Changes in the multidisciplinary management of rectal cancer from 2009 to 2015 and associated improvements in short-term outcomes.

AIM: Significant recent changes in management of locally advanced rectal cancer (LARC) include preoperative staging, use of extended neoadjuvant therapies and minimally invasive surgery (MIS). This study was aimed at characterizing these changes and associated short-term outcomes. METHOD: We retrospectively analysed treatment and outcome data from patients with T3/4 or N+ LARC ≤ 15 cm from the anal verge who were evaluated at a comprehensive cancer centre in 2009-2015. RESULTS: In total, 798 patients were identified and grouped into five cohorts based on treatment year: 2009-2010, 2011, 2012, 2013 and 2014-2015. Temporal changes included increased reliance on MRI staging, from 57% in 2009-2010 to 98% in 2014-2015 (P < 0.001); increased use of total neoadjuvant therapy, from 17% to 76% (P < 0.001); and increased use of MIS, from 33% to 70% (P < 0.001). Concurrently, median hospital stay decreased (from 7 to 5 days; P < 0.001), as did the rates of Grade III-V complications (from 13% to 7%; P < 0.05), surgical site infections (from 24% to 8%; P < 0.001), anastomotic leak (from 11% to 3%; P < 0.05) and positive circumferential resection margin (from 9% to 4%; P < 0.05). TNM downstaging increased from 62% to 74% (P = 0.002). CONCLUSION: Shifts toward MRI-based staging, total neoadjuvant therapy and MIS occurred between 2009 and 2015. Over the same period, treatment responses improved, and lengths of stay and the incidence of complications decreased.

Impact of multimodal therapy in locally recurrent rectal cancer.

BACKGROUND: The practice of salvaging recurrent rectal cancer has evolved. The aim of this study was to define the evolving salvage potential over time among patients with locally recurrent disease, and to identify durable determinants of long-term success. METHODS: The study included consecutive patients with recurrent rectal cancer undergoing multimodal salvage with curative intent between 1988 and 2012. Predictors of long-term survival were defined by Cox regression analysis and compared over time. Re-recurrence and subsequent treatments were evaluated. RESULTS: After multidisciplinary evaluation of 229 patients, salvage therapy with curative intent included preoperative chemotherapy and/or radiotherapy (73·4 per cent; with 41·3 per cent undergoing repeat pelvic irradiation), surgical salvage resection with or without intraoperative irradiation (36·2 per cent), followed by postoperative adjuvant chemotherapy (38·0 per cent). Multivisceral resection was undertaken in 47·2 per cent and bone resection in 29·7 per cent. The R0 resection rate was 80·3 per cent. After a median follow-up of 56·5 months, the 5-year overall survival rate was 50 per cent in 2005-2012, markedly increased from 32 per cent in 1988-1996 (P = 0·044). Long-term success was associated with R0 resection (P = 0·017) and lack of secondary failure (P = 0·003). Some 125 patients (54·6 per cent) developed further recurrence at a median of 19·4 months after salvage surgery. Repeat operative rescue was feasible in 21 of 48 patients with local re-recurrence alone and in 17 of 77 with distant re-recurrence, with a median survival of 19·8 months after further recurrence. CONCLUSION: The long-term salvage potential for recurrent rectal cancer improved significantly over time, with the introduction of an individualized treatment algorithm of multimodal treatments and surgical salvage. Durable predictors of long-term success were R0 resection at salvage operation, avoidance of secondary failure, and feasibility of repeat rescue after re-recurrence.

Radiation segmentectomy of hepatic metastases with Y-90 glass microspheres.

PURPOSE: To evaluate safety and efficacy of radiation segmentectomy (RS) with 90Y glass microspheres in patients with limited metastatic liver disease not amenable to resection or percutaneous ablation. METHODS: Patients with ≤ 3 tumors treated with RS from 6/2015 to 12/2017 were included. Target tumor radiation dose was > 190 Gy based on medical internal radiation dose (MIRD) dosimetry. Tumor response, local tumor progression (LTP), LTP-free survival (LTPFS) and disease progression rate in the treated segment were defined using Choi and RECIST 1.1 criteria. Toxicities were evaluated using modified SIR criteria. RESULTS: Ten patients with 14 tumors underwent 12 RS. Median tumor size was 3 cm (range 1.4-5.6). Median follow-up was 17.8 months (range 1.6-37.3). Response rates per Choi and RECIST 1.1 criteria were 8/8 (100%) and 4/9 (44%), respectively. Overall LTP rate was 3/14 (21%) during the study period. One-, two- and three-year LTPFS was 83%, 83% and 69%, respectively. Median LTPFS was not reached. Disease progression rate in the treated segment was 6/18 (33%). Median overall survival was 41.5 months (IQR 16.7-41.5). Median delivered tumor radiation dose was 293 Gy (range 163-1303). One major complication was recorded in a patient post-Whipple procedure who suffered anaphylactic reaction to prophylactic cefotetan and liver abscess in RS region 6.5 months post-RS. All patients were alive on last follow-up. CONCLUSION: RS of ≤ 3 hepatic segments can safely provide a 2-year local tumor control rate of 83% in selected patients with limited metastatic liver disease and limited treatment options. Optimal dosimetry methodology requires further investigation.

