Early assessment with 18F-fluorodeoxyglucose positron emission tomography/computed tomography can help predict the outcome of neoadjuvant chemotherapy in triple negative breast cancer

BackgroundIn patients with triple-negative breast cancer (TNBC), pathology complete response (pCR) to neoadjuvant chemotherapy (NAC) is associated with improved prognosis. This prospective study was designed and powered to investigate the ability of interim ¹⁸F-fluorodeoxyglucose positron emission tomography/computed tomography (¹⁸FDG-PET/CT) to predict pathology outcomes to NAC early during treatment.Patients and methodsConsecutive TNBC women underwent ¹⁸FDG-PET/CT at baseline and after two courses of NAC. Maximum standardised uptake value (SUV_max) in the primary tumour and lymph nodes at each examination and the evolution (ΔSUV_max) between the two scans were measured. NAC was continued irrespective of PET results. Correlations between PET parameters and pathology response, and between PET parameters and event-free survival (EFS), were examined.ResultsFifty patients without distant metastases were enroled. At completion of NAC, surgery showed pCR in 19 patients, while 31 had residual tumour. Mean follow-up was 30.3 months. Thirteen patients, all with residual tumour, experienced relapse. Of all assessed clinical, biological and PET parameters, ΔSUV_max in the primary tumour was the most predictive of pathology results (p < 0.0001; Mann–Whitney-U test) and EFS (p = 0.02; log rank test). A threshold of 42% decrease in SUV was identified because it offered the best accuracy in predicting EFS. There were 32 metabolic responders (⩾42% decrease in SUV_max) and 18 non-responders. Within responders, the pCR rate was 59% and the 3-year EFS 77.5%. In non-responders, the pCR rate was 0% and the 3-year EFS 47.1%.ConclusionInterim ¹⁸FDG can early predict the inefficacy of NAC in TNBC patients. It shows promise as a potential contributory biomarker in these patients.     

The prognostic value of 18F-FDG PET/CT taken immediately after completion of radiotherapy for lung cancer treated with concurrent chemoradiotherapy: A pilot study

PurposeThe prognostic value of F-18 fluorodeoxyglucose positron emission tomography/computed tomography (PET/CT) taken immediately after completion of radiotherapy in lung cancer patients is not well known. The purpose of this study is to assess the prognostic value of PET/CT taken immediately after completion of radiotherapy in lung cancer patients.Materials and methodsPatients with primary lung cancer planned to undergo concurrent chemoradiotherapy were enrolled. Patients underwent PET/CT scans at 3 time points: before radiotherapy, within 24 hours of completing radiotherapy (im-PET/CT), and 2–9 months after radiotherapy (post-PET/CT). Maximum standardized uptake value (SUV_max) was obtained. A post-PET/CT-SUV_max cut-off of 2.5 was determined as radiotherapy success.ResultsNineteen patients were enrolled. im-PET/CT-SUV_max for patients in the high post-PET/CT-SUV_max group was significantly higher than that of the low group (P = 0.004). Receiver operator curve analysis indicated that im-PET/CT-SUV_max of 4.35 was an optimal cut-off value to discriminate between the two groups. Multivariable analysis showed that a high im-PET/CT-SUV_max was significantly associated with a high post-PET/CT-SUV_max (P = 0.003).ConclusionPET/CT-SUV_max taken immediately following radiotherapy was associated with that evaluated 2–9 months after radiotherapy.     

Phase II study of the HSP90-inhibitor BIIB021 in gastrointestinal stromal tumors

BackgroundHSP90 inhibition leads to proteosomal degradation of activated KIT and has in vitro activity against gastrointestinal stromal tumors (GIST). BIIB021 is an oral non-ansamycin HSP90 inhibitor. We carried out a phase II study of BIIB021 in patients with GIST refractory to imatinib and sunitinib.Patients and methodsThe primary end-point was metabolic partial response (mPR) as assessed by fluorodeoxyglucose positron emission tomography (FDG-PET). The secondary end-points were pharmacokinetic assessments of BIIB021 and pharmacodynamic assessments of HSP70. Twenty-three patients were treated on two schedules: 12 pts received 600 mg twice a week (BIW) and 11 patients received 400 mg three times a week (TIW). All had prior imatinib and sunitinib but stopped >14 days before starting BIIB021.ResultsThe median age was 59 years (33–88 years), 61% male, 44% Eastern Cooperative Oncology Group 1 (ECOG1). The best response was PR by FDG-PET for five patients (3/12 at 600 mg BIW and 2/9 at 400 TIW) for an overall response rate of 22%. The response duration was 25–138 days. Adverse events (AEs) were mild to moderate. The mean C_max was 1.5 µmol and the mean AUC was 2.9 µmol h. C_max >1.5 µmol was associated with a decrease in standardized uptake value (SUV_max). HSP70 increased substantially following treatment.ConclusionsThis study met its primary end-point. BIIB021 leads to objective responses in refractory GIST patients. Pharmacodynamic studies confirmed HSP90 inhibition. Further evaluation of BIIB021 in GIST is warranted.     

