Phase II study of pemetrexed and carboplatin plus bevacizumab as first-line therapy in malignant pleural mesothelioma

Background:

The aim of this open label phase II study ({"type":"clinical-trial","attrs":{"text":"NCT00407459","term_id":"NCT00407459"}}NCT00407459) was to assess the activity of the vascular endothelial growth factor (VEGF) inhibitor bevacizumab combined with pemetrexed and carboplatin in patients with previously untreated, unresectable malignant pleural mesothelioma (MPM).

Methods:

Eligible patients received pemetrexed 500 mg m⁻², carboplatin area under the plasma concentration–time curve (AUC) 5 mg ml⁻¹ per minute and bevacizumab 15 mg kg⁻¹, administered intravenously every 21 days for six cycles, followed by maintenance bevacizumab. The primary end point of the study was progression-free survival (PFS). A 50% improvement in median PFS in comparison with standard pemetrexed/platinum combinations (from 6 to 9 months) was postulated.

Results:

Seventy-six patients were evaluable for analysis. A partial response was achieved in 26 cases (34.2%, 95% CI 23.7–46.0%). Forty-four (57.9%, 95% CI 46.0–69.1%) had stable disease. Median PFS and overall survival were 6.9 and 15.3 months, respectively. Haematological and non-haematological toxicities were generally mild; however, some severe adverse events were reported, including grade 3–4 fatigue in 8% and bowel perforation in 4% of patients. Three toxic deaths occurred.

Conclusion:

The primary end point of the trial was not reached. However, due to the limitation of a non-randomised phase II design, further data are needed before drawing any definite conclusion on the role of bevacizumab in MPM.     

Gemcitabine–oxaliplatin plus prednisolone is active in patients with castration-resistant prostate cancer for whom docetaxel-based chemotherapy failed

Background:

There has been no previous study on the activity of gemcitabine in combination with oxaliplatin (GemOx) for castration-resistant prostate cancer (CRPC).

Methods:

The GemOx was preclinically tested for cytotoxic activity in human prostate cancer cell lines. Clinically, patients with CRPC who failed prior docetaxel were treated with gemcitabine 1000 mg m⁻² and oxaliplatin 100 mg m⁻² intravenously every 2 weeks and prednisolone 5 mg orally twice daily. The primary end point was the prostate-specific antigen (PSA) response rate.

Results:

The GemOx displayed synergistic effects based on Chou and Talalay analysis. In the phase II study, 33 patients were accrued. The median dose of docetaxel exposure was 518 mg m⁻². A total of 270 cycles were administered with a median of eight cycles per patient. A PSA response rate was 55% (95% CI, 38–72) and radiologic response rate was 82% (9 out of 11). With a median follow-up duration of 20.5 months, the median time to PSA progression was 5.8 months (95% CI, 4.4–7.2) and the median overall survival was 17.6 months (95% CI, 12.6–22.6). The most frequently observed grade 3 or 4 toxicities were neutropenia (13%) and thrombocytopenia (13%).

Conclusions:

The GemOx is active and tolerable in patients with metastatic CRPC after docetaxel failure ({"type":"clinical-trial","attrs":{"text":"NCT 01487720","term_id":"NCT01487720"}}NCT 01487720).     

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.     

Phase I study of olaparib in combination with liposomal doxorubicin in patients with advanced solid tumours

Background:

Olaparib, an oral PARP inhibitor, has shown antitumour activity as monotherapy in patients with germline BRCA1/2 (gBRCA)-mutated breast and ovarian cancer. This study evaluated olaparib capsules in combination with liposomal doxorubicin (PLD) in patients with advanced solid tumours ({"type":"clinical-trial","attrs":{"text":"NCT00819221","term_id":"NCT00819221"}}NCT00819221).

Methods:

Patients received 28-day cycles of olaparib, continuously (days 1–28) or intermittently (days 1–7), plus PLD (40 mg m⁻², day 1); seven olaparib dose cohorts (50–400 mg bid) were explored to determine the recommended dose. Assessments included safety, pharmacokinetics, pharmacodynamics and preliminary efficacy (objective response rate (ORR)).

Results:

Of 44 patients treated (ovarian, n=28; breast, n=13; other/unknown, n=3), two experienced dose-limiting toxicities (grade 3 stomatitis and fatal pneumonia/pneumonitis (200 mg per 28-day cycle); grade 4 thrombocytopenia (400 mg per 7-day cycle)). The maximum tolerated dose was not reached using continuous olaparib 400 mg bid plus PLD. Grade ⩾3 and serious AEs were reported for 27 (61%) and 12 (27%) patients, respectively. No major pharmacokinetic interference was observed between olaparib and PLD. The ORR was 33% (n=14 out of 42; complete response, n=3). A total of 13 responders had ovarian cancer: 10 were platinum-sensitive, 11 had a gBRCA mutation.

