Dosimetric Comparison of Conventional Radiotherapy, Volumetric Modulated Arc Therapy, and Proton Beam Therapy for Palliation of Thoracic Spine Metastases Secondary to Breast or Prostate Cancer.

The aim of this planning study was to compare the dosimetric outcomes of Volumetric Modulated Arc Therapy (VMAT), Proton Beam Therapy (PBT), and conventional External Beam Radiation Therapy (cEBRT) in the treatment of thoracic spinal metastases originating from breast or prostate cancer. Our study utilized data from 30 different treatment plans and evaluated target coverage and doses to vital organs at risk (OARs), such as the spinal cord, heart, esophagus, and lungs. The results showed that VMAT and PBT achieved superior target coverage and significantly lower doses to the spinal cord compared to cEBRT (target: median PTVD95%: 75.2 for cEBRT vs. 92.9 and 91.7 for VMAT (p < 0.001) and PBT (p < 0.001), respectively; spinal cord: median Dmax%: 105.1 for cEBRT vs. 100.4 and 103.6 for VMAT (p < 0.001) and PBT (p = 0.002), respectively). Specifically, VMAT was notable for its superior target coverage and PBT for significantly lower doses to heart, lungs, and esophagus. However, VMAT resulted in higher lung doses, indicating potential trade-offs among different techniques. The study demonstrated the relative advantages of VMAT and PBT over traditional RT in the palliative treatment of spinal metastases using conventional fractionation. These findings underscore the potential of VMAT and PBT to improve dosimetric outcomes, suggesting that they may be more suitable for certain patient groups for whom the sparing of specific OARs is especially important.

Estimated Risk of Radiation-Induced Cancer after Thymoma Treatments with Proton- or X-ray Beams.

We compared the calculated risks of radiation-induced secondary malignant neoplasms (SMNs) for patients treated for thymic tumors with 3D-CRT, IMRT, or single-field uniform dose (SFUD) proton beam therapy (PBT) using the pencil beam scanning (PBS) technique. A cancer-induction model based on the organ equivalent dose (OED) concept was used. For twelve patients, treated with 3D-CRT for thymic tumors, alternative IMRT and SFUD plans were retrospectively prepared. The resulting DVHs for organs at risk (OARs) were extracted and used to estimate the risk of SMNs. The OED was calculated using a mechanistic model for carcinoma induction. Two limit cases were considered; the linear-exponential model, in which the repopulation/repair of the cells is neglected, and the plateau model, in which full repopulation/repair of the irradiated cells is assumed. The calculated risks for SMNs for the different radiation modalities and dose-relation models were used to calculate relative risks, which were compared pairwise. The risks for developing SMNs were reduced for all OARs, and for both dose-relation models, if SFUD was used, compared to 3D-CRT and IMRT. In conclusion, PBS shows a potential benefit to reduce the risk of SMNs compared to 3D-CRT and IMRT in the treatment of thymic tumors.

An in silico planning study comparing doses and estimated risk of toxicity in 3D-CRT, IMRT and proton beam therapy of patients with thymic tumours.

PURPOSE: To compare the dose distributions produced in patients (pts) treated for thymic tumours with spot-scanning proton beam therapy (PBT) implemented with single-field uniform dose (SFUD), intensity-modulated radiation therapy (IMRT) and three-dimensional conformal photon-beam based radiotherapy (3D-CRT). METHODS: Twelve pts, treated with 3D-CRT, were included. Alternative IMRT and SFUD plans were constructed. The IMRT plans were created using a setup with beams incident from 5 to 6 different angles. For the SFUD plans, a field-specific planning target volume (PTV) was created for each patient and a clinical target volume (CTV)-based robust optimization was performed. A robustness evaluation was performed for the CTV for all SFUD plans. A dosimetric evaluation was conducted for the doses to the CTV and organs at risk (OARs) for all plans. The normal tissue complication probability (NTCP), for different endpoints, was calculated using the Lyman-Kutcher-Burman (LKB)-model and compared between plans. RESULTS: SFUD was associated with significantly lower mean doses to the oesophagus, the heart, the left anterior descending coronary artery (LAD), lungs and breasts compared to 3D-CRT and IMRT. The maximum dose given to the spinal cord was significantly lower with SFUD. The risks for pneumonitis, esophagitis and myelopathy were significantly reduced in the SFUD plans. CONCLUSIONS: The present study showed dosimetric advantages of using scanned-beam PBT for the treatment of thymic tumours, as compared to 3D-CRT and IMRT, especially in regard to lower doses to the oesophagus and lungs. The risk of toxicity was reduced with SFUD.

