Correlation of BRAF and NRAS mutation status with outcome,site of distant metastasis and response to chemotherapy in metastatic melanoma

Background:

The prognostic significance of BRAF and NRAS mutations in metastatic melanoma patients remains uncertain, with several studies reporting conflicting results, often biased by the inclusion of patients treated with BRAF and MEK (MAPK) inhibitors. We therefore interrogated a historical cohort of patients free of the confounding influence of MAPK inhibitor therapy.

Methods:

Patients with available archival tissue first diagnosed with metastatic melanoma between 2002 and 2006 were analysed. Mutational analysis was performed using the OncoCarta Panel. Patient characteristics, treatment outcome and survival were correlated with BRAF/NRAS mutation status.

Results:

In 193 patients, 92 (48%) melanomas were BRAF-mutant, 39 (20%) were NRAS-mutant and 62 (32%) were wild-type for BRAF/NRAS mutations (wt). There was no difference in response to chemotherapy based on mutation status (35–37%). The distant disease-free interval (DDFI) was significantly shorter in patients with wt melanoma (27.9 months vs 35.1 for BRAF and 49.1 for NRAS) although this was not significant in multivariate analysis. Survival from stage IV melanoma diagnosis was not significantly different based on mutation status. The DDFI was significantly shorter in patients with BRAF^V600K/R versus BRAF^V600E melanoma in univariate and multivariate analyses.

Conclusions:

BRAF and NRAS mutation status does not influence survival in metastatic melanoma.     

Phase II study of single agent capecitabine in the treatment of metastatic non-pancreatic neuroendocrine tumours

Background:

This study sought to determine the safety of single agent capecitabine, a pro-drug of 5FU, in patients with metastatic non-pancreatic neuroendocrine tumours (NETs).

Methods:

Multicentre phase II, first-line study design. Oral capecitabine was administered on days 1–14 of 3-week cycles.

Results:

Treatment was safe and well tolerated. Common toxicities were diarrhoea and fatigue.

Conclusion:

The study provides evidence to support the use of capecitabine as a substitute for infusional 5FU in the management of NETs.     

Phase II study of pazopanib monotherapy in metastatic gastroenteropancreatic neuroendocrine tumours

Background:

Treatment options for patients with metastatic gastroenteropancreatic neuroendocrine tumours (GEP NETs) are still limited. We investigated the antitumour activity and safety profile of pazopanib – a multitarget drug with anti-angiogenic activity in patients with metastatic GEP NETs.

Methods:

This was a nonrandomised, open-labeled, single-center phase II study. Pazopanib was orally administered at a dose of 800 mg daily continuously with a 28-day cycle. The primary end point was an objective response rate according to Response Evaluation Criteria in Solid Tumors (RECIST). The secondary end points were progression-free survival (PFS), overall survival (OS) and safety. An independent review of objective response was planned. The trial is registered with ClinicalTrials.gov, NCT number 01099540. Correlative biomarker analyses were performed.

Results:

Between April 2010 and February 2012, a total of 37 patients were enrolled. Thirty-two percent of the enrolled patients had pancreatic primary and 22% of the patients had colorectal primary NETs. This phase II study demonstrated an objective response rate of 18.9% (7 of the 37, 95% CI 8.0–35.2) and a disease control rate (CR+confirmed PR+stable disease) of 75.7% (28 of the 37, 95% CI, 58.8–88.2) in metastatic GEP NETs. The independent review demonstrated a higher overall response rate of 24.3% (95% CI, 11.8–41.2%) with nine confirmed PRs.

Conclusion:

Pazopanib showed a comparable efficacy to other targeted agents not only in pancreatic NETs but also in NETs originating from gastrointestinal (GI) tract.     

Serial surveillance of carcinoid heart disease: factors associated with echocardiographic progression and mortality

Background:

Carcinoid heart disease is a complication of metastatic neuroendocrine tumours (NETs). We sought to identify factors associated with echocardiographic progression of carcinoid heart disease and death in patients with metastatic NETs.

Methods:

Patients with advanced non-pancreatic NETs and documented liver metastases and/or carcinoid syndrome underwent prospective serial clinical, biochemical, echocardiographic and radiological assessment. Patients were categorised as carcinoid heart disease progressors, non-progressors or deceased. Multinomial regression was used to assess the univariate association between variables and carcinoid heart disease progression.

