Preoperative intensity-modulated chemoradiotherapy with simultaneous integrated boost in rectal cancer: five-year follow-up results of a phase II study.

BACKGROUND: We conducted a phase II study to investigate the feasibility and safety of preoperative radiochemo-therapy experimental fractionation, using intensity-modulated radiation therapy with simultaneous integrated boost (IMRT SIB) to shorten the overall treatment time without dose escalation in intermediate/locally advanced rectal cancer with the aim to improving treatment outcome. PATIENTS AND METHODS: A total of 51 patients with operable stage II-III rectal carcinoma were included between January 2014 and January 2015. Fifty patients completed preoperative IMRT treatment with an elective dose of 41.8 Gy and simultaneously delivered 46.2 Gy to T2/T3 and 48.4 Gy to T4 tumour in 22 fractions, with concomitant capecitabine (825 mg/m2/12 h, including at weekends). Median follow-up was 70 months (range 11-80 m). RESULTS: Forty-seven patients completed treatment per protocol. Acute toxicity occurred in 2 (4%) patients. R0 resection was achieved in all but 1 and pathologic complete response (pCR) in 12 (25.5%) patients who had 5-year overall survival (OS), disease-free survival (DFS) and local control (LC) of 91.7%, 100% and 100%, respectively. The intention-to-treat analysis showed that the type of surgery significantly moderated OS and DFS, while total downstaging and pN were predictive for DFS only. For treatment per protocol 5-year OS, DFS and LC were 80.9% (95% confidence interval [CI] 69.7-92.1), 77.1% (95% CI 65.1-89.1) and 95.2% (95% CI 88.7-100), respectively. The proportion of patients with severe late (CTCAE G ≥ 3) gastrointestinal, urinary and sexual toxicity was 15%, 2% and 8% respectively, with one reported secondary carcinoma. CONCLUSIONS: Preoperative IMRT-SIB without dose escalation was well tolerated, with a low acute toxicity profile, we achieved a high rate of pCR and showed encouraging 5-year OS, DFS and LC.

Total neoadjuvant therapy vs standard therapy of locally advanced rectal cancer with high-risk factors for failure.

BACKGROUND: For locally advanced rectal cancer (LARC), standard therapy [consisting of neoadjuvant chemoradiotherapy (CRT), surgery, and adjuvant chemotherapy (ChT)] achieves excellent local control. Unfortunately, survival is still poor due to distant metastases, which remains the leading cause of death among these patients. In recent years, the concept of total neoadjuvant treatment (TNT) has been developed, whereby all systemic ChT-mainly affecting micrometastases-is applied prior to surgery. AIM: To compare standard therapy and total neoadjuvant therapy for LARC patients with high-risk factors for failure. METHODS: In a retrospective study, we compared LARC patients with high-risk factors for failure who were treated with standard therapy or with TNT. High-risk for failure was defined according to the presence of at least one of the following factors: T4 stage; N2 stage; positive mesorectal fascia; extramural vascular invasion; positive lateral lymph node. TNT consisted of 12 wk of induction ChT with capecitabine and oxaliplatin or folinic acid, fluorouracil and oxaliplatin, CRT with capecitabine, and 6-8 wk of consolidation ChT with capecitabine and oxaliplatin or folinic acid, fluorouracil and oxaliplatin prior to surgery. The primary endpoint was pathological complete response (pCR). In total, 72 patients treated with standard therapy and 89 patients treated with TNT were included in the analysis. RESULTS: Compared to standard therapy, TNT showed a higher proportion of pCR (23% vs 7%; P = 0.01), a lower neoadjuvant rectal score (median: 8.43 vs 14.98; P < 0.05), higher T-and N-downstaging (70% and 94% vs 51% and 86%), equivalent R0 resection (95% vs 93%), shorter time to stoma closure (mean: 20 vs 33 wk; P < 0.05), higher compliance during systemic ChT (completed all cycles 87% vs 76%; P < 0.05), lower proportion of acute toxicity grade ≥ 3 during ChT (3% vs 14%, P < 0.05), and equivalent acute toxicity and compliance during CRT and in the postoperative period. The pCR rate in patients treated with TNT was significantly higher in patients irradiated with intensity-modulated radiotherapy/volumetric-modulated arc radiotherapy than with 3D conformal radiotherapy (32% vs 9%; P < 0.05). CONCLUSION: Compared to standard therapy, TNT provides better outcome for LARC patients with high-risk factors for failure, in terms of pCR and neoadjuvant rectal score.

Laparoscopic insertion of pelvic tissue expander prior radiotherapy for sacral metastasis of alveolar maxillary rhabdomyosarcoma to prevent radiation enteritis.

