Helle Anita Jensen

Short-Time Infusion of Oxaliplatin (Eloxatin®) in Combination with Capecitabine (Xeloda®) in Patients with Advanced Colorectal Cancer

Neuropathy exacerbated by exposure to cold is a dose-limiting toxicity of oxaliplatin. The incidence of this side effect is claimed to dependent on infusion rate and therefore a 2-h infusion is often recommended. For practical reasons and for the convenience of the patient, we used XELOX (Xeloda 2000 mg/m2orally on days 1–14 and oxaliplatin 130 mg/m2as a 30-min infusion on day 1) in patients with advanced colorectal cancer resistant to irinotecan and 5-fluorouracil. Thirty-four consecutive patients received a median of 5 courses of XELOX. Nine patients obtained partial response (PR) (response rate (RR) 26%), 11 patients no change (NC), 7 patients disease progression (PD) and 7 patients were not evaluable. Median time to progression was 4.7 (2.6–7.6) months and median survival was 7.4 (6.0–11.3) months. Sixteen patients had neuropathy grade 1, four patients grade 2 and two patients grade 3. Short-time infusion of oxaliplatin and capecitabine is an active and convenient second-line regimen with a safety profile similar to that of other oxaliplatin schedules.

Phase II study of short-time oxaliplatin, capecitabine and epirubicin (EXE) as first-line therapy in patients with non-resectable gastric cancer

Epirubicin, cisplatin and continuous infusion of 5-FU is a widely used palliative regimen in patients with gastric cancer. If cisplatin is substituted by oxaliplatin and 5-FU by capecitabine this regimen can be administered in the outpatient setting. Dose-limiting toxicity of oxaliplatin is peripheral sensory neuropathy and it is recommended to give oxaliplatin as a 120 min infusion. However, in patients with colorectal cancer a 30 min infusion of oxaliplatin can safely be administered without increasing neurotoxicity, standard infusion time is 30 min at our departments. In our phase I study the recommended doses of EXE was established (Dupont et al, 2006). Patients with non-resectable gastric adenocarcinoma were eligible. Patients received EXE (epirubicin 50 mg m−2 day 1; capecitabine 1000 mg m−2 day−1 continuously and oxaliplatin 130 mg m−2 day 1) as outpatient therapy every third week for a maximum of 8 cycles. From June 2004 to September 2005, we enroled 54 patients. Median age was 60 years (31–74 years) Median number of courses was 6 (1–8). Response rate was 45%. Median PFS was 6.8 (5.2–7.9) months and median survival was 10.1 (7.9–11.1) months. Most important grade 3 toxicities were as follows: nausea, vomiting, and diarrhoea (6%). Neurotoxicity grade 2 was seen in 36.5%. We therefore conclude, that EXE every third week is a convenient regimen that easily can be administrated in the outpatient setting but the regimen needs further evaluation in a phase III study.

Long-term results of concurrent radiotherapy and UFT in patients with locally advanced pancreatic cancer.

BACKGROUND Definition and treatment options for locally advanced non-resectable pancreatic cancer (LAPC) vary. Treatment options range from palliative chemotherapy to chemoradiotherapy (CRT). Several studies have shown that a number of patients become resectable after complementary treatment prior to surgery. METHODS From 2001 to 2005, 63 consecutive patients with unresectable LAPC received CRT. CRT was given at a dose of 50 Gy/27 fractions, combined with UFT (300 mg/m(2)/day) and folinic acid. Re-evaluation of resectability was planned 4-6 weeks after completion of CRT. RESULTS Fifty-eight patients completed all 27 treatment fractions. Toxicity was generally mild, with 18 patients experiencing CTCAE grade 3 or worse acute reactions. One patient died following a treatment-related infection. Two patients developed grade 4 upper GI bleeding. Median survival was 10.6 (8-13) months. Eleven patients underwent resection, leading to a resection rate of 17%, and a median survival of 46 (23-nr) months. All 11 patients had a R0 resection. Median survival for the patients not resected was 8.8 (8-12) months. CONCLUSION CRT with 50 Gy combined with UFT, is a well-tolerated and effective treatment for patients with LAPC. R0 resection was possible in 17% leading to a long median survival of 46 months in resected patients.

