Phase II study of capecitabine as palliative treatment for patients with recurrent and metastatic squamous head and neck cancer after previous platinum-based treatment

Background:

Platinum-based therapy (PBT) is the standard therapy for recurrent and/or metastatic head and neck cancer (HNC), but the incidence of recurrence remains high. This study evaluates the efficacy and tolerability of capecitabine as palliative monotherapy for recurrent HNC previously treated with PBT.

Methods:

Patients aged 18–75 years, with Eastern Cooperative Oncology Group performance status 0–2, squamous HNC with locoregional and/or metastatic recurrence previously treated with PBT and adequate organ functions, were included. Capecitabine (1.250 mg m⁻² BID) was administered on days 1–14 every 21 days for at least two cycles.

Results:

A total of 40 male patients with a median age of 58 years were analysed. All patients received a median number of four cycles of capecitabine (range: 1–9) and the median relative dose intensity was 91%. Seven patients were not evaluable for response. Overall response rate was 24.2%. Median time to progression and overall survival were 4.8 and 7.3 months, respectively. Haematological adverse events (AEs) grade 3/4 were reported in six patients. Most common grade 3/4 non-haematological AEs were asthenia (12.5%), palmar-plantar eritrodisestesia (10%), mucositis (10%), dysphagia (10%) and diarrhoea (7.5%).

Conclusions:

Capecitabine seems to be an active, feasible and well-tolerated mode of palliative treatment for advanced HNC patients who have previously received PBT schedules.     

Regorafenib (BAY 73-4506) in advanced colorectal cancer: a phase I study

Background:

In a phase I dose-escalation study, regorafenib demonstrated tolerability and antitumour activity in solid tumour patients. The study was expanded to focus on patients with metastatic colorectal cancer (CRC).

Methods:

Patients received oral regorafenib 60–220 mg daily (160 mg daily in the extension cohort) in cycles of 21 days on, 7 days off treatment. Assessments included toxicity, response, pharmacokinetics and pharmacodynamics.

Results:

Thirty-eight patients with heavily pretreated CRC (median 4 prior lines of therapy, range 0–7) were enrolled in the dose-escalation and extension phases; 26 patients received regorafenib 160 mg daily. Median treatment duration was 53 days (range 7–280 days). The most common treatment-related toxicities included hand–foot skin reaction, fatigue, voice change and rash. Twenty-seven patients were evaluable for response: 1 achieved partial response and 19 had stable disease. Median progression-free survival was 107 days (95% CI, 66–161). At steady state, regorafenib and its active metabolites had similar systemic exposure. Pharmacodynamic assessment indicated decreased tumour perfusion in most patients.

Conclusion:

Regorafenib showed tolerability and antitumour activity in patients with metastatic CRC. This expanded-cohort phase I study provided the foundation for further clinical trials of regorafenib in this patient population.     

Paclitaxel-ifosfamide-carboplatin combination chemotherapy regimen in advanced uterine and adnexal malignant mixed Mullerian tumours

Background:

Malignant mixed Mullerian tumours (MMMTs) of the uterus and adnexa represent aggressive gynaecologic malignancies with a high rate of loco-regional and distant failure. For that reason, we evaluated the paclitaxel–ifosfamide–carboplatin (TICb) combination in patients with advanced MMMTs.

Methods:

Female patients with advanced MMMTs, WHO-PS 0–2, no prior chemotherapy for systemic disease, unimpaired haemopoietic and organ function were eligible. Chemotherapy was administered at the following doses; paclitaxel: 175 mg m^–2 on day 1, ifosfamide: 2.0g m^–2 day^–1 – days 1 and 2, and carboplatin at a target area under the curve 5 on day 2, with prophylactic G-CSF from day 3.

Results:

Forty patients of a median age 61 (45–72) years, performance status 0–2 with advanced MMMTs of the uterus (n=34), tubes (n=2) or ovary (n=4) have entered and all were evaluable for response and toxicity. Responses were as follows: 27 out of 40 (67.5%) evaluable patients responded, with 11 complete responses and 16 partial responses, while 10 had stable disease, and 3 developed progressive disease. The median response duration was 9 months (range, 4–40 months), median progression-free survival 13 months (range, 3–42 months), while median overall survival 18 months (range, 4–48 months). Grade 3/4 neutropenia was recorded in 22 out of 40 (55%) – with 13 developing grade 4 (⩽7 days) and 7 out of 40 (17.5%) of patients at least one episode of febrile neutropenia.