The integration of chemoradiation in the care of patient with localized pancreatic cancer.

The use of chemoradiation for patients with localized pancreatic cancer is controversial. Although some randomized trials have indicated that chemoradiation improves the median survival of patients with locally advanced as well as resected pancreatic cancer, other more recent trials have called into question the role of chemoradiation and have supported the use of chemotherapy. In the adjuvant setting, the high local tumor recurrence/persistence rate in all trials probably reflects the inclusion of patients with incompletely resected tumors, whose prognosis is similar to the prognosis of patients with locally advanced who do not undergo resection, making these trials difficult to interpret. More precise clinical staging and selection of patients appropriate for surgical resection is an important goal. The keys to the successful integration of radiotherapy in the care of patients with localized pancreatic cancer are selection, sequencing and smaller treatment volumes. A strategy of initial chemotherapy followed by consolidation with a well-tolerated chemoradiation regimen both in the adjuvant and locally advanced settings maximizes benefits of both treatment options, which are in fact complementary. Herein, we discuss the rationale for this approach as well as the ongoing investigation of novel radiation approaches designed to enhance outcome through the molecular and physical targeting of disease as well as the investigation of neoadjuvant chemoradiation in radiographically resectable and borderline resectable pancreatic cancer.

Recommendations for MRI-based contouring of gross tumor volume and organs at risk for radiation therapy of pancreatic cancer.

PURPOSE: Local recurrence is a common and morbid event in patients with unresectable pancreatic adenocarcinoma. A more conformal and targeted radiation dose to the macroscopic tumor in nonmetastatic pancreatic cancer is likely to reduce acute toxicity and improve local control. Optimal soft tissue contrast is required to facilitate delineation of a target and creation of a planning target volume with margin reduction and motion management. Magnetic resonance imaging (MRI) offers considerable advantages in optimizing soft tissue delineation and is an ideal modality for imaging and delineating a gross tumor volume (GTV) within the pancreas, particularly as it relates to conformal radiation planning. Currently, no guidelines have been defined for the delineation of pancreatic tumors for radiation therapy treatment planning. Moreover, abdominal MRI sequences are complex and the anatomy relevant to the radiation oncologist can be challenging. The purpose of this study is to provide recommendations for delineation of GTV and organs at risk (OARs) using MRI and incorporating multiple MRI sequences. METHODS AND MATERIALS: Five patients with pancreatic cancer and 1 healthy subject were imaged with MRI scans either on 1.5T or on 3T magnets in 2 separate institutes. The GTV and OARs were contoured for all patients in a consensus meeting. RESULTS: An overview of MRI-based anatomy of the GTV and OARs is provided. Practical contouring instructions for the GTV and the OARs with the aid of MRI were developed and included in these recommendations. In addition, practical suggestions for implementation of MRI in pancreatic radiation treatment planning are provided. CONCLUSIONS: With this report, we attempt to provide recommendations for MRI-based contouring of pancreatic tumors and OARs. This could lead to better uniformity in defining the GTV and OARs for clinical trials and in radiation therapy treatment planning, with the ultimate goal of improving local control while minimizing morbidity.

Paclitaxel-based chemoradiotherapy in localized gastric carcinoma: degree of pathologic response and not clinical parameters dictated patient outcome.