UFT (tegafur–uracil) in rectal cancer

BACKGROUND Major achievements in the treatment of localised rectal cancer include the development of total mesorectal excision and the perioperative administration of radiotherapy in combination with continuous infusion (CI) 5-fluorouracil (5-FU). This multimodal approach has resulted in extended survival and lower local relapse rates, with the potential for sphincter-preserving procedures. However, CI 5-FU is inconvenient for patients and is costly. Oral fluoropyrimidines like UFT (tegafur-uracil) offer a number of advantages over 5-FU. METHODS We undertook a review of published articles and abstracts relating to clinical studies of UFT in the treatment of locally advanced rectal cancer (LARC). Pre- and postoperative studies carried out in patients with newly diagnosed or recurrent disease were included. RESULTS The combination of UFT and radiotherapy was effective and well tolerated in the preoperative setting, while adjuvant UFT improved survival and reduced distant relapse compared with surgery alone. The efficacy of UFT appears comparable with that of 5-FU and capecitabine and its side-effect profile is favourable. CONCLUSION Clinical experience to date suggests that UFT is a valuable treatment option for the perioperative treatment of LARC. Further improvements in patient outcomes may result from the combination of UFT with targeted agents.

Multi-institutional Quantitative Evaluation and Clinical Validation of Smart Probabilistic Image Contouring Engine (SPICE) Autosegmentation of Target Structures and Normal Tissues on Computer Tomography Images in the Head and Neck, Thorax, Liver, and Male Pelvis Areas

PURPOSE Clinical validation and quantitative evaluation of computed tomography (CT) image autosegmentation using Smart Probabilistic Image Contouring Engine (SPICE). METHODS AND MATERIALS CT images of 125 treated patients (32 head and neck [HN], 40 thorax, 23 liver, and 30 prostate) in 7 independent institutions were autosegmented using SPICE and computational times were recorded. The number of structures autocontoured were 25 for the HN, 7 for the thorax, 3 for the liver, and 6 for the male pelvis regions. Using the clinical contours as reference, autocontours of 22 selected structures were quantitatively evaluated using Dice Similarity Coefficient (DSC) and Mean Slice-wise Hausdorff Distance (MSHD). All 40 autocontours were evaluated by a radiation oncologist from the institution that treated the patients. RESULTS The mean computational times to autosegment all the structures using SPICE were 3.1 to 11.1 minutes per patient. For the HN region, the mean DSC was >0.70 for all evaluated structures, and the MSHD ranged from 3.2 to 10.0 mm. For the thorax region, the mean DSC was 0.95 for the lungs and 0.90 for the heart, and the MSHD ranged from 2.8 to 12.8 mm. For the liver region, the mean DSC was >0.92 for all structures, and the MSHD ranged from 5.2 to 15.9 mm. For the male pelvis region, the mean DSC was >0.76 for all structures, and the MSHD ranged from 4.8 to 10.5 mm. Out of the 40 autocontoured structures reviews by experts, 25 were scored useful as autocontoured or with minor edits for at least 90% of the patients and 33 were scored useful autocontoured or with minor edits for at least 80% of the patients. CONCLUSIONS Compared with manual contouring, autosegmentation using SPICE for the HN, thorax, liver, and male pelvis regions is efficient and shows significant promise for clinical utility.

Prognostic Factors for Survival and Resection in Patients With Initial Nonresectable Locally Advanced Pancreatic Cancer Treated With Chemoradiotherapy