Results:

One hundred and thirty-seven patients were included. Thirteen patients (9%) were progressors, 95 (69%) non-progressors and 29 (21%) patients deceased. Baseline median levels of serum N-terminal pro-brain natriuretic peptide (NT-proBNP) and plasma 5-hydroxyindoleacetic acid (5-HIAA) were significantly higher in the progressors. Every 100 nmol l⁻¹ increase in 5-HIAA yielded a 5% greater odds of disease progression (OR 1.05, 95% CI: 1.01, 1.09; P=0.012) and a 7% greater odds of death (OR 1.07, 95% CI: 1.03, 1.10; P=0.001). A 100 ng l⁻¹ increase in NT-proBNP did not increase the risk of progression, but did increase the risk of death by 11%.

Conclusions:

The biochemical burden of disease, in particular baseline plasma 5-HIAA concentration, is independently associated with carcinoid heart disease progression and death. Clinical and radiological factors are less useful prognostic indicators of carcinoid heart disease progression and/or death.     

18F-FDG PET/CT surveillance at 3–6 and 12 months for detection of recurrence and second primary cancer in patients with head and neck squamous cell carcinoma

Background:

Early detection of recurrence of head and neck squamous cell carcinoma (HNSCC), which is often obscured by surgical or radiotherapy-induced tissue distortion, is essential for proper patient management.

Methods:

A total of 143 consecutive patients with previously untreated HNSCC were evaluated by whole-body fluorine 18-fluorodeoxyglucose positron emission tomography/computed tomography (¹⁸F-FDG PET/CT) and regular clinical follow-up after curative treatment. The ¹⁸F-FDG PET/CT was performed ∼3–6 and 12 months after treatment and findings suspicious for recurrence or SPC were confirmed using histopathology.

Results:

The sensitivities of 3–6- and 12-month PET/CT scans at patient level were 96% and 93%, respectively, and those of regular clinical follow-up were 11% and 19%, respectively (McNemar test, P<0.001). In patients with no clinical suspicion, PET/CT detected 95% and 91% of recurrent patients at 3–6 and 12 months, respectively. The sensitivity of PET/CT for the identification of SPC was 29% and 80% at 3–6 and 12 months, respectively. A positive interpretation of PET/CT was significantly associated with poor overall survival (log-rank test, P<0.001).

Conclusion:

The ¹⁸F-FDG PET/CT surveillance is beneficial for the detection of recurrence that may be missed by regular follow-up physical and endoscopic examinations of the head and neck area after curative treatment for HNSCC.     

Intermittent dosing of axitinib combined with chemotherapy is supported by 18FLT-PET in gastrointestinal tumours

Background:

We evaluated week-on/week-off axitinib dosing plus chemotherapy in patients with gastrointestinal tumours, including tumour thymidine uptake by fluorine-18 3′-deoxy-3′-fluorothymidine positron emission tomography (¹⁸FLT-PET).

Methods:

During a lead-in period, patients received twice daily (b.i.d.) axitinib 7 mg (n=3) or 10 mg (n=18) for 7 days followed by a 7-day dosing interruption; serial ¹⁸FLT-PET scans were performed before day 1 and on days 7, 10, and 14. Axitinib plus FOLFIRI or FOLFOX was then administered in 2-week cycles; axitinib was interrupted on day 10 of each cycle for 7 days.

Results:

The maximum tolerated dose of axitinib was 10 mg b.i.d., in a week-on/week-off schedule, combined with FOLFIRI or FOLFOX. Common all-causality grade 3 adverse events were neutropenia (38%), hypertension (33%), and fatigue (29%). Of 21 patients, 2 (10%) had a partial response and 12 (57%) had stable disease. Following 7 days of continuous axitinib dosing, tumour ¹⁸FLT uptake decreased –49% from baseline and recovered to –28% and –17% from baseline, respectively, after 3 and 7 days of axitinib interruption.

Conclusion:

Axitinib administered in a week-on/week-off schedule combined with FOLFIRI or FOLFOX is supported by ¹⁸FLT-PET data and was well tolerated in patients with gastrointestinal tumours.     