PURPOSE: Preoperative chemoradiotherapy may increase the R0 (curative) resection rate, overall survival (OS) duration, and disease-free survival (DFS) duration. We evaluated paclitaxel-based induction chemotherapy and chemoradiotherapy in patients with localized gastric or gastroesophageal adenocarcinoma to determine its feasibility, impact on the R0 resection rate, type of pathologic response, OS, and DFS. PATIENTS AND METHODS: Patients with operable, localized gastric, or gastroesophageal adenocarcinoma were eligible. Staging included endoscopic ultrasonography (EUS) and laparoscopy. Patients received two 28-day cycles of induction chemotherapy of fluorouracil, paclitaxel, and cisplatin followed by 45 Gy of radiation and concurrent fluorouracil plus paclitaxel. The cancer was restaged and surgery was attempted. Postsurgery pathologic findings and R0 resection were correlated with OS and DFS. RESULTS: Forty-one patients were enrolled. Most carcinomas were proximal (83%) and pretreatment stage EUST3 (85%). Forty patients (98%) underwent surgery, and 78% had an R0 resection. We observed a pathologic complete response (pathCR) rate of 20% and a pathologic partial response (pathPR) rate of 15% (< 10% residual cancer cells in the resected specimen). No pretreatment parameter (sex, cancer location, baseline T stage, or baseline N stage) predicted the type of postsurgery pathologic response, OS, or DFS. However, pathCR (P = .02), pathCR + pathPR (P = .006), R0 resection (P < .001), and postsurgery T and N stages (P = .01 and P < .001, respectively) were associated with OS. Same parameters were significantly correlated with DFS. Toxicity was manageable. CONCLUSION: The type of pathologic response but not pretreatment parameters was associated with OS and DFS. Efforts to increase the rate of pathologic response and better systemic cancer control are warranted.

Biologic mesh spacer placement facilitates safe delivery of dose-intense radiation therapy: A novel treatment option for unresectable liver tumors.

INTRODUCTION: Patients with unresectable liver tumors who fail initial treatment modalities have a poor prognosis (<1 yr). Although effective, delivery of high dose radiation therapy to these tumors is limited by proximity of radiosensitive bowel. We have previously reported that placement of a biologic mesh spacer (BMS) can effectively displace the bowel allowing for dose-intense radiation to be delivered with low short-term toxicity. The purpose of this study was to assess and report the long-term safety and oncologic outcomes of this cohort. METHODS: From 2012 to 2014 seven patients with unresectable hepatic malignancy (6 IHCC, 1 CRLM) underwent BMS (acellular human dermis) placement (2 open, 5 MIS) prior to radiation therapy. Prospective registry data were reviewed for tumor and treatment details, progression, metastasis and survival. RTOG guidelines were used to define radiation toxicities. RESULTS: Mean patient age was 50.4 years (30-62 years) and 4 patients were male (57.1%). Prior to surgery, all patients had been treated for an average of 12.5 months with surgery, chemotherapy, radiation and/or TACE. After surgery, all patients recovered well and received a mean radiation dose of 76.1 Gy (58.1-100 Gy) over 13-25 fractions. 1 patient received SBRT; 4 fractions, 10 Gy each. Maximum dose delivered was 100 Gy (Biologic Equivalent Dose of 140 Gy, α/ß = 10). Mean time to initiation of radiation therapy was 24 days (12-48 days) from surgery. No significant GI toxicity was recorded, and no GI bleeding or ulcers were observed. Mean follow-up after XRT was 18.2 months (5.5-31 months). Three patients had no loco-regional progression of disease. 2 patients had infield progression of liver disease and another had progressive lymphadenopathy. 3 patients developed pulmonary metastasis, at a mean time to distant failure of 3 months. There are 4 survivors over 2-years from surgery. CONCLUSION: For patients with unresectable liver tumors, placement of a BMS enhances the safety and efficacy of high-dose radiotherapy, providing a survival benefit via delay in time to progression compared to traditional treatments with no significant short or long term GI toxicity.

Preoperative chemoradiation for patients with pancreatic cancer: toxicity of endobiliary stents.

PURPOSE: A recent multicenter study of preoperative chemoradiation and pancreaticoduodenectomy for localized pancreatic adenocarcinoma suggested that biliary stent-related complications are frequent and severe and may prevent the delivery of all components of multimodality therapy in many patients. The present study was designed to evaluate the rates of hepatic toxicity and biliary stent-related complications and to evaluate the impact of this morbidity on the delivery of preoperative chemoradiation for pancreatic cancer at a tertiary care cancer center. PATIENTS AND METHODS: Preoperative chemoradiation was used in 154 patients with resectable pancreatic adenocarcinoma (142 patients, 92%) or other periampullary tumors (12 patients, 8%). Patients were treated with preoperative fluorouracil (115 patients), paclitaxel (37 patients), or gemcitabine (two patients) plus concurrent rapid-fractionation (30 Gy; 123 patients) or standard-fractionation (50.4 Gy; 31 patients) radiation therapy. The incidences of hepatic toxicity and biliary stent-related complications were evaluated during chemoradiation and the immediate 3- to 4-week postchemoradiation preoperative period. RESULTS: Nonoperative biliary decompression was performed in 101 (66%) of 154 patients (endobiliary stent placement in 77 patients and percutaneous transhepatic catheter placement in 24 patients). Stent-related complications (occlusion or migration) occurred in 15 patients. Inpatient hospitalization for antibiotics and stent exchange was necessary in seven of 15 patients (median hospital stay, 3 days). No patient experienced uncontrolled biliary sepsis, hepatic abscess, or stent-related death. CONCLUSION: Preoperative chemoradiation for pancreatic cancer is associated with low rates of hepatic toxicity and biliary stent-related complications. The need for biliary decompression is not a clinically significant concern in the delivery of preoperative therapy to patients with localized pancreatic cancer.

