Adjuvant chemoradiotherapy for high-risk pancreatic cancer.

INTRODUCTION: The role of adjuvant chemoradiotherapy for resected pancreatic cancer remains controversial. Several trials have failed to draw firm conclusions. The risk of local and metastatic relapse remains high after radical surgery. This is a single institutional review, evaluating the outcomes of patients with high-risk resected pancreatic cancer and treated with adjuvant chemoradiotherapy. METHODS: A retrospective review was conducted on 18 consecutive patients with pancreatic cancer and treated with adjuvant chemoradiotherapy at the Department of Radiation Oncology, National Cancer Centre, Singapore, between January 2000 and December 2004. 56 percent were women. The mean age was 61.5 (range 50-73) years. Patients had either AJCC 2002 Stage I (17 percent), Stage II (11 percent), Stage III (22 percent) or Stage IVA (50 percent). The median radiation dose delivered was 5,400 (range 4,140-5,500) cGy using 180 cGy fractions. Concurrent chemotherapy was administered with 5-fluorouracil (56 percent), gemcitabine (28 percent) or capacetabine (17 percent). RESULTS: The median follow-up of patients still alive at the time of analysis was 48 months. Metastatic disease had developed in 13 patients. Two patients had local recurrence within the radiation field. The median survival of the cohort is 21.6 (range 8.5-62.7) months. One-year survival is 89 percent, 2-year survival 39 percent and 3-year survival 28 percent. CONCLUSION: The data supports the use of adjuvant chemoradiotherapy for high-risk pancreatic cancer. Our results are comparable to published data from similar studies. Although radiotherapy is effective in reducing local failure, effective systemic treatment is also essential.

A phase I/II trial of celecoxib with chemotherapy and radiotherapy in the treatment of patients with locally advanced oesophageal cancer.

BACKGROUND: The study's aim was to determine the maximum tolerated dose (MTD) of celecoxib combined with chemoradiotherapy (CRT) for locally advanced oesophageal cancer (OC). METHODS: CRT comprised of 5FU (1000 mg/m(2)/day, days 1-4, weeks 1 & 5), cisplatin (75 mg/m(2), days 1 & 29) and radiotherapy (50 Gy in 25 fractions or 50.4 Gy in 28 fractions). Celecoxib was given daily during CRT at one of five doses (200 mg bd to 600 mg bd). Three to six patients were assigned per dose. RESULTS: Thirteen patients were recruited before trial closure due to external safety concerns regarding celecoxib. Median follow up was 17 months (95% CI 9 - >39). The highest administered dose was 400 mg bd (n=4) with one dose-limiting toxicity at this level: grade 3 rash. Five (38%) and 8(62%) patients had grade 3 non-haematological and haematological toxicities respectively. No grade 4 toxicities occurred. Radiological response rate was 54% (n=7: all CR). Six patients had resection with one pathological CR. Median progression-free and overall survival were 8.8 (95% CI 5.1 - >24.8) and 19.6 months (95% CI 7.3 - >39) respectively. CONCLUSIONS: A MTD was not reached. The regimen was tolerable, indicating that celecoxib can be safely administered with CRT for locally advanced OC.

Lessons learned from initial experience with peritonectomy and intra-peritoneal chemotherapy infusion.

