therapy (CRT) on the dose distribution by correcting patient setup uncertainty and inter-fraction tumour motion. This was a retrospective analysis that used five randomly selected prostate cancer patients that underwent approximately 15 computed tomography (CT) scans during their radiation treatment course. The beam arrangement from the treatment plan was imported into each repeat CT study and the dose distribution was recalculated for the new beam setups. Various setup scenarios were then compared to assess the impact of image guidance on radiation treatment precision. These included (1) daily alignment to skin markers, thus representing a conventional beam setup without image guidance, (2) alignment to bony anatomy for correction of daily patient setup error, thus representing on-line portal image guidance, and (3) alignment to the CTV of the day for correction of inter-fraction tumour motion, thus representing on-line CT or ultrasound image guidance. Treatment scenarios (1) and (3) were repeated with a reduced CTV to PTV margin, where the former represents a treatment using small margins without daily image guidance. Daily realignment of the treatment beams to the prostate showed an average increase in minimum tumour dose of 1.5 Gy, in all cases where tumour geographic miss without image guidance was apparent. However, normal tissue sparing did not improve unless the PTV margin was reduced. Daily realignment to the tumour combined with reducing the margin size by a factor of 2 resulted in an average escalation in tumour dose of 9.0 Gy for all five static plans. However, the prescription dose could be escalated by 13.8 Gy when accounting for changes in anatomy by accumulating daily doses using nonlinear image registration techniques. These results provide quantitative information on the effectiveness of image-guided radiation treatment of prostate cancer and demonstrate that the dosimetric impact is patient dependent.

Boosting imaging defined dominant prostatic tumors: A systematic review

INTRODUCTIONnDominant cancer foci within the prostate are associated with sites of local recurrence post radiotherapy. In this systematic review we sought to address the question: what is the clinical evidence to support differential boosting to an imaging defined GTV volume within the prostate when delivered by external beam or brachytherapy.nnnMATERIALS AND METHODSnA systematic review was conducted to identify clinical series reporting the use of radiation boosts to imaging defined GTVs.nnnRESULTSnThirteen papers describing 11 unique patient series and 833 patients in total were identified. Methods and details of GTV definition and treatment varied substantially between series. GTV boosts were on average 8 Gy (range 3-35 Gy) for external beam, or 150% for brachytherapy (range 130-155%) and GTV volumes were small (<10 ml). Reported toxicity rates were low and may reflect the modest boost doses, small volumes and conservative DVH constraints employed in most studies. Variability in patient populations, study methodologies and outcomes reporting precluded conclusions regarding efficacy.nnnCONCLUSIONSnDespite a large cohort of patients treated differential boosts to imaging defined intra-prostatic targets, conclusions regarding optimal techniques and/or efficacy of this approach are elusive, and this approach cannot be considered standard of care. There is a need to build consensus and evidence. Ongoing prospective randomized trials are underway and will help to better define the role of differential prostate boosts based on imaging defined GTVs.

Image-guided adaptive radiation therapy (IGART): Radiobiological and dose escalation considerations for localized carcinoma of the prostate

