Impact of the COVID-19 epidemic on cancer burden and cancer care in Slovenia: a follow-up study.

BACKGROUND: In Slovenia, cancer care services were exempt from government decrees for COVID-19 containment. Nevertheless, cancer control can be impacted also by access to other health services and changes in health-seeking behaviour. In this follow up study, we explored changes in cancer burden and cancer care beyond the first months after the onset of the COVID-19 epidemic. MATERIALS AND METHODS: We analysed routinely collected data for the period January 2019 through July 2022 from three sources: (1) pathohistological and clinical practice cancer notifications from two major cancer centres in Ljubljana and Maribor (source: Slovenian Cancer Registry); (2) referrals issued for oncological services (source: e-referral system); and (3) outpatient appointments and diagnostic imaging performed (source: administrative data of the Institute of Oncology Ljubljana - IOL). Additionally, changes in certain clinical and demographic characteristics in patients diagnosed and treated during the epidemic were analysed using the Hospital-Based Cancer Registry of the IOL (period 2015-2021). RESULTS: After a drop in referrals to follow-up cancer appointments in April 2020, in June-August 2020, there was an increase in referrals, but it did not make-up for the drop in the first wave; the numbers in 2021 and 2022 were even lower than 2020. Referrals to first cancer care appointments and genetic testing and counselling increased in 2021 compared to 2019 and in 2022 increased further by more than a quarter. First and follow-up outpatient appointments and cancer diagnostic imaging at the IOL dropped after the onset of the epidemic in March 2020 but were as high as expected according to 2019 baseline already in 2021. Some deficits remain for follow-up outpatients' appointments in surgical and radiotherapy departments. There were more CT, MRI and PET scans performed during the COVID-19 period than before. New cancer diagnoses dropped in all observed years 2020, 2021 and until July 2022 by 6%, 3% and 8%, respectively, varying substantially by cancer type. The largest drop was seen in the 50-64 age group (almost 14% in 2020 and 16% in 2021), while for patients older than 80 years, the numbers were above expected according to the 2015-2019 average (4% in 2020, 8% in 2021). CONCLUSIONS: Our results show a varying effect of COVID-19 epidemic in Slovenia for different types of cancers and at different stages on the patient care pathway - it is probably a mixture of changes in health-seeking behaviour and systemic changes due to modifications in healthcare organisation on account of COVID-19. A general drop in new cancer cases reflects disruptions in the pre-diagnostic phase and could have profound long-term consequences on cancer burden indicators.

Telemedicine in Radiation Oncology Post-COVID-19 Pandemic: There Is No Turning Back.

PURPOSE: We aimed to assess patients' and physicians' perspectives on wider implementation of telemedicine in radiation oncology practice, disrupted by the novel coronavirus disease 2019 (COVID-19). METHODS: Quantitative questionnaires were prepared and distributed between May 27 and June 11, 2020. A 29-question survey targeting patients with cancer was distributed electronically via cancer support organizations. Cross-sectional data from a selected weekday at a radiation oncology department were also analyzed. In addition, a 25-question survey was distributed to 168 physicians employed by a comprehensive cancer center. RESULTS: In total, we have analyzed 468 patients' and 101 physicians' responses. Among responding patients, 310 were undergoing active treatment and 158 were in follow-up care. Both patients and physicians reported no experiences with video consultations during the COVID-19 pandemic, but 15% of patients stated that they missed telemedicine services that would include a video call. Overall, 30.6% of patients expressed interest in more frequent usage of telemedicine and 23.3% would start using it. Sixty-seven percent of radiation oncologists expressed interest in more frequent usage of telemedicine, and 14% would use it similarly as in the past. For patients treated with radiation therapy (RT), 59.9% and 63.4% of the responding patients acknowledged that video consultations would be an important addition to medical care during RT course or after the completion of RT, respectively. Comparably, 61.1% and 63.9% of radiation oncologists believed video consultations would be useful or extremely useful for patients undergoing RT or for patients in the follow-up setting, respectively. CONCLUSIONS: The post-COVID-19 era represents a unique chance to improve and guarantee continuity of cancer care via telemedicine solutions, when appropriate.

Breast size and dose to cardiac substructures in adjuvant three-dimensional conformal radiotherapy compared to tangential intensity modulated radiotherapy.