Conclusions:

Continuous/intermittent olaparib (up to 400 mg bid) combined with PLD (40 mg m⁻²) was generally tolerated and showed evidence of antitumour activity in ovarian cancer.     

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).     

CYP2C19 genotype-based phase I studies of a c-Met inhibitor tivantinib in combination with erlotinib,in advanced/metastatic non-small cell lung cancer

Background:

A previous clinical study in non-small cell lung cancer (NSCLC) patients in Western countries suggested the potential for combination of a first-in-class non-ATP-competitive c-Met inhibitor tivantinib with an epidermal growth factor receptor-tyrosine kinase inhibitor erlotinib. Polymorphisms of CYP2C19, the key metabolic enzyme for tivantinib, should be addressed to translate the previous Western study to Asian population, because higher incidence of poor metabolisers (PMs) is reported in Asian population.

Methods:

Japanese patients with advanced/metastatic NSCLC received tivantinib in combination with erlotinib to evaluate safety and pharmacokinetics. Doses of tivantinib were escalated separately for extensive metabolisers (EMs) and PMs.

Results:

Tivantinib, when combined with erlotinib, was well tolerated up to 360 mg BID for EMs and 240 mg BID for PMs, respectively. Among 25 patients (16 EMs and 9 PMs), the adverse events (AEs) related to tivantinib and/or erlotinib (>20%, any grade) were rash, diarrhoea, dry skin and nausea. Grade ⩾3 AEs were leukopenia, anaemia and neutropenia. No dose-limiting toxicity was observed. Pharmacokinetics profile of tivantinib was not clearly different between the combination and monotherapy. Three partial response and three long-term stable disease (⩾24 weeks) were reported.

Conclusion:

Two doses of tivantinib in combination with erlotinib were recommended based on CYP2C19 genotype: 360 mg BID for EMs and 240 mg BID for PMs.     

Selecting first-line bevacizumab-containing therapy for advanced breast cancer: TURANDOT risk factor analyses

Background:

The randomised phase III TURANDOT trial compared first-line bevacizumab–paclitaxel (BEV–PAC) vs bevacizumab–capecitabine (BEV–CAP) in HER2-negative locally recurrent/metastatic breast cancer (LR/mBC). The interim analysis revealed no difference in overall survival (OS; primary end point) between treatment arms; however, progression-free survival (PFS) and objective response rate were significantly superior with BEV–PAC. We sought to identify patient populations that may be most appropriately treated with one or other regimen.

Methods:

Patients with HER2-negative LR/mBC who had received no prior chemotherapy for advanced disease were randomised to either BEV–PAC (bevacizumab 10 mg kg⁻¹ days 1 and 15 plus paclitaxel 90 mg m⁻² days 1, 8 and 15 q4w) or BEV–CAP (bevacizumab 15 mg kg⁻¹ day 1 plus capecitabine 1000 mg m⁻² bid days 1–14 q3w). The study population was categorised into three cohorts: triple-negative breast cancer (TNBC), high-risk hormone receptor-positive (HR+) and low-risk HR+. High- and low-risk HR+ were defined, respectively, as having ⩾2 vs ⩽1 of the following four risk factors: disease-free interval ⩽24 months; visceral metastases; prior (neo)adjuvant anthracycline and/or taxane; and metastases in ⩾3 organs.

Results:

The treatment effect on OS differed between cohorts. Non-significant OS trends favoured BEV–PAC in the TNBC cohort and BEV–CAP in the low-risk HR+ cohort. In all three cohorts, there was a non-significant PFS trend favouring BEV–PAC. Grade ⩾3 adverse events were consistently less common with BEV–CAP.

Conclusions:

A simple risk factor index may help in selecting bevacizumab-containing regimens, balancing outcome, safety profile and patient preference. Final OS results are expected in 2015 (ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00600340","term_id":"NCT00600340"}}NCT00600340).     

Supplemental folic acid in pregnancy and childhood cancer risk

Background:

We investigated the association between supplemental folic acid in pregnancy and childhood cancer in a nation-wide study of 687 406 live births in Norway, 1999–2010, and 799 children diagnosed later with cancer.