Conclusion:

In this study, it appears that the TICb combination, yielded important activity with manageable toxicity in females with advanced MMMTs warranting further randomised comparison with current standard regimens.     

Evaluation of the clinical benefits of nanoparticle albumin-bound paclitaxel in women with metastatic breast cancer in British Columbia

Background

Altered formulations of taxanes may lack cross-resistance with standardly used solvent-based taxanes. The primary objective of the present study was to assess the clinical benefit of nanoparticle albumin-bound (nab)–paclitaxel in women with metastatic breast cancer previously treated with and without adjuvant taxane in British Columbia.

Methods

The BC Cancer Agency Pharmacy data repository and Breast Cancer Outcomes Unit database were linked to identify all patients who received nab-paclitaxel in British Columbia since its introduction in 2007. Hormone receptor status, demographic characteristics, number of cycles prescribed, and time to treatment failure were extracted and analyzed.

Results

From 2007 to 2011, 138 patients in British Columbia received nab-paclitaxel, with 122 patients available for analysis. Most (70.5%) received adjuvant chemotherapy; about a quarter (24.6%) received an adjuvant taxane. Patients who received adjuvant taxane were more likely to have node-positive (86.7% vs. 48.9%, p = 0.007), estrogen receptor–negative (46.7% vs. 13.0% p < 0.001) disease and to receive initial adjuvant radiotherapy (76.7% vs. 51.1%, p < 0.001). For the entire cohort, the median number of nab-paclitaxel cycles prescribed was 4.4 (range: 0.3–13). The median number of nab-paclitaxel cycles was greater when that agent was given as first- or second-line therapy than as third-line or greater therapy (5.0 cycles vs. 3.7 cycles respectively). The median time to treatment failure was 96 days in the prior adjuvant taxane group (range: 0–361) and 73.5 days in the no prior adjuvant taxane group (range: 0–1176).

Conclusions

This retrospective study demonstrates potential clinical activity of nab-paclitaxel in metastatic breast cancer regardless of whether patients had prior exposure to adjuvant taxanes.     

Activity and safety of NGR-hTNF, a selective vascular-targeting agent, in previously treated patients with advanced hepatocellular carcinoma

Background:

Hepatocellular carcinoma (HCC) is a highly vascularised and poor-prognosis tumour. NGR-hTNF is a vascular-targeting agent consisting of human tumour necrosis factor-alpha fused to the tumour-homing peptide NGR, which is able to selectively bind an aminopeptidase N overexpressed on tumour blood vessels.

Methods:

Twenty-seven patients with advanced-stage disease resistant to either locoregional (59% range, 1–3), systemic treatments (52% range, 1–3) or both (33%) received NGR-hTNF 0.8 μg m⁻² once every 3 weeks. The primary aim of the study was progression-free survival (PFS).

Results:

No grade 3–4 treatment-related toxicities were noted. Common toxicity included mild-to-moderate, short-lived chills (63%). Median PFS was 2.3 months (95% CI: 1.7–2.9). A complete response ongoing after 20 months was observed in a sorafenib-refractory patient and a partial response in a Child-Pugh class-B patient, yielding a response rate of 7%. Six patients (22%) experienced stable disease. The disease control rate (DCR) was 30% and was maintained for a median PFS time of 4.3 months. Median survival was 8.9 months (95% CI: 7.5–10.2). In a subset of 12 sorafenib-resistant patients, the response rate was 8% and the median survival was 9.5 months.

Conclusion:

NGR-hTNF was well tolerated and showed single-agent activity in HCC. Further investigation in HCC is of interest.     

Addition of GM-CSF to trastuzumab stabilises disease in trastuzumab-resistant HER2+ metastatic breast cancer patients

Background:

One of the proposed mechanisms of trastuzumab-induced regression of human epidermal growth factor receptor 2-positive (HER2+) tumours includes facilitation of antibody-dependent cell-mediated cytotoxicity (ADCC). Granulocyte-macrophage colony-stimulating factor (GM-CSF) mediates ADCC. We presented our pilot study of adding GM-CSF to trastuzumab in patients with trastuzumab-resistant HER2+ metastatic breast cancer.