Estimation of Risk of Normal-tissue Toxicity Following Gastric Cancer Radiotherapy with Photon- or Scanned Proton-beams.

BACKGROUND/AIM: Gastric cancer (GC) radiotherapy involves irradiation of large tumour volumes located in the proximities of critical structures. The advantageous dose distributions produced by scanned-proton beams could reduce the irradiated volumes of the organs at risk (OARs). However, treatment-induced side-effects may still appear. The aim of this study was to estimate the normal tissue complication probability (NTCP) following proton therapy of GC, compared to photon radiotherapy. PATIENTS AND METHODS: Eight GC patients, previously treated with volumetric-modulated arc therapy (VMAT), were retrospectively planned with scanned proton beams carried out with the single-field uniform-dose (SFUD) method. A beam-specific planning target volume was used for spot positioning and a clinical target volume (CTV) based robust optimisation was performed considering setup- and range-uncertainties. The dosimetric and NTCP values obtained with the VMAT and SFUD plans were compared. RESULTS: With SFUD, lower or similar dose-volume values were obtained for OARs, compared to VMAT. NTCP values of 0% were determined with the VMAT and SFUD plans for all OARs (p>0.05), except for the left kidney (p<0.05), for which lower toxicity was estimated with SFUD. CONCLUSION: The NTCP reduction, determined for the left kidney with SFUD, can be of clinical relevance for preserving renal function after radiotherapy of GC.

Comparative study of the calculated risk of radiation-induced cancer after photon- and proton-beam based radiosurgery of liver metastases.

INTRODUCTION: The potential of proton therapy to improve the sparing of the healthy tissue has been demonstrated in several studies. However, even small doses delivered to the organs at risk (OAR) may induce long-term detriments after radiotherapy. In this study, we investigated the possibility to reduce the risk of radiation-induced secondary cancers with intensity modulated proton therapy (IMPT), when used for radiosurgery of liver metastases. MATERIAL AND METHODS: Ten patients, previously treated for liver metastases with photon-beam based stereotactic body radiation therapy (SBRT) were retrospectively planned for radiosurgery with IMPT. A treatment plan comparison was then performed in terms of calculated risk of radiation-induced secondary cancer. The risks were estimated using two distinct models (Dasu et al., 2005; Schneider et al., 2005, 2009). The plans were compared pairwise with a two-sided Wilcoxon signed-rank test with a significance level of 0.05. RESULTS: Reduced risks for induction of fatal and other types of cancers were estimated for the IMPT plans (p<0.05) with the Dasu et al. MODEL: Using the Schneider et al. model, lower risks for carcinoma-induction with IMPT were estimated for the skin, lungs, healthy part of the liver, esophagus and the remaining part of the body (p<0.05). The risk of observing sarcomas in the bone was also reduced with IMPT (p<0.05). CONCLUSION: The findings of this study indicate that the risks of radiation-induced secondary cancers after radiosurgery of liver metastases may be reduced, if IMPT is used instead of photon-beam based SBRT.

Comparison of gastric-cancer radiotherapy performed with volumetric modulated arc therapy or single-field uniform-dose proton therapy.