INTRODUCTION: Rhabdomyosarcoma is the most common soft tissue sarcoma seen in childhood and adolescence. The most frequent sites are head and neck. PRESENTATION OF CASE: A young female with maxillary rhabdomyosarcoma involving region of maxillary sinus with skeletal metastases was primary treated acccording to RMS 2005 protocol. She received 9 cycles of chemotherapy. Primary tumor of maxillary sinus was surgicaly removed after 4 cycles of chemotherapy, with 6th cycle of chemotherapy a radical radiotherapy of primary tumor location and metastasis in spinal vertebras, ribs, pelvic bone and left femoral bone started what leads to complete regression of skeletal metastases. In course of maintenance therapy MRI scan showed 12 × 28 × 23 mm lesion in sacrum in the vicinity of right sacroiliacal joint with caracteristics of metastasis. Because the region of right sacroiliacal joint with bowel was already included in primary radiation treatment, tissue expander was laparoscopicaly inserted in lower pelvis to displace bowel loops from radiation field to prevent radiation enteritis. After external beam radiotherapy to her sacrum, a good response without any side effects was achieved. DISCUSSION: Laparoscopic insertion of pelvic tissue expander prior EBRT and it's subsequent removal after EBRT is safe and effective method for displacing loops of bowel out of the pelvis. With minimal morbidity converts untreatable disease to treatable by allowing delivering high doses of radiation to the patient. CONCLUSION: After 2 years of follow up the disease is in remission and the patient without any major complaint.

Influence of concurrent capecitabine based chemoradiotherapy with bevacizumab on the survival rate, late toxicity and health-related quality of life in locally advanced rectal cancer: a prospective phase II CRAB trial.

Background Few studies reported early results on efficacy, toxicity of combined modality treatment for locally advanced rectal cancer (LARC) by adding bevacizumab to preoperative chemoradiotherapy, but long-term data on survival, and late complications are lacking. Further, none of the studies reported on the assessment of quality of life (QOL). Patients and methods After more than 5 years of follow-up, we updated the results of our previous phase II trial in 61 patients with LARC treated with neoadjuvant capecitabine, radiotherapy and bevacizumab (CRAB study) before surgery and adjuvant chemotherapy. Secondary endpoints of updated analysis were local control (LC), disease free (DFS) and overall survival (OS), late toxicity and longitudinal health related QOL (before starting the treatment and one year after the treatment) with questionnaire EORTC QLQ-C30 and EORTC QLQ-CR38. Results Median follow-up was 67 months. During the follow-up period, 16 patients (26.7%) died. The 5-year OS, DFS and LC rate were 72.2%, 70% and 92.4%. Patients with pathological positive nodes or pathological T3-4 tumors had significantly worse survival than patients with pathological negative nodes or T0-2 tumors. Nine patients (14.8%) developed grade 33 late complications of combined modality treatment, first event 12 months and last 87 months after operation (median time 48 months). Based on EORTC QLQ-C30 scores one year after treatment there were no significant changes in global QOL and three symptoms (pain, insomnia and diarrhea), but physical and social functioning significantly decreased. Based on QLQ-CR38 scores body image scores significantly increase, problems with weight loss significantly decrease, but sexual dysfunction in men and chemotherapy side effects significantly increase. Conclusions Patients with LARC and high risk factors, such as positive pathological lymph nodes and high pathological T stage, deserve more aggressive treatment in the light of improving long-term survival results. Patients after multimodality treatment should be given greater attention to the regulation of individual aspects of quality of life and the occurrence of late side effects.

Definitive radiochemotherapy in esophageal cancer - a single institution experience.

Background Definitive radiochemotherapy is the preferred treatment option in patients with the cancer of the cervical esophagus and a viable treatment option in patients with the cancer of lower two thirds of the esophagus, who decline proposed surgical treatment. The purpose of the study was to evaluate the treatment results with definitive radiochemotherapy of patients with esophageal cancer, treated in a single institution in the period from 2010 to 2017. Patients and methods All available medical data for 55 patients with esophageal cancer, who were treated with definitive radiochemotherapy with curative intent, were analyzed retrospectively. Patients were irradiated to a total dose to the tumor of 70 Gy (2 Gy per fraction) in upper third (cervical) tumors or to the mean total dose of 57.6 Gy (1.8 Gy per fraction) in middle third (intrathoracic) tumors. All but one patient received concomitant chemotherapy, with the majority of them (41 patients; 74.5%) receiving concomitant chemotherapy with 5-fluorouracil in continuous 96 hours infusion and cisplatin. The main endpoints of the study were overall survival (OS; death of any cause), locoregional control (LRC; local and/or regional disease recurrence) and disease-free survival (DFS; recurrence of any kind and/or new primary malignoma). Univariate analysis testing the impact of different parameters on survivals and analysis of treatment related side effects were performed as well. Results The mean age of patients was 62 years (SD 9 years; range: 29-80 years). Majority of them had squamous cell cancer (53 patients; 96.4%) in the stage T3 or T4 (47 patients; 85.5%) and/or N+ disease (35 patients; 63.6%). Median follow-up time for the whole group of patients was 16.8 months (range: 0.3-81.8 months). At the time of analysis 14 (25.5%) patients were still alive. Rates for OS, LRC and DFS at two and five years were as follows: 47% and 19.4%; 43.7% and 41%; 32.1% and 11.5%, respectively. Conclusions The study results of treatment with definitive radiochemotherapy in patients with esophageal cancer are similar to the results of other studies. Majority of patients ended the treatment according to the protocol, which at least in part can be attributed to the adequate and well organized supportive treatment in our institution.

