P.R. Anne

Longer time interval between completion of neoadjuvant chemoradiation and surgical resection does not improve downstaging of rectal carcinoma

AbstractPURPOSE: An interval of six to eight weeks between completion of preoperative chemoradiation therapy and surgical resection of advanced rectal cancer has been described. Our purpose was to determine whether a longer time interval between completion of therapy and resection increases tumor downstaging and affects perioperative morbidity. METHODS: Forty patients with advanced adenocarcinoma of the rectum underwent preoperative chemoradiation on a prospective trial with irinotecan (50 mg/m2), 5-fluorouracil (225 mg/m2), and concomitant external-beam radiation (45–54 Gy) followed by complete surgical resection of the tumor with total mesorectal excision. The time interval between completion of chemoradiation and surgical resection ranged from 28 to 97 days. The patients were divided into two groups with 33 eligible patients: Group A (4-week to 8-week time interval; 28–56 days) and Group B (10-week to 14-week interval; 67–97 days). Tumor downstaging was compared between these two groups. The number of patients downstaged by at least one T stage, those downstaged by at least one N stage, those with pathologic complete responses, and those with only residual microscopic tumor foci were compared. Postoperative length of stay, estimated blood loss, perioperative morbidity, and sphincter-sparing procedures were also compared. Chi-squared tests and Student’s t-test were calculated. RESULTS: Group A had 19 patients, and Group B had 14 patients. Patient demographics were comparable. Mean age was 52 years, and 70 percent of patients were male. There were no deaths. There were no statistical differences in perioperative morbidity, with three anastomotic leaks in Group A. Tumors were downstaged in 58 percent of patients in Group A and 43 percent of those in Group B (P = 0.61). Nodal downstaging occurred in 78 percent of Group A and 67 percent of Group B (P = 0.9). The pathologic complete response rate was 21 percent in Group A and 14 percent in Group B (P = 0.97), and a residual microfocus of tumor was found in 33 percent of patients in Group A and 42 percent of those in Group B (P = 0.90). These differences were not statistically significant. CONCLUSIONS: Perioperative morbidity is not affected by longer intervals. A longer interval between completion of neoadjuvant chemoradiation and surgical resection may not increase the tumor response rate of advanced rectal cancer in this cohort.

Variation of clinical target volume definition in three-dimensional conformal radiation therapy for prostate cancer

PURPOSE Currently, three-dimensional conformal radiation therapy (3D-CRT) planning relies on the interpretation of computed tomography (CT) axial images for defining the clinical target volume (CTV). This study investigates the variation among multiple observers to define the CTV used in 3D-CRT for prostate cancer. METHODS AND MATERIALS Seven observers independently delineated the CTVs (prostate +/- seminal vesicles [SV]) from the CT simulation data of 10 prostate cancer patients undergoing 3D-CRT. Six patients underwent CT simulation without the use of contrast material and serve as a control group. The other 4 had urethral and bladder opacification with contrast medium. To determine interobserver variation, we evaluated the derived volume, the maximum dimensions, and the isocenter for each examination of CTV. We assessed the reliability in the CTVs among the observers by correlating the variation for each class of measurements. This was estimated by intraclass correlation coefficient (ICC), with 1.00 defining absolute correlation. RESULTS For the prostate volumes, the ICC was 0.80 (95% confidence interval [CI]: 0.56-0.96). This changed to 0.92 (95% CI: 0.75-0.99) with the use of contrast material. Similarly, the maximal prostatic dimensions were reliable and improved. There was poor agreement in defining the SV. For this structure, the ICC never exceeded 0.28. The reliability of the isocenter was excellent, with the ICC exceeding 0.83 and 0.90 for the prostate +/- SV, respectively. CONCLUSIONS In 3D-CRT for prostate cancer, there was excellent agreement among multiple observers to define the prostate target volume but poor agreement to define the SV. The use of urethral and bladder contrast improved the reliability of localizing the prostate. For all CTVs, the isocenter was very reliable and should be used to compare the variation in 3D dosimetry among multiple observers.