Phase I/II study of sequential therapy with irinotecan and S-1 for metastatic colorectal cancer

Background:

Both irinotecan (CPT-11) and S-1 are active against colorectal cancer; however, as S-1 is a prodrug of 5-fluorouracil (5-FU), 5-FU and its metabolites might inhibit the antitumour effect of CPT-11. Therefore, we designed a sequential combination, in which CPT-11 infusion was given on day 1 and S-1 was given orally at 80 mg m⁻² per day on days 3–16 every 3 weeks.

Methods:

Twelve patients entered the phase I study, and the recommended doses were determined as a CPT-11 dose of 150 mg m⁻² and an S-1 dose of 80 mg m⁻².

Results:

In all, 36 patients entered the phase II study, of whom 4 and 16 had complete and partial responses. The overall response rate was 55.6% (95% confidence interval, 38.1–72.1%), and median progression-free survival was 7.7 months (95% confidence interval, 4.8–12.6 months). Grade 3 neutropenia was the most common haematological toxicity and occurred in 6.5% of 215 treatment courses. Grade 3 non-haematological toxicities included anorexia (1.4%) and diarrhoea (0.9%). There was no grade 4 toxicity of any kind.

Conclusion:

Our results suggest that this regimen is convenient, safe and promising, compared with conventional regimens for patients with metastatic colorectal cancer.     

Cetuximab plus oxaliplatin/leucovorin/5-fluorouracil in first-line metastatic gastric cancer: a phase II study of the Arbeitsgemeinschaft Internistische Onkologie (AIO)

Background:

Cetuximab enhances the efficacy of chemotherapy in several cancer types. This trial assessed the activity of cetuximab and chemotherapy in advanced gastric cancer.

Methods:

Patients with previously untreated, metastatic, gastric cancer received cetuximab 400 mg m⁻² at first infusion followed by weekly infusions of 250 mg m⁻² combined with FUFOX (oxaliplatin 50 mg m⁻², 5-FU 2000 mg m⁻², and DL-folinic acid 200 mg m⁻² d1, 8, 15 and 22 qd36). The primary endpoint was tumour response.

Results:

Overall, 52 patients were enrolled. The most common grade 3/4 toxicities were diarrhoea (33%), and skin toxicity (24%). Efficacy was evaluable in 46 patients who showed a response rate of 65% (CI 95%: 50–79%) including four complete responses. Time to progression (TTP) was 7.6 months (CI 95%: 5.0–10.1 months) and overall survival (OS) was 9.5 months (CI 95%: 7.9–11.1 months). Epidermal growth factor receptor (EGFR) was detectable in 60% of tumours but showed no correlation with treatment outcome. A KRAS mutation was found in only 1 of 32 (3%) tumour samples analysed.

Conclusion:

Cetuximab plus FUFOX showed an interesting high response rate in metastatic gastric cancer. Cetuximab plus platinum–fluoropyrimidine chemotherapy is at present being investigated in a phase III randomised controlled trial.     

Phase I/II study of 131I-MIBG with vincristine and 5 days of irinotecan for advanced neuroblastoma

Background:

¹³¹I-metaiodobenzylguanidine (MIBG) is an active radiopharmaceutical in neuroblastoma. A previous study demonstrated that MIBG could be combined with vincristine and prolonged irinotecan, although 25% of first courses had grade 3 diarrhoea. The current phase I/II study evaluated MIBG with vincristine and 5 days of higher-dose irinotecan.

Methods:

Patients 1–30 years old with advanced neuroblastoma were eligible. Patients received cefixime on days −1 to +6, irinotecan (50 mg m⁻² per dose IV) on days 0–4, vincristine (2 mg m⁻²) on day 0, MIBG (555 or 666 MBq kg⁻¹) on day 1, and peripheral blood stem cells on day 13. UGT1A1 genotyping was performed in consenting patients.