Total neoadjuvant treatment of locally advanced rectal cancer with high risk factors in Slovenia.

Background In the light of a high rate of distant recurrence and poor compliance of adjuvant chemotherapy in high risk rectal cancer patients the total neoadjuvant treatment was logical approach to gaining acceptance. We aimed to evaluate toxicity and efficiency of this treatment in patients with rectal cancer and high risk factors for local or distant recurrence. Patients and methods Patients with rectal cancer stage II and III and with at least one high risk factor: T4, presence of extramural vein invasion (EMVI), positive extramesorectal lymph nodes or mesorectal fascia (MRF) involvement were treated with four cycles of induction CAPOX/FOLFOX, followed by capecitabine-based radiochemotherapy (CRT) and two consolidation cycles of CAPOX/FOLFOX before the operation. Surgery was scheduled 8-10 weeks after completition of CRT. Results From November 2016 to July 2018 66 patients were evaluable. All patients had stage III disease, 24 (36.4%) had T4 tumors, in 46 (69.7%) EMVI was present and in 47 (71.2%) MRF was involved. After induction chemotherapy, which was completed by 61 (92.4%) of patients, radiologic downstaging of T, N, stage, absence of EMVI or MRF involvement was observed in 42.4%, 62.1%, 36.4%, 69.7% and 68.2%, respectively. All patients completed radiation and 54 (81.8%) patients received both cycles of consolidation chemotherapy. Grade 3 adverse events of neoadjuvant treatment was observed in 4 (6%) patients. Five patients rejected surgery, 3 of them with radiologic complete clinical remissions. One patient did not have definitive surgery of primary tumor due to unexpected cardiac arrest few days after sigmoid colostomy formation. Among 60 operated patients pathological complete response rate was 23.3%, the rate of near complete response was 20% and in 96.7% radical resection was achieved. Pathological T, N and stage downstaging was 65%, 96.7% and 83.4%, respectively. Grade ≥ 3 perioperative complications were anastomotic leakage in 3, pelvic abscess in 1 and paralytic ileus in 2 patients. The rate of pathologic complete response (pCR) in patients irradiated with 3D conformal technique was 12.1% while with IMRT and VMAT it was 37% (p < 0.05). Hypofractionation with larger dose per fraction and simultaneous integrated boost used in the latest two was the only factor associated with pCR. ConclusionsTotal neoadjuvant treatment of high risk rectal cancer is well tolerated and highly effective with excellent tumor and node regression rate and with low toxicity rate. Longer follow up will show if this strategy will improve distant disease control and survival.

Impact of perioperative treatment on survival of resectable gastric cancer patients after D2 lymphadenectomy: a single European centre propensity score matching analysis.

Background To determine the effects of perioperative treatment of gastric cancer patients, we conducted an analysis with propensity score matched patient groups to determine the role of perioperative chemotherapy in patients after D2 lymphadenectomy. Patients and methods From our database of 1563 patients, 482 patients were selected with propensity score matching and divided into two balanced groups: 241 patients in the surgery only group and 241 patients in the perioperative group. The long-term results of treatment were compared between the two groups. Results Most of the included patients received radio-chemotherapy with capecitabine (n = 111; 46%) and perioperative chemotherapy with epirubicin, oxalliplatin and capecitabine (n = 91; 37.7%). 92.9% of the patients received a D2 lymph node dissection. Perioperative morbidity was similar between surgery only (18.3%) and perioperative treatment groups (20.7%) (p = 0.537). The perioperative mortality was not influenced by perioperative treatment. A pathological response was observed in 12.5% of patients. The overall 5-year and median survivals were significantly higher in the perioperative treatment group (50.5%; 51.7 moths) compared to surgery only group (41.8%; 34.9 months; p = 0.038). The subgroup analysis revealed that only patients with the TNM stages T3 (p = 0.028), N2 (p = 0.009), N3b (p = 0.043), and UICC stages IIIb (p = 0.003) and IIIc (p = 0.03) significantly benefit from perioperative treatment. Conclusions Perioperative treatment in radically resected gastric cancer patients after D2 lymphadenectomy was beneficial in stages IIIb and IIIc. The effects of perioperative treatment in lower stages could be negated by the effects of the radical surgery in lower stages and in higher stages by the biology of the disease.

Induction chemotherapy, chemoradiotherapy and consolidation chemotherapy in preoperative treatment of rectal cancer - long-term results of phase II OIGIT-01 Trial.