Methods:

Adjusted hazard ratios (HRs) compared cancer risk in children by approximated periconceptional folic acid levels (folic acid tablets and multivitamins (0.6 mg), only folic acid (0.4 mg), only multivitamins (0.2 mg)) and cancer risk in unexposed.

Results:

Any folic acid levels were not associated with leukemia (e.g., high-level folic acid HR 1.25; 95% CI 0.89–1.76, P_Trend 0.20), lymphoma (HR 0.96; 95% CI 0.42–2.21, P_Trend 0.51), central nervous system tumours (HR 0.68; 95% CI 0.42–1.10, P_Trend 0.32), neuroblastoma (HR 1.05; 95% CI 0.53–2.06, P_Trend 0.85), Wilms'' tumour (HR 1.16; 95% CI 0.52–2.58, P_Trend 0.76), or soft-tissue tumours (HR 0.77; 95% CI 0.34–1.75, P_Trend 0.90).

Conclusions:

Folic acid supplementation was not associated with risk of major childhood cancers.     

Phase Ib study of CP-868,596, a PDGFR inhibitor, combined with docetaxel with or without axitinib, a VEGFR inhibitor

Background:

Tumoural interstitial hypertension, possibly modulated by platelet-derived and vascular endothelial growth factor receptors (PDGFR and VEGFR), may mediate resistance to chemotherapy.

Methods:

Forty-eight patients with advanced solid tumours received oral PDGFR inhibitor CP-868,596 (60–100 mg twice daily (BID)) and docetaxel (75–100 mg m^–2), or CP-868,596 (60 mg BID), docetaxel (75 mg m^–2), and VEGFR inhibitor axitinib (5 mg BID).

Results:

The CP-868,596/docetaxel was escalated as above. The CP-868,596/docetaxel/axitinib was not dose escalated because of increased incidence of mucositis-like adverse events (AEs) with concurrent neutropenia relative to that expected for docetaxel. All tested regimens were tolerable, including 100 mg BID CP-868,596 (recommended phase II dose) plus 100 mg m^–2 docetaxel (maximum approved dose). Most treatment-emergent AEs were mild–moderate and reversible, commonly including nausea, diarrhoea, vomiting, constipation, fatigue, and anaemia (CP-868,596/docetaxel), and hypertension, lethargy, diarrhoea, and fatigue (CP-868,596/docetaxel/axitnib). Pharmacokinetics were unaffected by co-administration. Twenty-one patients achieved stable disease, including all seven evaluable on CP-868,596/docetaxel/axitinib. All nine CP-868,596/docetaxel/axitinib patients received therapy for a median of six (range, 3–16) cycles.

Conclusions:

The CP-868,596/docetaxel was well tolerated, but increased efficacy was not observed. Addition of axitinib delivered greater benefits than expected in the number of patients achieving prolonged stable disease with a moderate increase in AEs.     

Intake of coffee,caffeine and other methylxanthines and risk of Type I vs Type II endometrial cancer

Background:

Coffee and other sources of methylxanthines and risk of Type I vs Type II endometrial cancer (EC) have not been evaluated previously.

Methods:

Prospective cohort of 23 356 postmenopausal women with 471 Type I and 71 Type II EC cases.

Results:

Type I EC was statistically significantly associated with caffeinated (relative risk (RR)=0.65 for 4+ cups per day vs ⩽1 cup per month: 95% confidence interval (CI): 0.47–0.89) but not decaffeinated (RR=0.76; 95% CI: 0.50–1.15) coffee intake; there were no associations with tea, cola or chocolate, or for Type II EC. The inverse association with caffeinated coffee intake was specific to women with a body mass index 30+ kg m⁻² (RR=0.56; 95% CI: 0.36–0.89).

Conclusion:

Coffee may protect against Type I EC in obese postmenopausal women.     

Phase I and pharmacological study of the broad-spectrum tyrosine kinase inhibitor JNJ-26483327 in patients with advanced solid tumours

Background:

JNJ-26483327 is an oral, potent, multi-targeted tyrosine kinase inhibitor, inhibiting kinases of epidermal growth factor receptor (EGFR)-1, -2 and -4, rearranged during transfection (RET) receptor, vascular endothelial growth factor receptor (VEGFR)-3 and Src family (Lyn, Fyn, Yes) at low nanomolar concentrations. This phase I, accelerated titration study assessed maximum tolerated dose, safety, pharmacokinetics and pharmacodynamic effects of JNJ-26483327.

Methods:

Nineteen patients with advanced cancers received JNJ-26483327 continuous twice daily (BID) in escalating dose cohorts ranging from 100 to 2100 mg. Pharmacodynamic effects were assessed in paired skin biopsies and blood.