The goal of this work was to evaluate the efficacy of various image-guided adaptive radiation therapy (IGART) techniques to deliver and escalate dose to the prostate in the presence of geometric uncertainties. Five prostate patients with 15-16 treatment CT studies each were retrospectively analyzed. All patients were planned with an 18 MV, six-field conformal technique with a 10 mm margin size and an initial prescription of 70 Gy in 35 fractions. The adaptive strategy employed in this work for patient-specific dose escalation was to increase the prescription dose in 2 Gy-per-fraction increments until the rectum normal tissue complication probability (NTCP) reached a level equal to that of the nominal plan NTCP (i.e., iso-NTCP dose escalation). The various target localization techniques simulated were: (1) daily laser-guided alignment to skin tattoo marks that represents treatment without image-guidance, (2) alignment to bony landmarks with daily portal images, and (3) alignment to the clinical target volume (CTV) with daily CT images. Techniques (1) and (3) were resimulated with a reduced margin size of 5 mm to investigate further dose escalation. When delivering the original clinical prescription dose of 70 Gy in 35 fractions, the CTV registration technique yielded the highest tumor control probability (TCP) most frequently, followed by the bone registration and tattoo registration techniques. However, the differences in TCP among the three techniques were minor when the margin size was 10 mm (⩽1.1%). Reducing the margin size to 5 mm significantly degraded the TCP values of the tattoo registration technique in two of the five patients, where a large difference was found compared to the other techniques (⩽11.8%). The CTV registration technique, however, did maintain similar TCP values compared to their 10 mm margin counterpart. In terms of normal tissue sparing, the technique producing the lowest NTCP varied from patient to patient. Reducing the margin size seemed the only sure way to reduce the NTCP significantly, irrespective of the IGART technique employed. In escalating the dose with the iso-NTCP constraint, the largest average gain in dose was observed with the tattoo registration technique, followed by the CTV registration and bone registration techniques. This is attributed to the fact that in three of the five patients, the tattoo registration technique yielded the lowest NTCP, hence a greater window of opportunity to escalate the dose was possible with this technique. However, the variation among the five patients was also largest with the tattoo registration technique where, in the case of one patient, the required dose actually needed to be below the original prescription dose of 70 Gy to satisfy the iso-NTCP constraint. This was not the case with the CTV registration technique where positive and similar dose escalation was allowed on all five patients. Based on these data, an attractive dose escalation strategy may be to implement the CTV registration technique (for consistent dosimetric coverage) for daily target localization in combination with a margin reduction (for increased normal tissue sparing).

On the performances of Intensity Modulated Protons, RapidArc and Helical Tomotherapy for selected paediatric cases

BackgroundTo evaluate the performance of three different advanced treatment techniques on a group of complex paediatric cancer cases.MethodsCT images and volumes of interest of five patients were used to design plans for Helical Tomotherapy (HT), RapidArc (RA) and Intensity Modulated Proton therapy (IMP). The tumour types were: extraosseous, intrathoracic Ewing Sarcoma; mediastinal Rhabdomyosarcoma; metastastis of base of skull with bone, para-nasal and left eye infiltration from Nephroblastoma of right kidney; metastatic Rhabdomyosarcoma of the anus; Wilms tumour of the left kidney with multiple liver metastases. Cases were selected for their complexity regardless the treatment intent and stage. Prescribed doses ranged from 18 to 53.2 Gy, with four cases planned using a Simultaneous Integrated Boost strategy. Results were analysed in terms of dose distributions and dose volume histograms.ResultsFor all patients, IMP plans lead to superior sparing of organs at risk and normal healthy tissue, where in particular the integral dose is halved with respect to photon techniques. In terms of conformity and of spillage of high doses outside targets (external index (EI)), all three techniques were comparable; CI90% ranged from 1.0 to 2.3 and EI from 0 to 5%. Concerning target homogeneity, IMP showed a variance (D5%–D95%) measured on the inner target volume (highest dose prescription) ranging from 5.9 to 13.3%, RA from 5.3 to 11.8%, and HT from 4.0 to 12.2%. The range of minimum significant dose to the same target was: (72.2%, 89.9%) for IMP, (86.7%, 94.1%) for RA, and (79.4%, 94.8%) for HT. Similarly, for maximum significant doses: (103.8%, 109.4%) for IMP, (103.2%, 107.4%) for RA, and (102.4%, 117.2%) for HT. Treatment times (beam-on time) ranged from 123 to 129 s for RA and from 146 to 387 s for HT.ConclusionFive complex pediatric cases were selected as representative examples to compare three advanced radiation delivery techniques. While differences were noted in the metrics examined, all three techniques provided satisfactory conformal avoidance and conformation.

Dosimetric evaluation of daily rigid and nonrigid geometric correction strategies during on-line image-guided radiation therapy (IGRT) of prostate cancer

