Locoregional recurrence after breast-conserving therapy remains an independent prognostic factor even after an event free interval of 10 years in early stage breast cancer

IntroductionLocoregional recurrence (LRR) after breast-conserving therapy is a well-known independent risk factor associated with unfavourable long-term outcome. Controversy exists concerning the prognostic impact of a LRR after a very long event-free interval.MethodPatients who underwent breast-conserving therapy for early stage breast cancer were pooled from four European Organisation for Research and Treatment of Cancer (EORTC) Breast Group trials. Only LRR as a first event was taken into account. Risk factors such as tumour size, nodal status, young age and chemotherapy were assessed in multivariate Cox regression analysis. LRR was used as a time-dependent variable in the landmark analysis for distant disease-free survival (DFS) and overall survival (OS). Patients were categorised as having at least 0, 5 or 10 years event-free survival.ResultsIn total, 7751 early stage breast cancer patients were included with a median follow-up of 10.9 years. Tumour size, nodal status, young age and chemotherapy are strong independent prognostic factors with a significant impact on long-term outcome, but lose their power and significance over time. Including all patients, LRR was the strongest prognostic factor for OS and distant DFS (resp. HR 5.01 and HR 5.31, p < 0.001). In the subgroup of patients developing a LRR after at least 5 or 10 years, LRR remained the strongest independent prognostic factor for OS (resp. HR 3.98, HR 4.96, p ⩽ 0.001) and distant DFS (HR 4.42, HR 7.57 p < 0.001).ConclusionThis is the first study which shows LRR after breast-conserving therapy is a very strong, time-independent prognostic factor for long term outcome in early stage breast cancer patients. These findings suggest that a LRR after a long event-free interval seems to be an indicator rather than an instigator of subsequent distant disease.     

Postmastectomy radiotherapy reduces locoregional recurrence in elderly women with high-risk breast cancer

AimsClinical trials of adjuvant radiotherapy after mastectomy have largely excluded women aged 70 years or over, even though they comprise 30% of the breast cancer population. This study examined outcomes in elderly women with high-risk breast cancer treated with or without postmastectomy radiotherapy (PMRT).Materials and methodsData were analysed for 233 women aged 70 years or over with high-risk breast cancer (tumours >5 cm or ≥4 positive axillary nodes) treated with mastectomy and referred to the British Columbia Cancer Agency from 1989 to 1997. Tumour and treatment characteristics were compared between two cohorts: women treated with PMRT (n = 147) vs women treated without PMRT (n = 86). Univariate and multivariate analyses of 10-year Kaplan–Meier locoregional recurrence (LRR), distant recurrence, breast cancer-specific survival and overall survival were carried out.ResultsMedian follow-up time was 5.5 years. The distribution of tumour sizes was similar in the two groups. Compared with women treated without PMRT, higher proportions of women who underwent PMRT had four or more positive nodes (83% vs 67%, P = 0.01) and positive surgical margins (14% vs 4%, P = 0.02). Systemic therapy, used in 94% of women, was comparable in the two cohorts (P = 0.63). Elderly women treated with PMRT had significantly lower LRR compared with women treated without PMRT (16% vs 28%, P = 0.03). No differences in distant recurrence, breast cancer-specific survival or overall survival were observed in the two treatment groups (all P > 0.05). On multivariate analysis, the omission of PMRT and the presence of high-grade histology were significant predictors of LRR, whereas an increasing number of positive nodes was significantly associated with distant recurrence and overall survival.ConclusionsIn women aged 70 years or over with tumours greater than 5 cm or four or more positive nodes, significantly lower LRR was observed in women treated with radiotherapy compared with women treated without radiotherapy. PMRT should be considered in the management of elderly women with these high-risk characteristics.     