The use of mixed-integer programming for inverse treatment planning with pre-defined field segments

Complex intensity patterns generated by traditional beamlet-based inverse treatment plans are often very difficult to deliver. In the approach presented in this work the intensity maps are controlled by pre-defining field segments to be used for dose optimization. A set of simple rules was used to define a pool of allowable delivery segments and the mixed-integer programming (MIP) method was used to optimize segment weights. The optimization problem was formulated by combining real variables describing segment weights with a set of binary variables, used to enumerate voxels in targets and critical structures. The MIP method was compared to the previously used Cimmino projection algorithm. The field segmentation approach was compared to an inverse planning system with a traditional beamlet-based beam intensity optimization. In four complex cases of oropharyngeal cancer the segmental inverse planning produced treatment plans, which competed with traditional beamlet-based IMRT plans. The mixed-integer programming provided mechanism for imposition of dose–volume constraints and allowed for identification of the optimal solution for feasible problems. Additional advantages of the segmental technique presented here are: simplified dosimetry, quality assurance and treatment delivery.

Randomized Phase II Trial Evaluating Two Paclitaxel and Cisplatin–Containing Chemoradiation Regimens As Adjuvant Therapy in Resected Gastric Cancer (RTOG-0114)

PURPOSE The investigational arm of INT0116, a fluorouracil (FU) and leucovorin-containing chemoradiotherapy regimen, is a standard treatment for patients with resected gastric cancer with a 2-year disease-free survival rate (DFS) of 52%. Toxicity is also significant. More beneficial and safer regimens are needed. PATIENTS AND METHODS We performed a randomized phase II study among 39 cancer centers to evaluate two paclitaxel and cisplatin-containing regimens, one with FU (PCF) and the other without (PC) in patients with resected gastric cancer. Patients received two cycles of postoperative chemotherapy followed by 45 Gy of radiation with either concurrent FU and paclitaxel or paclitaxel and cisplatin. The primary objective was to show an improvement in 2-year DFS to 67% as compared with INT 0116. RESULTS From May 2001 to February 2004 (study closure), 78 patients entered this study, and 73 were evaluable. At the planned interim analysis of 22 patients on PCF, grade 3 or higher GI toxicity was 59%. This was significantly worse than INT0116, and this arm was closed. Accrual continued on PC. The median DFS was 14.6 months for PCF and has not been reached for PC. For PC the 2-year DFS is 52% (95% CI, 36% to 68%). CONCLUSION Though PC appears to be safe and the median DFS favorable, the DFS failed to exceed the lower bound of 52.9% for the targeted 67% DFS at 2 years and can not be recommended as the adjuvant arm for future randomized trials.

Positive microscopic margins alter outcome in lymph node-negative cholangiocarcinoma when resection is combined with adjuvant radiotherapy.

Purpose:The purpose of this study was to evaluate the prognostic significance of positive microscopic margins in hilar cholangiocarcinoma in patients treated with resection and adjuvant radiotherapy. Materials and Methods:Between January 1983 and December 1997, 65 patients were definitively diagnosed with hilar cholangiocarcinoma and treated at our institution. Twenty-eight patients underwent curative resection. Of these patients, 23 received adjuvant radiotherapy with an average dose of 53 Gy (both external beam radiotherapy and low-dose rate brachytherapy). Portals included the preoperative primary tumor bed site with a 3- to 5-cm margin, the porta hepatis, and celiac lymph nodes. The patients with lymph node-negative pathologic specimens were reviewed, and an analysis of microscopic margins and subsequent impact on survival was determined with the Kaplan-Meier method and Wilcoxon test. Results:There were 16 patients who met inclusion criteria. There was no perioperative mortality. Seven patients had negative margins and 9 patients had positive microscopic margins. Median follow up was 55 months, and median survival was 24.5 months for the entire group. Median and 5-year survival were 21.5 months and 18.4% in the margin-negative group and 26 months and 15% in patients with positive margins (P = 0.45). These survival differences were not statistically significant. Discussion:Positive microscopic margins in lymph node-negative, resected hilar cholangiocarcinoma may not represent a negative prognostic factor when resection is combined with postoperative radiotherapy in this cohort. Further prospective, randomized studies are required to fully elucidate the benefits of adjuvant radiotherapy.

