Superselective intra-arterial cisplatin infusion and concomitant radiotherapy for maxillary sinus cancer

Background:

The purpose of this study was to evaluate the efficacy of superselective cisplatin infusion with concomitant radiotherapy (RADPLAT) for previously untreated patients with the squamous cell carcinoma of maxillary sinus (SCC-MS).

Methods:

Between 1999 and 2010, 54 patients were given superselective intra-arterial infusions of cisplatin (100–120 mg m⁻² per week) with simultaneous intra-venous infusions of thiosulfate to neutralise cisplatin toxicity and conventional radiotherapy (65–70 Gy).

Results:

One patient (1.9%) was diagnosed with T2, 14 (25.9%) with T3, 27 (50%) with T4a, and 12 (22.2%) with T4b disease. Lymph-node involvement was present in 12 patients (22.2%). During the median follow-up period of 6.4 years, the 5-year local progression-free and overall survival rates were 65.8 and 67.9% for all patients, respectively. No patient died as a result of treatment toxicity or experienced a cerebrovascular accident. Osteonecrosis (n=5), brain necrosis (n=1), and ocular/visual problems (n=14) were observed as late adverse reactions.

Conclusion:

We have shown excellent overall survival and local progression-free rate in SCC-MS patients treated by RADPLAT with acceptable rates of acute and late toxicity. A multi-institutional trial is needed to prove that this strategy is a feasible and effective approach for the treatment of SCC-MS.     

Docetaxel plus cetuximab as second-line treatment for docetaxel-refractory oesophagogastric cancer: the AGITG ATTAX2 trial

Background:

Cetuximab can reverse chemotherapy resistance in colorectal cancer. This study evaluated the efficacy and safety of the combination of docetaxel and cetuximab as a second-line treatment in docetaxel-refractory oesophagogastric cancer.

Methods:

Patients received docetaxel 30 mg m⁻² on days 1 and 8, every 3 weeks and cetuximab 400 mg m⁻² on day 1, then 250 mg m⁻² weekly. Biomarker mutation analysis was performed.

Results:

A total of 38 patients were enrolled. Response rates were PR 6% (95% CI 2–19%), s.d. 43% (95% CI 28–59%). Main grade 3/4 toxicities were febrile neutropenia, anorexia, nausea, diarrhoea, stomatitis, and acneiform rash. Median progression-free and overall survival were 2.1 and 5.4 months, respectively. A landmark analysis showed a trend to improved survival times with increased grade of acneiform rash. No KRAS, BRAF or PIK3CA mutations were observed.

Conclusion:

Cetuximab and docetaxel achieve modest responses rates, but maintain comparable survival times to other salvage regimens with low rates of toxicity.     

Prediction of vascular invasion in hepatocellular carcinoma by next-generation des-r-carboxy prothrombin

Background:

In hepatocellular carcinoma (HCC), des-r-carboxy prothrombin (DCP) more accurately reflects the malignant potential than alpha-fetoprotein (AFP). Next-generation DCP (NX-DCP) was created to overcome some of the limitations of conventional DCP. This study assessed the predictive value of NX-DCP for vascular invasion in HCC.

Methods:

We prospectively studied 82 consecutive patients who were scheduled to undergo resection for HCC. Patients were divided into two groups according to the presence or absence of pathological vascular invasion. The predictive powers of AFP, conventional DCP, and NX-DCP for vascular invasion were compared by receiver operating characteristic curve analysis, and correlations with tumour markers and the presence of vascular invasion were assessed.

Results:

Vascular invasion was pathologically confirmed in 21 patients (positive group) and absent in 61 patients (negative group). The NX-DCP level was significantly higher in the positive group than in the negative group (510.0 mAU ml⁻¹ (10–98 450) vs 34.0 mAU ml⁻¹ (12–541), P<0.0001), while the AFP level did not differ significantly between the groups (9.7 ng ml⁻¹ (1.6–43 960.0) vs 11.0 ng ml⁻¹ (1.6–1650.0), P=0.49). The area under the curve (AUC) of NX-DCP (AUC=0.813, sensitivity=71.4%, 1−specificity=13.1%) had good sensitivity for the prediction of vascular invasion, while the AUC of AFP was 0.550 (sensitivity=28.6%, 1−specificity=1.60%). The suitable cutoff value for identifying pathological vascular invasion in HCC was 33 mm (AUC: 0.783, sensitivity=71.43%, 1−specificity=11.48%).