Potential utility of early metabolic response by 18F-2-fluoro-2-deoxy-d-glucose-positron emission tomography/computed tomography in a selected group of breast cancer patients receiving preoperative chemotherapy

IntroductionTo assess ¹⁸F-2-fluoro-2-deoxy-d-glucose-positron emission tomography/computed tomography’s (¹⁸F-FDG-PET/CT) potential clinical utility to allow early treatment changes during preoperative chemotherapy (PCT) in patients with early/locally advanced breast cancer (BC).Patients and methodsSixty newly diagnosed early/locally advanced BC patients received 6–8 cycles of PCT. Optimal pathologic response (pR) was the absence of cancer cells in breast and axillary lymph nodes. All other conditions were defined as pathologic non-response (pNR). ¹⁸F-FDG-PET/CT maximum standardised uptake value (SUV_max) was measured at baseline and after 2 cycles of PCT. Metabolic response was defined as SUV_max percentage changes (Δ-SUV) >50% and was compared with pR rates.ResultsThirteen (22%) patients achieved pR; according to immunohistochemistry, 16% of ER-positive/HER2-negative patients, 29% and 27% of HER2-positive and triple negative patients respectively achieved pR. ¹⁸F-FDG-PET/CT showed the highest specificity (38%) and negative predictive value (100%) in ER-positive/HER2-negative patients. In this subgroup, at a median follow-up of 36.6 months, median disease-free survival was still not reached in metabolic responders while it was 37 months in metabolic non-responders (p = 0.049).DiscussionEarly metabolic non-response was always associated to pNR and poor prognosis in ER-positive/HER2-negative patients. In this subgroup, ¹⁸F-FDG-PET/CT might be useful to select patients who will probably benefit from early therapeutic strategy modifications.     

Volumetric and dosimetric impact of MRI in delineation of gross tumor volume of non-spinal vertebral metastases treated with stereotactic ablative radiation therapy

PurposeTo investigate the Gross Tumor Volumes (GTV) and its dosimetric impact of magnetic resonance imaging (MRI) assisted contouring for non-spinal metastasis treated with stereotactic ablative body radiotherapy (SABR).Material and methodsFive observer contours on CT (GTV_CT) and CT + MR (GTV_CT+MR) were evaluated against expert team contours (GTV_EC) for 14 selected cases. Dice Similarity Index (DSC) and Geographical Miss Index (GMI) quantify observer variation. We also analyze the maximum dose (D_max) and dose received by 0.35cc (D_0.35cc) of the spinal cord (SC) for GTV_CT and GTV_CT+MR, where optimization parameters and priorities were unchanged. Percent rank function is also evaluated for SC doses.ResultsThe mean DSC and GMI scores for the CT-only dataset are 0.6974 and 0.2851 and for CT + MR dataset is 0.7764 and 0.1907 respectively. Statistically, significant results were found for mean GTV volumes between GTV_EC versus GTV_CT and GTV_CT versus GTV_CT+MR (P < 0.001). Dosimetric analysis of D_max and D_0.35cc exceeded 84.2% and 88.5% of times its respective threshold doses for CT-only dataset, whereas for the CT + MR dataset, it exceeded only by 18% and 15.7% times. ‘Percent rank’ function analysis for SC doses also indicates the same.ConclusionThis study supports MRI fusion for GTV and OAR delineation for non-spinal metastasis. Our study showed that the dosimetric analysis is vital for observer variation studies and the addition of the MR data set is significant to improve the confidence of Stereotactic treatments.     