Combining gemcitabine with radiation in pancreatic cancer: understanding important variables influencing the therapeutic index.

We compared and evaluated available laboratory and clinical data on the use of concurrent gemcitabine (Gemzar; Eli Lilly and Company, Indianapolis, IN) and radiation in pancreatic cancer to provide guidance for subsequent prospective research initiatives. Preclinical data suggest that the timing of administration of gemcitabine with respect to radiotherapy is important, but this issue has not yet been confirmed by clinical data. Phase I clinical data indicate that the amount of acute toxicity from the combination of gemcitabine and radiotherapy is strongly related to the dose and schedule of administration of gemcitabine, as well as to the radiation field size. There also appears to be an inverse linear relationship between the maximum tolerated gemcitabine dose and radiation dose. Also important, but less clear, is the infusion rate of gemcitabine as it relates to the systemic efficacy of the drug. The combination of additional agents with gemcitabine and radiation appears to be feasible. Finally, the addition of radioprotectors may enable chemotherapy dose escalation, but safe escalation of the radiotherapy dose with newer techniques has not been established. Semin Oncol 28 (suppl 10):25-33.

Occult carcinoma discovered after simple hysterectomy treated with postoperative radiotherapy.

PURPOSE: Treatment of patients with occult carcinoma of the cervix discovered after simple hysterectomy is controversial. The purpose of this review is to examine our results with postoperative radiotherapy and to compare them to similar reports and to reports of treatment with radical parametrectomy. METHODS AND MATERIALS: Between November 1979 and April:, 18 patients were treated with radiotherapy at the University of Virginia for invasive carcinoma of the cervix discovered after simple hysterectomy. Simple hysterectomy was performed in all 18 patients for a variety of indications. After surgery gross residual carcinoma remained in four patients; and microscopic disease was present at the surgical margins in two patients. The remaining patients had no evidence of residual disease. All 18 patients had postoperative radiotherapy with or without brachytherapy. The endpoints for this study were local control, survival, and treatment-related toxicity. Actuarial rates were calculated using the Life Table method. RESULTS: Median follow-up for all 18 patients was 42 months (range 2-202 months). Both the 5 and the 10-year actuarial local control rates were 88%. Five and 10-year actuarial overall survival rates were both 93%. Two patients had both local and distant cancer recurrences. There were no recurrences among the six patients treated with external beam alone. The remaining patients are all alive without evidence of disease, including two patients who had gross residual disease after surgery, and one patient with both microscopic positive margin and a positive lymph node (the only patient to undergo lymph node sampling). There was no severe acute morbidity and only one patient had severe late morbidity. CONCLUSIONS: Invasive carcinoma found after simple hysterectomy may be treated safely and effectively with postoperative radiotherapy. Patients with known residual disease following surgery do poorly with either radiotherapy or reoperation, but treatment with radiotherapy alone may be less morbid. Also, for the treatment of minimal disease external beam radiation to the pelvis appears to be as effective and possibly less morbid than radical reoperation.

Prospective evaluation of the effect of ionizing radiation on the bladder tumor-associated (BTA) urine test.