The purpose of this study is to evaluate a geometric image guidance strategy that simultaneously correct for various inter-fractional rigid and nonrigid geometric uncertainties in an on-line environment, using field shape corrections (called the MU-MLC technique). The effectiveness of this strategy was compared with two other simpler on-line image guidance strategies that are more commonly used in the clinic. To this end, five prostate cancer patients, with at least 15 treatment CT studies each, were analyzed. The prescription dose was set to the maximum dose that did not violate the rectum and bladder dose-volume constraints, and hence, was unique to each patient. Deformable image registration and dose-tracking was performed on each CT image to obtain the cumulative treatment dose distributions. From this, maximum, minimum, and mean dose, as well as generalized equivalent uniform dose (gEUD) were calculated for each image guidance strategy. As expected, some dosimetric differences in the clinical target volume (CTV) were observed between the three image guidance strategies investigated. For example, up to +/-2% discrepancy in prostate minimum dose were observed among the techniques. Of them, only the MU -MLC technique did not reduce the prostate minimum dose for all patients (i.e., > or = 100%). However, the differences were clinically not significant to indicate the preference of one strategy over another, when using a uniform 5 mm margin size. For the organ-at-risks (OARs), the large rectum sparing effect (< or =5.7 Gy, gEUD) and bladder overdosing effect (< or = 16 Gy, gEUD) were observed. This was likely due to the use of bladder contrast during CT simulation studies which was not done during the treatment CT studies. Therefore, ultimately, strategies to maintain relatively constant rectum and bladder volumes, throughout the treatment course, are required to minimize this effect. In conclusion, the results here suggest that simple translational corrections based on three-dimensional (3D) images is adequate to maintain target coverage, for margin sizes at least as large as 5 mm. In addition, due to large fluctuations in OAR volumes, innovative image guidance strategies are needed to minimize dose and maintain consistent sparing during the whole course of radiation therapy.

Phase I Trial of Simultaneous In-Field Boost With Helical Tomotherapy for Patients With One to Three Brain Metastases

PURPOSEnStereotactic radiosurgery is an alternative to surgical resection for selected intracranial lesions. Integrated image-guided intensity-modulated-capable radiotherapy platforms such as helical tomotherapy (HT) could potentially replace traditional radiosurgery apparatus. The present studys objective was to determine the maximally tolerated dose of a simultaneous in-field boost integrated with whole brain radiotherapy for palliative treatment of patients with one to three brain metastases using HT.nnnMETHODS AND MATERIALSnThe inclusion/exclusion criteria and endpoints were consistent with the Radiation Therapy Oncology Group 9508 radiosurgery trial. The cohorts were constructed with a 3 + 3 design; however, additional patients were enrolled in the lower dose tolerable cohorts during the toxicity assessment periods. Whole brain radiotherapy (30 Gy in 10 fractions) was delivered with a 5-30-Gy (total lesion dose of 35-60 Gy in 10 fractions) simultaneous in-field boost delivered to the brain metastases. The maximally tolerated dose was determined by the frequency of neurologic Grade 3-5 National Cancer Institute Common Toxicity Criteria, version 3.0, dose-limiting toxicity events within each Phase I cohort.nnnRESULTSnA total of 48 patients received treatment in the 35-Gy (n = 3), 40-Gy (n = 16), 50-Gy (n = 15), 55-Gy (n = 8), and 60-Gy (n = 6) cohorts. No patients experienced dose-limiting toxicity events in any of the trial cohorts. The 3-month RECIST assessments available for 32 of the 48 patients demonstrated a complete response in 2, a partial response in 16, stable disease in 6, and progressive disease in 8 patients.nnnCONCLUSIONnThe delivery of 60 Gy in 10 fractions to one to three brain metastases synchronously with 30 Gy whole brain radiotherapy was achieved without dose-limiting central nervous system toxicity as assessed 3 months after treatment. This approach is being tested in a Phase II efficacy trial.

A Phase II Trial of Arc-Based Hypofractionated Intensity-Modulated Radiotherapy in Localized Prostate Cancer