Methods:

Patients with HER2+ metastatic breast cancer that progressed after trastuzumab +/− chemotherapy were continued on trastuzumab 2 mg kg^–1 intravenous weekly and GM-CSF 250 μg m^–2 subcutaneous daily. Patients were assessed for response every 8 weeks. Treatment was continued until disease progression or intolerable toxicity.

Results:

Seventeen patients were evaluable (median age 48 years, range 27–75 years). The median number of metastatic sites was 2 (range 1–3); the most common site was the liver (n=10). The median number of prior regimens for metastatic disease was 2 (range 1–5). No objective disease response was observed, but five patients (29%) had stable disease for a median duration of 15.8 (range 10–53.9) weeks. The most common adverse event was rash at the injection site. No grade 4 or irreversible adverse event was seen.

Conclusion:

The addition of GM-CSF to trastuzumab alone had a modest clinical benefit and acceptable safety profile in heavily pretreated patients with trastuzumab-resistant HER2+ metastatic breast cancer.     

A phase II study of weekly docetaxel and cisplatin plus oral tegafur/uracil and leucovorin as first-line chemotherapy in patients with locally advanced or metastatic gastric cancer

Background:

Docetaxel plus cisplatin and 5-fluorouracil has become a new standard for treating advanced gastric cancer. However, high rates of severe neutropenia limit its application. Modification of the regimen could be the solution to get similar activity but less myelosuppression.

Methods:

Patients with histologically confirmed, locally advanced, or recurrent/metastatic gastric adenocarcinoma without previous chemotherapy were enrolled. This regimen consisted of docetaxel (Tyxan, TTY, Taipei, Taiwan) 30-min infusion at a dose of 36 mg m⁻², followed by cisplatin 30 mg m⁻² infusion over 1 h on days 1 and 8, and oral tegafur/uracil 300 mg m⁻² per day plus leucovorin 90 mg per day on days 1–14, every 3 weeks. Tumour response was evaluated after every 2 cycles of treatment.

Results:

From August 2007 to March 2009, 45 patients were enrolled. The median age was 56 years (range: 22–75). Among the 40 patients evaluable for tumour response, one achieved a complete response, 22 had partial responses and 11 had stable disease. The overall response rates of the evaluable and intent-to-treat (ITT) populations were 58% (95% CI: 41–74%) and 53% (95% CI: 38–68%), respectively. The disease control rates in these populations were 85% (95% CI: 70–94%) and 82% (95% CI: 68–92%), respectively. In the ITT analysis, the median time to progression and overall survival were 6.8 and 13.9 months, respectively. Major grade 3–4 toxicities were neutropenia (51%), anaemia (22%), diarrhoea (16%), and infections (20%). No patient died of treatment-related toxicities.

Conclusion:

Concurrent weekly docetaxel and cisplatin plus oral tegafur/uracil and leucovorin are effective and well tolerated in the treatment of advanced gastric cancer.     

Sorafenib in patients with advanced biliary tract carcinoma: a phase II trial

Background:

Advanced biliary tract carcinoma has a very poor prognosis, with chemotherapy being the mainstay of treatment. Sorafenib, a multikinase inhibitor of VEGFR-2/-3, PDGFR-β, B-Raf, and C-Raf, has shown to be active in preclinical models of cholangiocarcinoma.

Methods:

We conducted a phase II trial of single-agent sorafenib in patients with advanced biliary tract carcinoma. Sorafenib was administered at a dose of 400 mg twice a day. The primary end point was the disease control rate at 12 weeks.

Results:

A total of 46 patients were treated. In all, 26 (56%) had received chemotherapy earlier, and 36 patients completed at least 45 days of treatment. In intention-to-treat analysis, the objective response was 2% and the disease control rate at 12 weeks was 32.6%. Progression-free survival (PFS) was 2.3 months (range: 0–12 months), and the median overall survival was 4.4 months (range: 0–22 months). Performance status was significantly related to PFS: median PFS values for ECOG 0 and 1 were 5.7 and 2.1 months, respectively (P=0.0002). The most common toxicities were skin rash (35%) and fatigue (33%), requiring a dose reduction in 22% of patients.

Conclusions:

Sorafenib as a single agent has a low activity in cholangiocarcinoma. Patients having a good performance status have a better PFS. The toxicity profile is manageable.     

Molecular Tumor Board: The University of California San Diego Moores Cancer Center Experience

Objective.