PURPOSE: To prospectively evaluate the effect of ionizing radiation on the results of the bladder tumor-associated antigen (BTA) test. By examining this question, we sought to determine its potential use as a monitoring test for the detection of recurrent transitional carcinoma of the bladder in patients who have received prior radiotherapy for bladder preservation. MATERIALS AND METHODS: Between February 1996 and April 1997, 18 patients with nonbladder pelvic malignancies and no history of bladder cancer, received irradiation to the bladder. These patients were prospectively evaluated using the BTA test at the end of the external-beam radiation (EBRT) and at 3-month follow-up intervals. Urine cytology was analyzed in 16 of the 18 patients at the end of EBRT. A median of 3 separate measurements were made (range 1-6) on each patient. The median dose of EBRT was 50.4 Gy (range 30-68 Gy). Seven patients underwent brachytherapy as part of their treatment course. BTA results and time intervals were recorded and analyzed using univariate and Kaplan-Meyer methodologies. RESULTS: A total of 10 (56%) of the 18 patients had a positive BTA test at some time following completion of EBRT. Of the 10 positive tests, 9 returned to negative in a median of 42 weeks from completion of EBRT. Treatment with chemotherapy, brachytherapy, calculated bladder dose, and total external beam dose did not significantly influence either the number of positive tests or the time to resolution of the positive test in this small group of patients. All screened urine samples were negative for malignant cells and 11 (69%) of 16 showed changes consistent with ionizing radiation. CONCLUSION: Our findings support the hypothesis that ionizing radiation can cause transient positive results in the BTA test, but that these normalize with time. Although it requires further testing, it seems that the BTA test may be useful in the detection of recurrence in patients with bladder cancer who have been treated with definitive irradiation for bladder preservation.

Preirradiation PSA predicts biochemical disease-free survival in patients treated with postprostatectomy external beam irradiation.

PURPOSE: To assess the clinical outcome and prostate-specific antigen (PSA) response and to determine prognostic factors for biochemical disease-free survival in patients treated with external beam radiotherapy following radical prostatectomy without hormonal therapy. METHODS AND MATERIALS: Forty-eight patients were treated after prostatectomy with radiotherapy between March, 1988 and December, 1993. Seven patients had undetectable PSA (<0.2) and the remainder had detectable PSA at the time of irradiation (overall: median 2.7, range 0-24.9). Nine patients had biopsy proven local recurrence, palpable local disease, or positive preirradiation imaging. No patients received hormonal therapy prior to irradiation. Median follow-up was 55 months. A median dose of 60 Gy (range 58-66) was given to the prostate bed. Survival was analyzed using the life-table method. Actuarial biochemical disease-free survival was the primary endpoint studied. RESULTS: In patients with detectable PSA, 51% had levels return to undetectable after irradiation. The actuarial 5-year freedom from biochemical failure for all patients was 24%. A significant difference in biochemical disease-free survival was seen for patients irradiated with preirradiation PSA that was undetectable (p < 0.001), or preirradiation PSA that was < or =2.7 (p = 0.002), vs. preirradiation PSA that was >2.7. Five-year actuarial biochemical disease-free survival values were 71, 48, and 0%, respectively, for the three groups. Biochemical disease-free survival was not affected by preoperative PSA level, clinical stage, Gleason's score, pathologic stage, surgical margins, presence of undetectable PSA after surgery, surgery to radiation interval, total dose, or presence of clinically suspicious local disease. Based on digital rectal exam, there were no local failures. CONCLUSION: Biochemical disease-free survival after postprostatectomy radiation is predicted by the PSA at the time of irradiation. Clinical local control is excellent, but distant failure remains a significant problem in this population. The addition of concomitant systemic therapy should be investigated in patients with PSA >2.7.

Effective pelvic symptom control using initial chemoradiation without colostomy in metastatic rectal cancer.

PURPOSE: To assess pelvic chemoradiotherapy (CXRT) without colostomy as a component of the multidisciplinary management of patients presenting with metastatic rectal cancer. METHODS AND MATERIALS: Eighty patients with synchronous distant metastases from rectal cancer were treated with initial CXRT. Hypofractionated radiotherapy was administered usually with concurrent 5-FU (92%, 300 mg/m(2)/day, M-F). Three-field belly-board technique was used in 89%. Group 1 had CXRT alone (n = 55). Group 2 (n = 25) patients were selected for primary disease resection, and sometimes HAI chemotherapy (n = 10) or hepatic resection (n = 5). Subsequently, 78% received systemic chemotherapy. RESULTS: Symptoms from primary tumor resolved in 94%. Endoscopic complete clinical response rate was 36%. Two-year survival (11% vs. 46%, p < 0.0001) and symptomatic pelvic control (PC, 81% vs. 91%, p = 0.111) were higher in Group 2, but colostomy-free rate (CFR) was lower (79% vs. 51% p = 0.02). CFR was 87% in Group 1 patients managed initially without fecal diversion (n = 50). Examining all patients using multivariate analysis, pelvic pain at presentation (p < 0.00001), BED (biologic equivalent dose at 2 Gy/fraction) < 35 Gy (p = 0.077), and poor differentiation (0.079) predicted worse PC. Poor differentiation (p = 0.017) and selection for CXRT alone (p < 0.0001) predicted worse survival. There were 4 RTOG of Grade 3 or greater acute complications, 5 severe perioperative complications, and no significant late treatment-related complications. CONCLUSION: Durable PC can be safely achieved without colostomy in most patients presenting with primary rectal cancer and synchronous systemic metastases using hypofractionated pelvic chemoradiation. A BED greater than 35 Gy is recommended. Selected patients appear to benefit from resection of primary disease. Higher doses should be investigated in patients with pelvic pain.

