Whole breast radiotherapy in cN0 early breast cancer patients with pathological sentinel lymph nodes (pN1mic, pN1a) without axillary dissection: preliminary results of the observational LISEN trial.

PURPOSE: Axillary management remains unclear when sentinel lymph node (SLN) results are positive in cN0 patients with breast cancer (BC). The trial ACOSOG Z0011 represented a revolution with axillary lymph node dissection (ALND) omission in SLN+ patients, despite critiques regarding non-uniformity of radiation fields. We conducted an observational study (LISEN) where whole breast radiotherapy (WBRT) was planned with tangential fields without nodal irradiation in patients eligible for the Z0011 trial. METHODS: Inclusion criteria were female patients with histologically proven BC, cT1-2cN0, planned conservative surgery, no neoadjuvant therapy. Patients were stratified into two groups: micrometastatic (pN1mic, group 1) and macrometastatic (pN1a, group 2) lymph nodes. Tangential field WBRT was mandatory. Clinical outcomes were analysed, measured from surgery until the first event. RESULTS: In all, 199 patients underwent conservative surgery and SLN biopsy; 133 patients meeting criteria were analysed: 41 patients (30.8%) pN1mic and 92 (69.2%) pN1a. The 5­year disease-free survival (DFS) was 95.0% (85.9-100%) in group 1 and 93.0% (86.3-100.0%) in group 2 (p = 0.78). Overall survival (OS) was 100% (100-100%) in group 1 and 97.4% (92.4-100%) in group 2 (p = 0.74). For the whole cohort DFS and OS were 93.6% (88.2-99.4%) and 96.9% (91.5-100.0%), respectively. For groups 1 and 2, the 5­year outcomes were 5.0% (0.0-14.4%) and 2.3% (0.0-6.1%) for local recurrence (p = 0.51), and 6.2% (0.0-17.4%) and 7.0% (0.0-13.7%) for distant metastasis (p = 0.61), respectively. In group 1, regional recurrence (RR) and local regional recurrence (LRR) were 5.0% (0.0-14.1%; p = 0.13). In group 2, RR and LRR were 0.0% (0.0-0.0%). CONCLUSION: Our results showed good regional control in patients who met the Z0011 trial criteria. WBRT, without nodal surgery or RT, avoiding axillary morbidity, seems to be a good choice.

Clinical outcomes in elderly rectal cancer patients treated with neoadjuvant chemoradiotherapy: impact of tumor regression grade : Tumor regression grade after neoadjuvant chemoradiotherapy in elderly rectal cancer patients.

PURPOSE: The effect of neoadjuvant chemoradiotherapy (CRT) and the relationship between pathological complete response (pCR) with clinical outcomes has been evaluated in elderly locally advanced rectal cancer (LARC) patients. METHODS: We retrospectively analyzed 117 LARC patients treated with conformal RT and concomitant fluoropirimidine-based chemotherapy. A dose of 4500 cGy, on the pelvis, up to 5500 cGy on the tumor was delivered. Multidisciplinary evaluation, including geriatric assessment, was previously performed to identify frail patients unsuitable for combined treatment. RESULTS: The median age was 75 (range 70-88 years), and 103 (88%) patients had ECOG Performance Status (PS) = 0. All patients except one completed CRT. Ten (8.5%) patients temporarily suspended CRT for acute severe hematologic complication, diarrhea and/or proctitis and hypokalemia. Of the 103 operated patients (88%), a pCR, according to Mandard tumor regression grade (TRG) score, was obtained in 28 patients (27.2%), with TRG1-2 rate of 43.7%. The 3- and 5-year overall survival (OS) rates were 80.2% ± 4.2% and 68.0% ± 5.2%, 72.4% ± 4.5% and 57.8% ± 5.2% for disease-free survival (DFS), and 92.2% ± 2.8% and 89.5% ± 3.9% for loco-regional control. Patients with TRG1-2 had 3- and 5-year OS rates of 84.1% ± 6.6% and 84.1% ± 6.6% compared with 82.8% ± 5.5% and 67.7% ± 7.2% for patients with TRG3-5 (p = 0.012). The 3- and 5-year DFS rates for patients with TRG1-2 were 77.6% ± 7.0% and 74.2% ± 7.5% compared with 70.9% ± 6.3% and 54.7% ± 7.3% for patients with TRG3-5 (p = 0.009). CONCLUSION: Our results reported good tolerability and clinical outcomes of neoadjuvant CRT, with a benefit in patients ≥ 70 years, confirming the prognostic role of pCR on clinical outcomes.

Long-term outcome of neoadjuvant endocrine therapy with aromatase inhibitors in elderly women with hormone receptor-positive breast cancer.