Background The purpose of the study was to improve treatment efficacy for locally advanced rectal cancer (LARC) by shifting half of adjuvant chemotherapy preoperatively to one induction and two consolidation cycles. Patients and methods Between October 2011 and April 2013, 66 patients with LARC were treated with one induction chemotherapy cycle followed by chemoradiotherapy (CRT), two consolidation cycles, surgery and three adjuvant capecitabine cycles. Radiation doses were 50.4 Gy for T2-3 and 54 Gy for T4 tumours in 1.8 Gy daily fraction. The doses of concomitant and neo/adjuvant capecitabine were 825 mg/m2/12h and 1250mg/m2/12h, respectively. The primary endpoint was pathologic complete response (pCR). Results Forty-three (65.1%) patients were treated according to protocol. The compliance rates for induction, consolidation, and adjuvant chemotherapy were 98.5%, 93.8% and 87.3%, respectively. CRT was completed by 65/66 patients, with G ≥ 3 non-hematologic toxicity at 13.6%. The rate of pCR (17.5%) was not increased, but N and the total-down staging rates were 77.7% and 79.3%, respectively. In a median follow-up of 55 months, we recorded one local relapse (LR) (1.6%). The 5-year disease-free survival (DFS) and overall survival (OS) rates were 64.0% (95% CI 63.89-64.11) and 69.5% (95% CI 69.39-69.61), respectively. Conclusions In LARC preoperative treatment intensification with capecitabine before and after radiotherapy is well tolerated, with a high compliance rate and acceptable toxicity. Though it does not improve the local effect, it achieves a high LR rate, DFS, and OS.

Preoperative Intensity-modulated Chemoradiation Therapy with Simultaneous Integrated Boost in Rectal Cancer: 2-year Follow-up Results of Phase II Study.

BACKGROUND: The aim of the study was to investigate the feasibility and safety of experimental fractionation using intensity modulated radiation therapy with a simultaneous integrated boost (IMRT-SIB) to shorten the overall treatment time without dose escalation in preoperative radiochemotherapy of locally advanced rectal cancer. PATIENTS AND METHODS: Between January 2014 and November 2015, a total of 51 patients with operable stage II-III rectal adenocarcinoma were treated. The preoperative treatment with intensity modulated radiation therapy (IMRT) and a pelvic dose of 41.8 Gy and simultaneously delivered 46.2 Gy to T2/3 and 48.4 Gy to T4 tumour in 22 fractions, with standard concomitant capecitabine, was completed in 50 patients out of whom 47 were operated. The median follow-up was 35 months. RESULTS: The rate of acute toxicity G ≥ 3 was 2.4%. The total downstaging rate was 89% and radical resection was achieved in 98% of patients. Pathologic complete response (pCR) was observed in 25.5% of patients, with 2-year local control (LC), disease free survival (DFS), and overall survival (OS) of 100% for this patient group. An intention-to-treat analysis revealed pN to be a significant prognostic factor for DFS and OS (P = 0.005 and 0.030, respectively). LC for the entire group was 100%, and 2-year DFS and OS were 90% (95 % CI 98.4-81.6) and 92.2% (95% CI 99.6-84.7), respectively. CONCLUSIONS: The experimental regime in this study resulted in a high rate of pCR with a low acute toxicity profile. Excellent early results translated into encouraging 2-year LC, DFS, and OS.

Health-related Quality of Life Assessed by the EORTC QLQ-C30 Questionnaire in the General Slovenian Population.

BACKGROUND: The aim of our study was to obtain reference data of the EORTC QLQ-C30 quality of life dimensions for the general Slovenian population. We intend to provide the researchers and clinicians in our country with the expected mean health-related quality of life (HRQL) scores for distinctive socio-demographic population groups. METHODS: The EORTC QLQ-C30 questionnaire supplemented by a socio-demographic inquiry was mailed or distributed to 1,685 randomly selected individuals in the Slovenian population aged 18 - 90. Answers from 1,231 subjects representing socio-demographic diversity of the Slovenian population were collected and transformed into EORTC dimensions and symptoms. The impact of socio-demographic features on HRQL scores was assessed by multiple linear regression models. RESULTS: Gender, age and self-rated social class are the important confounders in the quality of life scores in our population. Men reported better quality of life on the majority of the specific scales and, at the same time, reported fewer symptoms. There was no gender-specific difference in cognitive functioning. The mean scores were consistently lower with age in both sexes. CONCLUSIONS: This is the first study to report the normative EORTC QLQ-C30 scores for one of the south-eastern European populations. The reported expected mean scores allow Slovenian oncologists to estimate what the quality of life in cancer patients would be, had they not been ill. As they are derived by common methodology, our results can easily be included in any further international comparisons or in the calculation of European summarized HRQL scores.

The Influence of the Distal Resection Margin Length on Local Recurrence and long- term Survival in Patients with Rectal Cancer after Chemoradiotherapy and Sphincter- Preserving Rectal Resection.

