Lene Weber Vestermark

Predictive and prognostic factors for treatment and survival in 305 patients with advanced gastrointestinal neuroendocrine carcinoma (WHO G3): the NORDIC NEC study.

BACKGROUND As studies on gastrointestinal neuroendocrine carcinoma (WHO G3) (GI-NEC) are limited, we reviewed clinical data to identify predictive and prognostic markers for advanced GI-NEC patients. PATIENTS AND METHODS Data from advanced GI-NEC patients diagnosed 2000-2009 were retrospectively registered at 12 Nordic hospitals. RESULTS The median survival was 11 months in 252 patients given palliative chemotherapy and 1 month in 53 patients receiving best supportive care (BSC) only. The response rate to first-line chemotherapy was 31% and 33% had stable disease. Ki-67<55% was by receiver operating characteristic analysis the best cut-off value concerning correlation to the response rate. Patients with Ki-67<55% had a lower response rate (15% versus 42%, P<0.001), but better survival than patients with Ki-67≥55% (14 versus 10 months, P<0.001). Platinum schedule did not affect the response rate or survival. The most important negative prognostic factors for survival were poor performance status (PS), primary colorectal tumors and elevated platelets or lactate dehydrogenase (LDH) levels. CONCLUSIONS Advanced GI-NEC patients should be considered for chemotherapy treatment without delay.PS, colorectal primary and elevated platelets and LDH levels were prognostic factors for survival. Patients with Ki-67<55% were less responsive to platinum-based chemotherapy, but had a longer survival. Our data indicate that it may not be correct to consider all GI-NEC as one single disease entity.

Changes from 1992 to 2002 in the pretreatment delay for patients with squamous cell carcinoma of larynx or pharynx: A Danish nationwide survey from DAHANCA

In Denmark, a general impression of prolonged pretreatment delay for patients with head and neck cancer led to a nationwide study of time spans from symptom debut over first health care contact to start of treatment. Charts of consecutive new patients with squamous cell carcinoma of the pharynx and larynx, seen at the five Danish oncology centers in January–April 1992 and 2002, respectively, were reviewed. Of the 288 patients identified, definitive treatment was radiotherapy in 264 cases, surgery in one case. Twenty-three patients had neither surgery nor radiotherapy. Total time from first health care contact to start of definitive treatment was significantly longer in 2002 than in 1992 (median 70 versus 50 days, p < 0.001). There was no significantly difference in time used for diagnosis. Time for treatment preparation and planning was 46 days in 2002 versus 31 days in 1992 (p < 0.001). Significantly more diagnostic procedures (CT, MR, US, PET) were done in 2002. In conclusion, this nationwide study showed that waiting time before start of radiotherapy was significantly longer in 2002 compared to 1992. An increasing number of imaging procedures including CT-based dose planning was observed. The prolongation was mainly related to shortage of radiotherapy capacity. The three weeks extra pretreatment delay could theoretically lead to a 10% lower tumor control probability in 2002 compared to 1992.

A randomized study of KRAS-guided maintenance therapy with bevacizumab, erlotinib or metronomic capecitabine after first-line induction treatment of metastatic colorectal cancer: the Nordic ACT2 trial

BACKGROUND Maintenance treatment (mt) with bevacizumab (bev) ± erlotinib (erlo) has modest effect after induction chemotherapy in metastatic colorectal cancer (mCRC). We hypothesized the efficacy of erlo to be dependent on KRAS mutational status and investigated this by exploring mt strategies with bev ± erlo and low-dose capecitabine (cap). PATIENTS AND METHODS Included patients had mCRC scheduled for first-line therapy, Eastern Cooperative Oncology Group (ECOG) 0-1 and no major comorbidities. Treatment with XELOX/FOLFOX or XELIRI/FOLFIRI + bev was given for 18 weeks. After induction, patients without progression were eligible for randomization to mt; KRAS wild-type (wt) patients were randomized to bev ± erlo (arms wt-BE, N = 36 versus wt-B, N = 35), KRAS mutated (mut) patients were randomized to bev or metronomic cap (arms mut-B, N = 34 versus mut-C, N = 33). Primary end point was progression-free survival (PFS) rate (PFSr) at 3 months after start of mt. A pooled analysis of KRAS wt patients from the previous ACT study was performed. RESULTS We included 233 patients. Median age was 64 years, 62% male, 68% ECOG 0, 52% with primary tumor in situ. A total of 138 patients started mt after randomization. PFSr was 64.7% versus 63.6% in wt-B versus wt-BE, P = 1.000; and 75% versus 66.7% in mut-B versus mut-C, P = 0.579, with no significant difference in median PFS and overall survival (OS). In the pooled cohort, median PFS was 3.7 months in wt-B (N = 64) and 5.7 months in wt-BE (N = 62) (hazard ratios 1.03, 95% confidence interval 0.70-1.50, P = 0.867). The frequency of any grade 3/4 toxicities during mt was: 28%/58%/18%/15% (wt-B/wt-BE/mut-B/mut-C). CONCLUSIONS Addition of erlo to bev as mt in KRAS wt mCRC did not significantly improve PFS or OS, but it did increase toxicity. KRAS status does not seem to influence the outcome of treatment with erlotinib. Metronomic cap warrants further investigation in mt strategies, given our explorative results. CLINICALTRIALSGOV NCT01229813.