Results:

Thirty-two patients (12 phase I ; 20 phase II) received 42 courses. No dose-limiting toxicities were seen during dose escalation and the recommended administered activity was 666 MBq kg⁻¹. Myelosuppression and diarrhoea were the most common toxicities, with grade 3 diarrhoea in 6% of first courses. Patients homozygous for UGT1A1*28 had more grade 4 thrombocytopenia (80% vs 37% P=0.14). Responses (five complete and four partial) occurred in 9 out of 32 (28%) patients.

Conclusions:

MIBG (666 MBq kg⁻¹) with vincristine and this irinotecan schedule is tolerable and active, with less severe diarrhoea compared with a regimen using more protracted irinotecan.     

Circulating tumour cells are associated with increased risk of venous thromboembolism in metastatic breast cancer patients

Background:

Cancer is a risk factor for venous thromboembolism (VTE). Circulating tumour cells (CTCs) are an independent predictor of survival in metastatic breast cancer (MBC) patients. The aim of this study was to test the hypothesis that CTCs are associated with the risk of VTE in MBC patients.

Methods:

This retrospective study included 290 MBC patients treated in the MD Anderson Cancer Center from January 2004 to December 2007. Circulating tumour cells were detected and enumerated using the CellSearch system before starting new lines of therapy.

Results:

At a median follow-up of 12.5 months, 25 patients experienced VTE and 53 patients died without experiencing thrombosis. Cumulative incidence of thrombosis at 12 months was 8.5% (95% confidence interval (CI)=5.5%, 12.4%). Patients with CTCs ⩾1 and ⩾5 had a higher incidence of VTE compared with patients with 0 and <5 CTCs (12-month estimate, 11.7 and 11.6% vs 3 and 6.6%; P=0.006 and P=0.076, respectively). In the multivariate model, patients with CTCs⩾1 had a hazard ratio of VTE of 5.29 (95% CI=1.58, 17.7, P=0.007) compared with patients with no CTCs.

Conclusion:

These results suggest that CTCs in MBC patients are associated with increased risk of VTE. These patients should be followed up more closely for the risk of VTE.     

Phase II study of dovitinib in patients with metastatic and/or unresectable gastrointestinal stromal tumours after failure of imatinib and sunitinib

Background:

This prospective, phase II trial evaluated the efficacy and safety of dovitinib in patients with metastatic and/or unresectable gastrointestinal stromal tumours (GISTs) after failure of at least imatinib and sunitinib.

Methods:

Patients received oral dovitinib, 500 mg once daily, for 5 consecutive days, followed by a 2-day rest, every 28 days. The primary endpoint was disease control rate (DCR; objective response+stable disease (SD)) at 24 weeks, assessed by computed tomography (CT) scan according to RECIST v1.0. Metabolic response was evaluated by positron emission tomography (PET)–CT scans performed at baseline and after 4 weeks of treatment.

Results:

Between September 2011 and April 2012, 30 patients were enroled. DCR at 24 weeks by RECIST v1.0 was 13% and one patient (3%) had a partial response. Based on the European Organization for Research and Treatment of Cancer PET response criteria, four patients (13%) had a metabolic partial response after 4 weeks of treatment. At a median follow-up of 8.3 months (range, 6.3–12.2 months), median progression-free survival (PFS) was 3.6 months (95% confidence interval (CI), 3.5–3.7 months) and median overall survival was 9.7 months (95% CI, 6.0–13.4 months). Metabolic progressive disease at Week 4 was significantly associated with shorter PFS (P=0.03). Grade 3/4 adverse events included asthenia (20%), neutropenia (13%), thrombocytopenia (10%), and hypertriglyceridaemia (10%). Most toxicities were manageable by dose modification.

Conclusion:

Dovitinib showed modest antitumour activity with manageable toxicities in heavily pretreated patients with advanced GISTs.     

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.     

Sorafenib and irinotecan (NEXIRI) as second- or later-line treatment for patients with metastatic colorectal cancer and KRAS-mutated tumours: a multicentre Phase I/II trial

Background:

This trial evaluated the feasibility and efficacy of combined sorafenib and irinotecan (NEXIRI) as second- or later-line treatment of patients with KRAS-mutated metastatic colorectal cancer (mCRC), who had progressed after irinotecan-based chemotherapy.