BACKGROUND: Low recurrence rates and long term survival are the main therapeutic goals of rectal cancer surgery. Complete, margin- negative resection confers the greatest chance for a cure. The aim of our study was to determine whether the length of the distal resection margin was associated with local recurrence rate and long- term survival. PATIENTS AND METHODS: One hundred and nine patients, who underwent sphincter-preserving resection for locally advanced rectal cancer after preoperative chemoradiotherapy between 2006 and 2010 in two tertiary referral centres were included in the study. Distal resection margin lengths were measured on formalin-fixed, pinned specimens. Characteristics of patients with distal resection margin < 8 mm (Group I, n = 27), 8-20 mm (Group II, n = 31) and > 20 mm (Group III, n = 51) were retrospectively analysed and compared. Median (range) follow-up time in Group I was 89 (51-111), in Group II 83 (57-111) and in Group III 80 (45-116) months (p = 0.326), respectively. RESULTS: Univariate survival analysis showed that distal resection margin length was not statistically significantly associated with overall survival or local recurrence rate (p > 0.05). In a multiple Cox regression analysis, after adjusting for pathologic T and N stage (yT, yN), distal resection margin length was still not statistically significantly associated with overall survival. CONCLUSIONS: Our study shows that close distal resection margins can be accepted as oncologically safe for sphincter-preserving rectal resections after preoperative chemoradiotherapy.

Acute Toxicity and Tumor Response in Locally Advanced Rectal Cancer After Preoperative Chemoradiation Therapy With Shortening of the Overall Treatment Time Using Intensity-Modulated Radiation Therapy With Simultaneous Integrated Boost: A Phase 2 Trial.

BACKGROUND AND PURPOSE: This phase 2 study investigated the efficacy and safety of preoperative intensity modulated radiation therapy with a simultaneous integrated boost (IMRT-SIB) without dose escalation, concomitant with standard capecitabine chemotherapy in locally advanced rectal cancer. METHODS AND MATERIALS: Between January 2014 and March 2015, 51 patients with operable stage II-III rectal adenocarcinoma received preoperative IMRT with pelvic dose of 41.8 Gy and simultaneously delivered 46.2 Gy to T2/3 and 48.4 Gy to T4 tumor in 22 fractions, concomitant with capecitabine, 825 mg/m2/12 hours, including weekends. The primary endpoint was pathologic complete response (pCR). RESULTS: Fifty patients completed preoperative treatment according to the protocol, and 47 underwent surgical resection. The sphincter preservation rate for the low rectal tumors was 62%, and the resection margins were free in all but 1 patient. Decrease in tumor and nodal stage was observed in 32 (68%) and 39 (83%) patients, respectively, with pCR achieved in 12 (25.5%) patients. There were only 2 G ≥ 3 acute toxicities, with infectious enterocolitis in 1 patient and dermatitis over the sacral area caused by the bolus effect of the treatment table in the second patient. CONCLUSIONS: Preoperative IMRT-SIB without dose escalation is well tolerated, with a low acute toxicity profile, and can achieve a high rate of pCR and downstaging.

The impact of anaemia on treatment outcome in patients with squamous cell carcinoma of anal canal and anal margin.

BACKGROUND: Radiochemotherapy is the main treatment for patients with squamous cell carcinoma of the anal canal. Anaemia is reported to have adverse effect on survival in cancer patients. The aim of the study was to evaluate the influence of anaemia on radiochemotherapy treatment outcome in patients with squamous cell carcinoma of the anal canal. PATIENTS AND METHODS: One hundred consecutive patients with histologically confirmed squamous cell carcinoma of the anal canal were treated radically with 3-dimensional conformal or intensity-modulated radiation therapy followed by brachytherapy or external beam radiotherapy boost and with concurrent mitomycin C and 5-fluorouracil. The influence on survival of pre-treatment, mean on-treatment and end-of-treatment haemoglobin (Hb) concentrations was studied. RESULTS: The 5-year locoregional control, disease free survival, disease specific survival and overall survival rates for all patients were 72%, 71%, 77% and 62%, respectively. In univariate analysis, patients with pre-treatment and end-of-treatment Hb > 120 g/L survived statistically significantly better compared to patients with Hb ≤ 120 g/L. Patients with mean on-treatment Hb > 120 g/L only had statistically significant better locoregional control and overall survival than patients with Hb ≤ 120 g/L. In multivariate analysis, independent prognostic factors were pre-treatment Hb (> 120 g/L vs. ≤ 120 g/L) for overall survival (hazard ratio [HR] = 0.419, 95% confidence interval [CI] = 0.190-0.927, p = 0.032) and stage (I & II vs. III) for disease specific (HR = 3.523, 95% CI = 1.375-9.026, p = 0.009) and overall survival (HR = 2.230, 95% CI = 1.167-4.264, p = 0.015). CONCLUSIONS: The pre-treatment, mean on-treatment and end-of-treatment Hb concentration > 120 g/L carried better prognosis for patients for with squamous cell carcinoma of the anal canal treated with radiochemotherapy. The pre-treatment Hb > 120 g/L was an independent prognostic factor for overall survival of patients with anal canal cancer.