Prediction of local control in early glottic carcinoma using the maximum standardised uptake value

Purpose

This retrospective study aimed to determine whether the maximum standardised uptake value (SUV_max) can predict local tumour control in early glottic cancer (Tis, T1, and T2).

First-time-in-man and pharmacokinetic study of weekly oral perifosine in patients with solid tumours

AimTo identify the maximum-tolerated dose (MTD) and pharmacokinetics of oral perifosine.MethodsPatients with solid tumours received perifosine at dosages ranging from 100–800 mg/week. Eligibility criteria included life expectancy > 12 weeks, WHO performance status ? 2, normal blood, liver and renal functions and no recent anticancer treatment. Drug concentrations were analysed by HPLC–MS/MS.ResultsThirty six patients were recruited (75% males, mean age 54.7 years, performance status 1 in 72.2%). Adverse events included nausea (69.4%), diarrhoea (55.6%), vomiting (52.8%) and abdominal pain (13.9%). Antiemetic regimens including glucocorticoids, dopamine antagonists and 5-HT3-antagonists were used as treatment and/or prophylaxis in 50% of the patients. Though MTD was formally not reached with 800 mg/week, the treatment discontinuation due to diarrhoea and vomiting likely related to perifosine in two cases led to the decision to stop further dose escalation. Pharmacokinetics after a single dose were median t_max = 8.0–24.2 h, median t_1/2 = 81.0–115.9 h and mean_geo CL/f = 0.28–0.43 mL/min/kg. Urinary excretion was below 1%. Perifosine slightly accumulated and steady state was nearly reached after 2–3 weeks.ConclusionOral perifosine was tolerable up to 600 mg/week in cancer patients when administered with meal and prophylactic antiemetics. Based on its half-life of about 4 days, a weekly regimen may be appropriate.     

Dose painting by contours versus dose painting by numbers for stage II/III lung cancer: Practical implications of using a broad or sharp brush

Purpose

Local recurrence rates are high in patients with locally advanced NSCLC treated with 60 to 66 Gy in 2 Gy fractions. It is hypothesised that boosting volumes with high SUV on the pre-treatment FDG-PET scan potentially increases local control while maintaining acceptable toxicity levels. We compared two approaches: threshold-based dose painting by contours (DPBC) with voxel-based dose painting by numbers (DPBN).

Materials and methods

Two dose painted plans were generated for 10 stage II/III NSCLC patients with 66 Gy at 2-Gy fractions to the entire PTV and a boost dose to the high SUV areas within the primary GTV. DPBC aims for a uniform boost dose at the volume encompassing the SUV 50%-region (GTV_boost). DPBN aims for a linear relationship between the boost dose to a voxel and the underlying SUV. For both approaches the boost dose was escalated up to 130 Gy (in 33 fractions) or until the dose limiting constraint of an organ at risk was met.

Results

For three patients (with relatively small peripheral tumours) the dose within the GTV could be boosted to 130 Gy using both strategies. For the remaining patients the boost dose was confined by a critical structure (mediastinal structures in six patients, lungs in one patient). In general the amount of large brush DPBC boosting is limited whenever the GTV_boost is close to any serial risk organ. In contrast, small brush DPBN inherently boosts at a voxel-by-voxel basis allowing significant higher dose values to high SUV voxels more distant from the organs at risk. We found that the biological SUV gradients are reasonably congruent with the dose gradients that standard linear accelerators can deliver.

Conclusions

Both large brush DPBC and sharp brush DPBN techniques can be used to considerably boost the dose to the FDG avid regions. However, significantly higher boost levels can be obtained using sharp brush DPBN although sometimes at the cost of a less increased dose to the low SUV regions.     

Nomogram predicting response after chemoradiotherapy in rectal cancer using sequential PETCT imaging: A multicentric prospective study with external validation