INTRODUCTION: Patients diagnosed with peritoneal carcinomatous usually survive for less than 6 months. Cytoreductive surgery allows relief of the obstruction and improvement in functional status, while intraperitoneal chemotherapy infusion provides high local concentrations of chemotherapeutic agents. Our institutional experience is reviewed to assess the selection criteria, peri-operative complications, and outcomes. MATERIALS AND METHODS: We carried out a retrospective review of nine patients who had undergone aggressive cytoreductive surgery and hyperthermic intra- and early post-operative chemotherapy by a single surgeon between April 2000 and October 2004. The inclusion criteria were: (1) a demonstrated absence of extra-peritoneal and hepatic spread, (2) fitness of the patient and ability to tolerate cytoreductive surgery and intra-operative chemotherapy, and (3) the presence of a primary tumor originating form the gastro-intestinal tract (colonic, appendiceal, and gastric primaries). RESULTS: Seven women and two men, with a median age of 55 years, were treated. The median duration of the operation was 12 hours and 55 minutes. Seven of the nine patients required the insertion of at least one chest tube. All patients were monitored in the surgical intensive care unit (SICU) for a median of 1 day, started on feeds after a median of 6 days, and were hospitalized for a median of 16 days (range:11-18 days). There was no peri-operative mortality and only one major peri-operative complication (11.1%). At the time of analysis, the median follow-up was 16 months (range: 2-40 months), and the median disease-free survival was 8 months, with four of the nine patients showing no evidence of recurrence. To date, all of the patients are still alive. A 1-year survival rate of 100% is also documented. CONCLUSIONS: This article describes our initial experience with peritonectomy and intra-operative, intra-peritoneal chemotherapy infusion. Our initial problems included difficulty with leakage of the chemotherapeutic agents into the thoracic cavity that had to be overcome by the early insertion of chest-tubes. With appropriate patient selection, cytoreductive surgery with the infusion of intra-operative chemotherapy can be considered to be a therapeutic option for some patients with diffuse peritoneal metastases, and good disease-free and overall survival can be achieved with minimal morbidity.

Flip-flopping fractional flux quanta.

The d-wave pairing symmetry in high-critical temperature superconductors makes it possible to realize superconducting rings with built-in pi phase shifts. Such rings have a twofold degenerate ground state that is characterized by the spontaneous generation of fractional magnetic flux quanta with either up or down polarity. We have incorporated pi phase-biased superconducting rings in a logic circuit, a flip-flop, in which the fractional flux polarity is controllably toggled by applying single flux quantum pulses at the input channel. The integration of p rings into conventional rapid single flux quantum logic as natural two-state devices should alleviate the need for bias current lines, improve device symmetry, and enhance the operation margins.

Phase II trial of gemcitabine and cisplatin sequentially administered in Asian patients with unresectable or metastatic non-small cell lung cancer.

INTRODUCTION: The aim of this study was to assess toxicity and response in the sequential administration of gemcitabine followed by cisplatin in unresectable or metastatic non-small cell lung cancer. MATERIALS AND METHODS: Twenty-three patients were enrolled in this study. Gemcitabine was given at 1,250 mg/m2 on days 1 and 8, for four 21-day cycles. RESULTS: There were 4 patients with partial responses. 5 patients with stable disease and 10 patients with progressive disease, giving a response rate of 21%. The median time to disease progression was 3.3 months. The median overall survival was 14.6 months. Toxicities graded 3 or 4 included anaemia (13.0%), neutropaenia (13.0%), supraventricular tachycardia (4.3%), and nausea and vomiting (4.3%). CONCLUSION: Although these results show similar efficacy to single-agent treatment regimens, the low toxicity profile and promising survival outcome with this regimen are important points for consideration.

Concurrent chemoradiotherapy followed by surgery in locally advanced squamous cell carcinoma of the oesophagus: a single centre experience.

INTRODUCTION: Data on combined modality treatment for locally advanced squamous cell carcinoma of the oesophagus involving Asian patients are limited. MATERIALS AND METHODS: A retrospective study of 56 consecutive patients with this condition treated with concurrent chemoradiotherapy followed by surgery in a single tertiary institution in Singapore was performed. RESULTS: The median overall survival of the entire cohort was 14.1 months [95% confidence interval (CI); range, 8.6 to 19.6 months]. In patients who underwent successful oesophagectomy after chemoradiotherapy (n = 17), the median survival was 27.8 months compared to 9.8 months for those who did not have surgery (n = 39) (P = 0.046, log-rank test). The median time to first relapse for the entire cohort was 16.1 months (95% CI, 7.7 to 24.5 months). The time to first relapse was 23.9 months in the subgroup of patients with successful surgery and 12.1 months in the group which did not (P = 0.147, log-rank test). The high proportion of patients who were medically unfit for surgery or declined surgery may have conferred a selection bias. CONCLUSION: Concurrent chemoradiotherapy followed by surgery is feasible in selected patients. The benefit of adding of surgery to chemoradiotherapy is still controversial and we await the results of randomised controlled trials comparing chemoradiotherapy with surgery versus chemoradiotherapy alone.