T4 rectal cancer treated with preoperative chemoradiation to the posterior pelvis followed by multivisceral resection: patterns of failure and limitations of treatment.

PURPOSE: To analyze the overall pattern of treatment failure and sites of pelvic disease recurrence relative to the radiation fields used in treating patients with clinically staged T4 rectal cancer with preoperative chemoradiation followed by multivisceral resection. METHODS AND MATERIALS: Between 1990 and 1998, 45 patients with T4 rectal cancer were treated with preoperative chemoradiation. Clinical staging was according to the system of the American Joint Cancer Committee and was based on endoscopic ultrasonography, chemotherapy (CT), and physical examination. A diagnosis of T4 disease required evidence of invasion of a contiguous structure on CT (n = 31) or endorectal ultrasonography (n = 6), vaginal mucosal involvement on pelvic examination (n = 6), or a combination of these findings (n = 2). Chemoradiation was delivered with 18 MV photons using a 3-field belly-board technique. The median total dose was 45 Gy in all patients (range 45-63). Nine patients received a boost with external beam radiotherapy (EBRT) (n = 5, 1.8-18 Gy), intraoperative RT (n = 3, 10-20 Gy), or interstitial brachytherapy (n = 1, 20 Gy). All patients received concurrent chemotherapy consisting of protracted venous infusion 5-fluorouracil (300 mg/m(2), 5 d/wk). Resection was not performed in 13 (29%) of the 45 patients because of metastases detected before resection or patient refusal. Multivisceral resection and pelvic exenteration was required in 21 (66%) and 11 (34%) of 32 patients, respectively. We compared the location of pelvic disease recurrence with the RT simulation films. The Kaplan-Meier method was used to calculate the 4-year actuarial pelvic and distant recurrent rates and the overall survival rate. RESULTS: The median length of follow-up was 31.0 months for all patients and 40.0 months for patients alive at last follow-up. When only the resected cases were considered, the local recurrence rate was 20%. Distant metastases occurred in 44% of cases; the overall survival rate was 69%. When all patients were considered, the local recurrence rate was similar (24%), but the rate of distant recurrence (51%) was higher and the overall survival rate lower (50%). Pelvic disease was controlled in all 8 patients whose disease responded well to chemoradiation (either a histologically complete response or microscopic residual disease). Three of 4 patients with close or positive margins had pelvic recurrences despite intraoperative RT and brachytherapy. Nine of the 10 pelvic recurrences occurred in the radiation field. Elective external iliac nodal irradiation was not used, and nodal metastases were not seen in that region. In 1 case, marginal recurrence occurred in a common iliac node at the superior edge of the treatment field. CONCLUSIONS: Despite aggressive multimodality therapy including multivisceral resection, a high rate of pelvic and distant disease recurrence occurred in patients with clinically staged T4 disease. Regional disease recurred almost exclusively in the radiation field. The intraoperative RT and interstitial brachytherapy doses used did not prevent pelvic disease recurrence in patients with close or positive margins. Novel strategies such as higher preoperative doses of RT with or without altered fractionation or more effective radiosensitizers are needed to improve locoregional control in patients with T4 disease. Future strategies must also include more effective systemic therapy.

Neoadjuvant strategies for pancreatic cancer.

Recent prospective and retrospective data suggest that the use of multimodality therapy combining pancreaticoduodenectomy with postoperative adjuvant chemotherapy (fluorouracil) and external-beam radiation therapy maximizes local tumor control and improves the length of survival in pancreatic cancer patients, compared with surgery alone. Since postoperative chemoradiation is often delayed in these patients due to the morbidity and prolonged recovery time associated with surgery, investigators are assessing the efficacy of administering chemoradiation before pancreaticoduodenectomy in patients with potentially resectable pancreatic adenocarcinoma. When given prior to surgery, chemoradiation is not delayed and patients found to have disease progression after chemoradiation are not subjected to an unnecessary laparotomy.

