Javier Aristu

Intensity-modulated radiation therapy (IMRT) vs. 3D conformal radiotherapy (3DCRT) in locally advanced rectal cancer (LARC): dosimetric comparison and clinical implications

PurposeTo compare target dose distribution, comformality, normal tissue avoidance, and irradiated body volume (IBV) in 3DCRT using classic anatomical landmarks (c3DCRT), 3DCRT fitting the PTV (f3DCRT), and intensity-modulated radiation therapy (IMRT) in patients with locally advanced rectal cancer (LARC).Materials and methodsFifteen patients with LARC underwent c3DCRT, f3DCRT, and IMRT planning. Target definition followed the recommendations of the ICRU reports No. 50 and 62. OAR (SB and bladder) constraints were D5 ≤ 50 Gy and Dmax < 55 Gy. PTV dose prescription was defined as PTV95 ≥ 45 Gy and PTVmin ≥ 35 Gy. Target coverage was evaluated with the D95, Dmin, and Dmax. Target dose distribution and comformality was evaluated with the homogeneity indices (HI) and Conformity Index (CI). Normal tissue avoidance of OAR was evaluated with the D5 and V40. IBV at 5 Gy (V5), 10 Gy (V10), and 20 Gy (V20) were calculated.ResultsThe mean GTV95, CTV95, and PTV95 doses were significantly lower for IMRT plans. Target dose distribution was more inhomogeneous after IMRT planning and 3DCRTplans had significantly lower CI. The V40 and D5 values for OAR were significantly reduced in the IMRT plans .V5 was greater for IMRT than for f3DCRT planning (p < 0.05) and V20 was smaller for IMRT plans(p < 0.05).ConclusionsIMRT planning improves target conformity and decreases irradiation of the OAR at the expense of increased target heterogeneity. IMRT planning increases the IBV at 5 Gy or less but decreases the IBV at 20 Gy or more.

Intraoperative and external radiotherapy in resected gastric cancer: Updated report of a phase II trial

From September 1984 to August 1991, 48 evaluable patients with resected gastric cancer and apparent disease confined to locoregional area were treated with intraoperative electron beam boost to the celiac axis and peripancreatic nodal areas (15 Gy) and external irradiation (40 to 46 Gy in 4 to 5 weeks) including the gastric bed and upper abdominal nodal draining regions. At the time of evaluation for IORT, the disease was primary in 38 cases, recurrent but resectable in four (anastomosis), and unresectable in four (nodal). Post operative complications were reversible. Acute tolerance to the complete treatment program was acceptable. Late complications included life-threatening events: Six episodes of gastro intestinal bleeding (three of them had an arteriographic documentation of arterioenteric fistula) and nine with severe enteritis (five required reoperation). Other long-term treatment related complications were six cases of vertebral collapse. The median follow-up time for the entire group is 22 months. Locoregional recurrence/persistence of disease has been identified in five patients (three with residual and/or recurrent postsurgical tumor). Systemic tumor progression has been detected in 15 patients (11 in intra-abdominal sites). Overall actuarial survival for patients with positive or negative serosal involvement was 33% versus 56%. It is concluded that the treatment program described is able to induce a high locoregional tumor control rate (100%) when used strictly in an adjuvant setting and might control long term, a small portion of patients not amenable for curative surgery (2 out of 8 patients with confirmed residual post-surgical disease). Gastrointestinal bleeding and enteritis are findings that indicate treatment intensity at the upper limits of tissue tolerance. Assessment of long term tolerance of pancreatic parenchyma and large blood vessels (tissues included in the IRORT field) are pending for longer follow-up and the appropriate selective studies.

Long-term normal tissue effects of intraoperative electron radiation therapy (IOERT) : Late sequelae, tumor recurrence, and second malignancies