Methods:

In Phase I, in a 3+3 dose escalation schedule, patients received irinotecan (125, 150 or 180 mg m⁻² every 2 weeks), in combination with 400 mg sorafenib b.d. The primary end point was the maximum-tolerated dose of irinotecan. In Phase II, the primary end point was disease control rate (DCR). Secondary end points were progression-free survival (PFS), overall survival (OS) and toxicity.

Results:

Phase I included 10 patients (median age 63 (49–73)); no dose-limiting toxicity was seen. In Phase II, 54 patients (median age 60 (43–80) years) received irinotecan 180 mg m⁻² every 2 weeks with sorafenib 400 mg b.d. Nine patients (17%) remained on full-dose sorafenib. The DCR was 64.9% (95% CI, 51–77). Median PFS and OS were 3.7 (95% CI, 3.2–4.7) and 8.0 (95% CI, 4.8–9.7) months, respectively. Toxicities included Grade 3 diarrhoea (37%), neutropenia (18%), hand-foot syndrome (13%) and Grade 4 neutropenia (17%).

Conclusion:

The NEXIRI regimen showed promising activity as second- or later-line treatment in this heavily pretreated mCRC population (ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00989469","term_id":"NCT00989469"}}NCT00989469).     

Early detection of metastatic disease in asymptomatic breast cancer patients with whole-body imaging and defined tumour marker increase

Background:

Follow-up care in breast cancer is still an issue of debate. Diagnostic methods are more sensitive, and more effective therapeutic options are now available. The risk of recurrence is not only influenced by tumour stage but also by the different molecular subtypes. This study was performed to evaluate the use of whole-body imaging combined with tumour marker monitoring for the early detection of asymptomatic metastatic breast cancer (MBC).

Methods:

This analysis was performed as part of a follow-up study evaluating 813 patients with a median follow-up of 63 months. After primary therapy, all patients underwent tumour marker monitoring for CEA, CA 15-3 and CA 125 at 6-week intervals within an intensified diagnostic aftercare algorithm. A reproducible previously defined increase was considered as a strong indicator of MBC. From 2007 to 2010, 44 patients with tumour marker increase underwent whole-body magnetic resonance imaging and/or an FDG-PET/CT scan. Histological clarification and/or imaging follow-up were done.

Results:

Metastases were detected in 65.9% (29/44) of patients, 13.6% (6/44) had secondary malignancies besides breast cancer and 20.5% (9/44) had no detectable malignancy. Limited disease was found in 24.1% (7/29) of patients. Median progression-free survival of MBC was 9.2 months and median overall survival was 41.1 months. The 3- and 5-year survival rates were 64.2% and 40.0%, respectively.

Conclusions:

A reproducible tumour marker increase followed by whole-body imaging is highly effective for early detection. By consequence, patients might benefit from earlier detection and improved therapeutic options with a prolonged survival.     

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.     

Phase II study of first-line sagopilone plus prednisone in patients with castration-resistant prostate cancer: a phase II study of the Department of Defense Prostate Cancer Clinical Trials Consortium

Background:

Preclinical studies in prostate cancer (PC) models demonstrated the anti-tumour activity of the first fully synthetic epothilone, sagopilone. This is the first study to investigate the activity and safety of sagopilone in patients with metastatic castration-resistant PC (CRPC).

Methods:

Chemotherapy-naïve patients with metastatic CRPC received sagopilone (one cycle: 16 mg m⁻² intravenously over 3 h q3w) plus prednisone (5 mg twice daily). The primary efficacy evaluation was prostate-specific antigen (PSA) response rate (⩾50% PSA reduction confirmed ⩾28 days apart). According to the Simon two-stage design, ⩾3 PSA responders were necessary within the first 13 evaluable patients for recruitment to continue until 46 evaluable patients were available.

Results:

In all, 53 patients received ⩾2 study medication cycles, with high compliance. Mean individual dose was 15.1±1.4 mg m⁻² during initial six cycles, mean dose intensity 94±9%. The confirmed PSA response rate was 37%. Median overall progression-free survival was 6.4 months. The most commonly reported adverse events (>10% of patients) were peripheral neuropathy (94.3%), fatigue (54.7%) and pain in the extremities (47.2%). Sagopilone was associated with very little haematological toxicity.