BACKGROUND: Aromatase inhibitors (AIs) are more effective than tamoxifen as neoadjuvant endocrine therapy (NET) for hormone receptor (HR)-positive breast cancer. Here we report the surgical and long-term outcome of elderly postmenopausal patients with locally advanced, HR-positive breast cancer treated with preoperative AIs. METHODS: Between January 2003 and December 2012, 144 postmenopausal patients inoperable with breast conservative surgery (BCS) received letrozole, anastrozole, or exemestane as NET. Patients underwent breast surgery and received adjuvant AIs. Adjuvant systemic therapy, chemotherapy and/or trastuzumab, and adjuvant radiotherapy were administered as appropriate, but limited to high-risk patients with few or no comorbidities. RESULTS: After a median follow-up of 49 months, 4 (3.0 %) patients had local relapse, 18 (12.5 %) had distant metastases, and 24 (17.0 %) died. BCS was performed in 121 (84.0 %) patients. A tumor size <3 cm and human epidermal growth factor receptor 2 (HER2) negativity were predictors of BCS. The achievement of BCS and grade G1 were significantly associated with longer disease-free survival (DFS) (p = 0.009 and p = 0.01, respectively) and overall survival (p = 0.002 and p = 0.005, respectively). Residual tumor ≤2 cm (yT0-yT1) in the longest diameter after NET was also statistically associated with longer DFS (p = 0.005). CONCLUSIONS: The results of this retrospective study indicate that elderly breast cancer patients with a tumor size <3 cm at diagnosis and HER2 negativity have a higher probability of achieving BCS after NET. Moreover, patients treated with BCS and with grade G1 tumor have a reduced risk of recurrence and death in the long-term follow-up.

The case of a patient affected by primary gliosarcoma and neuroendocrine pancreatic cancer with prolonged survival.

Primary gliosarcoma (PGS) is a rare neoplasm with a poor prognosis. It is considered as a variant of glioblastoma multiforme (GBM) and as a grade IV neoplasm. There is little evidence on the optimal therapy for this disease: treatment of PGS includes surgery, radiotherapy and chemotherapy, and often the same treatment used for GBM is employed for PGS. Several studies have demonstrated that somatostatin receptors are overexpressed in gliomas; somatostatin analogues could therefore also be employed in this mixed form but to date the experience reported in the literature is unclear and there are no studies about the use of these agents in PGS. We present the case of a patient affected by both PGS and neuroendocrine pancreatic cancer. The case is interesting for the prolonged survival and for the stabilization of disease obtained during therapy with somatostatin analogues.

Long-term outcome of neoadjuvant systemic therapy for locally advanced breast cancer in routine clinical practice.

PURPOSE: The aim of this study is to evaluate the long-term outcome of patients with locally advanced breast cancer treated with neoadjuvant systemic chemotherapy (NST) in routine clinical practice. METHODS: Four hundred and nine patients were identified between January 1999 and December 2011. All patients received NST followed by surgery, adjuvant treatments and radiotherapy, as appropriate. RESULTS: At Kaplan-Meier analysis, patients with surgical stage III disease were more likely to develop distant metastasis and die from breast cancer (p < 0.001). Luminal A and luminal B/HER2-negative patients had better prognosis; moreover, patients with hormone receptor (HR)-positive tumors had a significantly longer DRFS (p < 0.0049) and OS (p < 0.0001) compared with patients with HR-negative tumors as well as patients who underwent breast-conserving surgery (DRFS and OS: p < 0.001). In multivariate analysis, HR negativity (p < 0.001 for both DRFS and OS), mastectomy (DRFS: p = 0.009; OS: p = 0.05) and stage III disease (DRFS: p < 0.001; OS: p = 0.003) were associated with shorter DRFS and OS. CONCLUSIONS: HR negativity, mastectomy and pathological stage III disease are the variables independently associated with a worse outcome in our cohort of patients. These data are of high interest since they derive from a very heterogeneous group of patients, treated with different neoadjuvant/adjuvant regimens outside of clinical trials and with a long follow-up period.

Effects of preoperative radiochemotherapy with capecitabine for resectable locally advanced rectal cancer in elderly patients.

AIMS AND BACKGROUND: Rectal cancer is a common disease of elderly people. However, patients over 70 years of age are often not included in clinical trials. There is a lack of data concerning the use of radiochemotherapy with capecitabine in elderly patients. The aim of this study was to retrospectively evaluate the impact of preoperative radiochemotherapy with capecitabine on downstaging and sphincter preservation and to assess treatment compliance and toxicity in elderly patients. METHODS: Twenty-six patients with resectable locally advanced rectal cancer (stage II-III/TNM) aged >70 years received preoperative radiotherapy and concurrent oral capecitabine 825 mg/m² twice daily during the whole period of radiotherapy. Two patients who refused surgery after chemoradiation therapy were excluded from the analysis. Results. Eighty-one percent of patients underwent anterior resection and 18.1% underwent abdominoperineal resection. Overall tumor downstaging, considering both T and N categories, was observed in 18/24 patients (75%). Treatment compliance was good and toxicity rates were similar to those of younger people. CONCLUSIONS: Age is not a contraindication to any therapy and elderly patients who can tolerate radiochemotherapy should be treated like younger patients. Preoperative radiochemotherapy with capecitabine for patients aged >70 years has a good impact on tumor downstaging, increases the feasibility of sphincter-preserving surgery, and is also safe and well tolerated.