PURPOSE To evaluate long-term survivors treated with intraoperative electron radiation therapy (IOERT) as a component, with particular emphasis on analyzing late normal tissue toxicity, second malignancies, and patterns of delayed tumor recurrence. METHODS AND MATERIALS From September 1984 to December 1991, 739 patients were treated with IOERT. One hundred ninety-five patients were alive at least 5 years after IOERT (26%). Patient information regarding late complications related symptoms, incidence of second tumors, and delayed relapses were analyzed. Normal tissue changes were categorized by a modified LENT/SOMA scale (Grade 0-1, Grade 2, and Grade 3-4). Risk of late toxicity was grouped by type and number of cancer treatment modalities employed in each patient: surgery + IOERT alone (17 patients, 9%); IOERT + external radiotherapy +/- chemosensibilization (90 patients, 46%); IOERT +/- external radiotherapy +/- neoadjuvant chemotherapy (+/- previous radiotherapy) (88 patients, 45%). Biologic effective doses (BED) were calculated for alpha/beta = 3.5 for late fibrosis. RESULTS With a mean follow-up time of the surviving patients of 94 months (range: 55-162 months), 99 patients (51%) had Grade 0-1 toxicity, 52 (27%) had Grade 2, and 44 patients (23%) presented Grade 3-4 late normal tissue complications. Risk groups by treatment intensity did correlate with severity of observed toxicity (p < 0.001). BED estimations did not correlate with late normal tissue damage. The tumor type with higher toxicity scores was bone sarcoma (28/46, 60%), in which the estimated BED = 100.5 Gy. Peripheral neuropathy was the dominant IOERT-specific toxicity present in 24 patients (12%). Second malignancies were identified in 8 patients (4%), none inside the IOERT field (3 questionable to be marginal to the external beam radiotherapy volume). In 36 patients (18%), recurrence of the originally treated tumor was detected, including 11 (7%) local relapses. CONCLUSIONS The incidence of late normal tissue complications (50%) and severity (23%) is significant in a cohort of patients surviving more the 5 years after IOERT. The understanding of the contribution of IOERT to late tissue damage requires specific analysis. Peripheral neuropathy is a characteristic finding in IOERT trials. Second malignancies inside the IOERT field were not identified during the study period. The risk of recurrences, including local failures, requires an intensive follow-up of long-term survivors from IOERT trials.

External-beam radiation therapy and high-dose rate brachytherapy combined with long-term androgen deprivation therapy in high and very high prostate cancer: preliminary data on clinical outcome.

PURPOSE To determine the feasibility of combined long-term androgen deprivation therapy (ADT) and dose escalation with high-dose-rate (HDR) brachytherapy. METHODS AND MATERIALS Between 2001 and 2007, 200 patients with high-risk prostate cancer (32.5%) or very high-risk prostate cancer (67.5%) were prospectively enrolled in this Phase II trial. Tumor characteristics included a median pretreatment prostate-specific antigen of 15.2 ng/mL, a clinical stage of T2c, and a Gleason score of 7. Treatment consisted of 54 Gy of external irradiation (three-dimensional conformal radiotherapy [3DCRT]) followed by 19 Gy of HDR brachytherapy in four twice-daily treatments. ADT started 0-3 months before 3DCRT and continued for 2 years. RESULTS One hundred and ninety patients (95%) received 2 years of ADT. After a median follow-up of 3.7 years (range, 2-9), late Grade ≥2 urinary toxicity was observed in 18% of the patients and Grade ≥3 was observed in 5%. Prior transurethral resection of the prostate (p = 0.013) and bladder D(50) ≥1.19 Gy (p = 0.014) were associated with increased Grade ≥2 urinary complications; age ≥70 (p = 0.05) was associated with Grade ≥3 urinary complications. Late Grade ≥2 gastrointestinal toxicity was observed in 9% of the patients and Grade ≥3 in 1.5%. CTV size ≥35.8 cc (p = 0.007) and D(100) ≥3.05 Gy (p = 0.01) were significant for increased Grade ≥2 complications. The 5-year and 9-year biochemical relapse-free survival (nadir + 2) rates were 85.1% and 75.7%, respectively. Patients with Gleason score of 7-10 had a decreased biochemical relapse-free survival (p = 0.007). CONCLUSIONS Intermediate-term results at the 5-year time point indicate a favorable outcome without an increase in the rate of late complications.

Accuracy of endoscopic ultrasound to assess tumor response after neoadjuvant treatment in rectal cancer: can we trust the findings?

BACKGROUND: The finding that some rectal cancers respond to neoadjuvant chemoradiation is broadening new surgical options for the treatment of some of these tumors that, until now, required a total mesorectal excision. Nevertheless, a fine match between clinical and pathological response is required when planning conservative surgical approaches. OBJECTIVE: This study aims to prospectively validate the use of endoscopic ultrasound as a predictor of clinical and pathological tumor response in patients with locally advanced rectal cancer. DESIGN: This is an observational study of a cohort of patients undergoing chemoradiation followed by surgery. SETTINGS: This study was conducted at a tertiary medical center. PATIENTS: A total of 235 consecutive patients who underwent chemoradiation followed by surgery at a single institution during a 7-year period were included. MAIN OUTCOME MEASURES: All tumors were staged and restaged at 4 to 6 weeks after neoadjuvant treatment. Downsizing and downstaging were calculated between the initial and posttreatment measures and correlated to the pathological stage. The accuracy of endoscopic ultrasound to predict response was determined. RESULTS: Findings after chemoradiation showed T-downstaging in 54 patients (23%) and N-downstaging in 110 (47%). Overstaging occurred in 88 (37%) patients and was more commonly observed than understaging (21 patients; 9%). Related to the pathological report, endoscopic ultrasound correctly matched the T stage in 54% and the N stage in 75% of tumors. Sensitivity, specificity, and positive and negative predictive values to predict nodal involvement were 39%, 91%, 67%, and 76%. Accuracy was not influenced by such factors as age, distance of the tumor from the anal verge, or time to surgery. LIMITATIONS: This study was limited by the lack of comparison with other imaging methods. CONCLUSIONS: Endoscopic ultrasound allows prediction of involved lymph nodes in 75% of the cases; however, 1 in 5 patients are missclassified as uN0 after neoadjuvant treatment. In our point of view, this percentage is too high to rely only on this diagnostic modality to support a “wait and see” approach.