Rôle de l’irradiation ganglionnaire chez les patientes indemnes d’envahissement ganglionnaire après chimiothérapie néoadjuvante pour un cancer du sein : expérience du centre René-Huguenin

PurposeNeoadjuvant chemotherapy generally induces significant changes in the pathological extent of disease. This potential down-staging challenges the standard indications of adjuvant radiation therapy. We assessed the utility of lymph node irradiation in breast cancer patients with pathological N0 status (pN0) after neoadjuvant chemotherapy and breast-conserving surgery.Patients and materialsAmong 1054 breast cancer patients treated with neoadjuvant chemotherapy in our institution between 1990 and 2004, 248 patients with clinical N0 or N1-N2 lymph node status at diagnosis had pN0 status after neoadjuvant chemotherapy and breast-conserving surgery. Cox regression analysis was used to identify factors influencing locoregional recurrence-free survival, disease-free survival and overall survival.ResultsAll 248 patients received breast irradiation, and 158 patients (63.7%) also received lymph node irradiation. With a median follow-up of 88 months, the 5-year locoregional recurrence-free survival and overall survival rates were respectively 89.4% and 88.7% with lymph node irradiation and 86.2% and 92% without lymph node irradiation (no significant difference). Survival was poorer among patients who did not have a pathological complete primary tumor response (pCR) (hazards ratio [HR] = 3.05; 95% CI, 1.17 to 7.99) and in patients with N1-N2 clinical status at diagnosis ([HR] = 2.24; 95% CI, 1.15 to 4.36). Lymph node irradiation did not significantly affect survival.ConclusionsRelative to combined breast and local lymph node irradiation, isolated breast irradiation does not appear to be associated with a higher risk of locoregional relapse or death among breast cancer patients with pN0 status after neoadjuvant chemotherapy. These results need to be confirmed in a prospective study.     

The efficacy of zoledronic acid in breast cancer adjuvant therapy: a meta-analysis of randomised controlled trials

BackgroundThe effect of zoledronic acid in breast cancer adjuvant therapy concerning improvement of patient survival has yet to be confirmed. We performed a meta-analysis of published and unpublished randomised controlled trials with the aim of accurate evaluation between clinical outcome and the association of the addition of zoledronic acid to adjuvant therapy.MethodsWe searched PubMed (from 1966 to present) and online abstracts from the proceeding Annual Meetings of the American Society of Clinical Oncology (ASCO) (years 1992–2010) and online abstracts from San Antonio Breast Cancer Symposium (years 2004–2010). A total of five eligible studies including 3676 subjects and 3678 controls met our search criteria and were evaluated. Random and fixed-effects meta-analytical models were used where indicated, and between-study heterogeneity was assessed. The primary study end-points were the disease free survival (DFS). Secondary end-points were overall survival (OS), distant or loco-regional recurrence free survival and bone metastasis free survival.FindingsCompared with the control arm, adjuvant breast cancer treatment with zoledronic acid did not significantly improve overall survival, disease free survival, bone metastasis free survival, distant and locoregional recurrence free survival. However, in the postmenopausal subgroup, the addition of zoledronic acid to standard therapy could significantly improve DFS (relative risk (RR) = 0.763, 95% confidence interval (CI) 0.658–0.884, p < 0.001) and reduce the risk of distant (RR = 0.744, 95% CI 0.611–0.906, p = 0.003) and locoregional recurrence (RR = 0.508, 95% CI 0.340–0.760, p = 0.001).InterpretationAdjuvant zoledronic acid did not significantly improve the prognosis of breast cancer patients. Due to the highly variable definitions of menopause utilised in different studies, we hypothesise that zoledronic acid may have a potential effect on postmenopausal patients. Additional studies are needed to evaluate the value of adjuvant treatment of zoledronic acid in premenopausal counterparts, differing disease stages and various pathological types of breast cancer.     

Obesity increases the incidence of distant metastases in oestrogen receptor-negative human epidermal growth factor receptor 2-positive breast cancer patients

BackgroundObesity is a major negative determinant of breast cancer outcome. However, there are contrasting data on the differential impact of obesity on specific breast cancer subtypes. In particular, very little is known on human epidermal growth factor receptor 2-positive (HER2+) tumours.Patients and methodsWe assessed the prognostic role of increased body mass index (BMI) on a consecutive series of non-metastatic HER2+ patients treated at our institution before the introduction of adjuvant Trastuzumab. We separately analysed oestrogen receptor-positive (ER+) and -negative (ER?) HER2+ cases.ResultsIn ER?/HER2+ tumours we observed a significantly worse overall survival (Hazard ratio (HR) 1.79, p-value 0.041) and cumulative incidence of distant metastases (HR 2.03, p-value 0.019) in obese (BMI > 30) versus normal/underweight (BMI < 25) patients. Local relapses appeared to be non-significantly reduced in obese patients, masking the overall effect on disease-free survival. Outcome in ER+ tumours, instead, was not significantly different between BMI groups.ConclusionsObesity significantly correlates with worse overall survival and cumulative incidence of distant metastases in ER?/HER2 positive breast cancer. Differences in the biology of breast tumours may determine individual susceptibility to obesity. The biology of the underlying tumour should be taken into account in the design of dietary intervention trials in breast cancer.     