BACKGROUND: Proton-beam therapy of large abdominal cancers has been questioned due to the large variations in tissue density in the abdomen. The aim of this study was to evaluate the importance of these variations for the dose distributions produced in adjuvant radiotherapy of gastric cancer (GC), implemented with photon-based volumetric modulated arc therapy (VMAT) or with proton-beam single-field uniform-dose (SFUD) method. MATERIAL AND METHODS: Eight GC patients were included in this study. For each patient, a VMAT- and an SFUD-plan were created. The prescription dose was 45 Gy (IsoE) given in 25 fractions. The plans were prepared on the original CT studies and the doses were thereafter recalculated on two modified CT studies (one with extra water filling and the other with expanded abdominal air-cavity volumes). RESULTS: Compared to the original VMAT plans, the SFUD plans resulted in reduced median values for the V18 of the left kidney (26%), the liver mean dose (14.8 Gy (IsoE)) and the maximum dose given to the spinal cord (26.6 Gy (IsoE)). However, the PTV coverage decreased when the SFUD plans were recalculated on CT sets with extra air- (86%) and water-filling (87%). The added water filling only led to minor dosimetric changes for the OARs, but the extra air caused significant increases of the median values of V18 for the right and left kidneys (10% and 12%, respectively) and of V10 for the liver (12%). The density changes influenced the dose distributions in the VMAT plans to a minor extent. CONCLUSIONS: SFUD was found to be superior to VMAT for the plans prepared on the original CT sets. However, SFUD was inferior to VMAT for the modified CT sets.

Dosimetric Comparison of Plans for Photon- or Proton-Beam Based Radiosurgery of Liver Metastases.

PURPOSE: Radiosurgery treatment of liver metastases with photon beams has been an established method for more than a decade. One method commonly used is the stereotactic body radiation therapy (SBRT) technique. The aim of this study was to investigate the potential sparing of the organs at risk (OARs) that the use of intensity-modulated proton therapy (IMPT), instead of SBRT, could enable. PATIENTS AND METHODS: A comparative treatment-planning study of photon-beam and proton-beam based liver-cancer radiosurgery was performed. Ten patients diagnosed with liver metastasis and previously treated with SBRT at the Karolinska University Hospital were included in the study. New IMPT plans were prepared for all patients, while the original plans were set as reference plans. The IMPT planning was performed with the objective of achieving the same target dose coverage as with the SBRT plans. Pairwise dosimetric comparisons of the treatment plans were then performed for the OARs. A 2-sided Wilcoxon signed-rank test with significance level of 5% was carried out. RESULTS: Improved sparing of the OARs was made possible with the IMPT plans. There was a significant decrease of the mean doses delivered to the following risk organs: the nontargeted part of the liver (P = .002), the esophagus (P = .002), the right kidney (P = .008), the spinal cord (P = .004), and the lungs (P = .002). The volume of the liver receiving less than 15 Gy was significantly increased with the IMPT plans (P = .004). CONCLUSION: The IMPT-based radiosurgery plans provided similar target coverage and significant dose reductions for the OARs compared with the photon-beam based SBRT plans. Further studies including detailed information about varying tissue heterogeneities in the beam path, due to organ motion, are required to evaluate more accurately whether IMPT is preferable for the radiosurgical treatment of liver metastases.

Optimal duration and timing of adjuvant chemotherapy after definitive surgery for ductal adenocarcinoma of the pancreas: ongoing lessons from the ESPAC-3 study.

PURPOSE: Adjuvant chemotherapy improves patient survival rates after resection for pancreatic adenocarcinoma, but the optimal duration and time to initiate chemotherapy is unknown. PATIENTS AND METHODS: Patients with pancreatic ductal adenocarcinoma treated within the international, phase III, European Study Group for Pancreatic Cancer-3 (version 2) study were included if they had been randomly assigned to chemotherapy. Overall survival analysis was performed on an intention-to-treat basis, retaining patients in their randomized groups, and adjusting the overall treatment effect by known prognostic variables as well as the start time of chemotherapy. RESULTS: There were 985 patients, of whom 486 (49%) received gemcitabine and 499 (51%) received fluorouracil; 675 patients (68%) completed all six cycles of chemotherapy (full course) and 293 patients (30%) completed one to five cycles. Lymph node involvement, resection margins status, tumor differentiation, and completion of therapy were all shown by multivariable Cox regression to be independent survival factors. Overall survival favored patients who completed the full six courses of treatment versus those who did not (hazard ratio [HR], 0.516; 95% CI, 0.443 to 0.601; P < .001). Time to starting chemotherapy did not influence overall survival rates for the full study population (HR, 0.985; 95% CI, 0.956 to 1.015). Chemotherapy start time was an important survival factor only for the subgroup of patients who did not complete therapy, in favor of later treatment (P < .001). CONCLUSION: Completion of all six cycles of planned adjuvant chemotherapy rather than early initiation was an independent prognostic factor after resection for pancreatic adenocarcinoma. There seems to be no difference in outcome if chemotherapy is delayed up to 12 weeks, thus allowing adequate time for postoperative recovery.