Biologically effective dose and breast cancer conservative treatment: is duration of radiation therapy really important?

To evaluate if biologically effective dose (BED), and in particular the duration of radiation treatment, has an effect on local relapse risk. Between January 2000 and December 2008 a total of 762 patients with T1-2 N0/+ breast cancer was treated with breast-conserving surgery and radiotherapy, with and without hormone therapy and chemotherapy. Adjuvant radiation therapy was administered to a total dose of 60-66 Gy in 30-33 fractions. The computed BEDs were divided in four groups: <43.1, 43.1-44.9, 45.0-46.1, and >46.1 Gy (A-D, respectively). Kaplan-Meier method was used to calculate local relapse rates. Cox regression method was used to identify prognostic factors of local relapse. Evaluated variables were age, tumor histology, tumor size, surgical margin status, axillary nodal status, tumor grading, adjuvant therapies, adjuvant chemotherapy alone, adjuvant hormone therapy alone, adjuvant anthracyclines, and BEDs values. 8-year local relapse rates were 18.0% for group A, 8.5% for group B, 4.6% for group C, and 2.7% for group D (P=0.008). Multivariate Cox regression analysis showed that BEDs values were associated with higher local relapse risk (P=0.001). In our study, a prolongation of radiotherapy treatment, intended as a lower BED value, after breast-conserving surgery is associated with an increased risk of local relapse. Considering the wide range of results published in other studies, hypofractionation for breast cancer should be considered, at the moment, feasible in selected patients.

Abeta(1-42) stimulated T cells express P-PKC-delta and P-PKC-zeta in Alzheimer disease.

The protein kinase C (PKC) family of enzymes is a regulator of transmembrane signal transduction, and involvement of some PKC isoforms in T-cell activation has been demonstrated. Nevertheless, very little is known about their involvement in the Amyloid beta (Abeta)-dependent molecular signals in the T lymphocytes of Alzheimer disease (AD) patients. Therefore, the aim of this study was to investigate the involvement of PKC-alpha, PKC-delta and PKC-zeta expression and activity in the signaling machinery activated in Abeta-reactive T cells, in adult healthy individuals, elderly healthy subjects, and from patients with AD. The results show that in peripheral T-cells from early AD patients, Abeta(1-42) produced a distinct subpopulation highly expressing P-PKC-delta, while in severe AD patients the same treatment induced two distinct P-PKC-delta and P-PKC-zeta T-cell subpopulations. Such subpopulations were not noticeable following CD3/CD28 treatment of the same samples or after treatment of peripheral T cells from healthy adult or elderly subjects with Abeta(1-42) or with CD3/CD28. We believe that these findings may be of help in possible attempts to develop further diagnostic strategies useful for the characterization of AD.

Dose fractionation and biological optimization in breast cancer.

Standard radiotherapy in breast cancer is performed at the dose of 1.8-2 Gy daily 5 fractions a week for a total dose between 45 and 60 Gy. However research is addressed to different fractionations. For total time reduction, the interest was focused on conventional brachytherapy which radiobiologically represents "continuous" accelerated hyperfractionation, as well as on conventional external beam radiotherapy with accelerated hyperfractionation. A phase I study was conducted to define and validate a radiotherapy schedule with non conventional fractionation. Nine patients with metastatic breast cancer were enrolled in the study. None of them had undergone breast surgery or lymph node dissection. They were sequentially divided into three different, progressively increasing dose levels administered with double daily fractionation. Each schedule of accelerated fractionation (AF) included the administration of 1.8 Gy in two daily fractions, at least six hours apart for 10, 11 and 12 days and a total dose of 36, 39.6 and 43.2 Gy, respectively. Results of dose escalation, acute toxicity and mathematical calculation of radiobiological equivalence led to consider the dose of 36 Gy in 20 fractions during 10 days the most suitable for cost/benefit ratio within a non conventional fractionation.

Pain in osseous metastases: results of radiotherapy.

Seventy-nine patients with osseous metastases were prospectively evaluated bone pain. The evaluation of pain has been accomplished using the Keele Scale system. All cases have been treated with radiotherapy. The therapeutic response for analgesic effect has been evaluated in complete response (CR) when total disappearance of pain was present; in partial response (PR) with the reduction of at least 1 point on the Keele Scale: in non-responsive (NR) when patients showed worsening or no change in pain symptomatology during or following therapy. 51.8% have presented complete response, 36.8% partial response and 11.3% no response. The global response (CR + PR) has been 88.6%. This response was evaluated in relation to fractionating daily dose of radiotherapy and minimum dose necessary for analgesia.