Cholangiocarcinoma: The Impact of Tumor Location and Treatment Strategy on Outcome

The purpose of this study was to evaluate how the outcome of patients with extrahepatic cholangiocarcinoma (EHBC) may have been influenced by tumor location and treatment selection. The primary endpoint of this study is overall survival (OS). Between January 1983 and December 1997, 221 patients with biliary tumors were evaluated at Thomas Jefferson University Hospital. Of these, 118 fit the inclusion criteria for this study. The extent of disease was assessed by computed tomography, percutaneous transhepatic cholangiography or endoscopic retrograde cholangiopancreatography, magnetic resonance imaging, and ultrasonography. All patients had histologic confirmation of malignancy. Roux-en Y, hepaticojejunostomy, or choledochojejunostomy followed surgical resection of the primary tumor. Palliative measure (PS) included biliary catheter placement without brachytherapy or external beam irradiation (RT). RT was delivered via high-energy photons. Intraluminal brachytherapy was performed via percutaneous biliary catheterization with iridium-192 ribbon sources. Chemotherapy consisted of either intravenous 5-fluorouracil alone or in combination with doxorubicin, mitomycin C, or paclitaxel. PS consisted of metal bile duct stent placement. Median follow-up time for the entire group was 102 months and 43 months for patients who were still alive at the conclusion of the study period. Patients with proximal tumors underwent resection (n = 5), surgery and RT (n = 23), RT only (n = 31), chemotherapy only (n = 6), or PS (n = 12). Patients with distal tumors were treated with surgical resection (n = 17) or a combination of surgery and RT (n = 13), RT only (n = 6), or PS (n = 4). Median survival time (MST) for all 118 patients was 22 months. The MST for patients with distal tumors was 47 months versus 17 months for those with proximal tumors. The MST has not been reached for patients with distal EHBC treated with surgical resection and postoperative RT, whereas the median survival for those treated with surgery alone is 62.5 months. However, 4 of 17 of these patients had in situ carcinoma. Six patients had distal tumors treated with RT only with a MST of 6 months. Patients with proximal tumors treated with surgery and RT had a superior OS at 5 years compared to patients treated with RT alone (24 vs. 13 months; p = 0.007). There was an improved OS in patients with proximal tumors treated with surgical resection and RT compared to surgery alone (p = 0.023). There is no discernable influence of chemotherapy on outcome in patients with proximal EHBC. The MST for patients treated with PS was 3.5 months. Surgery and postoperative RT appear to be better than either surgery or RT alone in patients with proximal EHBC. In patients with distal EHBC, the addition of resection and RT appears to offer an advantage, which is increasingly apparent with longer follow-up time. The prognosis remains dismal for patients treated with palliative intent.

Head and Neck Carcinoma in the United States First Comprehensive Report of the Longitudinal Oncology Registry of Head and Neck Carcinoma (LORHAN)

Detailed information about how patients with head and neck carcinoma (HNC) are treated across practice settings does not exist. The authors conducted a prospective, observational study to examine the patterns of care for a series of patients with newly diagnosed HNC in the United States and to test 2 hypotheses: 1) There is no difference in the pattern of care between community and academic settings; and 2) the results of major randomized clinical trials will change the pattern of care in both practice settings within 1 year of publication in peer‐reviewed journals.

NRG Oncology Radiation Therapy Oncology Group 0822: A Phase 2 Study of Preoperative Chemoradiation Therapy Using Intensity Modulated Radiation Therapy in Combination With Capecitabine and Oxaliplatin for Patients With Locally Advanced Rectal Cancer

PURPOSE To evaluate the rate of gastrointestinal (GI) toxicity of neoadjuvant chemoradiation with capecitabine, oxaliplatin, and intensity modulated radiation therapy (IMRT) in cT3-4 rectal cancer. METHODS AND MATERIALS Patients with localized, nonmetastatic T3 or T4 rectal cancer <12 cm from the anal verge were enrolled in a prospective, multi-institutional, single-arm study of preoperative chemoradiation. Patients received 45 Gy with IMRT in 25 fractions, followed by a 3-dimensional conformal boost of 5.4 Gy in 3 fractions with concurrent capecitabine/oxaliplatin (CAPOX). Surgery was performed 4 to 8 weeks after the completion of therapy. Patients were recommended to receive FOLFOX chemotherapy after surgery. The primary endpoint of the study was acute grade 2 to 5 GI toxicity. Seventy-one patients provided 80% probability to detect at least a 12% reduction in the specified GI toxicity with the treatment of CAPOX and IMRT, at a significance level of .10 (1-sided). RESULTS Seventy-nine patients were accrued, of whom 68 were evaluable. Sixty-one patients (89.7%) had cT3 disease, and 37 (54.4%) had cN (+) disease. Postoperative chemotherapy was given to 42 of 68 patients. Fifty-eight patients had target contours drawn per protocol, 5 patients with acceptable variation, and 5 patients with unacceptable variations. Thirty-five patients (51.5%) experienced grade ≥ 2 GI toxicity, 12 patients (17.6%) experienced grade 3 or 4 diarrhea, and pCR was achieved in 10 patients (14.7%). With a median follow-up time of 3.98 years, the 4-year rate of locoregional failure was 7.4% (95% confidence interval [CI]: 1.0%-13.7%). The 4-year rates of OS and DFS were 82.9% (95% CI: 70.1%-90.6%) and 60.6% (95% CI: 47.5%-71.4%), respectively. CONCLUSION The use of IMRT in neoadjuvant chemoradiation for rectal cancer did not reduce the rate of GI toxicity.