Phase I study of concomitant gemcitabine and IMRT for patients with unresectable adenocarcinoma of the pancreatic head.

PURPOSE: We hypothesized that dynamic intensity-modulated radiotherapy (IMRT) would protect normal tissues enough to allow the escalation of either the gemcitabine or radiotherapy dose in unresectable pancreatic cancer patients. METHODS AND MATERIALS: The trial was designed to build on a previous phase I trial that determined the maximum tolerated dose (MTD) of gemcitabine (350 mg/m2) with concurrent radiotherapy (30 Gy/10 fractions). Only patients with unresectable disease based on established criteria were eligible. The plan was to alternate escalating the radiation dose by 3 Gy and the gemcitabine dose by 50 mg/m2. The starting dose of gemcitabine was 350 mg/m2 and 33 Gy/11 fractions of IMRT to the regional lymphatics and primary disease. The NCI Common Toxicity Criteria were used for dose-limiting toxicity (DLT). RESULTS: All three patients in the first cohort treated suffered DLT. Therefore, a second cohort of patients received a lower gemcitabine dose (250 mg/m2). Both patients treated at this dose level experienced DLT. The DLTs were all due to myelosuppression and upper gastrointestinal toxicity. All patients required a gemcitabine dose reduction. Also, four patients required hospital admission for supportive care, while the fifth died of an unrelated cause shortly after completing therapy. The trial was then closed due to excessive toxicity. CONCLUSION: Hypofractionated dynamic IMRT to the primary site and regional lymphatics did not permit escalation of either the radiation or gemcitabine dose. Dynamic IMRT requires further investigation before it can be applied to toxic combinations of chemotherapy and radiation in the upper abdomen.

Optimization of beam orientations and weights for coplanar conformal beams in treating pancreatic cancer.

In treating pancreatic cancer with external-beam radiotherapy, radiation dose given to the tumor volume is largely limited by the tolerance of the normal structures near the disease site, including the kidneys, liver, stomach, small bowel, and spinal cord. The purpose of this work was to investigate whether a coplanar conformal therapy technique with beam optimization could reduce dose to the normal tissues compared to the conventional 4-field technique; and if this was true, whether other beam arrangements were more effective than the 4-field technique in treating pancreatic cancer. In this study, 9 patients who were treated previously for T3N0 or T3N1 pancreatic cancer with external-beam therapy of 30 Gy in 10 fractions were selected. Beam orientations and weights were optimized for 4 to 6 coplanar conformal beams using a simulated annealing algorithm to minimize the kidney volume receiving more than 20 Gy. Optimized plans were compared with standard plans using a 4-field technique with respect to the isodose distributions and dose volume histograms. For the standard 4-field plans giving 30 Gy to the tumor volume, the total kidney volume above 20 Gy ranged from 10% to 35%, with a mean of 22% and a standard deviation of 7%. Optimization of the beam orientations and weights reduced this volume by approximately 2 times without a significant increase of dose to the liver, stomach, and small bowel. This indicated that the radiation toxicity to the kidneys could be reduced substantially by a careful selection of oblique beam angles and weights. Analysis of the optimized plans showed that beam arrangements which involved left and right anterior oblique beams were superior to the conventional 4-field technique for reducing the kidney dose in treating pancreatic cancer.

Staging of pancreatic cancer with multidetector CT in the setting of preoperative chemoradiation therapy.

BACKGROUND: Preoperative chemoradiation can potentially improve outcomes in patients with pancreatic cancer. This study addresses its effect on staging pancreatic cancer with multidetector computed tomography (MDCT). METHODS: Fifty-five patients underwent a dual-phase MDCT pancreas protocol for proved pancreatic cancer. Of these, 16 patients underwent preoperative chemoradiation. Three radiologists independently reviewed images to assess for locally advanced disease, liver and peritoneal metastases on baseline studies of all 55 patients, and on follow-up preoperative studies for the 16 patients receiving preoperative therapy. Overall score for resectability was graded on a scale from 1 to 5 (1, definitely resectable; 5. definitely unresectable). Receiver operating characteristic curves and weighted (kappa statistics were determined. RESULTS: The areas under the receiver operating characteristic curves for readers 1, 2, and 3 were 0.98, 0.96, and 0.90, respectively. Weighted kappa values for reader 1 versus reader 2, reader 1 versus reader 3, and reader 2 versus reader 3 were 0.90, 0.57, and 0.54, respectively. Interpreting scores of 1 to 3 for resectability as resectable disease, the mean values for sensitivity, specificity, negative predictive value, positive predictive value, and accuracy were 0.92, 0.91, 0.74, 0.98, and 0.92 respectively. CONCLUSION: The negative predictive value for MDCT for identifying unresectable pancreatic cancer in the setting of preoperative therapy is comparable to that reported in the absence of neoadjuvant therapy.