Lack of TIMP-1 tumour cell immunoreactivity predicts effect of adjuvant anthracycline-based chemotherapy in patients (n = 647) with primary breast cancer. A Danish Breast Cancer Cooperative Group Study

PurposeA number of prospective studies have shown that adjuvant CEF significantly improves disease-free and overall survival as compared to CMF in breast cancer patients. Our aim was to determine whether the benefit of epirubicin versus methotrexate differs according to TIMP-1 tumour cell immunoreactivity.Experimental designTissue micro arrays from 647 patients randomly assigned to CMF or CEF in DBCG trial 89D were included. The primary end-point was invasive disease-free survival (IDFS). A central assessment of tissue inhibitor of metalloproteinases 1 (TIMP-1) status was performed using immunohistochemistry (IHC). Tumours were regarded as TIMP-1 positive if epithelial breast cancer cells were stained using the anti-TIMP-1 monoclonal antibody VT7.ResultsBy central assessment 75% of tumours were classified as tumour cell TIMP-1 positive. Among CEF-treated patients, individuals with TIMP-1 negative tumours had a significant longer IDFS than patients with TIMP-1 positive tumours (p = 0.047). The multivariate Cox regression analysis of IDFS showed that CEF was superior to CMF among patients with TIMP-1 negative tumours (hazard ratio (HR) = 0.51; 95% confidence interval (CI): 0.31–0.84, p = 0.0085), while no significant difference could be demonstrated among patients with TIMP-1 positive tumours (HR = 0.88; 95% CI: 0.68–1.13, p = 0.32). A non-significant TIMP-1 status (positive or negative) versus treatment (CMF or CEF) interaction was detected for IDFS (p = 0.06) and OS (p = 0.21).ConclusionLack of TIMP-1 tumour cell immunoreactivity seems to predict a favourable effect of epirubicin-containing adjuvant therapy in primary breast cancer. However, an independent study is awaited to validate the potential predictive value of TIMP-1 immunoreactivity.     

Zoledronate for patients with invasive residual disease after anthracyclines-taxane-based chemotherapy for early breast cancer – The Phase III NeoAdjuvant Trial Add-oN (NaTaN) study (GBG 36/ABCSG 29)

BackgroundPatients with invasive residual disease after neoadjuvant chemotherapy (NACT) are considered to have chemo-resistant breast cancer. Bisphosphonates are an established treatment for bone metastases and are of potential benefit as adjuvant treatment in early breast cancer.Patients and methodsPatients who had invasive tumour residuals (ypT1-4 and/or ypN+) after a minimum of four cycles of anthracycline-taxane-containing NACT were eligible for the NeoAdjuvant Trial Add-oN study. Patients were randomised within 3 years after surgery to receive zoledronate 4 mg i.v. for 5 years versus observation. Zoledronate was given every 4 weeks for the first 6 months, every 3 months for the following 2 years, and every 6 months for the last 2.5 years. Primary objective was disease-free survival.ResultsAfter a median time of 54.7 months no difference in disease-free survival was observed between the zoledronate and observation groups (hazard ratio [HR] 0.960, 95% confidence interval [CI] 0.709–1.30, log rank P = 0.789). Various subgroups were examined without identifying a treatment effect of zoledronate. Patients over 55 years of age showed a HR of 0.832 in favour of zoledronate, but the result was not significant (P = 0.480). A similar result was obtained for overall survival with a HR of 1.19 (95% CI 0.79–1.79; log rank P = 0.408). Zoledronate was well tolerated and no new toxicity signal was identified.ConclusionPostneoadjuvant treatment with zoledronate does not improve outcome in patients without pathological complete response after neoadjuvant anthracycline-taxane-based chemotherapy for early breast cancer.     