Intraoperative radiotherapy during lung cancer surgery: Technical description and early clinical results

A phase I-II study of intraoperative radiotherapy (IORT) for Stage III lung cancer was performed in 34 patients during a period of 58 months. Loco-regional treatment included tumor resection if technically feasible, IORT boost of electron beams using moderate single doses (10-15 Gy) to tumor bearing areas and external photon beam irradiation (46-50 Gy in 5 weeks) using conventional fields. Indications for this study were unresectable hiliar tumors (14, 41%), and mediastinal, hiliar and/or chest wall residual disease following resection (20, 59%). Thirty-four procedures, with 40 IORT fields, have been analyzed to describe the relevant technical aspects and the toxicity. IORT was delivered using acrylic transparent cones of different diameters. Surgical approach consisted in a lateral thoracotomy in all patients (21 right side and 13 left side). Tissues included within the IORT field were: tumor or residual tumor tissues (34, 100%), collapsed lung parenchyma and main bronchus not surgically manipulated (14, 41%), bronchial stump and vascular suture following resection (19, 55%), mediastinal structures (20, 58%), and brachial plexus (1, 3%). The bronchial suture was covered with pleural or pericardial flap after IORT in 10 cases (29%). Life threatening toxicity related to IORT consisted in broncho-pleural fistula (1, 3%) and massive hemoptysis (1, 3%). Other reversible toxic events were acute pneumonitis (12, 85%) and esophagitis (10, 50%). Long term asymptomatic lung fibrosis was detected in 11 cases (32%). Median survival time for the entire group has been 12 months. With a median follow-up time of 12 months the freedom from thoracic recurrence rate is 30% (65% in cases with tumor resection). Projected actuarial survival rates at 4 years were 28% for resected group and 7% for unresected cases. This experience supports IORT as a feasible alternative modality to be used in the management of locally advanced lung cancer. Tolerance of thoracic organs to moderate doses of IORT appeared to be adequate and local control is achieved in certain patients. These results deserve further investigation and confirmation trials.

Analysis of Early Postoperative Morbidity Among Patients with Rectal Cancer Treated with and without Neoadjuvant Chemoradiotherapy

BackgroundThe impact of neoadjuvant treatment and their subsequent early complications in the treatment of rectal cancer has not been adequately assessed. The aim of this prospective study was to evaluate early postoperative morbidity and mortality among patients with rectal cancer treated with adjuvant radiotherapy and chemotherapy followed by surgery, compared with patients treated with surgery alone. We also identified independent risk factors associated with early major complications.MethodsBetween 1995 and 2004, 273 consecutive patients underwent treatment for rectal cancer. A total of 170 patients (group A) received preoperative radiotherapy with a total of 45–50.4 Gy (180 cGy per day) and 5-fluorouracil-based chemotherapy, followed by surgery; 103 patients (group B) were treated with surgery alone. Dependent variables related to patients, treatment, radiotherapy, and tumor were analyzed.ResultsBoth groups were similar with regard to age, sex, body mass index, American Society of Anesthesiologists (ASA) score, and tumor location but not for ileostomy (27% in group A vs. 6.8% in group B). The number of complications was similar in both groups (43.1% in group A vs. 44.6% in group B). No differences in wound infection (8.2% vs. 7.8%), intra-abdominal abscess (4.7% vs. 4.9%), anastomotic dehiscence (4.2% vs. 3.8%), postoperative hemorrhage (3.5% vs. 3.9%), urinary complications (6.5% vs. 4.9%), paralytic ileus (8.9% vs. 9.7%), or general complications (7.1% vs. 9.6%) were found. The global mortality in the first 30 days after surgery was .7%. An ASA score of III–IV and surgery duration longer than 3 hours were identified as independent prognostic factors for early complications.ConclusionsPreoperative chemoradiation in patients with rectal cancer treated with surgery is not associated with a higher incidence of early postoperative complications. The patient’s preoperative clinical condition and lengthy surgery time are prognostic factors for early complications.