Planned neck dissection as an adjunct to the management of patients with advanced neck disease treated with definitive radiotherapy: for some or for all?

BACKGROUND: Management of patients with head and neck carcinoma and advanced nodal disease is controversial. The purpose of this analysis was to evaluate the efficacy and toxicity of definitive radiotherapy followed by planned neck dissection in patients with bulky neck disease. MATERIALS AND METHODS: The records of 52 patients who were treated between 1989 and 1995 at the Peter MacCallum Cancer Institute with a planned neck dissection after radical radiotherapy were reviewed. All had advanced neck disease with one or more nodes >/=3 cm in maximum diameter, 94% being staged N2-3. The most common primary site was the oropharynx (56%). Sixty percent of patients had either T2 or T3 primaries and all were AJCC stage IV. Treatment consisted of high-dose radiotherapy to the primary and involved neck sites using various fractionation protocols followed by radical or modified radical neck dissection after confirmation of a complete response at the primary site. The median follow-up for living patients was 58 months (range 32-97). RESULTS: There were nine regional failures, of which three were outside the dissected neck, yielding a 5-year actuarial overall neck control rate of 83% and an in-field control rate of 88%. In-field control rates by neck stage were N1 3/3; N2 31/35; N3 11/13 and NX 1/1. There was only one in-field failure among 28 patients who had pathologically negative neck specimens compared with five in 24 patients with morphologic evidence of residual disease. Of the 24 patients with pathologically positive necks, 5 were long-term survivors and were probably cured by their surgery. Another 4 died of intercurrent disease without documented recurrence of their head and neck cancer. Ten patients recurred at their primary sites (5-year actuarial control 79%) and 8 developed distant metastases (5-year actuarial rate 20%). A total of 21 patients failed at one or more sites and none was salvaged. Five-year actuarial disease-free survival was 57% and overall survival 38%. Nine patients (17%) sustained significant complications following neck dissection. CONCLUSIONS: In patients with advanced neck disease who are treated primarily with radical radiotherapy, planned neck dissection provides excellent regional control and appears to cure a subset of patients. However, routine neck dissection adds significant morbidity to treatment and should ideally be avoided in those patients in whom surgery is either unnecessary (no residual tumor) or futile (unsalvageable disease recurrence outside the dissected neck). Based on our analysis and other recently reported series, we now recommend observing patients who have a complete response to high-dose radiotherapy (+/- chemotherapy). The ability of PET imaging to detect residual viable tumor in the head and neck or at distant sites is under investigation.

WR-2721 reduces intestinal toxicity from concurrent gemcitabine and radiation treatment.

BACKGROUND: The nucleoside analog gemcitabine is a potent radiosensitizer of both tumor and normal mucosa, so severe toxic reactions have resulted from its combination with radiation in some clinical treatment schedules for pancreatic cancer. WR-2721 (amifostine) has been shown to reduce normal tissue toxicity produced from both radiation treatment and some chemotherapeutics. The aim of this study was to determine if WR-2721 can protect the gastrointestinal mucosa from injury by concurrent gemcitabine and radiation treatment. METHODS AND MATERIALS: Gemcitabine was injected ip into C3Hf/Kam mice at a concentration of 33 mg/kg 24 h before whole-body irradiation. A single dose (200 mg/kg) of WR-2721 was given 30 min before the radiation treatment or 30 min before gemcitabine or at both times. A quantitative assessment of the chemotherapy/radiation-induced damage was carried out using the mouse microcolony assay for stem cell survival in the intestinal crypts. RESULTS: WR-2721 given 30 min before gemcitabine followed 24 h later by radiation did not confer any protection to the jejunum (DMF 0.95). However, WR-2721 administered 30 min before radiation without or with prior gemcitabine produced protection factors (PF) of 1.35 and 1.42 CONCLUSIONS: WR-2721 did not directly protect the gastrointestinal mucosa from gemcitabine toxicity, but it did protect the gemcitabine-radiosensitized mucosa from acute radiation damage by a factor of 1.42. Therefore, in clinical treatment protocols using concurrent chemoradiation with gemcitabine, WR-2721 may have clinical utility in protecting against radiation-induced mucosal toxicity.