Neo-adjuvant chemotherapy followed by surgery and chemotherapy or by surgery and chemoradiotherapy for patients with resectable gastric cancer (CRITICS).

BACKGROUND: Radical surgery is the cornerstone in the treatment of resectable gastric cancer. The Intergroup 0116 and MAGIC trials have shown benefit of postoperative chemoradiation and perioperative chemotherapy, respectively. Since these trials cannot be compared directly, both regimens are evaluated prospectively in the CRITICS trial. This study aims to obtain an improved overall survival for patients treated with preoperative chemotherapy and surgery by incorporating radiotherapy concurrently with chemotherapy postoperatively. METHODS/DESIGN: In this phase III multicentre study, patients with resectable gastric cancer are treated with three cycles of preoperative ECC (epirubicin, cisplatin and capecitabine), followed by surgery with adequate lymph node dissection, and then either another three cycles of ECC or concurrent chemoradiation (45 Gy, cisplatin and capecitabine). Surgical, pathological, and radiotherapeutic quality control is performed. The primary endpoint is overall survival, secondary endpoints are disease-free survival (DFS), toxicity, health-related quality of life (HRQL), prediction of response, and recurrence risk assessed by genomic and expression profiling. Accrual for the CRITICS trial is from the Netherlands, Sweden, and Denmark, and more countries are invited to participate. CONCLUSION: Results of this study will demonstrate whether the combination of preoperative chemotherapy and postoperative chemoradiotherapy will improve the clinical outcome of the current European standard of perioperative chemotherapy, and will therefore play a key role in the future management of patients with resectable gastric cancer. TRIAL REGISTRATION: clinicaltrials.gov NCT00407186.

Randomized phase II study of sequential docetaxel and irinotecan with 5-fluorouracil/folinic acid (leucovorin) in patients with advanced gastric cancer: the GATAC trial.

BACKGROUND: The optimal chemotherapy in patients with advanced gastric carcinoma (GC) is yet to be determined. We compared sequential administration of docetaxel and irinotecan, both in combination with infused 5-fluorouracil/leucovorin (5-Fu/Lv), and randomly assigned patients to start with either of the two. METHODS: Patients with previously untreated locally advanced or metastatic GC and with measurable lesions (response evaluation criteria in solid tumors; RECIST) were randomly assigned to start with docetaxel 45 mg/m(2) (arm T) or irinotecan 180 mg/m(2) (arm C) with bolus/44-h infusion of 5-Fu/Lv (day 1 every 2 weeks). After four courses, there was a prescheduled crossover to the alternative regimen for four additional courses. RESULTS: Eighty-one patients were randomized and 78 started treatment. Complete and partial responses were seen in 31 (40%) patients after 8 weeks and in 32 (41%) after 16 weeks, with similar results in both study arms. The median overall survival (OS) was 11.5 and 10.6 months in arms T and C, respectively (P = 0.3). The two schedules were feasible and did not differ in the overall rate of severe adverse events (SAEs). CONCLUSION: This is the first randomized comparison of two of the newer cytostatic drugs in GC therapy. No differences favoring either arm T or arm C were found with respect to response rate, OS, or toxicity. The median OS of 11 months indicates that sequential administration of the two combinations is effective and is similar to triple combinations. Thus, comparable efficacy to platinum combinations appears to be obtained with newer, less toxic regimens when given sequentially.

Adjuvant chemotherapy with fluorouracil plus folinic acid vs gemcitabine following pancreatic cancer resection: a randomized controlled trial.