DNA sequencing tests are enabling physicians to interrogate the molecular profiles of patients’ tumors, but most oncologists have not been trained in advanced genomics. We initiated a molecular tumor board to provide expert multidisciplinary input for these patients.

Materials and Methods.

A team that included clinicians, basic scientists, geneticists, and bioinformatics/pathway scientists with expertise in various cancer types attended. Molecular tests were performed in a Clinical Laboratory Improvement Amendments environment.

Results.

Patients (n = 34, since December 2012) had received a median of three prior therapies. The median time from physician order to receipt of molecular diagnostic test results was 27 days (range: 14–77 days). Patients had a median of 4 molecular abnormalities (range: 1–14 abnormalities) found by next-generation sequencing (182- or 236-gene panels). Seventy-four genes were involved, with 123 distinct abnormalities. Importantly, no two patients had the same aberrations, and 107 distinct abnormalities were seen only once. Among the 11 evaluable patients whose treatment had been informed by molecular diagnostics, 3 achieved partial responses (progression-free survival of 3.4 months, ≥6.5 months, and 7.6 months). The most common reasons for being unable to act on the molecular diagnostic results were that patients were ineligible for or could not travel to an appropriately targeted clinical trial and/or that insurance would not cover the cognate agents.

Conclusion.

Genomic sequencing is revealing complex molecular profiles that differ by patient. Multidisciplinary molecular tumor boards may help optimize management. Barriers to personalized therapy include access to appropriately targeted drugs.     

All-oral combination of oral vinorelbine and capecitabine as first-line chemotherapy in HER2-negative metastatic breast cancer: an International Phase II Trial

Background:

This multicentre, international phase II trial evaluated the efficacy and safety profile of a first-line combination of oral vinorelbine plus capecitabine for women with metastatic breast cancer (MBC).

Methods:

Patients with measurable, HER2-negative disease received, as a first line in metastatic setting, 3-weekly cycles of oral vinorelbine 80 mg m⁻² (after a first cycle at 60) on day 1 and day 8, plus capecitabine 1000 mg m⁻² (750 if ⩾65 years of age) twice daily, on days 1–14. Treatment was continued until progression or unacceptable toxicity.

Results:

A total of 55 patients were enrolled and 54 were treated (median age: 58.5 years). Most (78%) had visceral involvement and 63% had received earlier (neo)adjuvant chemotherapy. The objective response rate (RECIST) in 49 evaluable patients was 51% (95% confidence interval (CI), 36–66), including complete response in 4%. The clinical benefit rate (response or stable disease for ⩾6 months) was 63% (95% CI, 48–77). The median duration of response was 7.2 months (95% CI, 6.4–10.2). After a median follow-up of 41 months, median progression-free survival was 8.4 months (95% CI, 5.8–9.7) and median overall survival was 29.2 months (95% CI, 18.2–40.1). Treatment-related adverse events were manageable, the main grade 3–4 toxicity was neutropaenia (49%); two patients experienced febrile neutropaenia and three patients had a neutropaenic infection (including one septic death). A particularly low rate of alopaecia was observed.

Conclusion:

These results show that the all-oral combination of oral vinorelbine and capecitabine is an effective and well-tolerated first-line regimen for MBC.     

Frequency,Outcome, and Predictors of Success Within 6 Weeks of an Opioid Rotation Among Outpatients with Cancer Receiving Strong Opioids

Background.

Opioid rotation is used to treat uncontrolled pain and/or opioid-related adverse effects. Our aim was to determine the frequency, indications, outcomes, and predictors of successful opioid rotation in outpatients with cancer.

Methods.

Medical records of consecutive outpatients with cancer who received strong opioids and returned for follow-up visit within ≤6 weeks to our supportive care center from January to December 2008 were reviewed. Data on patient characteristics, symptoms, opioid use, indications for opioid rotation, outcomes, and morphine equivalent daily dose were collected. Successful opioid rotation was defined as a two-point or 30% reduction in the symptom score or the resolution of opioid-induced neurotoxicity and continuation of the new opioid at follow-up.

Results.