Conclusions:

The NX-DCP level can be used to predict the presence of vascular invasion in HCC.     

HCC-ART score,a simple,highly sensitive and specific test for early diagnosis of hepatocellular carcinoma: a large-scale,multicentre study

Background:

A simple scoring system is needed to discriminate HCC from patients with chronic liver diseases (CLD). The simplest score would be one that requires only variables that can be documented simply from routine laboratory tests without the need for sophisticated tests.

Methods:

Data from the estimation group (1351 patients) and the validation group (2208 patients) were retrospectively analysed. Liver fibrosis-negative control and liver cirrhosis were compared with HCC. Area under ROC curve (AUC) were used to develop HCC-α-fetoprotein-routine test (HCC-ART).

Results:

Hepatocellular carcinoma-AFP-routine test showed diagnostic accuracy for liver cirrhosis vs HCC with ROC curves of 0.99%, sensitivity of 97%, and specificity of 96% in the estimation, and 0.95%, 90%, and 83%, respectively, in the validation. Sensitivity (97%) and specificity (100%) were obtained to discriminate HCC from liver fibrosis. Area under curve for AFP at 400 U l⁻¹ was 0.70, sensitivity was 41%, and specificity was 99% in the estimation, and 0.77%, 54%, and 99%, respectively, in the validation. The AUC for HCC-ART in HCC with single tumour, absent vascular invasion, size <2 cm and CLIP score (0–1) were 0.95, 0.93, 0.86, 0.87, respectively, compared with 0.72, 0.71, 0.71, 0.50, respectively, for AFP.

Conclusion:

Hepatocellular carcinoma-AFP-routine test could increase the accuracy of HCC screening and surveillances and could be used worldwide without extra efforts.     

Cost-effectiveness of alternative strategies for integrating MRI into breast cancer screening for women at high risk

Background:

Magnetic resonance imaging (MRI) is recommended for women at high risk for breast cancer. We evaluated the cost-effectiveness of alternative screening strategies involving MRI.

Methods:

Using a microsimulation model, we generated life histories under different risk profiles, and assessed the impact of screening on quality-adjusted life-years, and lifetime costs, both discounted at 3%. We compared 12 screening strategies combining annual or biennial MRI with mammography and clinical breast examination (CBE) in intervals of 0.5, 1, or 2 years vs without, and reported incremental cost-effectiveness ratios (ICERs).

Results:

Based on an ICER threshold of $100 000/QALY, the most cost-effective strategy for women at 25% lifetime risk was to stagger MRI and mammography plus CBE every year from age 30 to 74, yielding ICER $58 400 (compared to biennial MRI alone). At 50% lifetime risk and with 70% reduction in MRI cost, the recommended strategy was to stagger MRI and mammography plus CBE every 6 months (ICER=$84 400). At 75% lifetime risk, the recommended strategy is biennial MRI combined with mammography plus CBE every 6 months (ICER=$62 800).

Conclusions:

The high costs of MRI and its lower specificity are limiting factors for annual screening schedule of MRI, except for women at sufficiently high risk.     

The risk of cancer in primary care patients with hypercalcaemia: a cohort study using electronic records

Background:

The risk of cancer with hypercalcaemia in primary care is unknown.

Methods:

This was a cohort study using calcium results in patients aged ⩾40 years in a primary care electronic data set. Diagnoses of cancer in the following year were identified.

Results:

Participants (54 267) had calcium results: 1674 (3%) were ⩾2.6 mmol l⁻¹. Hypercalcaemia was strongly associated with cancer, especially in males: OR 2.92, 95% CI 2.17–3.93, P=<0.001; positive predictive value (PPV) 11.5% females: OR 1.86, 95% CI 1.39–2.50, P<0.001: PPV 4.1%.

Conclusions:

Hypercalcaemia is strongly associated with cancer in primary care, with men at most risk, despite hypercalcaemia being more common in women.     