Results:

JNJ-26483327 was well tolerated in doses up to 1500 mg BID, with target-inhibition-related toxicity such as diarrhoea and skin rash, and other common reported toxicities being nausea, vomiting, anorexia and fatigue. At 2100 mg, two episodes of dose-limiting toxicity were observed, consisting of grade 3 anorexia and a combination of grade 3 anorexia and fatigue, respectively. Pharmacokinetics were dose proportional up to 1500 mg in which plasma levels were obtained showing anti-tumour activity in xenograft mouse models. Pharmacodynamic analysis did not show a substantial effect on expression of Ki-67, p27^kip1, phosphorylated mitogen-activated protein kinase, phosphorylated Akt and EGFR, and serum levels of sVEGFR-2, VEGF-C and VEGF-D remained unchanged. Stable disease was noted in six patients (32%).

Conclusion:

JNJ-26483327 is well tolerated and shows a predictable pharmacokinetic profile; the recommended dose for further studies is 1500 mg BID.     

S0941: a phase 2 SWOG study of sorafenib and erlotinib in patients with advanced gallbladder carcinoma or cholangiocarcinoma

Background:

Gallbladder cancers and cholangiocarcinomas make up a heterogenous group of tumours with a poor prognosis in advanced stages. On the basis of evidence of dysregulation of the epidermal growth factor receptor, vascular endothelial growth factor and mitogen-activated protein kinase pathways in biliary cancers, we performed a phase 2 trial of sorafenib and erlotinib in patients with advanced biliary cancers.

Methods:

Eligible patients were previously untreated in the advanced setting with adequate hepatic and bone marrow function. Sorafenib and erlotinib were administered continuously at 400 mg BID and 100 mg daily, respectively.

Results:

Thirty-four eligible patients were recruited. The study was terminated after the first stage of accrual owing to failure to meet the predetermined number of patients who were alive and progression free at 4 months. There were two unconfirmed partial responses (6%, 95% CI: 1–20%), with a median progression-free survival of 2 months (95% CI: 2–3), and median overall survival of 6 months (95% CI: 3–8 months). Grade 3 and 4 adverse events included hypertension, AST/ALT increase, bilirubin increase, diarrhoea, hypokalaemia, hypophosphatemia and rash.

Conclusions:

Despite compelling preclinical rationale, the combination of sorafenib and erlotinib does not have promising clinical activity in an unselected population of patients with biliary cancers. Improved patient selection based on tumour biology and molecular markers is critical for future evaluation of targeted therapies in this disease.     

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.     

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.     

A phase I,dose-finding study of sunitinib in combination with irinotecan in patients with advanced solid tumours

Background:

Sunitinib is a multitargeted, oral tyrosine kinase inhibitor with antitumour and antiangiogenic activity. We investigated the safety and pharmacokinetics of sunitinib in combination with irinotecan in patients with advanced, refractory solid tumours.

Methods:

Sunitinib was initially administered once daily at 37.5 mg per day on days 1–14 of a 21-day cycle, in which irinotecan 250 mg m⁻² was given on day 1. In a second cohort, the sunitinib dose was reduced to 25 mg per day. Blood samples were collected for pharmacokinetic studies.

Results:

In the sunitinib 37.5 mg per day cohort, 3 out of 10 evaluable patients had objective responses, but dose-limiting toxicities (DLTs) of neutropenia, pneumococcal sepsis, and fatigue were observed. There were no DLTs in the sunitinib 25 mg per day cohort. Paired observations of pharmacokinetic parameter values of sunitinib and irinotecan alone vs the combination did not reveal significant drug–drug interactions. The maximum tolerated dose was defined as sunitinib 25 mg per day (days 1–14) with irinotecan 250 mg m⁻² (day 1), but no activity was observed at this dose.

Conclusion:

Although a higher sunitinib dose of 37.5 mg per day (days 1–14) with irinotecan showed preliminary evidence of antitumour activity, this dose was poorly tolerated. Therefore, this particular combination will not be pursued for further studies.     

High-risk features in radiation-associated breast angiosarcomas

Background:

Radiation-associated breast angiosarcoma (RT-AS) is an uncommon malignancy with an incidence of less than 1 % of all soft tissue sarcomas. The overall prognosis is quite dismal with high rates of recurrences and poor overall survival. There is an obvious paucity of data regarding clinical outcomes of patients with breast RT-AS.

Methods:

We identified all patients with RT-AS treated at the Memorial Sloan-Kettering Cancer Center between 1982–2011 and collected their correlative clinical information.