Preoperative treatment with radiochemotherapy for locally advanced gastroesophageal junction cancer and unresectable locally advanced gastric cancer.

BACKGROUND: To purpose of the study was to analyze the results of preoperative radiochemotherapy in patients with unresectable gastric or locoregionally advanced gastroesophageal junction (GEJ) cancer treated at a single institution. PATIENTS AND METHODS: Between 1/2004 and 6/2012, 90 patients with locoregionally advanced GEJ or unresectable gastric cancer were treated with preoperative radiochemotherapy at the Institute of Oncology Ljubljana. Planned treatment schedule consisted of induction chemotherapy with 5-fluorouracil and cisplatin, followed by concomitant radiochemotherapy four weeks later. Three-dimensional conformal external beam radiotherapy was delivered by dual energy (6 and 15 MV) linear accelerator in 25 daily fractions of 1.8 Gy in 5 weeks with two additional cycles of chemotherapy repeated every 28 days. Surgery was performed 4-6 weeks after completing radiochemotherapy. Following the surgery, multidisciplinary advisory team reassessed patients for the need of adjuvant chemotherapy. The primary endpoints were histopathological R0 resection rate and pathological response rate. The secondary endpoints were toxicity of preoperative radiochemotherapy and survival. RESULTS: Treatment with preoperative radiochemotherapy was completed according to the protocol in 84 of 90 patients (93.3%). Twenty patients (22.2%) did not undergo the surgery because of the disease progression, serious comorbidity, poor performance status or still unresectable tumour. In 13 patients (14.4%) only exploration was performed because the tumour was assessed as unresectable or diffuse peritoneal carcinomatosis was established. Fifty-seven patients (63.4%) underwent surgery with the aim of complete removal of the tumour. Radical resection was achieved in 50 (55.6%) patients and the remaining seven (7.8%) patients underwent non-radical surgery (R1 in five and R2 in two patients). In this group of patients (n = 57), pathological complete response of tumour was achieved in five patients (5.6% of all treated patients or 8.8% of all operated patients). Down-staging was recorded in 49 patients (86%), in one patient (1.8%) the stage after radiochemotherapy was unchanged while in seven patients (12.3%) the pathological stage was higher than clinical, mainly due to higher pN stage. No death was recorded during preoperative radiochemotherapy. Most grade 3 and 4 toxicities were due to vomiting, nausea and bone marrow suppression (granulocytopenia). Twenty-six (45.6%) patients died due to GEJ or gastric carcinoma, one died because of septic shock following the surgery and a reason for two deaths was unknown. Twenty-eight patients (49.1%) were disease free at the time of analysis, while 29 patients (50.9%) developed the recurrence, mostly as distant metastases. At two years, locoregional control, disease-free survival, disease-specific survival and overall survival were 82.9%, 43.9%, 56.9% and 53.9%, respectively. CONCLUSIONS: Preoperative radiochemotherapy was feasible in our group of patients and had acceptable toxicity. Majority of patients achieved down-staging, allowing greater proportion of radical resections (R0), which are essential for patients' cure.

Mesenteric ischemia after capecitabine treatment in rectal cancer and resultant short bowel syndrome is not an absolute contraindication for radical oncological treatment.

BACKGROUND: Thrombotic events, arterial or venous in origin, still remain a source of substantial morbidity and mortality in cancer patients. The propensity for their development in oncology patients is partially a consequence of the disease itself and partially a result of our attempts to treat it. One of the rarest and deadliest thromboembolic complications is arterial mesenteric ischemia. The high mortality rate is caused by its rarity and by its non-specific clinical presentation, both of which make early diagnosis and treatment difficult. Hence, most diagnoses and treatments occur late in the course of the disease. The issue survivors of arterial mesenteric ischemia may face is short bowel syndrome, which has become a chronic condition after the introduction of parenteral nutrition at home. CASE REPORT: We present a 73-year-old rectal cancer patient who developed acute arterial mesenteric thrombosis at the beginning of the pre-operative radiochemotherapy. Almost the entire length of his small intestine, except for the proximal 50 cm of it, and the ascending colon had to be resected. After multiorgan failure his condition improved, and he was able to successfully complete radical treatment (preoperative radiotherapy and surgery) for the rectal carcinoma, despite developing short bowel syndrome (SBS) and being dependent upon home-based parenteral nutrition to fully cover his nutritional needs. CONCLUSIONS: Mesenteric ischemia and resultant short bowel syndrome are not absolute contraindications for radical oncological treatment since such patients can still achieve long-term remission.

Capecitabine in adjuvant radiochemotherapy for gastric adenocarcinoma.