Conclusion:

This study shows that first-line sagopilone has noteworthy anti-tumour activity and a clinically significant level of neuropathy for patients with metastatic chemotherapy-naïve CRPC.     

Efficacy and tolerability of bevacizumab plus capecitabine as first-line therapy in patients with advanced hepatocellular carcinoma

Background:

Molecularly targeted agents with anti-angiogenic activity, including bevacizumab, have demonstrated clinical activity in patients with advanced/metastatic hepatocellular carcinoma (HCC). This multicentre phase II study involving patients from several Asian countries sought to evaluate the safety and efficacy of bevacizumab plus capecitabine in this population.

Methods:

Histologically proven/clinically diagnosed advanced HCC patients received bevacizumab 7.5 mg kg^–1 on day 1 and capecitabine 800 mg m^–2 twice daily on days 1–14 every 3 weeks as first-line therapy.

Results:

A total of 45 patients were enrolled; 44 (96%) had extrahepatic metastasis and/or major vessel invasion and 30 (67%) had hepatitis B. No grade 3/4 haematological toxicity occurred. Treatment-related grade 3/4 non-haematological toxicities included diarrhoea (n=2, 4%), nausea/vomiting (n=1, 2%), gastrointestinal bleeding (n=4, 9%) and hand–foot syndrome (n=4, 9%). The overall response rate (RECIST) was 9% and the disease control rate was 52%. Overall, median progression-free survival (PFS) and overall survival (OS) were 2.7 and 5.9 months, respectively. Median PFS and OS were 3.6 and 8.2 months, respectively, for Cancer of the Liver Italian Programme (CLIP) score ⩽3 patients, and 1.4 and 3.3 months, respectively, for CLIP score 4 patients.

Conclusion:

The bevacizumab–capecitabine combination shows good tolerability and modest anti-tumour activity in patients with advanced HCC.     

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.     

The effect of DCIS grade on rate, type and time to recurrence after 15 years of follow-up of screen-detected DCIS

Background:

The incidence of ductal carcinoma in situ (DCIS) rose rapidly when the NHS Breast Screening Programme (NHSBSP) started in 1988. Some authorities consider that this represents both over-diagnosis and over-treatment. We report long-term follow-up of DCIS diagnosed in the first 10 years (April 1988 to March 1999) of the West Midlands NHSBSP.

Methods:

840 noninvasive breast cancers were recorded on the national breast screening computer system. Following exclusions, and thorough case note and pathology review, 700 DCIS cases were identified for follow-up.

Results:

After a median follow-up of 183 (range 133 to 259) months, 102 (14.6%) first local recurrences were identified, 49 (48%) were invasive. Median time to first noninvasive recurrence was 15 months, and 60 months for invasive recurrence. Median time to invasive recurrence was 76 months from initially high-grade DCIS, and 131 months from low/intermediate grade DCIS. For the seven women, presenting with metastasis as their first event, the median time was 82 (range 15 to 188) months. The cumulative proportion developing recurrence at 180 months was twice as high as at 60 months.

Interpretation:

Short-term follow-up of patients diagnosed with DCIS will miss significant numbers of events, especially invasive local recurrences.     

Sorafenib and dacarbazine as first-line therapy for advanced melanoma: phase I and open-label phase II studies

Method:

The safety of oral sorafenib up to a maximum protocol-specified dose combined with dacarbazine in patients with metastatic, histologically confirmed melanoma was investigated in a phase I dose-escalation study and the activity of the combination was explored in an open-label phase II study.

Results:

In the phase I study, three patients were treated with sorafenib 200 mg twice daily (b.i.d.) plus 1000 mg m⁻² dacarbazine on day 1 of a 21-day cycle and 15 patients had the sorafenib dose escalated to 400 mg b.i.d. without reaching the maximum tolerated dose of the combination. In the phase II study (n=83), the overall response rate was 12% (95% CI: 6, 21): one complete and nine partial, with median response duration of 46.7 weeks. Stable disease was the best response in 37% median duration was 13.3 weeks. Median overall survival (OS) was 37.0 weeks (95% CI: 33.9, 46.0).

Conclusion:

Oral sorafenib combined with dacarbazine had acceptable toxicity and some antineoplastic activity against metastatic melanoma.