Physical function as a prognostic biomarker among cancer survivors

Background:

We tested the hypothesis that objectively measured physical function predicts mortality among cancer survivors.

Methods:

We assessed objectively measured physical function including the short physical performance battery (SPPB) and fast walk speed in older adult cancer survivors.

Results:

Among 413 cancer survivors, 315 (76%) died during a median follow-up of 11.0 years. In multivariable-adjusted analyses, each 1-unit increase in the SPPB score and 0.1 m s⁻¹ increase in fast walk speed predicted a 12% reduction in mortality (hazard ratio (HR): 0.88 (95% confidence interval (CI): 0.82–0.94); P<0.001, and HR: 0.88 (95% CI: 0.82–0.96); P=0.003, respectively).

Conclusions:

Objectively measured physical function may predict mortality among cancer survivors.     

Phase I study of afatinib combined with nintedanib in patients with advanced solid tumours

Background:

This Phase I study evaluated continuous- and intermittent-dosing (every other week) of afatinib plus nintedanib in patients with advanced solid tumours.

Methods:

In the dose-escalation phase (n=45), maximum tolerated doses (MTDs) were determined for continuous/intermittent afatinib 10, 20, 30 or 40 mg once daily plus continuous nintedanib 150 or 200 mg twice daily. Secondary objectives included safety and efficacy. Clinical activity of continuous afatinib plus nintedanib at the MTD was further evaluated in an expansion phase (n=25).

Results:

The most frequent dose-limiting toxicities were diarrhoea (11%) and transaminase elevations (7%). Maximum tolerated doses were afatinib 30 mg continuously plus nintedanib 150 mg, and afatinib 40 mg intermittently plus nintedanib 150 mg. Treatment-related adverse events (mostly Grade ⩽3) included diarrhoea (98%), asthenia (64%), nausea (62%) and vomiting (60%). In the dose-escalation phase, two patients had partial responses (PRs) and 27 (60%) had stable disease (SD). In the expansion phase, one complete response and three PRs were observed (all non-small cell lung cancer), with SD in 13 (52%) patients. No pharmacokinetic interactions were observed.

Conclusions:

MTDs of continuous or intermittent afatinib plus nintedanib demonstrated a manageable safety profile with proactive management of diarrhoea. Antitumour activity was observed in patients with solid tumours.     

Phase III randomised controlled trial of neoadjuvant chemotherapy plus radical surgery vs radical surgery alone for stages IB2, IIA2, and IIB cervical cancer: a Japan Clinical Oncology Group trial (JCOG 0102)

Background:

A phase III trial was conducted to determine whether neoadjuvant chemotherapy (NACT) before radical surgery (RS) improves overall survival.

Methods:

Patients with stage IB2, IIA2, or IIB squamous cell carcinoma of the uterine cervix were randomly assigned to receive either BOMP (bleomycin 7 mg days 1–5, vincristine 0.7 mg m⁻² day 5, mitomycin 7 mg m⁻² day 5, cisplatin 14 mg m⁻² days 1–5, every 3 weeks for 2 to 4 cycles) plus RS (NACT group) or RS alone (RS group). Patients with pathological high-risk factors received postoperative radiotherapy (RT). The primary end point was overall survival.

Results:

A total of 134 patients were randomly assigned to treatment. This study was prematurely terminated at the first planned interim analysis because overall survival in the NACT group was inferior to that in the RS group. Patients who received postoperative RT were significantly lower in the NACT group (58%) than in the RS group (80% P=0.015). The 5-year overall survival was 70.0% in the NACT group and 74.4% in the RS group (P=0.85).

Conclusion:

Neoadjuvant chemotherapy with BOMP regimen before RS did not improve overall survival, but reduced the number of patients who received postoperative RT.     

Gemcitabine alone or in combination with cisplatin in patients with biliary tract cancer: a comparative multicentre study in Japan

Background:

A British randomised study of gemcitabine plus cisplatin (GC) combination showed promising results in biliary tract cancer (BTC) patients. In our study, we evaluated the efficacy and safety of this combination compared with gemcitabine alone (G) in Japanese BTC patients.