PURPOSEnTo evaluate acute and late genitourinary (GU) and gastrointestinal (GI) toxicity and biochemical control of hypofractionated, image-guided (fiducial markers or ultrasound guidance), simplified intensity-modulated arc therapy for localized prostate cancer.nnnMETHODS AND MATERIALSnThis Phase II prospective clinical trial for T1a-2cNXM0 prostate cancer enrolled 66 patients who received 63.2 Gy in 20 fractions over 4 weeks. Fiducial markers were used for image guidance in 30 patients and daily ultrasound for the remainder. Toxicity was scored according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 3.0.nnnRESULTSnMedian follow-up was 36 months. Acute Phase Grade 2 and 3 toxicity was 34% and 9% for GU vs. 25% and 10% for GI symptoms. One Grade 4 acute GI toxicity occurred in a patient with unrecognized Crohns disease. Late Grade 2 and 3 toxicity for GU was 14% and 5%, and GI toxicity was 25% and 3%. One late GI Grade 4 toxicity was observed in a patient with significant comorbidities (anticoagulation, vascular disease). Acute GI toxicity ≥ Grade 2 was shown to be a predictor for late toxicity Grade ≥ 2 (p < 0.001). The biochemical disease-free survival at 3 years was 95%.nnnCONCLUSIONSnHypofractionated simplified intensity-modulated arc therapy radiotherapy given as 63.2 Gy in 20 fractions demonstrated promising biochemical control rates; however, higher rates of acute Grade 3 GU and GI toxicity and higher late Grade 2 GU and GI toxicity were noted. Ongoing randomized controlled trials should ultimately clarify issues regarding patient selection and the true rate of severe toxicity that can be directly attributed to hypofractionated radiotherapy.

Extended Followup Oncologic Outcome of Randomized Trial Between Cryoablation and External Beam Therapy for Locally Advanced Prostate Cancer (T2c-T3b)

PURPOSEnWe assessed and compared the survival outcomes between cryoablation and external beam radiation therapy in patients with locally advanced prostate cancer (cT2c-cT3b).nnnMATERIALS AND METHODSnPatients with locally advanced prostate cancer, recruited from 1999 to 2002, were randomized to primary cryoablation or external beam radiotherapy. All patients received neoadjuvant hormonal therapy for 3 months before and 3 months after the procedures. Patients underwent followup transrectal ultrasound guided biopsy (at 3, 6, 12, 18 and 24 months for cryoablation, and at 18 and 24 months for external beam radiotherapy) and as clinically indicated thereafter. Biochemical failure was based on the Phoenix criterion (prostate specific antigen nadir +2 ng/dl).nnnRESULTSnA total of 62 patients completed the trial. Median followup was 105.2 months (SD ±35.8). Accrual was limited due to newer data favoring longer neoadjuvant hormonal therapy and higher external beam radiotherapy dose for locally advanced prostate cancer. There was a greater reduction in prostate volume in the cryoablation group after intervention (-54% vs -34%, p ≤0.01). Disease specific survival and overall survival were comparable between the groups. However, the 8-year biochemical disease-free survival rate was significantly lower in the cryoablation group (17.4% vs 59.1%) (p = 0.01).nnnCONCLUSIONSnThis randomized trial with median followup approaching 9 years showed that cryoablation was inferior in attaining biochemical disease-free survival in patients with locally advanced prostate cancer (cT2c-T3). Cryoablation may be more suited for less bulky prostate cancer. Longer duration neoadjuvant hormonal therapy or a multimodal approach may provide optimal biochemical disease-free survival in this patient population.

Schedule for CT image guidance in treating prostate cancer with helical tomotherapy

The aim of this study was to determine the effect of reducing the number of image guidance sessions and patient-specific target margins on the dose distribution in the treatment of prostate cancer with helical tomotherapy. 20 patients with prostate cancer who were treated with helical tomotherapy using daily megavoltage CT (MVCT) imaging before treatment served as the study population. The average geometric shifts applied for set-up corrections, as a result of co-registration of MVCT and planning kilovoltage CT studies over an increasing number of image guidance sessions, were determined. Simulation of the consequences of various imaging scenarios on the dose distribution was performed for two patients with different patterns of interfraction changes in anatomy. Our analysis of the daily set-up correction shifts for 20 prostate cancer patients suggests that the use of four fractions would result in a population average shift that was within 1 mm of the average obtained from the data accumulated over all daily MVCT sessions. Simulation of a scenario in which imaging sessions are performed at a reduced frequency and the planning target volume margin is adapted provided significantly better sparing of organs at risk, with acceptable reproducibility of dose delivery to the clinical target volume. Our results indicate that four MVCT sessions on helical tomotherapy are sufficient to provide information for the creation of personalised target margins and the establishment of the new reference position that accounts for the systematic error. This simplified approach reduces overall treatment session time and decreases the imaging dose to the patient.