PurposeTo develop and externally validate a predictive model for pathologic complete response (pCR) for locally advanced rectal cancer (LARC) based on clinical features and early sequential ¹⁸F-FDG PETCT imaging.Materials and methodsProspective data (i.a. THUNDER trial) were used to train (N = 112, MAASTRO Clinic) and validate (N = 78, Università Cattolica del S. Cuore) the model for pCR (ypT0N0). All patients received long-course chemoradiotherapy (CRT) and surgery. Clinical parameters were age, gender, clinical tumour (cT) stage and clinical nodal (cN) stage. PET parameters were SUV_max, SUV_mean, metabolic tumour volume (MTV) and maximal tumour diameter, for which response indices between pre-treatment and intermediate scan were calculated. Using multivariate logistic regression, three probability groups for pCR were defined.ResultsThe pCR rates were 21.4% (training) and 23.1% (validation). The selected predictive features for pCR were cT-stage, cN-stage, response index of SUV_mean and maximal tumour diameter during treatment. The models’ performances (AUC) were 0.78 (training) and 0.70 (validation). The high probability group for pCR resulted in 100% correct predictions for training and 67% for validation. The model is available on the website www.predictcancer.org.ConclusionsThe developed predictive model for pCR is accurate and externally validated. This model may assist in treatment decisions during CRT to select complete responders for a wait-and-see policy, good responders for extra RT boost and bad responders for additional chemotherapy.     

Phase I and pharmacodynamic study of an orally administered novel inhibitor of histone deacetylases,SB939, in patients with refractory solid malignancies

BackgroundThe objective of this study was to assess the safety, maximum tolerated dose (MTD), pharmacokinetics, pharmacodynamics, and preliminary efficacy of SB939, a novel histone deacetylase (HDAC) inhibitor, in patients with advanced solid malignancies.Patients and methodsDose-escalating cohorts of three to six patients received SB939 orally thrice weekly for 3 weeks in a 4-week cycle. Acetylated histone H3 (acH3) was measured in peripheral blood mononuclear cells (PBMCs).ResultsThirty patients treated at one of five doses (10–80 mg/day) received 79 cycles of SB939 (range, 1–12 cycles). Dose-limiting toxic effects were fatigue, hypokalemia, troponin T elevation, and QTc prolongation. Peak plasma concentration (C_max) and area under the concentration–time curve extrapolated to infinity increased dose proportionally. The MTD of SB939 was 80 mg/day. The mean elimination half-life and oral clearance of SB939 were 7.2 ± 0.6 h and 53.0 ± 8.5 l/h, respectively, with no substantial accumulation on day 15. An increase in acH3 was observed at hour 3 and correlated with dose and C_max. Stable disease was seen in several tumor types treated at ≥40 mg. HDAC inhibition was consistently observed at 60 mg, the recommended dose.ConclusionsSB939 can be safely administered at the recommended dose and reaches plasma levels that strongly inhibit HDAC in PBMCs. These data support further efficacy studies of SB939.     

Skull Base Meningioma — Comparison of Intensity-modulated Radiotherapy Planning Techniques using the Moduleaf Micro-multileaf Collimator and Helical Tomotherapy

AimsTherapeutic radiotherapy to lesions of the skull base is limited by complex target shapes and their proximity to organs at risk. Intensity-modulated radiotherapy (IMRT) using helical tomotherapy may result in improved dose distributions and safer dose escalation. The aim of this study was to compare plan efficacy and efficiency using, linac-based micro-multileaf collimator (mMLC) IMRT and helical tomotherapy.Materials and methodsFive cases of skull base meningioma, previously treated with three-dimensional conformal radiotherapy (50 Gy/30 fractions) were identified. They were re-planned to a dose of 60 Gy/30 fractions using IMRT with Moduleaf mMLC (2.5 mm) and helical tomotherapy. Plan efficacy was compared using measures of PTV₆₀ coverage (D_min, D_max, V_90%, V_95% and V_100%). Plan efficiency was assessed by comparing estimated beam-on times.ResultsThe critical structure dose was limited to below predetermined tolerance levels in all cases, with similar doses obtained between techniques. The average PTV₆₀ D_max, D_min, D_med, D_mean, V_90%, V_95% and V_100% across the five cases achieved were as follows: mMLC IMRT: 64.9 Gy, 40.1 Gy, 60 Gy, 59.6 Gy, 95.4%, 88.8% and 69.2%, respectively; helical tomotherapy: 67.2 Gy, 50.3 Gy, 60 Gy, 59.9 Gy, 95.8%, 83.5% and 51.9%, respectively. The average treatment time per fraction was 18.4 min for IMRT with mMLC and 6.7 min for helical tomotherapy.DiscussionThis study shows that safe dose escalation to a dose of 60 G y to skull base lesions can be achieved; using either mMLC- or helical tomotherapy-based IMRT. A plan comparison between the two solutions is difficult, but they seem to be similar in efficacy with any small differences being difficult to interpret and of questionable clinical significance. Helical tomotherapy has the advantage of a significantly decreased beam-on time.     