Methods:

Overall, 84 advanced BTC patients were randomised to either cisplatin 25 mg m⁻² plus gemcitabine 1000 mg m⁻² on days 1, 8 of a 21-day cycle (GC-arm), or single-agent gemcitabine 1000 mg m⁻² on days 1, 8 and 15 of a 28-day cycle (G-arm). Treatments were repeated for at least 12 weeks until disease progression or unacceptable toxicity occurred, up to a maximum of 48 weeks.

Results:

A total of 83 patients were included in the analysis. For the GC and G-arms, respectively, the 1-year survival rate was 39.0 vs 31.0%, median survival time 11.2 vs 7.7 months, median progression-free survival time 5.8 vs 3.7 months and overall response rate 19.5 vs 11.9%. The most common grade 3 or 4 toxicities (GC-arm/G-arm) were neutropenia (56.1%/38.1%), thrombocytopenia (39.0%/7.1%), leukopenia (29.3%/19.0%), haemoglobin decrease (36.6%/16.7%) and γ-GTP increase (29.3%/35.7%).

Conclusions:

Gemcitabine plus cisplatin combination therapy was found to be effective and well tolerated, suggesting that it could also be a standard regimen for Japanese patients.     

Randomised phase II trial of S-1 plus oxaliplatin vs S-1 in patients with gemcitabine-refractory pancreatic cancer

Background:

This randomised, open-label, multicenter phase II study compared progression-free survival (PFS) of S-1 plus oxaliplatin (SOX) with that of S-1 alone in patients with gemcitabine-refractory pancreatic cancer.

Methods:

Patients with confirmed progressive disease following the first-line treatment with a gemcitabine-based regimen were randomised to receive either S-1 (80/100/120 mg day⁻¹ based on body surface area (BSA), orally, days 1–28, every 6 weeks) or SOX (S-1 80/100/120 mg day⁻¹ based on BSA, orally, days 1–14, plus oxaliplatin 100 mg m⁻², intravenously, day 1, every 3 weeks). The primary end point was PFS.

Results:

Between January 2009 and July 2010, 271 patients were randomly allocated to either S-1 (n=135) or SOX (n=136). Median PFS for S-1 and SOX were 2.8 and 3.0 months, respectively (hazard ratio (HR)=0.84; 95% confidence interval (CI), 0.65–1.08; stratified log-rank test P=0.18). Median overall survival (OS) was 6.9 vs 7.4 months (HR=1.03; 95% CI, 0.79–1.34; stratified log-rank test P=0.82). The response rate (RR) was 11.5% vs 20.9% (P=0.04). The major grade 3/4 toxicities (S-1 and SOX) were neutropenia (11.4% and 8.1%), thrombocytopenia (4.5% and 10.3%) and anorexia (12.9% and 14.7%).

Conclusions:

Although SOX showed an advantage in RR, it provided no significant improvement in PFS or OS compared with S-1 alone.     

Adjuvant chemotherapy for gastric cancer: a randomised phase 3 trial of mitomycin-C plus either short-term doxifluridine or long-term doxifluridine plus cisplatin after curative D2 gastrectomy (AMC0201)

Background:

This phase 3 study evaluated the efficacy of new adjuvant chemotherapy (MFP), which intensified the mitomycin-C (MMC) plus short-term doxifluridine (Mf) for gastric cancer.

Patients and methods:

A total of 855 patients (424 in Mf, 431 in MFP) with pathological stage II–IV (M0) gastric cancer after D2 gastrectomy were randomly assigned to receive either Mf (MMC 20 mg m⁻², followed by oral doxifluridine 460–600 mg m⁻² per day for 3 months) or MFP (MMC 20 mg m⁻², followed by oral doxifluridine 460–600 mg m⁻² per day for 12 months with 6 monthly infusions of 60 mg m⁻² of cisplatin) chemotherapy.

Results:

With a median follow-up of 6.6 years, there was no difference between the two groups in recurrence-free survival (RFS) (5-year RFS 61.1% in Mf and 57.9% in MFP; hazard ratio 1.10 (95% CI 0.89–1.35); P=0.39) and overall survival (OS) (5-year OS 66.5% in Mf and 65.0% in MFP; hazard ratio 1.11 (95% CI 0.89–1.39); P=0.33).