Active Breathing Coordinator reduces radiation dose to the heart and preserves local control in patients with left breast cancer: Report of a prospective trial

PURPOSE Incidental radiation dose to the heart and lung during breast radiation therapy (RT) has been associated with an increased risk of cardiopulmonary morbidity. We conducted a prospective trial to determine if RT with the Active Breathing Coordinator (ABC) can reduce the mean heart dose (MHD) by ≥20% and dose to the lung. METHODS AND MATERIALS Patients with stages 0-III left breast cancer (LBC) were enrolled and underwent simulation with both free breathing (FB) and ABC for comparison of dosimetry. ABC was used during the patients RT course if the MHD was reduced by ≥5%. The median prescription dose was 50.4 Gy plus a boost in 77 patients (90%). The primary endpoint was the magnitude of MHD reduction when comparing ABC to FB. Secondary endpoints included dose reduction to the heart and lung, procedural success rate, and adverse events. RESULTS A total of 112 patients with LBC were enrolled from 2002 to 2011 and 86 eligible patients underwent both FB and ABC simulation. Ultimately, 81 patients received RT using ABC, corresponding to 72% procedural success. The primary endpoint was achieved as use of ABC reduced MHD by 20% or greater in 88% of patients (P < .0001). The median values for absolute and relative reduction in MHD were 1.7 Gy and 62%, respectively. RT with ABC provided a statistically significant dose reduction to the left lung. After a median follow up of 81 months, 8-year estimates of locoregional relapse, disease-free, and overall survival were 7%, 90%, and 96%, respectively. CONCLUSIONS ABC was well tolerated and significantly reduced MHD while preserving local control. Use of the ABC device during RT should be considered to reduce the risk of ischemic heart disease in populations at risk.

Impact of Her-2 Neu overexpression on outcome of elderly women treated with wide local excision and breast irradiation for early stage breast cancer: an exploratory analysis.

Objective:The purpose of this study was to investigate the prognostic significance of Her-2 neu status in elderly patients managed with breast conservation strategy for stage I–II breast cancer. Methods:We conducted an IRB approved retrospective review of 153 women age 70 and older with stage I–II breast cancer, managed with wide local excision and breast radiation between January 1997 and December 2002. The subset of 106 patients had a known Her-2 neu status and was analyzed for primary patient and tumor characteristics. These characteristics were correlated with cause specific survival (CSS), overall survival (OS), and combined nodal and distant failure (NDF). Her-2 neu positivity was confirmed with FISH HercepTestTM. Statistical tests included Cox regression, contingency table and Kaplan-Meier analysis. Results:Median follow-up was 55 months and patients median age was 76. Twenty two percent of patients were Her-2 neu positive and 78% were Her-2 neu negative. Her-2 neu positivity was significantly associated with high histologic grade (P = 0.008), T2 stage (P = 0.001) and positive axillary lymph nodes (P = 0.02) among 73 patients who had surgical assessment of axilla. Overall, only 15 patients (14%) received chemotherapy. There were no recurrences in the breast. Her-2 neu positivity predicted for NDF and CSS on multivariate analysis. Projected 5-year freedom from NDF was 70% for Her-2 neu positive and 97% for Her-2 neu negative patients (P < 0.01, log-rank). CSS was 86% for Her-2 neu positive and 98% for Her-2 neu negative patients (P < 0.01, log-rank). OS was no different between Her-2 neu positive and Her-2 neu negative patients (80% versus 85%, P = 0.25). Conclusions:Her-2 neu amplification predicts development of NDF and negatively influences CSS, but not local control or OS in elderly patients treated with breast conservation. Similar to the trend in younger patients, Her-2 neu positivity may be used in the future to consider more aggressive treatment strategies in elderly patients.