Long-term results of a phase II trial of high-dose radiotherapy (60 Gy) and UFT/l-leucovorin in patients with non-resectable locally advanced rectal cancer (LARC)

Background. Preoperative radiochemotherapy is a cornerstone in patients with non- resectable locally advanced rectal cancer (LARC). To improve outcome (number of R0 resections and survival) high-dose radiotherapy (RT) was combined with oral UFT/l-leucovorin to allow tumour regression before radical intended surgery. Methods. Pelvic RT was delivered with megavoltage photons using a 5 field technique. RT was CT-based, given 5 days a week through one posterior field and two lateral fields (48.6 Gy/27 fractions) to encompass the primary tumour and the regional lymph nodes. In addition, the tumour bed received a concurrent boost (5.4 Gy/27 fractions) and a final boost (6 Gy/3 fractions); thus GTV received 60 Gy/30 fractions. Concurrent with RT patients received a daily dose of oral UFT 300 mg/m2 plus l-leucovorin 22.5 mg 5/7days (divided in three doses). Results. From September 2000 to November 2004, 52 patients (median age 60 years (32–83); median PS 0 (0–2)) with LARC (36 primary, 16 recurrent) were included in this phase II study. All but three patients received the planned 60 Gy, median duration of RT was 42 days (25–49). Toxicity was very modest; only four patients had a dose reduction of UFT. No hematological toxicity of clinical significance was seen. Non-hematological toxicity grade 1 (GI-toxicity, fatigue and/or dysuria) was frequently observed but only four patients experienced grade 3 toxicity (diarrhoea and/or nausea/vomiting). Forty patients (77%) were operated (30 R0, 5 R1, 5 R2) median 55 days (27–112) after completion of RT. Seven (13%) patients had a pathological complete response (pCR). Thirty-one patients (60%) died after median 25.4 months (1.6–45.2 months). Twenty-one patients (40%) are still alive June 2007. Conclusions. Preoperative high-dose RT and concomitant UFT produces major regression in most patients with non-resectable LARC and thus a good chance of cure.

A phase II study of thalidomide in patients with brain metastases from malignant melanoma

Introduction. Brain metastases develop in nearly half of the patients with advanced melanoma and in 15 to 20% of these patients CNS is the first site of relapse. Overall median survival is short, ranging from 2 to 4 months. Thalidomide has antiangiogenic and immunomodulatory effects. Results obtained in prior trials indicate that Thalidomide acts as a cytostatic agent in metastatic melanoma. We evaluated single agent antitumour activity and toxicity of Thalidomide in a phase II setting in patients with brain metastases associated with metastatic melanoma. Material and methods. Patients with measurable metastatic melanoma in progression and with PS≤2 were enrolled in the study. Thalidomide was given orally. Dose was escalated over 4 weeks from 100 mg/day to 400 mg/day. Primary objective of the study was to determine response rate, according to RECIST. Secondary objectives were to estimate time to progression, overall survival and to evaluate tolerability of the regimen. Results. Twenty five men and 11 women were enrolled in the study, median age 48 years. Among 36 eligible patients 35 were evaluable for response. None of the patients obtained a response in brain metastases. Three patients obtained a partial response in extracranial lesions. Toxicity was acceptable and manageably. Median time to progression and overall survival time was 1.7 and 3.1 months, respectively. Conclusion. There were no objective responses in the brain but single agent Thalidomide has some activity in melanoma patients with brain metastases. It has encouraged us to investigate Thalidomide in combination with Temozolomide, a very lipophilic agent, in this group of 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.

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.

Intrahepatic and systemic therapy with oxaliplatin combined with capecitabine in patients with hepatic metastases from breast cancer

BACKGROUND The aim was to evaluate activity and toxicity of hepatic arterial infusion of oxaliplatin in combination with capecitabine in patients with metastatic breast cancer with liver metastases and limited extrahepatic disease. PATIENTS AND METHODS Sixteen consecutive patients received capecitabine 13 00mg/m(2) daily combined with oxaliplatin 85 mg/m(2) every two weeks. Seven patients alternated between intrahepatic and systemic oxaliplatin, and in 9 oxaliplatin was primarily given intrahepatic. Five patients had liver-only metastases and 11 had additionally bone metastases. The patients had received median two previous chemotherapeutic regimens for metastatic disease. RESULTS The response rate was 50% and the stable disease (≥6 months) rate 44%. Median progression free and overall survival was 7.9 and 19.2 months, respectively. The toxicity was moderate with abdominal pain, neuropathy, and hand foot syndrome as the most common adverse events. CONCLUSION The combination of capecitabine and intrahepatic/systemic therapy with oxaliplatin was active in pretreated patients with liver metastasis from breast cancer.

Clinical outcome in 520 consecutive Danish rectal cancer patients treated with short course preoperative radiotherapy

AIM The purpose of this study was to analyse the results of preoperative short course radiotherapy in a consecutive, national cohort of patients with rectal cancer. METHODS Through a validated, prospective national database we identified 520 Danish patients who presented with high-risk mobile tumours in the lower two thirds of the rectum and were referred for preoperative radiotherapy with 5 x 5 Gy. The inclusion period was 56 months. Radiotherapy data was retrospectively collected. RESULTS Of the 520 patients, 514 completed radiotherapy and 506 had surgery. Surgery was considered curative in 439 patients. The 3-year local recurrence rate was 4.0% (95% CI 2.5-6.5%) and the distant recurrence rate at 3 years was 18.7% (95% CI 15.4-22.5%). The 5-year disease free survival rate was 40.2% (95% CI 27.0-53.1%) and overall survival 50.4% (95% CI 36.1-63.1%). Most tumours (61%) were classified as T3 or T4 and 41% of the local recurrences occurred in patients with a fixed tumour at surgery. CONCLUSION This study confirms data from randomised studies that the short course 5 x 5 Gy regime is a feasible treatment for locally advanced rectal cancer even when applied in a population outside clinical trials.

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.