Conclusion:

Intensification of Mf adjuvant chemotherapy by prolonging the duration of oral fluoropyrimidine and adding cisplatin was safe but not effective to improve the survivals in curatively resected gastric cancer patients.     

A multi-centre randomised trial comparing ultrasound vs mammography for screening breast cancer in high-risk Chinese women

Background:

Chinese women tend to have small and dense breasts and ultrasound is a common method for breast cancer screening in China. However, its efficacy and cost comparing with mammography has not been evaluated in randomised trials.

Methods:

At 14 breast centres across China during 2008–2010, 13 339 high-risk women aged 30–65 years were randomised to be screened by mammography alone, ultrasound alone, or by both methods at enrolment and 1-year follow-up.

Results:

A total of 12 519 and 8692 women underwent the initial and second screenings, respectively. Among the 30 cancers (of which 15 were stage 0/I) detected, 5 (0.72/1000) were in the mammography group, 11 (1.51/1000) in the ultrasound group, and 14 (2.02/1000) in the combined group (P=0.12). In the combined group, ultrasound detected all the 14 cancers, whereas mammography detected 8, making ultrasound more sensitive (100 vs 57.1%, P=0.04) with a better diagnostic accuracy (0.999 vs 0.766, P=0.01). There was no difference between mammography and ultrasound in specificity (100 vs 99.9%, P=0.51) and positive predictive value (72.7 vs 70.0% P=0.87). To detect one cancer, the costs of ultrasound, mammography, and combined modality were $7876, $45 253, and $21 599, respectively.

Conclusions:

Ultrasound is superior to mammography for breast cancer screening in high-risk Chinese women.     

Chemoradiotherapy with capecitabine for locally advanced anal carcinoma: an alternative treatment option

Background:

Capecitabine is an established treatment alternative to intravenous 5-fluorouracil (5-FU) for patients with rectal cancer receiving chemoradiotherapy. Its place in the treatment of locally advanced anal carcinoma (AC), however, remains undetermined. We investigated whether capecitabine is as effective as 5-FU in the treatment of patients with locally advanced AC.

Methods:

One hundred and five patients with squamous cell AC stage T2-4 (T2>4 cm), N0-1, M0 or T1-4, N2-3, M0, were included in this retrospective study. Forty-seven patients were treated with continuous 5-FU (750 mg m⁻²) on days 1–5 and 29–33, mitomycin C (MMC, 10 mg m⁻²) on day 1, and radiotherapy; 58 patients were treated with capecitabine (825 mg m⁻² b.i.d. on weekdays), MMC (10 mg m⁻²) on day 1, and radiotherapy. The primary end points of the study were: clinical complete response rate, locoregional control (LRC) and overall survival (OS). Secondary end points were: colostomy-free survival (CFS), toxicity and associations of genetic polymorphisms (GSTT1, GSTM1, GSTP1 and TYMS) with outcome and toxicity.

Results:

Clinical complete response was achieved in 41/46 patients (89.1%) with 5-FU and in 52/58 patients (89.7%) with capecitabine. Three-year LRC was 76% and 79% (P=0.690, log-rank test), 3-year OS was 78% and 86% (P=0.364, log-rank test) and CFS was 65% and 79% (P=0.115, log-rank test) for 5-FU and capecitabine, respectively. GSTT1 and TYMS genotypes were associated with severe (grade 3–4) toxicity.

Conclusions:

Capecitabine combined with MMC and radiotherapy was equally effective as 5-FU-based chemoradiotherapy. This study shows that capecitabine can be used as an acceptable alternative to 5-FU for the treatment of AC.     

A phase I study of the safety and pharmacokinetics of the histone deacetylase inhibitor belinostat administered in combination with carboplatin and/or paclitaxel in patients with solid tumours

Background:

This phase I study assessed the maximum tolerated dose, dose-limiting toxicity (DLT) and pharmacokinetics of belinostat with carboplatin and paclitaxel and the anti-tumour activity of the combination in solid tumours.

Methods:

Cohorts of three to six patients were treated with escalating doses of belinostat administered intravenously once daily, days 1–5 q21 days; on day 3, carboplatin (area under the curve (AUC) 5) and/or paclitaxel (175 mg m⁻²) were administered 2–3 h after the end of the belinostat infusion.