Background The aim of the study was to quantify planned doses to the heart and specific cardiac substructures in free-breathing adjuvant three-dimensional radiation therapy (3D-CRT) and tangential intensity modulated radiotherapy (t-IMRT) for left-sided node-negative breast cancer, and to assess the differences in planned doses to organs at risk according to patients' individual anatomy, including breast volume. Patients and methods In the study, the whole heart and cardiac substructures were delineated for 60 patients using cardiac atlas. For each patient, 3D-CRT and t-IMRT plans were generated. The prescribed dose was 42.72 Gy in 16 fractions. Patients were divided into groups with small, medium, and large clinical target volume (CTV). Calculated dose distributions were compared amongst the two techniques and the three different groups of CTV. Results Mean absorbed dose to the whole heart (MWHD) (1.9 vs. 2.1 Gy, P < 0.005), left anterior descending coronary artery mean dose (8.2 vs. 8.4 Gy, P < 0.005) and left ventricle (LV) mean dose (3.0 vs. 3.2, P < 0.005) were all significantly lower with 3D-CRT technique compared to t-IMRT. Apical (8.5 vs. 9.0, P < 0.005) and anterior LV walls (5.0 vs. 5.4 Gy, P < 0.005) received the highest mean dose (Dmean). MWHD and LV-Dmean increased with increasing CTV size regardless of the technique. Low MWHD values (< 2.5 Gy) were achieved in 44 (73.3%) and 41 (68.3%) patients for 3D-CRT and t-IMRT techniques, correspondingly. Conclusions Our study confirms a considerable range of the planned doses within the heart for adjuvant 3D-CRT or t-IMRT in node-negative breast cancer. We observed differences in heart dosimetric metrics between the three groups of CTV size, regardless of the radiotherapy planning technique.

Impact of COVID-19 on cancer diagnosis and management in Slovenia - preliminary results.

Background The COVID-19 pandemic has disrupted the provision and use of healthcare services throughout the world. In Slovenia, an epidemic was officially declared between mid-March and mid-May 2020. Although all non-essential health care services were put on hold by government decree, oncological services were listed as an exception. Nevertheless, as cancer control depends also on other health services and additionally major changes in people's behaviour likely occurred, we aimed to analyse whether cancer diagnosis and management were affected during the COVID-19 epidemic in Slovenia. Methods We analysed routine data for the period November 2019 through May 2020 from three sources: (1) from the Slovenian Cancer Registry we analysed data on pathohistological and clinical practice cancer notifications from two major cancer centres in Ljubljana and Maribor; (2) from the e-referral system we analysed data on all referrals in Slovenia issued for oncological services, stratified by type of referral; and (3) from the administrative data of the Institute of Oncology Ljubljana we analysed data on outpatient visits by type as well as on diagnostic imaging performed. Results Compared to the November 2019 - February 2020 average, the decrease in April 2020 was about 43% and 29% for pathohistological and clinical cancer notifications; 33%, 46% and 85% for first, control and genetic counselling referrals; 19% (53%), 43% (72%) and 20% (21%) for first (and control) outpatient visits at the radiotherapy, surgery and medical oncology sectors at the Institute of Oncology Ljubljana, and 48%, 76%, and 42% for X-rays, mammograms and ultrasounds performed at the Institute, respectively. The number of CT and MRI scans performed was not affected. Conclusions Significant drops in first referrals for oncological services, first visits and imaging studies performed at the Institute, as well as cancer notifications in April 2020 point to a possibility of a delayed cancer diagnosis for some patients during the first surge of SARS-CoV-2 cases in Slovenia. The reasons for the delay cannot be ascertained with certainty and could be linked to health-seeking behaviour of the patients, the beliefs and practices of doctors and/ or the health system management during the epidemic. Drops in control referrals and control visits were expected and are most likely due to the Institute of Oncology Ljubljana postponing non-essential follow-ups through May 2020.

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.

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.

Breast size impact on adjuvant radiotherapy adverse effects and dose parameters in treatment planning.

Background Breast radiotherapy is an established adjuvant treatment after breast conserving surgery. One of the important individual factors affecting the final cosmetic outcome after radiation is breast size. The purpose of this review is to summarise the clinical toxicity profile of adjuvant radiotherapy in women with breasts of various sizes, and to evaluate the treatment planning studies comparing target coverage and dose to thoracic organs at risk in relation to breast size. Conclusions Inhomogeneity and excessive radiation dose (hot spots) in the planning of target volume as well as large volume of the breast per se, all contribute to a higher rate of acute adverse events and suboptimal final cosmetic outcome in adjuvant breast cancer radiotherapy, regardless of the fractionation schedule. Improved homogeneity leads to a lower rate of ≥ grade 2 toxicity and can be achieved with three-dimensional conformal or modulated radiotherapy techniques. There may be an association between body habitus (higher body mass index, bigger breast size, pendulous breast, and large chest wall separation) and a higher mean dose to the ipsilateral lung and whole heart. A combination of the technical innovations (i.e. the breath-hold technique, prone position with or without holding breath, lateral decubitus position, and thermoplastic bra), dose prescription (i.e. moderate hypofractionation), and irradiated volume (i.e. partial breast irradiation) should be tailored to every single patient in clinical practice to mitigate the risk of radiation adverse effects.