CONTEXT: Adjuvant fluorouracil has been shown to be of benefit for patients with resected pancreatic cancer. Gemcitabine is known to be the most effective agent in advanced disease as well as an effective agent in patients with resected pancreatic cancer. OBJECTIVE: To determine whether fluorouracil or gemcitabine is superior in terms of overall survival as adjuvant treatment following resection of pancreatic cancer. DESIGN, SETTING, AND PATIENTS: The European Study Group for Pancreatic Cancer (ESPAC)-3 trial, an open-label, phase 3, randomized controlled trial conducted in 159 pancreatic cancer centers in Europe, Australasia, Japan, and Canada. Included in ESPAC-3 version 2 were 1088 patients with pancreatic ductal adenocarcinoma who had undergone cancer resection; patients were randomized between July 2000 and January 2007 and underwent at least 2 years of follow-up. INTERVENTIONS: Patients received either fluorouracil plus folinic acid (folinic acid, 20 mg/m(2), intravenous bolus injection, followed by fluorouracil, 425 mg/m(2) intravenous bolus injection given 1-5 days every 28 days) (n = 551) or gemcitabine (1000 mg/m(2) intravenous infusion once a week for 3 of every 4 weeks) (n = 537) for 6 months. MAIN OUTCOME MEASURES: Primary outcome measure was overall survival; secondary measures were toxicity, progression-free survival, and quality of life. RESULTS: Final analysis was carried out on an intention-to-treat basis after a median of 34.2 (interquartile range, 27.1-43.4) months' follow-up after 753 deaths (69%). Median survival was 23.0 (95% confidence interval [CI], 21.1-25.0) months for patients treated with fluorouracil plus folinic acid and 23.6 (95% CI, 21.4-26.4) months for those treated with gemcitabine (chi(1)(2) = 0.7; P = .39; hazard ratio, 0.94 [95% CI, 0.81-1.08]). Seventy-seven patients (14%) receiving fluorouracil plus folinic acid had 97 treatment-related serious adverse events, compared with 40 patients (7.5%) receiving gemcitabine, who had 52 events (P < .001). There were no significant differences in either progression-free survival or global quality-of-life scores between the treatment groups. CONCLUSION: Compared with the use of fluorouracil plus folinic acid, gemcitabine did not result in improved overall survival in patients with completely resected pancreatic cancer. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00058201.

Interobserver variation of clinical target volume delineation in gastric cancer.

PURPOSE: To evaluate interobserver variability in clinical target volume (CTV) delineation in gastric cancer performed with the help of a delineation guide. PATIENTS AND METHODS: Ten radiotherapy centers that participate in the CRITICS Phase III trial were provided with a delineation atlas, preoperative CT scans, a postoperative planning CT scan, and clinical information for a gastric cancer case and were asked to construct a CTV and create a dosimetric plan according to departmental policy. RESULTS: The volumes of the CTVs and planning target volumes (PTVs) differed greatly, with a mean (SD) CTV volume of 392 (176) cm(3) (range, 240-821 cm(3)) and PTV volume of 915 (312) cm(3) (range, 634-1677 cm(3)). The overlapping volume was 376 cm(3) for the CTV and 890 cm(3) for the PTV. The greatest differences in the CTV were seen at the cranial and caudal parts. After planning, dose coverage of the overlapping PTV volume showed less variability than the CTV. CONCLUSION: In this series of 10 plans, variability of the CTV in postoperative chemoradiotherapy for gastric cancer is large. Strict and clear delineation guidelines should be provided, especially in Phase III multicenter studies. Adaptations of these guidelines should be evaluated in clinical studies.

Efficacy of preoperative radiochemotherapy in patients with locally advanced pancreatic carcinoma.

