Quality of life in patients after combined modality treatment of rectal cancer: Report of a prospective phase II study
Background. The literature reports are unclear whether a permanent stoma reduces the quality of life (QOL) of patients with locally advanced rectal cancer (T3-4 and/or N+). Our aim was to compare the QLQ of patients with abdominoperineal resection and with restorative surgery, treated with preoperative radiochemotherapy in a prospective phase II clinical trial.
Methods. Fifty-seven patients were irradiated to 45 Gy in 25 fractions over 5 weeks to the pelvis concomitantly with oral capecitabine 825 mg/m2, twice a day, including weekends. Surgery was scheduled 4-6 weeks after the completion of the chemoradiotherapy. Four courses of chemotherapy were planned postoperatively. Patients still alive and without recurrence of the disease, with a minimum follow up of 2 years, were surveyed with two self-rating questionnaires developed by the European Organisation for Research and Treatment of Cancer (EORTC): one was cancer specific (EORTC QLQ-C30) and one was site specific (EORTC QLQ-C38).
Results. QLQ was assessed in 28 of 32 patients eligible (87.5%). The median time from surgery to filling in the questionnaires was 35 months. For all scales of EORTC QLQ-C30 and EORTC QLQ-C38, no significant differences in median scores were observed between the two groups of patients.
Conclusions. QOL did not differ in patients with abdominoperineal resection from patients with sphinctersparing surgery.
Postoperative radiochemotherapy for gastric adenocarcinoma: long term results
Background. To analyze the efficacy of postoperative radiochemotherapy with 5-florouracil (5-FU) and leucovorin (LV) applied in the patients with gastric carcinoma treated in a single institution.
Patients and methods. Between 2001 and 2004, 123 patients with resected gastric adenocarcinoma were treated with postoperative concomitant radiochemotherapy with 5-FU and LV. The adjuvant treatment consisted of five cycles of chemotherapy with 5-FU (425mg/m2 IV) and LV (20 mg/m2 IV) and concomitant radiotherapy with the total dose of 45 Gy.
Results. The treatment was completed according to the protocol in 82% of patients. The frequency and severity of early toxic effects induced by radiochemotherapy were manageable. Median follow-up time of 56 survivors was 64.5 months (range: 51.7-96.4 months). The 5-year locoregional control (LRC), disease-free survival (DFS), disease-specific survival (DSS) and overall survival (OS) were 81%, 48.3%, 50.4%, and 48.4%, respectively. The multivariate analysis showed that the tumor involvement of cardia and low intensity of chemotherapy were independent adverse prognostic factors for DSS and OS. More advanced pT-stage and tumors with diffuse growth type according to Lauren were identified as negative independent prognostic factor for OS. They were also on the threshold of statistical significance for DSS.
Conclusions. Postoperative radiochemotherapy for gastric carcinoma has acceptable toxicity, and is effective particularly in regard to LRC. High incidence of distant metastases calls for more effective systemic regimens.
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/m2 twice daily, orally) for 2 weeks followed by cetuximab alone (400 mg/m2 for 1 week) and then with CRT (250 mg/m2/week) comprising capecitabine (825 mg/m2 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/m2 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.
Differences in plasma TIMP-1 levels between healthy people and patients with rectal cancer stage II or III
Background. The purpose of the study was to analyse whether the levels of the tissue inhibitor of matrix metalloproteinases-1 (TIMP-1) are higher in patients with rectal cancer as compared with healthy blood donors.
Patients and methods. Two hundred and seventeen patients (147 male, 70 female) with histologically confirmed non-metastatic rectal cancer (clinical stage II-III) and 45 healthy blood donors (15 male, 30 female) were included in analysis. Patient's mean age was 66 years (range: 34-87 years) and healthy blood donor's mean age was 35 years (range: 18-64 years). Plasma TIMP-1 concentrations were measured with an enzyme-linked immunosorbent assay (ELISA) using commercially available TIMP-1 ELISA kit. Mann-Whitney-test for independent groups was used to assess the differences of plasma TIMP-1 levels and clinicopathological parameters. Two-sided tests were used and the differences at P<0.05 were considered as statistically significant.
Results. Median patients TIMP-1 level was 180 ng/mL (range: 22-538 ng/mL); the mean (±SD) level was 193.7 (79.5) ng/mL. The median healthy blood donors TIMP-1 level was 112 ng/mL (range: 48-211 ng/mL); the mean (±SD) level was 115 (35.7) ng/mL. TIMP-1 levels in patients with rectal cancer were statistically significantly higher than TIMP-1 levels in healthy blood donors (P<0.0001). Significant differences in TIMP-1 levels were not found comparing gender (P=0.43), but in both groups TIMP-1 levels were increased with higher age (P=0.007).
Conclusions. Patients with rectal cancer had statistically significantly higher mean and median TIMP-1 level than healthy blood donors which is in accordance with the results published in other publications. These findings suggest possibility that plasma TIMP-1 levels could be used as new biological markers for early cancer detection.
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.
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.
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 followup 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
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). Twentysix (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, diseasefree 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.
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 multi-organ 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.