Treatment-related Cardiovascular Toxicity in Long-term Survivors of Testicular Cancer.

BACKGROUNDS: Testicular cancer is the most common malignancy in young men. Considering increasing incidence, exceptionally high cure rate, as well as long life expectancy, assessment of long term toxicity in testicular cancer survivors is of great importance. In the last decades a major effort has been made in order to reduce toxicity of treatment, while maintaining its high effectiveness. CONCLUSIONS: Actual knowledge on treatment toxicity is based on outdated treatment modalities. Hopefully, modern treatment modalities could reduce toxicity, but, there is no firm confirmation for that at the moment, as data dealing with late sequelae of modern treatment of testicular cancer are not available yet due to the short period of observation. The life-threatening cardiovascular toxicity in testicular cancer survivors is major complication of platinum-based chemotherapy, mediastinal radiotherapy and even subdiaphragmatic radiotherapy.

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 first survival score for patients with brain metastases from small cell lung cancer (SCLC).

OBJECTIVE: Survival scores can help physicians select appropriate treatment for patients with brain metastasis. Primary tumors have different biological behavior justifying separate scoring systems for different tumors. In this study, a survival score was developed for patients with brain metastasis from SCLC. METHODS: Data of 172 patients receiving whole-brain radiotherapy alone for brain metastasis from SCLC were included. Patients were assigned to a test (N=86) or a validation group (N=86). In the test group, Karnofsky Performance Score, number of brain metastases, and extracranial metastasis were associated with survival and included in the score. Scores for each factor were obtained from the 6-month survival rate divided by 10. According to the total scores, which represented the sum of the three scores, three prognostic groups were formed. RESULTS: 6-Month survival rates in the test group were 3% for 5-8 points, 40% for 9-12 points, and 89% for 15 points (p<0.001). In the validation group, 6-month survival rates were 3%, 41%, and 89% (p<0.001). The comparisons between the three prognostic groups of the test group and the validation group did not show significant differences. CONCLUSIONS: This new score appears valid and reproducible. It can be used to personalize the treatment to patients with brain metastasis from SCLC.

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.

Neoadjuvant capecitabine, radiotherapy, and bevacizumab (CRAB) in locally advanced rectal cancer: results of an open-label phase II study.

BACKGROUND: Preoperative capecitabine-based chemoradiation is a standard treatment for locally advanced rectal cancer (LARC). Here, we explored the safety and efficacy of the addition of bevacizumab to capecitabine and concurrent radiotherapy for LARC. METHODS: Patients with MRI-confirmed stage II/III rectal cancer received bevacizumab 5 mg/kg i.v. 2 weeks prior to neoadjuvant chemoradiotherapy followed by bevacizumab 5 mg/kg on Days 1, 15 and 29, capecitabine 825 mg/m2 twice daily on Days 1-38, and concurrent radiotherapy 50.4 Gy (1.8 Gy/day, 5 days/week for 5 weeks + three 1.8 Gy/day), starting on Day 1. Total mesorectal excision was scheduled 6-8 weeks after completion of chemoradiotherapy. Tumour regression grades (TRG) were evaluated on surgical specimens according to Dworak. The primary endpoint was pathological complete response (pCR). RESULTS: 61 patients were enrolled (median age 60 years [range 31-80], 64% male). Twelve patients (19.7%) had T3N0 tumours, 1 patient T2N1, 19 patients (31.1%) T3N1, 2 patients (3.3%) T2N2, 22 patients (36.1%) T3N2 and 5 patients (8.2%) T4N2. Median tumour distance from the anal verge was 6 cm (range 0-11). Grade 3 adverse events included dermatitis (n = 6, 9.8%), proteinuria (n = 4, 6.5%) and leucocytopenia (n = 3, 4.9%). Radical resection was achieved in 57 patients (95%), and 42 patients (70%) underwent sphincter-preserving surgery. TRG 4 (pCR) was recorded in 8 patients (13.3%) and TRG 3 in 9 patients (15.0%). T-, N- and overall downstaging rates were 45.2%, 73.8%, and 73.8%, respectively. CONCLUSIONS: This study demonstrates the feasibility of preoperative chemoradiotherapy with bevacizumab and capecitabine. The observed adverse events of neoadjuvant treatment are comparable with those previously reported, but the pCR rate was lower.