Results:

In all 23 patients received 600–1000 mg m⁻² per day of belinostat with carboplatin and/or paclitaxel. No DLT was observed. The maximal administered dose of belinostat was 1000 mg m⁻² per day for days 1–5, with paclitaxel (175 mg m⁻²) and carboplatin AUC 5 administered on day 3. Grade III/IV adverse events were (n; %): leucopenia (5; 22%), neutropenia (7; 30%), thrombocytopenia (3; 13%) anaemia (1; 4%), peripheral sensory neuropathy (2; 9%), fatigue (1; 4%), vomiting (1; 4%) and myalgia (1; 4%). The pharmacokinetics of belinostat, paclitaxel and carboplatin were unaltered by the concurrent administration. There were two partial responses (one rectal cancer and one pancreatic cancer). A third patient (mixed mullerian tumour of ovarian origin) showed a complete CA-125 response. In addition, six patients showed a stable disease lasting ⩾6 months.

Conclusion:

The combination was well tolerated, with no evidence of pharmacokinetic interaction. Further evaluation of anti-tumour activity is warranted.     

A phase II study of weekly neoadjuvant chemotherapy followed by radical chemoradiation for locally advanced cervical cancer

Background:

We investigated the feasibility of dose-dense neoadjuvant chemotherapy (NACT) with paclitaxel and carboplatin before radical chemoradiation (CRT) and assessed the response rate to such a regimen.

Methods:

CxII is a single-arm phase II trial of 46 patients, with locally advanced cervical cancer (stage Ib2-IVa). Patients received dose-dense carboplatin (AUC2) and paclitaxel (80 mg m⁻²) weekly for six cycles followed by CRT (40 mg m⁻² of weekly cisplatin, 50.4 Gy, 28 fractions plus brachytherapy). The primary end point was response rate 12 weeks post-CRT.

Results:

Baseline characteristics were: median age at diagnosis 43 years; 72% squamous, 22% adenocarcinoma and 7% adenosquamous histologies; FIGO stage IB2 (11%), II (50%), III (33%), IV (7%). Complete or partial response rate was 70% (95% CI: 54–82) post-NACT and 85% (95% CI: 71–94) post-CRT. The median follow-up was 39.1 months. Overall and progression-free survivals at 3 years were 67% (95% CI: 51–79) and 68% (95% CI: 51–79), respectively. Grade 3/4 toxicities were 20% during NACT (11% haematological, 9% non-haematological) and 52% during CRT (haematological: 41%, non-haematological: 22%).

Conclusion:

A good response rate is achieved by dose-dense weekly NACT with carboplatin and paclitaxel followed by radical CRT. This treatment regimen is feasible as evidenced by the acceptable toxicity of NACT and by the high compliance to radiotherapy (98%).     

Treatment with docetaxel and cisplatin in advanced adrenocortical carcinoma,a phase II study

Background:

Adrenocortical carcinoma (ACC) is a rare disease with a poor response to chemotherapy. Cisplatin is the most widely investigated drug in the treatment of ACC and in vitro studies have indicated activity of taxanes. The objectives of this study were to evaluate the efficacy and toxicity of cisplatin combined with docetaxel as first-line treatment of advanced ACC.

Methods:

Patients with advanced ACC were included in this phase II trial investigating the response to a combination of cisplatin (50 mg m⁻²) and docetaxel (60 mg m⁻²) administered with a 3-week interval.

Results:

Nineteen patients were included in this study. The response rate was 21% (95% CI: 3–39%). No patients obtained a complete response, 32% had stable disease, and 37% progressed while on treatment. The median progression-free survival (PFS) was 3 months (95% CI: 0.7–5.3 months) and 1 year PFS was 21% (95% CI: 3–39%). Median survival was 12.5 months (95% CI: 6–19 months). The predominant grade 3/4 toxicity was neutropenia (35%); febrile neutropenia occurred in 5% of cycles.

Conclusion:

This study could not demonstrate that the combination of cisplatin and docetaxel has higher efficacy than other regimens reported in previous studies.     

Insulin-like growth factors and liver cancer risk in male smokers

Background:

The liver is the primary source of circulating insulin-like growth factor (IGF)-I, yet the relation between IGFs and liver cancer is uncertain.