Resumption or persistence of menstruation after cytotoxic chemotherapy is a prognostic factor for poor disease-free survival in premenopausal patients with early breast cancer

BackgroundWe investigated the relationship between resumption or persistence of menstruation after cytotoxic chemotherapy (RM) and disease-free survival (DFS) in premenopausal patients with early breast cancer.MethodsMedical records from 872 patients who received cytotoxic chemotherapy for stage I to III breast cancer were retrospectively reviewed.ResultsThe median patient age was 41 years (range, 21–54) and the median follow-up duration was 6.2 years (range, 0.7–10.4). Six hundred ninety-two patients (79.4%) were hormone receptor (HR) positive and the majority of these received tamoxifen therapy after completing chemotherapy. The chemotherapy-induced amenorrhea (CIA) rate was 76.7% (n = 669), and 51.8% (n = 452) experienced RM during the follow-up period. One hundred twenty-one (13.9%) patients had persistent menstruation without CIA. DFS was significantly affected by younger age at diagnosis (≤35 years) (P = 0.013), tumor size > 2 cm (P < 0.001), node positivity (P < 0.001), HR negativity (P < 0.001), HER2 positivity (P = 0.010), and RM (P < 0.001). HR negativity [hazard ratio 1.7, 95% confidence interval (CI) 1.2–2.4, P = 0.006], tumor size > 2 cm (hazard ratio 2.1, 95% CI 1.4–3.0, P < 0.001), node positivity (hazard ratio 3.0, 95% CI 2.0–4.7, P < 0.001), and RM (hazard ratio 1.8, 95% CI 1.2–2.7, P = 0.004) remained significant factors for DFS on multivariate analysis.ConclusionsA considerable proportion of premenopausal patients treated with chemotherapy experienced RM after CIA. RM was a poor prognostic factor for DFS in premenopausal patients with early breast cancer.     

Résultats de la radiothérapie dans les carcinomes épidermoïdes du larynx avec atteinte sous-glottique

BackgroundSquamous cell carcinoma of larynx with subglottic extension is a rare location described to carry a poor prognosis. The aim of this study was to analyze outcomes and feasibility of definitive radiotherapy in patients with squamous cell carcinoma.Patients and methodsBetween 1998 and 2012, 56 patients with squamous cell carcinoma were treated at our institution and included in the analysis. Patients received definitive radiotherapy/chemoradiotherapy alone (63%) or after induction chemotherapy (37%) at our institute.ResultsThe 5-year actuarial overall survival, progression-free survival and specific survival were 64% (CI 95%: 48–90), 45% (CI 95%: 28–61), 88% (CI 95%: 78–98), respectively, with median follow-up of 74 months. The 5-year locoregional control was 69% (CI 95%: 56–83) and the 5-year distant control was 95% (CI 95%: 89–100). There was no difference in overall survival and locoregional control according to front-line treatments or between primary subglottic cancer and glotto-supraglottic cancers with subglottic extension. In the multivariate analysis, performance status of at least 1 and positive N stage were the only predictors for overall survival (hazard ratio [HR] [CI 95%]: 6.5 [1.3–34; P = 0.03] and 11 [1.6–75; P = 0.02], respectively). No difference of locoregional control was observed according to the first received therapy. The univariate analysis retrieved that T3–T4 patients had a lower locoregional control (HR: 3.1; CI 95%: 1.1–9.2, P = 0.04), but no prognostic factor was retrieved in the multivariate analysis. In patients receiving a larynx preservation protocol, 5-year larynx preservation rate was 88% (CI 95%: 78–98), and 58% in T3 patients. The 5-year larynx preservation rate was 91% (CI 95%: 79–100) and 83% (CI 95%: 66–100) for patients who received radiotherapy/chemoradiotherapy or induction chemotherapy as a front-line treatment, respectively.ConclusionThis analysis suggests that the results for squamous cell carcinoma patients treated with radiotherapy/chemoradiotherapy are comparable to those obtained for other laryngeal tumors. This thus suggests the feasibility of laryngeal preservation protocols for infringement subglottic for selected cases. Further studies are needed to clarify these preliminary data.     