BACKGROUND: In patients with non-metastatic gastric cancer surgery still remains the treatment of choice. Postoperative radiochemotherapy with 5-fluorouracil and leucovorin significantly improves the treatment outcome. The oral fluoropyrimidines, such as capecitabine, mimic continuous 5-fluorouracil infusion, are at least as effective as 5-fluorouracil, and such treatment is more comfortable for the patients. PATIENTS AND METHODS: In the period from October 2006 to December 2009, 101 patients with gastric cancer in stages Ib-IIIc were treated with postoperative chemoradiation with capecitabine. Distal subtotal resection of the stomach was performed in 46.3%, total resection in 50.5% and multivisceral resection in 3.2% of patients. The main endpoints of this study were loco-regional control (LRC), disease-free survival (DFS), disease-specific survival (DSS) and overall survival (OS). The rates of acute side-effects were also estimated. RESULTS: Seventy-seven percent of patients completed the treatment according to the protocol. The median follow-up time of all patients was 3.9 years (range: 0.4-6.3 years) and in survivors it was 4.7 years (range: 3.2-6.3 years). No death occurred due to the therapy. Acute toxicity, such as nausea and vomiting, stomatitis, diarrhoea, hand-foot syndrome and infections of grade 3 or 4, occurred in 5%, 1%, 2%, 8.9% and 18.8% of patients, respectively. On the close-out date 63.4% patients were still alive and with no signs of the disease. The 4-years follow-up survey showed that LRC, DFS, DSS and OS were 95.5%, 69.2%, 70.7%, and 66.2%, respectively. Higher pN-stage and splenectomy were found to be independent prognostic factors for all four types of survival and perineural invasion and lower treatment intensity for DFS, DSS and OS. CONCLUSIONS: Postoperative radiochemotherapy with capecitabine is feasible, with low toxicity and the results of such treatment are good.

The correlation between the levels of tissue inhibitor of metalloproteinases 1 in plasma and tumour response and survival after preoperative radiochemotherapy in patients with rectal cancer.

BACKGROUND: The aim of this study was to analyse whether the level of tissue inhibitor of metalloproteinases (TIMP) 1 is associated with the tumour response and survival to preoperative radiochemotherapy in rectal cancer patients. PATIENTS AND METHODS: Ninety-two patients with histologically confirmed non-metastatic rectal cancer of clinical stage I- III were treated with preoperative radiochemotherapy, surgery and postoperative chemotherapy. Plasma TIMP-1 concentrations were measured prior to the start of the treatment with an enzyme-linked immunosorbent assay (ELISA). RESULTS: Median follow-up time was 68 months (range: 3-93 months) while in survivors it was 80 months (range: 68-93 months). The 5-year locoregional control (LRC), disease-free survival (DFS), disease-specific survival (DSS) and overall survival (OS) rates for all patients were 80.2%, 56.4%, 63.7% and 52.2%, respectively. The median TIMP-1 level was 185 ng/mL (range: 22-523 ng/mL) and the mean level (±standard deviation) was 192 (±87) ng/mL. Serum TIMP-1 levels were found to be significantly increased in patients with preoperative CRP>12 mg/L and in those who died from rectal cancer or had cT4 tumours. No correlation was established for age, gender, carcinoembriogenic antigene (CEA) level, platelets count, histopathological grade, response to preoperative therapy, resectability and disease reappearance. On univariate analysis, various parameters favourably influenced one or more survival endpoints: TIMP-1 <170 ng/mL, CRP <12 mg/L, platelets count <290 10E9/L, CEA <3.4mg/L, age <69 years, male gender, early stage disease (cN0 and/or cT2-3), radical surgery (R0) and response to preoperative radiochemotherapy. In multivariate model, LRC was favourably influenced by N-downstage, DFS by lower CRP and N-downstage, DSS by lower CRP and N-downstage and OS by lower TIMP-1 level, lower CRP and N-downstage. CONCLUSIONS: Although we did not find any association between pretreatment serum TIMP-1 levels and primary tumour response to preoperative radiochemotherapy in our cohort of patients with rectal cancer, TIMP-1 levels were recognized as an independent prognostic factor for OS in these patients.

Long term outcome after combined modality treatment for anal cancer.