Methods:

In a case–cohort study within a cohort of 29 133 male smokers we examined associations of serum IGF-I and IGF binding protein (IGFBP)-3 with liver cancer (50 cases).

Results:

Nonlinear associations between liver cancer and IGF-I and IGFBP-3 were observed (P=0.04 and P<0.01, respectively), strongest association at lowest levels (odds ratio (OR)=0.2, 95% confidence interval (CI)=0.1–0.7 for 80 vs 30 ng ml⁻¹ of IGF-I; OR=0.2, 95% CI=0.1–0.6 for 1400 vs 700 ng ml⁻¹ of IGFBP-3).

Conclusions:

Low IGF-I and IGFBP-3 levels in male smokers are associated with increased risk of liver cancer.     

A multicenter phase 1 study of PX-866 in combination with docetaxel in patients with advanced solid tumours

Background:

This phase I, dose-finding study determined the safety, maximum tolerated dose (MTD)/recommended phase 2 dose (RP2D), pharmacokinetics, and antitumour activity of PX-866, a phosphatidylinositol 3-kinase inhibitor, combined with docetaxel in patients with incurable solid tumours.

Methods:

PX-866 was administered at escalating doses (4–8 mg daily) with docetaxel 75 mg m⁻² intravenously every 21 days. Archived tumour tissue was assessed for potential predictive biomarkers.

Results:

Forty-three patients were enrolled. Most adverse events (AEs) were grade 1 or 2. The most frequent study drug-related AE was diarrhoea (76.7%), with gastrointestinal disorders occurring in 79.1% (docetaxel-related) and 83.7% (PX-866-related). No dose-limiting toxicities were observed. The RP2D was 8 mg, the same as the single-agent MTD. Co-administration of PX-866 and docetaxel did not affect either drug''s PKs. Best responses in 35 evaluable patients were: 2 partial responses (6%), 22 stable disease (63%), and 11 disease progression (31%). Eleven patients remained on study for >180 days, including 8 who maintained disease control on single-agent PX-866. Overall median progression-free survival (PFS) was 73.5 days (range: 1–569). A non-significant association between longer PFS for PIK3CA-MUT/KRAS-WT vs PIK3CA-WT/KRAS-WT was observed.

Conclusion:

Treatment with PX-866 and docetaxel was well tolerated, without evidence of overlapping/cumulative toxicity. Further investigation with this combination is justified.     

Phase I trial of axitinib combined with platinum doublets in patients with advanced non-small cell lung cancer and other solid tumours

Background:

This phase I dose-finding trial evaluated safety, efficacy and pharmacokinetics of axitinib, a potent and selective second-generation inhibitor of vascular endothelial growth factor receptors, combined with platinum doublets in patients with advanced non-small cell lung cancer (NSCLC) and other solid tumours.

Methods:

In all, 49 patients received axitinib 5 mg twice daily (b.i.d.) with paclitaxel/carboplatin or gemcitabine/cisplatin in 3-week cycles. Following determination of the maximum tolerated dose, a squamous cell NSCLC expansion cohort was enroled and received axitinib 5 mg b.i.d. with paclitaxel/carboplatin.

Results:

Two patients experienced dose-limiting toxicities: febrile neutropenia (n=1) in the paclitaxel/carboplatin cohort and fatigue (n=1) in the gemcitabine/cisplatin cohort. Common nonhaematologic treatment-related adverse events were hypertension (36.7%), diarrhoea (34.7%) and fatigue (28.6%). No grade⩾3 haemoptysis occurred among 12 patients with squamous cell NSCLC. The objective response rate was 37.0% for patients receiving axitinib/paclitaxel/carboplatin (n=27) and 23.8% for patients receiving axitinib/gemcitabine/cisplatin (n=21). Pharmacokinetics of axitinib and chemotherapeutic agents were similar when administered alone or in combination.

Conclusion:

Axitinib 5 mg b.i.d. may be combined with standard paclitaxel/carboplatin or gemcitabine/cisplatin regimens without evidence of overt drug–drug interactions. Both combinations demonstrated clinical efficacy and were well tolerated.