Adjuvant therapy with pegylated interferon alfa-2b (36 months) versus low-dose interferon alfa-2b (18 months) in melanoma patients without macrometastatic nodes: An open-label,randomised, phase 3 European Association for Dermato-Oncology (EADO) study

AimBoth low-dose interferon (IFN) alfa-2b and pegylated interferon (Peg-IFN) alfa-2b have been shown to be superior to observation in the adjuvant treatment of melanoma without macrometastatic nodes, but have never been directly compared. Peg-IFN facilitates prolongation of treatment, which could provide additional benefit. This multicentre, open-label, randomised, phase 3 trial compared standard low-dose interferon IFN and prolonged treatment with Peg-IFN.Patients and methodsPatients with resected melanoma ?1.5 mm thick and without clinically detectable node metastases were randomised 1:1 to treatment with IFN 3 MU subcutaneously (SC) three times weekly for 18 months or Peg-IFN 100 μg SC once weekly for 36 months. Sentinel lymph node dissection (SLND) was optional. The primary endpoint was disease-free survival (DFS). Secondary endpoints included distant metastasis-free survival (DMFS), overall survival (OS) and adverse events (AEs) grade 3–4.ResultsOf 898 patients enrolled, 896 (443 Peg-IFN, 453 IFN) were eligible for evaluation (median follow-up 4.7 years). SLND was performed in 68.2% of patients. There were no statistical differences between the two arms for the primary outcome of DFS (hazard ratio [HR] 0.91, 95% confidence interval [CI] 0.73–1.15) or the secondary outcomes of DMFS (HR 1.02, 95% CI 0.80–1.32) and OS (HR 1.09, 95% CI 0.82–1.45). Peg-IFN was associated with higher rates of grade 3–4 AEs (47.3% versus 25.2%; p < 0.0001) and discontinuations (54.3% versus 30.4%) compared with IFN.ConclusionThis trial did not show superiority for adjuvant Peg-IFN over conventional low-dose IFN in melanoma patients without clinically detectable nodes. ClinicalTrials.gov identifier: NCT00221702.     

Survival of older patients with metastasised breast cancer lags behind despite evolving treatment strategies – A population-based study

BackgroundOlder women are more likely to be diagnosed with primary metastasised breast cancer than their younger counterparts. Evolving treatment strategies of metastasised breast cancer have resulted in improved survival in younger patients, but it remains unclear if this improvement has occurred in older patients as well. The aim of this study was to assess changes in treatment strategies over time in relation to overall and relative survival of older patients compared to younger patients with primary metastasised breast cancer.MethodsAll patients with a breast cancer diagnosis and distant metastases at first presentation (stage IV), between 1990 and 2012, were selected from the Netherlands Cancer Registry. Changes in treatment over time per age-group (<65 years, 65–75 years and >75 years) were assessed using logistic regression. Overall survival over time was calculated using Cox Regression Models and relative survival was assessed using the Ederer II method.ResultsOverall, 14,310 patients were included. Treatment strategies have strongly changed in the past twenty years; especially the use of chemotherapy has increased (P < 0.001 in all age-groups). Overall survival of patients <65 has significantly improved (Hazard Ratio (HR) per year 0.98, 95% Confidence Interval (CI) 0.98–0.99, P < 0.001), but the survival of older patients has not improved (HR 1.00, 95% CI 0.99–1.01, P = 0.86 for patients aged 65–75 and HR 1.00, 95% CI 1.00–1.01, P = 0.46 for patients aged >75). Similarly, relative survival has improved in patients <65 but not in women aged 65–75 and >75.ConclusionOverall and relative survival of older patients with metastasised breast cancer at first presentation have not improved in recent years in contrast with the survival of younger patients, despite increased treatment with chemotherapy for women of all ages. Future studies should focus on stratification models that can be used to predict which patients may benefit from specific treatment options.     

Prognostic value of haemoglobin levels during concurrent radio-chemotherapy in the treatment of oesophageal cancer