BACKGROUND: The optimal care for patients with unresectable, non-metastatic pancreatic adenocarcinoma (PAC) is debated. We treated 17 consecutive cases with preoperative radiochemotherapy (RCT) as a means for downstaging their tumours and compared outcome with 35 patients undergoing direct surgery for primarily resectable PAC during the same time period. METHODS: The patients had biopsy proven, unresectable, non-metastatic PAC which engaged >or=50% of the circumference of a patent mesenteric/portal vein for a distance >or=2 cm and/or <50% of the circumference of a central artery for <2 cm. The preop therapy included two courses of Xelox (oxaliplatin 130 mg/m(2) d1; capecitabine 2 000 mg/m(2) d1-14 q 3 w) followed by 3-D conformal radiotherapy (50.4 Gy; 1.8 Gy fractions) with reduced Xelox (d1-5 q 1 w X 6). RESULTS: No incident of RCT-related CTC Grade 3-4 haematologic and six cases of non-haematologic side-effects were diagnosed. Sixteen patients completed the RCT and were rescanned with CT and reevaluated for surgery 4 weeks post-RCT. Five cases were diagnosed with new metastases to the liver. Eleven patients were accepted for surgery whereof eight underwent a curative R(0)-resection. The median overall survival for the latter group was 29 months, which compared favourably with our control group of patients undergoing direct curative surgery for primarily resectable PAC (median OS: 16 months; R(O)-rate: 75%). Perioperative morbidity was similar in the two cohorts but the duration of surgery was longer (576 vs. 477 min) and the op blood loss was greater (3288 vs. 1460 ml) in the RCT-cohort (p < 0.05). The 30-day mortality was zero in both groups. CONCLUSION: Preoperative RCT in patients with locally advanced PAC resulted in a high rate of curative resections and promising median survival in our treatment series. This trimodality approach merits further exploration in new studies, which are currently underway at our Department.

Quantitative assessment of lung density changes after 3-D radiotherapy for breast cancer.

Our aim was to reduce the rates of clinical and radiological pneumonitis in local-regional radiotherapy (RT) for breast cancer compared to a previous treatment series by applying a pre-planned lung dose volume constraint. 3-D dose planning was performed in 66 women with the aim of not exceeding an ipsilateral V20 of 30%. The patients were followed for short-term signs/symptoms of post-RT pneumonitis and radiological changes on chest CT 4 months after RT. Radiological abnormalities were scored with a CT-adapted modification of a semi-quantitative classification system originally proposed by Arriagada which accounts for severity and affected lung regions. The abnormal subvolumes were contoured and the mean doses were calculated. Three cases of mild and one case of moderate symptomatic pneumonitis were diagnosed. The mean V20 was higher in symptomatic than in unaffected patients, 29% vs. 24% (p =0.04). Mild/moderate radiological changes were frequently observed on CT in regions with average doses >30 Gy. According to multivariate modeling, a trend for association was found between the studied dosimetric factors V13, V20, V30 and mean lung dose, and moderate-severe changes on CT but not with patient specific covariates, e.g. chemotherapy or tamoxifen exposure. 3-D planned local-regional RT with a preplanned lung dose volume constraint of V20 <30% resulted in few cases of moderate symptomatic pneumonitis. Mild/moderate radiological changes were still detectable on CT in subvolumes receiving doses >30 Gy. Long-term follow-up for evaluation of possible late morbidity is warranted.

Efficacy of pegylated liposomal doxorubicin in patients with advanced hepatocellular carcinoma.

Presently, no effective systemic therapy is available for patients with advanced hepatocellular carcinoma (aHCC). We sought to determine whether systemic treatment with pegylated liposomal doxorubicin (PLD) would yield a response rate of 20% in chemotherapy naïve patients with aHCC. The study was designed according to the phase II Gehan two-step procedure with a precision of 10%. Enrollment criteria included histological diagnosis and radiological documentation of unresectable/metastatic HCC, WHO PS 0-2, relatively normal organ function, life expectancy greater than three months, lack of cardiomyopathy and active cardiac disease NYHA > or = II. PLD (40 mg/m(2) IV 1h-infusion) was administered on d1 q 4 wk and response to treatment was evaluated radiologically every 3rd cycle (WHO-criteria). Secondary endpoints included overall (OS) and progression free survival (PFS) and registration of toxicity. The median number of administered PLD cycles was 3. The best radiological response among the first 14 patients was 1 PR, 5 SD, 3 PD, and 6 NE due to progressive disease clinically (Step 1). The 15th patient did not respond to the PLD-therapy and the study was closed for accrual as the pre-planned analysis could be executed (Step 2). A response rate > or = 20% could be ruled out. The median PFS and OS survival was 82 days and 130 days, respectively. Adverse events were generally mild in the subgroup of patients without signs of moderate hepatic failure at base line. Patients with WHO PS 2, liver tumour involvement >50%, bilirubin > or = 34 micromol/L, albumin <33 g/L, and/or Child Pugh B were unlikely to survive >90 days. PLD can be delivered safely in patients with aHCC and no signs of moderate hepatic failure. The therapy resulted, however, in few responses or cases of disease stabilization and has thus very limited activity in aHCC. Future studies on systemic chemotherapy should focus on patients without moderate hepatic failure, with WHO PS <2, and with liver tumour involvement <50%.