Unusual case of bowel infarction with invasive Aspergillus in an immunocompromised patient.

INTRODUCTION: We report a patient with bowel infarction due to invasive Aspergillus infection as a result of prolonged chemotherapy-induced neutropenia. CLINICAL PICTURE: The patient was given neoadjuvant chemotherapy with doxorubicin, docetaxel, and capecitabine for a breast tumour. She developed prolonged neutropenia, Escherichia coli and Candida krusei sepsis, acute arterial thrombosis of the left lower limb, and invasive aspergillus infection. TREATMENT: She underwent a subtotal colectomy, small intestine resection and an above-knee amputation. OUTCOME: The hospitalisation was complicated with methicillin-resistant Staphylococcus aureus pneumonia and short gut syndrome. She subsequently underwent simple mastectomy with axillary clearance and received adjuvant chemotherapy and radiation without complication. CONCLUSION: Chemotherapy should be protocol-directed. In a non-trial situation, protocol must have a sound basis, proven safety, and efficacy. Aspergillus infection is uncommon in patients with solid tumours; prompt treatment must be started on high suspicion.

Gastric carcinoma presenting with cellulitis-like cutaneous metastasis.

INTRODUCTION: A case of carcinoma of the stomach presenting with cellulitis-like cutaneous metastasis is reported. CLINICAL PICTURE: This patient was diagnosed to have early stage carcinoma of the prostate (T1bN0M0), which was treated with radiotherapy and hormonal therapy. He presented with an erythematous area of induration over the right neck a few weeks after the completion of radical radiotherapy. The CT scan of the neck showed features suggestive of cellulitis of the right cervical region. Due to the lack of response to intravenous antibiotics, a fine needle aspiration biopsy of the indurated area was done. This confirmed the presence of adenocarcinoma. Due to the presence of iron-deficiency anaemia and the positive occult blood test in the stool, an upper gastrointestinal endoscopy was done. This confirmed the presence of adenocarcinoma of the stomach of the signet-ring cell type. OUTCOME: He had a rapid downhill course after the diagnosis and died four weeks after the diagnosis was made. CONCLUSION: Carcinoma of the stomach can rarely present with cutaneous metastasis as a cellulitis-like picture.

A Bayesian re-assessment of two Phase II trials of gemcitabine in metastatic nasopharyngeal cancer.

The Simon two-stage minimax design is a popular statistical design used in Phase II clinical trials. The analysis of the data arising from the design typically involves the use of frequentist statistics. This paper presents an alternative, Bayesian, approach to the design and analysis of Phase II clinical trials. In particular, we consider how a Bayesian approach could have affected the design, analysis and interpretation of two parallel Phase II trials of the National Cancer Centre Singapore, on the activity of gemcitabine in chemotherapy-naïve and in previously treated patients with metastatic nasopharyngeal carcinoma. We begin by explaining the Bayesian methodology and contrasting it with the frequentist approach. We then carry out a Bayesian analysis of the trial results. The conclusions drawn using the Bayesian approach were in general agreement with those obtained from the frequentist analysis. However they had the advantage of allowing for different and potentially more useful interpretations to be made regarding the trial results, as well as for the incorporation of external sources of information. In particular, using a Bayesian trial design, we were able to take into account the results of the parallel trial results when deciding whether to continue each trial beyond the interim stage.

Gemcitabine in metastatic nasopharyngeal carcinoma of the undifferentiated type.