AimsTo evaluate the prognostic value of haemoglobin levels during radio-chemotherapy for overall survival, metastases-free survival (MFS) and locoregional control in patients with locally advanced oesophageal cancer.Materials and methodsAge, gender, performance status, tumour location, tumour length, histology, histologic grading, T-stage, N-stage, UICC-stage and weekly haemoglobin levels during concurrent radio-chemotherapy were retrospectively investigated and related to outcome in 108 patients, who received radio-chemotherapy for stage II/III oesophageal cancer. Radio-chemotherapy consisted of 59.4–60 Gy irradiation, two to four courses of cisplatin (75 mg/m² on day 1) and 5-fluorouracil (1000 mg/m² on days 1–5). Haemoglobin levels during radio-chemotherapy were compared among the following three groups: patients with over 60% of haemoglobin levels less than 12 g/dl; patients with over 60% of haemoglobin levels at 12–14 g/dl; and patients with over 60% of haemoglobin levels greater than 14 g/dl.ResultsOn univariate analysis, haemoglobin levels of 12–14 g/dl and greater than 14 g/dl during concurrent radio-chemotherapy provided better outcomes than haemoglobin levels less than 12 g/dl. The 2-year overall survival rates were 34%, 35% and 16%, respectively (P = 0.002). The 2-year MFS survival rates were 23%, 46% and 21%, respectively (P = 0.06). The 2-year locoregional control rates were 44%, 58% and 19%, respectively (P < 0.001). ECOG performance status (1 better than 2–3) was significantly associated with overall survival (P = 0.013), tumour length (<7 cm better than ≥7 cm) with overall survival (P = 0.002) and MFS (P = 0.002), N-stage (N0 better than N1) with overall survival (P = 0.004) and MFS (P < 0.001), and UICC-stage (stage II better than III) with overall survival (P = 0.025) and MFS (P = 0.010). On multivariate analysis, haemoglobin levels during radio-chemotherapy maintained significance for overall survival (P = 0.002) and locoregional control (P < 0.001), tumour length for overall survival (P = 0.002) and MFS (P = 0.008), and N-stage for MFS (P = 0.003).ConclusionsHaemoglobin during radiotherapy and concurrent radio-chemotherapy is an independent prognostic factor in oesophageal cancer treatment. To improve outcome, it seems important to maintain the haemoglobin at 12–14 g/dl.     

First-line anthracycline-based chemotherapy for angiosarcoma and other soft tissue sarcoma subtypes: Pooled analysis of eleven European Organisation for Research and Treatment of Cancer Soft Tissue and Bone Sarcoma Group trials

BackgroundAngiosarcoma is a rare subtype of soft tissue sarcoma (STS). Doxorubicin is the standard first-line chemotherapy for advanced STS. It is not known whether angiosarcoma response to anthracycline-based chemotherapy is different to other STS subtypes.MethodsPooled data were analysed from 11 prospective randomised and non-randomised European Organisation for Research and Treatment of Cancer (EORTC) clinical trials of first-line anthracycline-based chemotherapy for advanced STS. Baseline patient characteristics, chemotherapy response, progression free survival (PFS) and overall survival (OS) of angiosarcoma patients were compared with other STS patients. Analysis was performed to identify factors prognostic for angiosarcoma response to chemotherapy, PFS and OS.ResultsWith a median follow-up of 4.2 years, data from 108 locally advanced and metastatic angiosarcoma patients and 2557 patients with other STS histologies were analysed. 25% of angiosarcoma patients had a complete or partial response to chemotherapy compared to 21% for other STS histotypes. The median PFS was 4.9 months and OS 9.9 months, which were not significantly different from other STS histotypes. In univariate analysis, bone metastases were an adverse prognostic factor for OS (hazard ratio (HR) 1.66, 95% confidence interval (CI) 1.03–2.67; p = 0.036). Tumour grade was as an adverse prognostic factor for PFS (HR 1.72, 95% CI 1.01–2.92; p = 0.044) and OS (HR 2.03; 95% CI 1.16–3.56; p = 0.011). Compared to single agent anthracyclines, doxorubicin + ifosfamide was associated with improved PFS (HR 0.53, 95% CI 0.33–0.86; p = 0.010) and OS (HR 0.53, 95% CI 0.32–0.90; p = 0.018).ConclusionsAngiosarcoma response and survival following first-line anthracycline-based chemotherapy was similar to other STS histotypes. Our analysis provides a useful measure of angiosarcoma response to chemotherapy for comparison with future clinical trials.     

Radical radiotherapy in head and neck squamous cell carcinoma: an analysis of prognostic and therapeutic factors