BACKGROUND: The aim of the retrospective study was to evaluate the effectiveness and toxicity of radiochemotherapy in patients with squamous cell carcinoma of the anal canal treated at a single institution. PATIENTS AND METHODS: Between 1/2003 and 9/2010, 84 patients were treated with radical radiochemotherapy at the Institute of Oncology Ljubljana, Slovenia. The treatment consisted of 3-dimensional conformal external beam radiotherapy with concurrent chemotherapy (5-fluorouracil and mytomycin C), followed by brachytherapy or external beam boost. The toxicity of therapy and its effectiveness were assessed. RESULTS: The treatment was completed according to the protocol in 79.8% of patients. The median follow-up time of 55 survivors was 53 months (range: 16-105 months). The 5-year locoregional control (LRC), disease-free survival (DFS), disease-specific survival (DSS), overall survival (OS) and colostomy-free survival (CFS) rates were 71%, 68%, 81%, 67% and 85%, respectively. No treatment-related mortality was observed. The most frequent acute side-effect of the treatment was radiodermatitis (grade 3-4 in 58.2% of patients). LENT-SOMA grade 3-4 late radiation side effects were observed in 15 (18%) patients. In patients with brachytherapy boost a trend of less late side effects was observed compared to patients with external beam boost (P=0.066). On multivariate analysis, complete clinical disease response was identified as an independent prognostic factor for LRC, DFS and DSS, the salvage surgery for LRC and DFS, whereas Hb below 120 g/l retained its independent prognostic value for OS. CONCLUSIONS: Radiochemotherapy provides an excellent disease control and the survival with preserving anal sphincter function in majority of patients. Surgical salvage with abdominoperineal resection for persistent or recurrent disease has curative potential.

Cetuximab in preoperative treatment of rectal cancer - term outcome of the XERT trial.

BACKGROUND: Preoperative capecitabine-based chemoradiotherapy (CRT) is feasible for the treatment of resectable locally advanced rectal cancer (LARC). To try to improve efficacy, we conducted a phase II study in which the epidermal growth factor receptor-targeting monoclonal antibody cetuximab was added to capecitabine-based CRT. The results for long-term survival and for an analysis investigating the relationship between survival and patient and disease characteristics, including tumour KRAS mutation status, and surgery type, are presented. PATIENTS AND METHODS.: Patients with resectable LARC received capecitabine (1250 mg/m(2) twice daily, orally) for 2 weeks followed by cetuximab alone (400 mg/m(2) for 1 week) and then with CRT (250 mg/m(2)/week) comprising capecitabine (825 mg/m(2) twice daily) and radiotherapy to the small pelvis (45 Gy in 25 1.8-Gy fractions), five days a week for five weeks. Surgery was conducted six weeks following CRT, with post-operative chemotherapy with capecitabine (1250 mg/m(2) twice daily for 14 days every 21 days) three weeks later. RESULTS: Forty-seven patients were enrolled and 37 underwent treatment. Twenty-eight of the patients (75.7%) had T3N+ disease. Thirty-six patients were evaluable for efficacy. The median follow-up time was 39.0 months (range 5.0--87.0). The three-year local control, disease-free survival, relapse-free survival and overall survival rates were 96.9% (95% CI 90.0--100), 72.2% (57.5--86.9), 74.3% (95% CI 59.8--88.8) and 68.1% (95% CI 36.7--99.4), respectively. There was no significant association between survival and gender, age, tumour location in the rectum, type of surgery, pathological T or N status, tumour regression grade or tumour KRAS mutation status, although sample sizes were small. CONCLUSIONS: Preoperative cetuximab plus capecitabine-based CRT was feasible in patients with resectable LARC and was associated with an impressive three-year local control rate. The use of tumour KRAS mutation status as a biomarker for the efficacy of cetuximab-based regimens in this setting requires further investigation.

Results of postoperative radiochemotherapy of the patients with resectable gastroesophageal junction adenocarcinoma in Slovenia.

BACKGROUND.: Although the incidence of adenocarcinomas of the gastroesophageal junction (GEJ) is sharply rising in the Western world, there are still some disagreements about the staging and the treatment of this disease. The aim of this retrospective study was to analyse the effectiveness and safety of postoperative radiochemotherapy in patients with a GEJ adenocarcinoma treated at the Institute of Oncology Ljubljana. PATIENTS AND METHODS.: Seventy patients with GEJ adenocarcinoma, who were treated with postoperative radiochemotherapy between January 2005 and June 2010, were included in the study. The treatment consisted of 6 cycles of chemotherapy with 5-FU and cisplatin and concomitant radiotherapy with the total dose of 45 Gy. RESULTS.: Twenty-six patients (37.1%) completed the treatment according to the protocol. The median follow-up time was 17.7 months (range: 3.3-64 months). Acute toxicity grade 3 or more, such as stomatitis, dysphagia, nausea or vomiting, and infection, occurred in 2.9%, 34.3%, 38.6% and 41.5% of patients, respectively. At 3 years locoregional control (LRC), disease-free survival (DFS), disease-specific survival (DSS) and overall survival (OS) were 78.2%, 25.3%, 35.8%, and 33.9%, respectively. In the multivariate analysis of survival, splenectomy and level of Ca 19-9 >20 kU/L before the adjuvant treatment were identified as independent prognostic factors for lower DFS, DSS and OS. Age <60 years, higher number of involved lymph nodes and advanced disease stage were identified as independent prognostic factors for lower DSS and OS. CONCLUSIONS.: In patients with GEJ adenocarcinoma who first underwent surgery, postoperative radiochemotherapy is feasible, but we must be aware of a high risk of acute toxic side effects.