Advances in the treatment of patients with gastric adenocarcinoma.

Despite a decline in its incidence in the Western world, gastric cancer (GC) remains the fourth most frequent cancer diagnosis worldwide and is, after lung cancer, the second leading cause of death from a malignant disease globally. Based on the published literature, treatment guidelines and reports from international meetings, we here review the current treatment options for GC and discuss insights and perspectives from the latest clinical studies. The management of GC in the early stages of the disease is based on an optimal surgical resection of the primary tumor and the regional lymph nodes. However, less than one third of patients have a resectable disease at diagnosis and among those operated, more than half are not cured by surgery alone, due to a high rate of relapse. Thus, for the majority of patients, systemic cytotoxic therapy, and sometimes radiotherapy, is a treatment option both as an adjunct to surgery and in the palliative setting. Adjuvant chemotherapy offers only a marginal benefit and has not become a standard of care in the West. In North America, adjuvant chemoradiation is broadly used, shown to significantly improve overall survival, albeit with the cost of high toxicity. Furthermore, a recently reported study from the United Kingdom demonstrated a significant disease-free and survival benefit by the use of perioperative combination chemotherapy. Several chemotherapeutic agents have been tested as a palliative therapy in advanced GC including 5- fluorouracil (5-FU), oral pyrimidines, platinum derivatives, anthracyclines, taxanes and camptothecans. It is now accepted that chemotherapy is better than best supportive care only and that 5-FU based combinations are more effective than monotherapy. However, the response rates have generally been moderate and there is no consensus on the optimal combination of cytotoxic agents and the potential role of more recently developed "targeted therapies".

ROC curves and evaluation of radiation-induced pulmonary toxicity in breast cancer.

PURPOSE: To study clinical, radiologic, and physiologic pulmonary toxicity in 128 women after adjuvant radiotherapy (RT) for breast cancer in relation to dosimetric factors. METHODS AND MATERIAL: The patients underwent pulmonary function testing before and 5 months post-RT. Similarly, computer tomography of the chest was repeated 4 months post-RT and changes were scored with a semiquantitative system. Clinical symptoms were registered and scored according to Common Toxicity Criteria. All patients underwent three-dimensional dose planning, and the ipsilateral lung volume receiving > or = 13 Gy (V13), V20, and V30 were calculated. Multiple logistic or regression analyses were used for multivariate modeling. The relation between the dosimetric factors and side effects was also analyzed with receiver operating characteristic (ROC) curves. RESULTS: V20 was, according to multivariate modeling, the most important variable for the occurrence of the three studied side effects (p < 0.01). Age was also related to symptomatic and radiologic pneumonitis. Reduced pre-RT functional level was more common in patients developing symptomatic toxicity. The ROC areas for symptomatic pneumonitis in relation to V13, V20, and V30 were 0.69, 0.69, and 0.67, and for radiologic pneumonitis 0.85, 0.85, and 0.81. CONCLUSIONS: Our results support the use of three-dimensional planning aimed at minimizing the percent of incidentally irradiated lung volume to reduce pulmonary toxicity. Age was also correlated with post-RT side effects. According to ROC analysis, V20 could well predict the risk for radiologic pneumonitis for the studied semiquantitative model.

Capecitabine as third line therapy in patients with advanced colorectal cancer.