AimsHead and neck squamous cell carcinoma (HNSCC) continues to be a leading cancer in developing countries. Definitive radiation therapy either primary or as postoperative adjuvant is offered to most patients. We aimed to identify prognostic and therapeutic factors that affect locoregional control and survival in patients undergoing radical radiotherapy for head and neck squamous cell cancers.Materials and methodsA retrospective analysis of 568 previously untreated patients with squamous head and neck cancers, who received radical radiotherapy between 1990 and 1996, using local control, locoregional control and disease-free survival (DFS) as outcome measures.ResultsWith a median follow-up of 18 months for living patients, the 5-year local control, locoregional control and DFS for all 568 patients were 53%, 45% and 41%, respectively, for all stages combined. The 5-year local control, locoregional control and DFS as per the American Joint Committee on Cancer stage grouping were 78%, 70% and 70%; 64%, 59% and 57%; 51%, 42% and 37%; and 40%, 27% and 22% from stages I to IV, respectively, with highly significant P values. Patients receiving higher doses (≥66 Gy) had a significantly better outcome compared with lower doses. The 5-year local control (59% vs 48%, P = 0.0015), locoregional control (47% vs 41%; P = 0.0043) and DFS (44% vs 37%; P = 0.0099) were significantly better in patients receiving ≥66 Gy. Site of primary also affected outcome significantly, with oral cavity lesions faring badly.ConclusionTumour stage remains the most important factor affecting outcome in radical radiotherapy of HNSCC. A definite dose–response relationship exists with higher total doses, leading to better local control, locoregional control and DFS in all stages. Site of primary affects outcome too, with laryngeal primaries doing well and oral cavity cancers faring the worst.     

Local recurrence following breast-conserving treatment in women aged 40 years or younger: Trends in risk and the impact on prognosis in a population-based cohort of 1143 patients

AimTo evaluate trends in the risk of local recurrences after breast-conserving treatment (BCT) and to examine the impact of local recurrence (LR) on distant relapse-free survival in a large, population-based cohort of women aged ?40 years with early-stage breast cancer.MethodsAll women (n = 1143) aged ?40 years with early-stage (pT1-2/cT1-2, N0-2, M0) breast cancer who underwent BCT in the south of the Netherlands between 1988 and 2010 were included. BCT consisted of local excision of the tumour followed by irradiation of the breast.ResultsAfter a median follow-up of 8.5 (0.1–24.6) years, 176 patients had developed an isolated LR. The 5-year LR-rate for the subgroups treated in the periods 1988–1998, 1999–2005 and 2006–2010 were 9.8% (95% confidence interval (CI) 7.1–12.5), 5.9% (95% CI 3.2–8.6) and 3.3% (95% CI 0.6–6.0), respectively (p = 0.006). In a multivariate analysis, adjuvant systemic treatment was associated with a reduced risk of LR of almost 60% (hazard ratio (HR) 0.42; 95% CI 0.28–0.60; p < 0.0001). Patients who experienced an early isolated LR (?5 years after BCT) had a worse distant relapse-free survival compared to patients without an early LR (HR 1.83; 95% CI 1.27–2.64; p = 0.001). Late local recurrences did not negatively affect distant relapse-free survival (HR 1.24; 95% CI 0.74–2.08; p = 0.407).ConclusionLocal control after BCT improved significantly over time and appeared to be closely related to the increased use and effectiveness of systemic therapy. These recent results underline the safety of BCT for young women with early-stage breast cancer.     

L1 cell adhesion molecule is a strong predictor for distant recurrence and overall survival in early stage endometrial cancer: Pooled PORTEC trial results

BackgroundL1 cell adhesion molecule (L1CAM) expression has been implicated as risk factor for disease recurrence in endometrial cancer (EC), most likely due to its role in promoting tumour cell motility. We tested the performance of L1CAM expression in predicting the risk of recurrence in the randomised post operative radiation therapy in endometrial carcinoma (PORTEC)-1 and -2 trials.MethodsIn the PORTEC trials, stage I EC patients were randomised to external beam radiotherapy (EBRT) versus no additional treatment (PORTEC-1, n = 714), or to EBRT versus vaginal brachytherapy (PORTEC-2, n = 427). Tumour samples of 865 (75.8%) patients were available for L1CAM expression analysis by immunohistochemistry. An established scoring system for EC was used, with >10% L1CAM staining defined as positive.ResultsPositive L1CAM expression was significantly correlated with risk of distant recurrence, with a hazard ratio (HR) of 5.1 (95% confidence interval (CI) 3.1–8.7) but not with vaginal relapse, while a trend for pelvic nodal relapse was found. Tumours with the highest expression levels (>50% positive) had the strongest risk of distant recurrence (HR 5.3, CI 2.7–10.4). In multivariate Cox analysis with the risk factors age, depth of invasion, grade, lympho-vascular space invasion (LVSI) and treatment, L1CAM expression remained an independent prognostic factor for distant recurrence (HR 3.5, CI 1.92–6.30) and overall survival (HR 2.1, CI 1.41–2.98).ConclusionL1CAM expression is a strong independent predictor for distant recurrence and overall survival in stage I endometrial cancer. These results warrant prospective validation of L1CAM as marker for selecting patients who could benefit from more extensive diagnostic and/or therapeutic procedures.     