Opioid rotation was performed in 120 of 385 patients (31%). The median patient age was 55 years. There were 6/120 patients with missing data. Of the 114 evaluable patients, 68 (60%) were men, 81 (71%) were white, 27 (24%) had gastrointestinal cancer, and 90 (80%) had advanced-stage disease. The median Eastern Cooperative Oncology Group score was 1 (interquartile range: 1–2) and the median time between opioid rotation and follow-up was 14 days (interquartile range: 7–21 days). The most common indications for opioid rotation were uncontrolled pain (95/114; 83%) and opioid-induced neurotoxicity (13/114; 12%). A total of 35 patients (31%) had partial opioid rotation. The median improvements in pain and symptom distress score were −2 (interquartile range: −4 to 0; p < .001) and −5 (interquartile range: −14 to 7; p = .004), respectively. The morphine equivalent daily dose did not change significantly after opioid rotation (p = .156). A total of 65% of patients (74/114) had successful opioid rotation. There were no clinically significant independent predictors for successful opioid rotation.

Conclusion.

Opioid rotation was conducted in 31% of outpatients with cancer, with a 65% success rate. The most frequent reason for opioid rotation was uncontrolled pain. There were no independent predictors for successful opioid rotation.     

Accelerated BEP: a phase I trial of dose-dense BEP for intermediate and poor prognosis metastatic germ cell tumour

Background:

We used bleomycin, etoposide, cisplatin (BEP), the most effective regimen in the treatment of germ cell tumours (GCTs) and increased dose-density by using pegfilgrastim to shorten cycle length. Our aim was to assess safety and tolerability.

Methods:

Sixteen male patients with intermediate or poor prognosis metastatic GCT were treated with four cycles of 3-day BEP with G-CSF on a 14-day cycle for a planned relative dose-density of 1.5 compared with standard BEP.

Results:

Eleven intermediate and five poor prognosis patients were treated. In all, 14 of 16 patients completed the study treatment. Toxicities were comparable to previous studies using standard BEP, except for mucositis and haematological toxicity that were more severe. The overall relative dose-density for all 16 patients was mean 1.38 (range 0.72–1.5; median 1.46). Complete response was achieved after chemotherapy alone in two patients (13%) and following chemotherapy plus surgery in nine additional patients (56%). Four patients (25%) had a partial response and normalised their marker levels. At a median follow-up of 4.4 years (range 2.1–6.8) the estimated 5-year progression-free survival probability is 81% (95% CI 64–100%).

Conclusion:

Accelerated BEP is tolerable without major additional toxicity. A randomised controlled trial will be required to obtain comparative efficacy data.     

Treatment of HER2-positive metastatic breast cancer with lapatinib and capecitabine in the lapatinib expanded access programme, including efficacy in brain metastases �C the UK experience

Background:

The global lapatinib expanded access programme provided access to lapatinib combined with capecitabine for women with HER2-positive metastatic breast cancer (MBC) who previously received anthracycline, taxane and trastuzumab.

Methods:

Progression-free survival (PFS) and safety data for 356 patients recruited from the United Kingdom are reported. Efficacy was assessed in 162 patients from the five lead centres, including objective tumour response rate (ORR), time to disease progression (TTP) and efficacy in those with central nervous system (CNS) metastases. Correlation of PFS and ORR with previous capecitabine treatment was also documented.

Results:

Overall, PFS for the 356 UK patients was 21 weeks (95% CI: 17.6–24.7). In the 162 assessable patients, ORR was 21% (95% CI: 15–27%) and median TTP was 22 weeks (95% CI: 17–27). Efficacy was greater in capecitabine-naive patients (ORR 23 vs 16.3%, P=0.008). For 34 patients with CNS metastases, ORR was 21% (95% CI: 9–39%), with evidence of improvement in neurological symptoms, and median TTP was 22 weeks (95% CI: 15–28).

Conclusions:

Lapatinib combined with capecitabine is an active treatment option for women with refractory HER2-positive MBC, including those with progressive CNS disease.     

An external validation study of nomograms designed to predict isolated loco-regional and distant endometrial cancer recurrences: how applicable are they?

Background:

To externally validate and assess the robustness of two nomograms to predict the recurrence risk of women with endometrial cancer (EC).

Methods:

Using an independent, multicentre external patient cohort we assessed the discrimination and calibration of two nomograms – the 3-year isolated loco-regional (ILRR) and distant (DR) recurrence nomograms – in women with surgically treated stage I–III EC.