BACKGROUND AND PURPOSE Controversies regarding the optimal therapy for patients with locally advanced pancreatic cancer (LAPC) exist. Although the prognosis as a whole remains dismal, subgroups are known to benefit from intensive therapy, including chemoradiotherapy (CRT). We describe the results in 178 patients treated from 2001 to 2010 and have developed a prognostic model for both survival and the possibility of a subsequent resection in these patients. METHODS AND MATERIALS From 2001 until 2010, 178 consecutive patients with LAPC were treated and included in the present study, with CRT consisting of 50 Gy in 27 fractions combined with tegafur-uracil(UFT)/folinic acid(FA). RESULTS The median survival from diagnosis was 11.5 months. Adverse events of Grade 3 or above were seen in 36% of the patients. Ninety-three percent of the patients completed all fractions. A Cox regression model for survival demonstrated resection (hazard ratio [HR] 0.12; 95% confidence interval [CI], 0.1-0.3) and pre-CRT gemcitabine-based therapy (HR 0.57; 95% CI, 0.4-0.9) as being associated with a favorable outcome, increasing gross tumor volume (HR 1.14; 95% CI, 1.0-1.3) was associated with shorter survival. A logistic regression model showed Stage III disease (odds ratio [OR] 0.16; 95% CI, 0.0-1.1) and abnormal hemoglobin (OR 0.26; 95% CI, 0.0-1.2) as being associated with lower odds of resection. CONCLUSION This study confirms the favorable prognosis for patients receiving gemcitabine therapy before CRT and the poor prognosis associated with increasing tumor volume. In addition, CRT in patients with abnormal hemoglobin and Stage III disease rarely induced tumor shrinkage allowing subsequent resection.

Phase I study of docetaxel, oxaliplatin and capecitabine (TEX) as first line therapy to patients with advanced gastro-oesophageal cancer.

Abstract Background. ECF (epirubicin, cisplatin, 5-FU) has been a standard first-line regimen in patients with advanced gastro-esophageal cancer (GEC). If cisplatin is substituted by oxaliplatin (Eloxatin®) – E) and 5-FU by capecitabine (X – Xeloda®) this regimen is easily administered with at least comparable efficacy and lower toxicity. Recent studies indicate that efficacy can be improved by adding docetaxel (Taxotere® – T) to CF. We initiated a phase I trial of T, short-time infusion of E and continuously X (TEX) as first-line therapy in GEC to establish the recommended dose (RD) for further therapy. Materials and methods. Patients were enrolled in cohorts of three at five dose levels. Patients had histologically confirmed GEC adenocarcinoma. Therapy was administered day 1 with escalating doses of docetaxel (60 mg/m2 to 75 mg/m2 iv as a 60 minutes infusion), oxaliplatin (85 to 130 mg/m2 iv as a 30 minutes infusion) and oral capecitabine (1 000 to 1 250 mg/m2/day). TEX was repeated every third week for a maximum of eight cycles. Toxicity was evaluated according to CTCAE v3.0 and dose limiting toxicity (DLT) was evaluated after the first course of TEX. Results. From June 2007 to April 2009, 23 consecutive patients received TEX. At dose level V, two of four patients experienced DLT and therefore we included additional seven patients at dose level IV. Only one of seven experienced DLT but dose-intensity was reduced to 75% in four of seven patients after three courses of TEX. Therefore we defined dose level III as RD. Efficacy was promising with response rate 38%, PFS 9.4 months and OS 12.5 months. Conclusion. The recommended dose of TEX (docetaxel 60 mg/m2 iv day 1, oxaliplatin 115 mg/m2 iv day 1 and oral capecitabine 1250 mg/m2/day continuously) every three weeks is easily administered in an out-patient setting. Efficacy is promising and will be evaluated in a phase II study.

Phase I study of short-time oxaliplatin, capecitabine and epirubicin (EXE) as first line therapy in patients with non-resectable gastric cancer

A phase I trial of short-time oxaliplatin (E), capecitabine (X) and epirubicin (E) for patients with metastatic gastric cancer was initiated to establish the recommended dose for further therapy with short-time EXE. Patients received out-patient therapy with a fixed dose of epirubicin 50 mg/m2 day 1; escalating doses of capecitabine (1 000 to 1 250 mg/m2/day continuously) and escalating doses of oxaliplatin (85 to 130 mg/m2 day 1 as a 30 minutes infusion). Cycles were repeated every 21 days for a maximum of 8 cycles. From June 2003 to June 2004, 31 patients were treated. Median age was 61 years (39–75 years), and median performance status was 0 (0–2). At level 3, one of six patients developed DLT and at dose level 4, two of six patients developed DLT (both patients had grade 4 hematological toxicities) and thus further dose escalation was not attempted. Median number of cycles was 6 (1–8), median survival was 9.2 months and median TTP was 7.5 months. A combination of epirubicin 50 mg/m2 day 1, capecitabine 1 000 mg/m2 continuously and oxaliplatin 130 mg/m2 day 1 each 3 weeks is an easily administered and well tolerated out-patient regimen for patients with non-resectable gastric cancer.