Different treatment planning protocols can lead to large differences in organ at risk sparing

Background and purposeDifferent planning protocols may define varying planning target volume (PTV) dose criteria. We investigated the hypothesis that this could result in differences in organ-at-risk (OAR) sparing.Material and methodsVolumetric modulated arc therapy plans were created for ten locally advanced head and neck cancer patients following PTV criteria specified by the RTOG, EORTC and institutional (VUmc) protocols. Resulting plans were evaluated on the basis of the homogeneity index, calculated for the boost/elective PTVs as HI_B/HI_E = 100% * (D2% − D98%)/D50% and mean dose to individual and composite salivary (comp_sal) and swallowing (comp_swal) OARs.ResultsRTOG plans were the most homogeneous, with mean HI_B of 8.2 ± 0.9%, compared to 9.5 ± 1.0%/11.6 ± 1.5% for the VUmc/EORTC plans. EORTC plans provided most OAR sparing, with comp_sal/comp_swal doses of 24.6 ± 7.7/22.9 ± 4.2 Gy, compared to 32.2 ± 9.7/29.9 ± 4.2 Gy and 28.4 ± 8.1/24.7 ± 5.3 Gy for RTOG and VUmc, respectively. EORTC provided 7.2/7.7 Gy mean dose reductions to the contra/ipsilateral parotid glands compared to RTOG.ConclusionsDifferent planning protocols resulted in different levels of PTV dose homogeneity. We observed differences of up to ⩾7 Gy in composite and individual mean OAR doses. This could influence rates of toxicity and should be taken into account when comparing clinical studies. A consensus should be reached between major trial groups on appropriate PTV parameters.     

Implementation of an optimization method for parotid gland sparing during inverse planning for head and neck cancer radiotherapy

PurposeTo guide parotid gland (PG) sparing at the dose planning step, a specific model based on overlap between PTV and organ at risk (Moore et al.) was developed and evaluated for VMAT in head-and-neck (H&N) cancer radiotherapy.Materials and methodsOne hundred and sixty patients treated for locally advanced H&N cancer were included. A model optimization was first performed (20 patients) before a model evaluation (110 patients). Thirty cases were planned with and without the model to quantify the PG dose sparing. The inter-operator variability was evaluated on one case, planned by 12 operators with and without the model. The endpoints were PG mean dose (D_mean), PTV homogeneity and number of monitor units (MU).ResultsThe PG D_mean predicted by the model was reached in 89% of cases. Using the model significantly reduced the PG D_mean: −6.1 ± 4.3 Gy. Plans with the model showed lower PTV dose homogeneity and more MUs (+10.5% on average). For the inter-operator variability, PG dose volume histograms without the optimized model were significantly different compared to those with the model; the D_mean standard deviation for the ipsilateral PG decreased from 2.2 Gy to 1.2 Gy. For the contralateral PG, this value decreased from 2.9 Gy to 0.8 Gy.ConclusionDuring the H&N inverse planning, the optimized model guides to the lowest PG achievable mean dose, allowing a significant PG mean dose reduction of −6.1 Gy. Integrating this method at the treatment-planning step significantly reduced the inter-patient and inter-operator variabilities.     

Dovitinib and erlotinib in patients with metastatic non-small cell lung cancer: A drug–drug interaction