BACKGROUND: We conducted two parallel phase II trials in chemonaïve and previously treated patients with metastatic nasopharyngeal carcinoma (NPC) to evaluate the tumour response, progression-free and overall survival, and toxicity of gemcitabine. PATIENTS AND METHODS: Gemcitabine 1250 mg/m2 was given on days 1 and 8 of a 21-day cycle. Patients with an Eastern Cooperative Oncology Group performance status <2, adequate renal, hepatic and bone marrow function, and radiologically measurable NPC were eligible. RESULTS: Twenty-five chemonaïve and 27 previously treated patients were enrolled. The overall response rate was 28% [95% confidence interval (CI) 14% to 48%] for the chemonaïve and 48% (95% CI 31% to 66%) for previously treated patients. Toxicities greater than or equal to grade 3 occurred in 15 (60%) chemonaïve and 13 (48%) previously treated patients. Neutropenia was uncommon in chemonaïve patients, but occurred in 37% of previously treated patients. The median time to progression was 3.6 months (range 0.9-7.9) for chemonaïve and 5.1 months (0.9-13.1) for previously treated patients. Median overall survival time was 7.2 months (1.4-15.6) and 10.5 months (2.4-15.0) for chemonaïve and previously treated patients, respectively. CONCLUSIONS: Gemcitabine has moderate activity in NPC with minimal toxicity, and is also an effective salvage agent for patients who have failed or progressed after treatment with other agents.

A case of alpha-fetoprotein-producing gastric cancer.

INTRODUCTION: A case of alpha-fetoprotein (AFP)-producing gastric cancer is described in a 57-year-old Chinese woman. CLINICAL PICTURE: She presented with bleeding tendency and bone pain, and was found to have haematological evidence of disseminated intravascular coagulation and spinal metastasis. Her tumour markers, including AFP, Ca 19-9 and carcinoembryonic antigen (CEA) were elevated. In view of the elevated tumour markers, there was an exhaustive search for a primary lesion in the gastrointestinal tract, liver and ovaries. There was no radiological evidence to suggest any lesion in the chest, liver or pelvis. Lectin affinity electrophoresis of the AFP showed AFP-L2 and AFP-L3 bands, which are suggestive of a non-hepatoma malignancy. MANAGEMENT: Gastroscopy showed a gastric ulcer and she developed bleeding after the gastric biopsy which required urgent surgery. Intraoperatively she was found to have carcinomatous peritone and a malignant ulcer in the greater curve of the stomach. Histology confirmed a linitis plastica like adenocarcinoma which stains for AFP. OUTCOME: She died from multi-organ failure 3 days after surgery. CONCLUSION: AFP-producing adenocarcinoma of the stomach is not uncommon. Lectin affinity electrophoresis of AFP is helpful in the differentiation between hepatoma and non-hepatoma malignancies.

Concurrent chemoradiotherapy followed by adjuvant chemotherapy in Asian patients with nasopharyngeal carcinoma: toxicities and preliminary results.

PURPOSE: Nasopharyngeal carcinoma (NPC) is endemic in Singapore. Nearly 60% of the patients diagnosed with NPC will present with locally advanced disease. The North American Intergroup study 0099 reported improved survival outcome in patients with locally advanced NPC who received combined chemoradiotherapy when compared to radiotherapy alone. Hence we explored the feasibility and efficacy of a similar protocol in our patients. METHODS AND MATERIALS: Between June 1996 and December 1997, 57 patients were treated with the following schedule as described. Radical radiotherapy (RT) of 66-70 Gy to the primary and neck with cisplatin (CDDP) 25 mg/m2 on days 1-4 given by infusion over 6-8 hours daily on weeks 1, 4, and 7 of the RT. This is followed by a further 3 cycles of adjuvant chemotherapy starting from week 11 from the first dose of radiation (CDDP 20 mg/m2/d and 5-fluorouracil [5-FU] 1 gm/m2/d on days 1-4 every 28 days). RESULTS: The majority of patients (68%) had Stage IV disease. About 54% of patients received all the intended treatment; 75% received all 3 cycles of CDDP during the RT phase and 63% received all three cycles of adjuvant chemotherapy. The received dose intensity of CDDP and 5-FU of greater than 0.8 was achieved in 58% and 60% of the patients respectively. Two treatment-related deaths due to reactivation of hepatitis B and neutropenic sepsis respectively, were encountered. At median follow-up of 16 months, 14 patients had relapsed, 12 systemically and 2 loco-regionally. CONCLUSION: Due to the acceptable tolerability of such a protocol in our cohort of patients, we have embarked on a Phase III study to confirm the results of the 0099 Intergroup study in the Asian context.