High-dose radiotherapy (60 Gy) with oral UFT/folinic acid and escalating doses of oxaliplatin in patients with non-resectable locally advanced rectal cancer (LARC): A phase I trial

Background. Consensus is that patients with locally advanced rectal cancer (LARC) should receive long-term chemoradiotherapy (CRT) before surgery. With the intent to offer the patients intensified concomitant chemotherapy (CT) to improve outcome and to assess tolerability and toxicity of oxaliplatin (Ox) a phase I trial of high dose pelvic radiotherapy (RT), fixed dose of oral UFT/l-leucovorin and increasing doses of weekly Ox were performed. Methods. Pelvic RT with 48.6 Gy/27 fractions was given to the primary tumour and the regional lymph nodes and a concurrent boost of 5.4 Gy/27 fractions with a final boost of 6 Gy/3 fractions was given to the gross tumour volume (GTV) (60 Gy/30 fractions). Concurrent with RT patients received a daily dose of UFT 300 mg/m2 plus fixed dose l-leucovorin 22.5 mg 5/7 days and increasing weekly doses of Ox with 10 mg/m2/week from a start dose of 30 mg/m2/week to a maximum of 60 mg/m2/week. In addition, before and after CRT the patients received one course of TEGAFOX (UFT 300 mg/m2 with l/leucovorin 22.5 mg Days 1–14 and Ox 130 mg/m2 given on Day 1). Surgery was planned at least six weeks after the completion of the CRT. Results. From May 2005 to March 2009, 18 patients with LARC (16 primary, two recurrent) were included in this phase I trial. Toxicity was low with only 5–17% grade 3–4 toxicity. Fifteen patients (83%) were operated (14 R0 resection and 1 R1 resection) after completion of CRT. Five (33%) patients had a pathological complete response (ypCR). When ypCR was combined with yp few residual cells, the rate was 60%. Thirteen patients are still alive December 2011. Conclusion. Preoperative high-dose RT and concomitant UFT with increasing doses of Ox up to 60 mg/m2/week was feasible with low toxicity, high ypCR rates and promising OS in patients with non-resectable LARC.

Experience with S-1 in older Caucasian patients with metastatic colorectal cancer (mCRC): Findings from an observational chart review

Abstract Background: An aging population will increase the number of older patients with metastatic colorectal cancer (mCRC). However, there is limited knowledge about treatment in older patients as they are under-represented in clinical trials. The oral fluoropyrimidine S-1 is associated with a lower rate of adverse events than capecitabine and may therefore be a suitable drug for elderly. However, data on the use of S-1 in Caucasian mCRC patients are lacking/scarce. Material and methods: In the present study we evaluated safety and the efficacy of S-1 alone or in combination with oxaliplatin (SOx) or irinotecan (IRIS) in older mCRC patients. Patients who received at least one cycle of S-1 (first-line therapy), SOx (mainly first-line therapy) or IRIS (second-line therapy) were included. Results: From June 2012 to December 2014, 71 older patients received ≥1 cycle of either S-1 (n = 9), SOx (n = 44) or IRIS (n = 18) for mCRC. Median age was 76 years and most patients had a WHO performance status of 0 (32%) or 1 (56%). All patients were evaluable for response and safety. In the SOx group, 18 (41%) and 20 patients (45%) had partial response (PR) and stable disease (SD), respectively (disease control rate 86%). Median progression-free survival (PFS) was 8.5 months and median overall survival (OS) was 18.5 months. In the S-1 group (median age 82 years), PR was 22%, median PFS 6.4 months and median OS 15.8 months. In the IRIS group, PR was 28%, median PFS 7.8 months and the median OS 16.5 months. In general, therapy was well tolerated; main non-hematological toxicities were fatigue and diarrhea. Conclusion: S-1 monotherapy, SOx and IRIS were well tolerated for older patients with mCRC and could become alternative regimens in older mCRC patients. These regimens are now further evaluated in the randomized ongoing NORDIC9 trial.