Results:

Two hundred and seventy one eligible women were identified from two university hospital databases and the Senti-Endo trial. The median follow-up and initial recurrence time were 38.1 (range: 12–69) and 22.0 (range: 8.3–55) months, respectively. The overall recurrence rate was 13.8% (37 out of 271). Predictive accuracy according to the discrimination was 0.69 (95% CI, 0.58–0.79) and 0.66 (95% CI, 0.60–0.71) for the 3-year ILRR and DR nomograms, respectively. The correspondence between observed recurrence rate and the nomogram predictions suggests a moderate calibration of the nomograms in the validation cohort.

Conclusion:

The nomograms were externally validated and shown to be partly generalisable to a new and independent patient population. The tools need to be improved by including information on the lymph node status and adjuvant therapies.     

Multi-centre phase II clinical trial of yttrium-90 resin microspheres alone in unresectable, chemotherapy refractory colorectal liver metastases

Background:

This multi-centre phase II clinical trial is the first prospective evaluation of radioembolisation of patients with colorectal liver metastases (mCRC) who failed previous oxaliplatin- and irinotecan-based systemic chemotherapy regimens.

Methods:

Eligible patients had adequate hepatic, haemopoietic and renal function, and an absence of major hepatic vascular anomalies and hepato-pulmonary shunting. Gastroduodenal and right gastric arteries were embolised before hepatic arterial administration of yttrium-90 resin microspheres (median activity, 1.7 GBq; range, 0.9–2.2).

Results:

Of 50 eligible patients, 38 (76%) had received ⩾4 lines of chemotherapy. Most presented with synchronous disease (72%), >4 hepatic metastases (58%), 25–50% replacement of total liver volume (60%) and bilateral spread (70%). Early and intermediate (>48 h) WHO G1–2 adverse events (mostly fever and pain) were observed in 16 and 22% of patients respectively. Two died due to renal failure at 40 days or liver failure at 60 days respectively. By intention-to-treat analysis using Response Evaluation Criteria in Solid Tumours, 1 patient (2%) had a complete response, 11 (22%) partial response, 12 (24%) stable disease, 22 (44%) progressive disease; 4 (8%) were non-evaluable. Median overall survival was 12.6 months (95% CI, 7.0–18.3); 2-year survival was 19.6%.

Conclusion:

Radioembolisation produced meaningful response and disease stabilisation in patients with advanced, unresectable and chemorefractory mCRC.     

Circulating tumour cells in the central and the peripheral venous compartment in patients with metastatic breast cancer

Background:

The enumeration of circulating tumour cells (CTC) has prognostic significance in patients with metastatic breast cancer (MBC) and monitoring of CTC levels over time has considerable potential to guide treatment decisions. However, little is known on CTC kinetics in the human bloodstream.

Methods:

In this study, we compared the number of CTC in both 7.5 ml central venous blood (CVB) and 7.5 ml peripheral venous blood (PVB) from 30 patients with MBC starting with a new line of chemotherapy.

Results:

The number of CTC was found to be significantly higher in CVB (median: 43.5; range: 0–4036) than in PVB (median: 33; range: 0–4013) (P=0.001). When analysing samples pairwise, CTC counts were found to be significantly higher in CVB than in PVB in 12 out of 26 patients with detectable CTC. In contrast, only 2 out of 26 patients had higher CTC counts in PVB as compared with CVB, whereas in 12 remaining patients no significant difference was seen. The pattern of CTC distribution was independent of the sites of metastatic involvement.

Conclusion:

A substantial difference in the number of CTC was observed between CVB and PVB of patients with MBC. Registration of the site of blood collection is warranted in studies evaluating the role of CTC assessment in these patients.     

Long-term survival after treatment for Hodgkin's disease (1973-2002): improved survival with successive 10-year cohorts

Background:

The Nottinghamshire Lymphoma Registry contains the details of all the patients diagnosed with lymphoma (since 1 January 1973) within a defined geographical area with a population of 1.1 million. It was therefore possible to study the outcome of treatment for Hodgkin''s disease for three 10-year cohorts (1973–1982, 1983–1992 and 1993–2002).The aims of the study were to compare survival time among the three patient cohorts, to identify prognostic factors and to estimate relative survival.

Methods:

A total of 745 patients diagnosed between 1973 and 2002 were analysed for survival. Survivorship was estimated by the Kaplan-Meier method and parametric survival models. An accelerated failure-time regression was used for multivariate analysis.