Long-course preoperative chemoradiation versus 5 × 5 Gy and consolidation chemotherapy for clinical T4 and fixed clinical T3 rectal cancer: long-term results of the randomized Polish II study

BackgroundThis trial evaluated whether preoperative short-course radiotherapy and consolidation chemotherapy (CCT) were superior to chemoradiation in rectal cancers with clinical (c)T4 or fixed cT3. Previously, we reported early results showing no differences in the radical surgery rate (primary end point). In the short-course/CCT group, we observed lower acute toxicity of preoperative treatment and better overall survival (OS). We updated results to determine whether the benefit in OS was sustained and to evaluate late complications.Patients and methodsPatients with cT4 or fixed cT3 rectal cancer were randomized either to preoperative 5 × 5 Gy and three cycles of FOLFOX4 or to chemoradiation (50.4 Gy with bolus 5-Fu, leucovorin and oxaliplatin).ResultsPatients (N = 515) were eligible for analysis, 261 in the short-course/CCT group and 254 in the chemoradiation group. The median follow-up was 7.0 years. The difference in OS was insignificant [hazard ratio (HR) 0.90; 95% confidence interval (CI) 0.70–1.15; P = 0.38). However, the difference in early OS favouring short-course/CCT previously reported was observed again, being 9% at 3 years (95% CI 0.5% to 17%). This difference disappeared later; at 8 years OS was 49% in both groups. There was no difference in disease-free survival (HR 0.95; 95% CI 0.75–1.19; P = 0.65) at 8 years 43% versus 41% in the short-course/CCT group versus the chemoradiation group, respectively. The corresponding values for cumulative incidences of local failure and distant metastases did not differ and were HR = 1.08, 95% CI 0.70–1.23, P = 0.60, 35% versus 32% and HR = 1.10, 95% CI 0.68–1.23, P = 0.54, 36% versus 34%, respectively. The rate of late complications was similar (P = 0.66), grade 3+ being 11% versus 9% in the short-course/CCT group versus the chemoradiation group, respectively.ConclusionThe superiority of preoperative short-course/CCT over chemoradiation was not demonstrated.Clinical trial numberThe trial is registered as ClinicalTrials.gov number NCT00833131.     

Efficacité et tolérance de la radiothérapie externe pour les patients atteints d'une récidive d'un carcinome différencié de la thyroïde

PurposeRadiation therapy is often the last resource treatment for cervical relapse in iodine refractory differentiated thyroid cancer. We present locoregional control data in patients with cervical relapse treated with curative intent radiation therapy with or without concomitant carboplatin.Material and methodsThis monocentric retrospective study gathered data on patients with differentiated thyroid carcinoma – vesicular or papillary – in relapse after thyroidectomy who received a curative intent cervical radiation therapy. Locoregional progression free survival (LRPFS), progression free survival (PFS), overall survival (OS) were gathered as well as acute and chronic adverse events assessed with the CTCAE v4.ResultsThirty-nine patients were consecutively included between 2005 and 2019. The median follow-up was 36.6 months. Fifteen patients (38%) had a locoregional relapse, locoregional control at 2 years was 66.7%. The median LRPFS was 48 months [32.9–not reached] and the median overall survival 49 months [38.8–not reached]. In multivariate analysis, initial incomplete resection was associated with poorer OS (HR: 24.39 [3.57–166.78], P = 0.00113) and LRPFS (HR: 33.91 [4.46–257.61], P = 0.00066), extra nodal spread was associated with poorer LRPFS (HR: 13.45 [1.81–99,76], P = 0.011). ECOG performance status was associated with OS (HR: 5.11 [1.57–16.66], P = 0.00688). Carboplatin association with radiation therapy was not associated with improved survivals (OS: P = 0.34, LRPFS: P = 0.84). The rate of acute grade 3 toxicities was 14%.ConclusionSalvage cervical radiation therapy was associated with a locoregional control of 66.7% at 2 years with a reasonable toxicity rate. Carboplatin association with radiation therapy did not improve locoregional control nor overall survival in comparison with radiotherapy alone.