IntroductionErlotinib is a FDA approved small molecule inhibitor of epidermal growth factor receptor and dovitinib is a novel small molecule inhibitor of fibroblast growth factor and vascular endothelial growth factor receptor. This phase 1 trial was conducted to characterize the safety and determine the maximum tolerated dose of erlotinib plus dovitinib in patients with previously treated metastatic non-small cell lung cancer.MethodsEscalating dose cohorts of daily erlotinib and dovitinib dosed 5 days on/2 days off, starting after a 2-week lead-in of erlotinib alone, were planned. A potential pharmacokinetic interaction was hypothesized as dovitinib induces CYP1A1/1A2. Only cohort 1 (150 mg erlotinib + 300 mg dovitinib) and cohort -1 (150 mg erlotinib + 200 mg dovitinib) enrolled. Plasma concentrations of erlotinib were measured pre- and post-dovitinib exposure.ResultsTwo of three patients in cohort 1 had a DLT (grade 3 transaminitis and grade 3 syncope). Two of 6 patients in cohort -1 had a DLT (grade 3 pulmonary embolism and grade 3 fatigue); thus, the study was terminated. Erlotinib exposure (average C_max 2308 ± 698 ng/ml and AUC _0–24 41,030 ± 15,577 ng × h/ml) approximated previous reports in the six patients with pharmacokinetic analysis. However, erlotinib C_max and AUC_0–24 decreased significantly by 93% (p = 0.02) and 97% (p < 0.01), respectively, during dovitinib co-administration.ConclusionsThis small study demonstrated considerable toxicity and a significant pharmacokinetic interaction with a marked decrease in erlotinib exposure in the presence of dovitinib, likely mediated through CYP1A1/1A2 induction. Given the toxicity and the pharmacokinetic interaction, further investigation with this drug combination will not be pursued.     

Can we predict the cardiac benefit of deep inspiration breath hold for left breast and regional nodal irradiation?

PurposeDeep inspiration breath hold (DIBH) is used to decrease the dose of radiotherapy delivered to the heart. There is a need to define criteria to select patients with the potential to derive a real clinical benefit from DIBH treatment. Our study's main goal was to investigate whether two CT-scan cardiac anatomical parameters, cardiac contact distance in the parasagittal plane (CCDps) and lateral heart-to-chest distance (HCD), were predictive of unmet dosimetric cardiac constraints for left breast and regional nodal irradiation (RNI).Materials and methodsThis retrospective single-institution dosimetric study included 62 planning CT scans of women with left-sided breast cancer (BC) from 2016 to 2021. Two independent radiation oncologists measured HCD and CCDps twice to assess inter- and intra-observer reproducibility. Dosimetric constraints to be respected were defined, and dosimetric parameters of interest were collected for each patient.ResultsMean heart dose was 7.9 Gy. Inter-rater reproducibility between the two readers was considered excellent. The mean heart dose constraint < 8 Gy was not achieved in 25 patients (40%) and was achieved in 37 patients (60%). There was a significant correlation between mean heart dose and HCD (r_s = –0.25, P = 0.050) and between mean heart dose and CCDps (r_s = 0.25, P = 0.047). The correlation between HCD and CCDps and unmet cardiac dosimetric constraints was not statistically significant.ConclusionOur dosimetric analysis did not find that the cardiac anatomical parameters HCD and CCDps were predictive of unmet dosimetric cardiac constraints, nor that they were good predictors for cardiac exposure in left-sided BC radiotherapy comprising RNI.     

Cardiorespiratory fitness,lifestyle factors and cancer risk and mortality in Finnish men

BackgroundPhysical fitness along with lifestyle factors may have important roles in the prevention of cancer. We examined the relationship between common lifestyle factors such as energy expenditure, physical activity and maximal oxygen uptake (VO_2max), nutrition and smoking habits and the risk of cancer.MethodsA population-based cohort study was carried out in 2268 men from Eastern Finland with no history of cancer. They were followed up for an average of 16.7 years. The outcome measures were cancer incidence (n = 387) and cancer mortality (n = 159).ResultsMen with VO_2max of more than 33.2 mL/kg/min (highest tertile) had 27% (95% confidence interval (CI) 0.56–0.97) decreased cancer incidence and 37% (95% CI 0.40–0.97) reduced cancer mortality than men with VO_2max of less than 26.9 mL/kg/min (lowest tertile) after adjustment for age, examination year, alcohol, smoking, socioeconomic status, waist-to-hip ratio and energy, fibre and fat intake. The risk reduction was mainly due to decreased risk of lung cancer in fit men. The adjusted risk of cancer was 0.73 (95% CI 0.55–0.98) among fit (VO_2max ? 26.9 mL/kg/min) men with the total energy expenditure of physical activity over 2500 kcal/week. A total of 290 active (energy expenditure >2500 kcal and at least 2 h of physical activity per week) men with a favourable lifestyle (good fitness, balanced diet and non-smoking) had an adjusted relative risk of 0.63 (95% CI 0.46–0.87) for cancer.ConclusionFavourable lifestyle including good cardiorespiratory fitness and healthy dietary habits with active and non-smoking lifestyle considerably reduces the risk of cancer.