Results:

We identified 79 women with RT-AS with a median age of 68 (range 36–87). The median interval between radiation and development of RT-AS was 7 years (range 3–19). The median time to local and distant recurrence was 1.29 years (95 % CI 0.72–NA) and 2.48 years (95 % CI 1.29–NA), respectively. The median disease-specific survival was 2.97 years (95 % CI 2.21–NA). Independent predictors of worse disease-specific survival included age ⩾68 years (HR 3.11, 95 % CI 1.20–8.08, P=0.020) and deep tumors (HR 3.23, 95 % CI 1.02–10.21, P=0.046.)

Conclusion:

RT-AS has high local/distant recurrence rates, limited duration on standard chemotherapy and poor disease-specific survival.     

A study to investigate dose escalation of doxorubicin in ABVD chemotherapy for Hodgkin lymphoma incorporating biomarkers of response and toxicity

Background:

Myelotoxicity during initial cycles of chemotherapy for Hodgkin lymphoma is associated with better outcome, supporting the concept of individualised dosing based on pharmacodynamic end points to optimise results. This study was performed to identify the maximum tolerated dose (MTD) of doxorubicin within cycles 1–3 ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine). Circulating biomarkers of response (nucleosomal DNA, nDNA) and epithelial toxicity (Cytokeratin 18, CK18) were also measured.

Methods:

Dose escalation of doxorubicin in cycles 1–3 ABVD supported by pegfilgrastim was performed on a six-patient cohort basis (35, 45 and 55 mg m^–2) with doxorubicin reduced to 25 mg m^–2 or omitted in cycles 4–6 to maintain cumulative exposure of 103–130% standard ABVD. BVD was given at standard doses throughout. Six additional subjects were recruited at the MTD.

Results:

Twenty-four subjects were recruited. Dose-limiting toxicities (DLTs) of grade 3 neuropathy, pneumonitis, palmar-plantar erythema and neutropenic infection were observed at 55 mg m^–2, so 45 mg m^–2 was declared the MTD. In patients who subsequently experienced DLT at any time, large increases in CK18 were seen on day 3 of cycle 1 ABVD.

Conclusion:

Escalated ABVD incorporating doxorubicin at 45 mg m^–2 in cycles 1–3 can be delivered safely with pegfilgrastim support. Circulating cell death biomarkers may assist in the development of future individualised dosing strategies.     

Long-term and baseline recreational physical activity and risk of endometrial cancer: the California Teachers Study

Background:

Physical activity may be associated with decreasing endometrial cancer risk; it remains unclear whether the association is modified by body size.

Methods:

Among 93 888 eligible California Teachers Study participants, 976 were diagnosed with incident endometrial cancer between 1995–1996 and 2007. Cox proportional hazards regression methods were used to estimate relative risks (RRs) and 95% confidence intervals (CIs) for endometrial cancer associated with long-term (high school through age 54 years) and baseline (3 years prior to joining the cohort) strenuous and moderate recreational physical activity, overall and by body size.

Results:

Increased baseline strenuous recreational physical activity was associated with decreased endometrial cancer risk (P_trend=0.006) with approximately 25% lower risk among women exercising >3 h per week per year than among those exercising <1/2 h per week per year (RR, 0.76; 95% CI, 0.63–0.92). This inverse association was observed among overweight/obese women (body mass index ≥25 kg m⁻²; P_trend=0.006), but not among thinner women (P_trend=0.12). Baseline moderate activity was associated with lower risk among overweight/obese women.

Conclusion:

Increasing physical activity, particularly strenuous activity, may be a lifestyle change that overweight and obese women can implement to reduce their endometrial cancer risk.     

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.     

Timing of radiotherapy in breast-conserving therapy: a large prospective cohort study of node-negative breast cancer patients without adjuvant systemic therapy

Background:

To investigate the issue of timing of radiation therapy (RT) after lumpectomy in relation to recurrences and outcome.

Methods:

Analysis was done on 1107 breast-conserving therapies (BCT) with 1070 women, all without lymph node metastasis and without any adjuvant systemic therapy. Timing was defined as time from lumpectomy till RT. Patients were categorised into tertiles: <45 days, 45–56 days, and 57–112 days.

Results:

Local control did not show a difference between the tertiles. The distant metastasis-free survival as well as the disease-specific survival showed a decreased outcome starting the RT to early after the lumpectomy.

Conclusion:

The results of this cohort study further refines the hypothesis that timing of RT in BCT might have an impact on outcome. It suggests that a randomised trial in timing of RT in BCT seems necessary to give a definite answer.