Four-Week Neoadjuvant Intensity-Modulated Radiation Therapy With Concurrent Capecitabine and Oxaliplatin in Locally Advanced Rectal Cancer Patients: A Validation Phase II Trial

PURPOSE To validate tolerance and pathological complete response rate (pCR) of a 4-week preoperative course of intensity-modulated radiation therapy (IMRT) with concurrent capecitabine and oxaliplatin (CAPOX) in patients with locally advanced rectal cancer. METHODS AND MATERIALS Patients with T3 to T4 and/or N+ rectal cancer received preoperative IMRT (47.5 Gy in 19 fractions) with concurrent capecitabine (825 mg/m(2) b.i.d., Monday to Friday) and oxaliplatin (60 mg/m(2) on Days 1, 8, and 15). Surgery was scheduled 4 to 6 weeks after the completion of chemoradiation. Primary end points were toxicity and pathological response rate. Local control (LC), disease-free survival (DFS), and overall survival (OS) were also analyzed. RESULTS A total of 100 patients were evaluated. Grade 1 to 2 proctitis was observed in 73 patients (73%). Grade 3 diarrhea occurred in 9% of the patients. Grade 3 proctitis in 18% of the first 50 patients led to reduction of the dose per fraction to 47.5 Gy in 20 treatments. The rate of Grade 3 proctitis decreased to 4% thereafter (odds ratio, 0.27). A total of 99 patients underwent surgery. A pCR was observed in 13% of the patients, major response (96-100% of histological response) in 48%, and pN downstaging in 78%. An R0 resection was performed in 97% of the patients. After a median follow-up of 55 months, the LC, DFS, and OS rates were 100%, 84%, and 87%, respectively. CONCLUSIONS Preoperative CAPOX-IMRT therapy (47.5 Gy in 20 fractions) is feasible and safe, and produces major pathological responses in approximately 50% of patients.

Patterns of Response After Preoperative Treatment in Gastric Cancer

PURPOSE To analyze the rate of pathologic response in patients with locally advanced gastric cancer treated with preoperative chemotherapy with and without chemoradiation at our institution. METHODS AND MATERIALS From 2000 to 2007 patients were retrospectively identified who received preoperative treatment for gastric cancer (cT3-4/ N+) with induction chemotherapy (Ch) or with Ch followed by concurrent chemoradiotherapy (45 Gy in 5 weeks) (ChRT). Surgery was planned 4-6 weeks after the completion of neoadjuvant treatment. Pathologic assessment was used to investigate the patterns of pathologic response after neoadjuvant treatment. RESULTS Sixty-one patients were analyzed. Of 61 patients, 58 (95%) underwent surgery. The R0 resection rate was 87%. Pathologic complete response was achieved in 12% of the patients. A major pathologic response (<10% of residual tumor) was observed in 53% of patients, and T downstaging was observed in 75%. Median follow-up was 38.7 months. Median disease-free survival (DFS) was 36.5 months. The only patient-, tumor-, and treatment-related factor associated with pathologic response was the use of preoperative ChRT. Patients achieving major pathologic response had a 3-year actuarial DFS rate of 63%. CONCLUSIONS The patterns of pathologic response after preoperative ChRT suggest encouraging intervals of DFS. Such a strategy may be of interest to be explored in gastric cancer.

Pathological vertebral fracture after stereotactic body radiation therapy for lung metastases. Case report and literature review.

BackgroundStereotactic body radiation therapy (SBRT) is a radiation technique used in patients with oligometastatic lung disease. Lung and chest wall toxicities have been described in the patients but pathological vertebral fracture is an adverse effect no reported in patients treated with SBRT for lung metastases.Case presentationA 68-year-old woman with the diagnosis of a recurrence of a single lung metastatic nodule of urothelial carcinoma after third line of chemotherapy. The patient received a hypo-fractionated course of SBRT.A 3D-conformal multifield technique was used with six coplanar and one non-coplanar statics beams. A total dose of 48 Gy in three fractions over six days was prescribed to the 95% of the CTV. Ten months after the SBRT procedure, a CT scan showed complete response of the metastatic disease without signs of radiation pneumonitis. However, rib and vertebral bone toxicities were observed with the fracture-collapse of the 7th and 8th vertebral bodies and a fracture of the 7th and 8th left ribs. We report a unique case of pathological vertebral fracture appearing ten months after SBRT for an asymptomatic growing lung metastases of urothelial carcinoma.ConclusionThough SBRT allows for minimization of normal tissue exposure to high radiation doses SBRT tolerance for vertebral bone tissue has been poorly evaluated in patients with lung tumors. Oncologists should be alert to the potential risk of fatal bone toxicity caused by this novel treatment. We recommend BMD testing in all woman over 65 years old with clinical risk factors that could contribute to low BMD. If low BMD is demonstrated, we should carefully restrict the maximum radiation dose in the vertebral body in order to avoid intermediate or low radiation dose to the whole vertebral body.