This study sought to determine whether third line therapy with capecitabine (cap.) could provide any clinical benefit in patients with advanced colorectal cancer who have progressed on 5-Fu combination therapy with both irinotecan and oxaliplatin. Twenty patients who were pretreated with and had progressed on irinotecan+Nordic FLv (5-Fu/leukovorin) and oxaliplatin+c.i. 5-Fu/leukovorin were studied. Cap. was administered at 1000-1250 mg/m2 bid d1-14 q 3 w. Time to progression (TTP) (either radiological or clinical) and overall survival (OS) were estimated with the Kaplan-Meier actuarial method. The median number of administered cap. courses was four. No radiological or biochemical responses were observed. Three patients were classified as having stable disease at three months. Two of these patients had, however, minor radiological progression and a =100% increase in CEA compared to base line. Seventeen patients were classified as having progressive disease during the first three months period. Median TTP and OS were 2.8 months and 6.1 months, respectively. A response rate of =15% for third line cap. in metastatic CRC can be ruled out. Median PFS was limited in the study population. This observation and the few cases with SD at three months, lead us to believe that little or no clinical benefit can be expected from single drug cap. in patients with irinotecan- and oxaliplatin-combination resistant advanced colorectal cancer.

Breast conservation rates-barriers between tertiary care and community practice.

PURPOSE: Low rates of breast conservation therapy (BCT) are reported in the southern United States. We evaluated the influence on BCT rates of opening a radiotherapy (RT) clinic at a community hospital in North Carolina. Before opening, RT was available 5 miles away at a tertiary care center. METHODS AND MATERIALS: A review of the pathology database of the community hospital identified patients who underwent definitive surgery for invasive breast malignancy or ductal carcinoma in situ between 1994 and 1995, and 1997 and 1998, before and after the opening of the RT clinic in 1996. From these data, the mode of therapy, mastectomy or BCT, was determined. The results were compared using logistic regression analysis. Surgical and RT physician staffing were unchanged throughout the study period. RESULTS: A total of 586 patients was evaluated. The BCT rate at the community hospital for 1994-1995 and 1997-1998 was 29% and 44%, respectively. On both univariate and multivariate logistic regression analysis, the era of treatment was statistically significant in its impact on the procedure performed (p <0.001). CONCLUSION: The use of BCT increased at a community hospital after the opening of an on-site RT facility, even though RT was available 5 miles away previously.

Myocardial perfusion changes in patients irradiated for left-sided breast cancer and correlation with coronary artery distribution.

PURPOSE: To evaluate postradiation regional heart perfusion changes with single photon emission tomography (SPECT) myocardial perfusion imaging in 69 patients treated with tangential photon beams radiation therapy (RT) for left-sided breast cancer. To correlate SPECT changes with percent irradiated left ventricle (LV) volume and risk factors for coronary artery disease (CAD). METHODS AND MATERIALS: Rest SPECT of the LV was acquired pre-RT and at 6-month intervals post-RT. The extent of defects (%) with a severity > 1.5 standard deviations below the mean was quantitatively analyzed for the distributions of the left anterior descending (LAD) artery, left circumflex (LCX) artery, and right coronary artery (RCA) based on computer assisted polar map reconstruction (i.e., bull's-eye-view). Changes in perfusion were correlated with percent irradiated LV receiving > 25 Gy (range 0-32%). Data on patient- and treatment-related factors were collected prospectively (e.g., cardiac premorbidity, risk factors for CAD, chemotherapy, and hormonal treatment). RESULTS: In the LAD distribution, there were increased perfusion defects at 6 months (median 11%; interquartile range 2-23) compared with baseline (median 5%; interquartile range 1-14) (p < 0.001). There were no increases in perfusion defects in the LCX or RCA distributions. In multivariate analysis, the SPECT perfusion changes in the LAD distribution at 6 months were independently associated with percent irradiated LV (p < 0.001), hormonal therapy (p = 0.005), and pre-RT hypercholesterolemia (p = 0.006). The SPECT defects in the LAD distribution at 12 and 18 months were not statistically different from those at 6 months. The perfusion defects in the LAD distribution were limited essentially to the regions of irradiated myocardium. CONCLUSION: Tangential photon beam RT in patients with left-sided breast cancer was associated with short-term SPECT defects in the vascular distribution corresponding to the radiation portals. Factors related to the extent of perfusion defects included the percent irradiated LV, hormonal treatment, and pre-RT hypercholesterolemia.