Results:

Overall, patients were observed for 9.8 (0.3–34.82) years (median(range)), on average. One, five and fifteen-year disease-specific survival was found to be 87% (85–90%), 77% (74–80%) and 70% (67–74%), respectively. For those for diagnosed between 1973 and 1982, the 15-year survival was found to be 57% for 1983–1992, it was 74% and for 1993–2002, it was 83% (P<0.001). The difference remained significant after adjusting for prognostic factors. The actuarial risk of developing a second malignancy at 20 years was for the 1973–1982 cohort, 12.4%, and for the 1983–1992 cohort, 18.8%.

Conclusion:

Treatment advances and effective management of toxicities of treatment over time, have resulted in a significantly longer survival for patients with Hodgkin''s disease diagnosed within a defined population.     

Measures of promptness of cancer diagnosis in primary care: secondary analysis of national audit data on patients with 18 common and rarer cancers

Background:

Evidence is needed about the promptness of cancer diagnosis and associations between its measures.

Methods:

We analysed data from the National Audit of Cancer Diagnosis in Primary Care 2009–10 exploring the association between the interval from first symptomatic presentation to specialist referral (the primary care interval, or ‘interval'' hereafter) and the number of pre-referral consultations.

Results:

Among 13 035 patients with any of 18 different cancers, most (82%) were referred after 1 (58%) or 2 (25%) consultations (median intervals 0 and 15 days, respectively) while 9%, 4% and 5% patients required 3, 4 or 5+ consultations (median intervals 34, 47 and 97 days, respectively) (Spearman''s r=0.70). The association was at least moderate for any cancer (Spearman''s r range: 0.55 (prostate)−0.77 (brain)). Patients with cancers with a higher proportion of three or more pre-referral consultations typically also had longer median intervals (e.g., multiple myeloma) and vice versa (e.g., breast cancer).

Conclusion:

The number of pre-referral consultations has construct validity as a measure of the primary care interval. Developing interventions to reduce the number of pre-referral consultations can help improve the timeliness of cancer diagnosis, and constitutes a priority for early diagnosis initiatives and research.     

No association between germline allele-specific expression of TGFBR1 and colorectal cancer risk in Caucasian and Ashkenazi populations

Background:

Germline allele-specific expression (ASE) of the TGFBR1 gene has been reported as a strong risk factor for colorectal cancer (CRC) with an odds ratio close to 9. Considering the potential implications of the finding, we undertook the task of validating the initial results in this study.

Methods:

Allele-specific expression was measured using the highly quantitative and robust technique of pyrosequencing. Individuals from two different populations were studied, one Caucasian-dominated and the other of Ashkenazi Jewish descent, with different sources of non-tumoral genetic material in each.

Results:

Our results showed no statistically significant differences in the degree of ASE between CRC patients and controls, considering ASE as either a quantitative or a binary trait. Using defined cutoff values to categorise ASE, 1.0% of blood lymphocytes from informative Israeli cases (total n=96) were ASE positive (median 1.00; range 0.76–1.31) and 2.2% of informative matched controls (total n=90) were ASE positive (median 1.00; range 0.76–1.87). Likewise, normal mucosae from Spanish patients (median 1.03; range: 0.68–1.43; n=75) did not show significant differences in the degree of ASE when compared with the Israeli patients or controls.

Conclusions:

Taken together, these results suggest that ASE of TGFBR1 does not confer an increased risk of CRC.     

Prognosis and prognostic factors of patients with mesothelioma: a population-based study

Background:

It is important to regularly update survival estimates of patients with malignant mesothelioma as prognosis may vary according to epidemiologic factors and diagnostic and therapeutic management.

Methods:

We assessed overall (baseline) survival as well as related prognostic variables in a large cohort of 1353 patients with a confirmed diagnosis of malignant mesothelioma between 2005 and 2008.

Results:

About 50% of the patients were 70 years or older at diagnosis and the median latency time since start of asbestos exposure was 49 years. One year after diagnosis, 47% of the patients were alive, 20% after 2 years and 15% after 3 years. Prognostic variables independently associated with worse survival were: older age (HR=1.04 per year 95% CI (1.03–1.06)), sarcomatoid subtype (HR=2.45 95% CI (2.06–2.90)) and non-pleural localisation (HR=1.67 95% CI (1.26–2.22)).

Conclusion:

Survival of patients with malignant mesothelioma is still limited and depends highly on patient age, mesothelioma subtype and localisation. In addition, a substantial part of the patients had a long latency time between asbestos exposure and diagnosis.