Domenico Genovesi

Prognostic value of pathologic complete response after neoadjuvant therapy in locally advanced rectal cancer: long-term analysis of 566 ypCR patients.

PURPOSE In the literature, a favorable prognosis was observed for complete pathologic response after preoperative therapy (ypCR) in patients with locally advanced rectal cancer. The aim of this study is to verify whether ypCR predicts a favorable outcome in a large series of patients. METHODS AND MATERIALS The Gastro-Intestinal Working Group of the Italian Association of Radiation Oncology collected clinical data for 566 patients with ypCR (ypT0N0) after neoadjuvant therapy. Eligibility criteria included locally advanced rectal cancer with no evidence of metastases at the time of diagnosis, evidence of ypCR after preoperative radiotherapy +/- chemotherapy (CT). RESULTS Median radiation dose was 50 Gy. A total of 527 patients (93%) received one of 12 different neoadjuvant CT schedules. Sphincter preservation, anteroposterior resection, and endoscopic surgery were performed in 73%, 22%, and 5% of patients, respectively. Adjuvant CT was administered to 22% of patients. Median follow-up was 46.4 months. Locoregional recurrence occurred in 7 patients (1.6%). Distant metastases occurred in 49 patients (8.9%). Overall, 5-year rates of disease-free survival, overall survival, and cancer-specific survival were 85%, 90%, and 94%, respectively. In multivariate analysis, only age and clinical stage statistically correlated with survival outcome. Adjuvant CT was still of borderline significance (worse for adjuvant CT). No relation was found between survival and neoadjuvant CT schedules. CONCLUSION A ypCR after neoadjuvant therapy identified a favorable group of patients, even in this large series of 566 patients collected in 61 centers. Locoregional recurrence occurred only in 1.6% patients.

Prognostic value of breast cancer subtypes on breast cancer specific survival, distant metastases and local relapse rates in conservatively managed early stage breast cancer: A retrospective clinical study

AIM To ascertain if breast cancer subtypes had prognostic effect on breast cancer specific survival, distant metastases and local relapse rates in women affected by early stage breast cancer. PATIENTS AND METHODS Data of 774 patients affected by early stage breast cancer and treated with breast-conserving therapy were reviewed. Patients were grouped, based on steroid receptor status and HER2 status as: Luminal A (ER+/PR+/HER2-), Luminal B (ER+/PR+/HER2+), Basal-like (ER-/PR-/HER2-) and HER2 (ER-/PR-/HER2+). Distribution of variables among subtypes was evaluated with Pearsons test. Survival rates were calculated with life tables; Cox regression stepwise method was used to identify predictive variables of survival. RESULTS Median age was 55.0 years old (range 27-80) and median follow up time of 59.0 months (range 13.6-109.7). Breast cancer specific survival and distant metastases rates were different among breast cancer subtypes (both outcomes P=0.00001) but there was no difference regarding local relapse rates (P=0.07). Axillary nodes status (P=0.00001), adjuvant therapy (P=0.03) and breast cancer subtypes (P=0.03) resulted prognostic factors of breast cancer specific survival; axillary node status (P=0.00001) and breast cancer subtypes (P=0.00001) had an impact on distant metastases. Age (P=0.003), tumor size (P=0.0001), positive or close surgical margin (P=0.00001) and tumor grade 3 (P=0.049) resulted prognostic factors of local relapse. CONCLUSIONS In our study, breast cancer subtype seems a prognostic factor of breast cancer specific survival and distant metastases rates, but not of local relapse rate. Patients could be submitted to conservative surgery, if feasible, but considering the differences in survivals, patients with worse prognosis should receive more aggressive adjuvant treatments.

Role of microRNA in response to ionizing radiations: evidences and potential impact on clinical practice for radiotherapy

MicroRNAs (miRNA) are small, non-coding, RNAs with gene expression regulator roles. As an important class of regulators of many cellular pathways, miRNAs are involved in many signaling pathways and DNA damage repair processes, affecting cellular radiosensitivity. Their role has led to interest in oncological implications to improve treatment results. MiRNAs represent a great opportunity to enhance the efficacy of radiotherapy treatments—they can be used to profile the radioresistance of tumors before radiotherapy, monitor their response throughout the treatment, thus helping to select intensification strategies, and also to define the final response to therapy along with risks of recurrence or metastatization. Even though many interesting studies support such potential, nowadays most studies on patient data are limited to experiments profiling tumor aggressiveness and response to radiotherapy. Moreover many studies report different although not conflicting results on the miRNAs evaluated for each tumor type. Without doubt, the clinical potential of such molecules for radiotherapy is striking and of high interest.

Five fractions of preoperative radiotherapy for selected cases of rectal carcinoma: long-term tumor control and tolerance to treatment.

BACKGROUND Randomized Swedish studies demonstrate the efficacy of a 5-fraction course of preoperative radiotherapy for rectal carcinoma. The present study evaluates the results in a single U.S. institution over a 20-year period with a similar regimen. METHODS AND MATERIALS During the period of 1975-1995, 83 patients received pelvic radiotherapy of 20 Gy/5 fractions, followed by immediate surgery for rectal cancer. These patients represented 21% of cases receiving preoperative treatment; the remainder received 45-50 Gy preoperatively. The 5-fraction course was used for lesions deemed readily resectable but too bulky for conservative endocavitary treatment. Since 1990, it has been our policy to administer postoperative chemotherapy to medically fit patients who prove to have pathologic Stage II or III disease. Patient characteristics including age (mean 65 years, range 23-90), gender (45% male), and location within the rectum were comparable to our previously reported cases that received 45 Gy/25 fractions preoperatively. However, the group selected for 5 fractions preoperatively had relatively fewer lesions that were tethered (20% vs. 61%), circumferential (11% vs. 20%), or near obstructing (1% vs. 16%). RESULTS With a post treatment follow-up of 1-15 years (mean 4.7), there have been 3 local failures and 12 distant failures, with an actuarial local control of 95%, and disease-specific survival of 77% at 5 and 10 years. Grade > or = 3 perioperative or late toxicity occurred in 11 cases (13%), including 3 (3.5%) late bowel obstructions. Stage II or III disease was found in 56% of the cases, 74% of which were free of disease at last follow-up. However, patients with Stage II or III lesions that were significantly tethered or fixed had a 40% greater likelihood of recurring than similar stage lesions that were, at most, slightly tethered. Sphincter-preserving surgery was possible in 60% of the patients. In recent years, postoperative chemotherapy has been administered to 16 patients with Stage II or III disease; this has been well tolerated, with only 1 late toxicity (cystitis managed medically). When compared with a matched group of cases receiving conventionally fractionated preoperative radiation, there were no significant differences in perioperative morbidity and nonradiotherapeutic cost generating factors (length of hospital stay, duration of postoperative antibiotics, blood loss at surgery). CONCLUSION Patients with resectable rectal cancer who received 20 Gy/5 fractions preoperative radiotherapy to the pelvis had excellent local and distant control of disease. These patients were able to undergo sphincter-preserving surgery and postoperative chemotherapy. It would be of interest to conduct a randomized trial comparing short course with longer course (45 or 50 Gy) preoperative radiotherapy for resectable T3 lesions. The results of this study suggest that, in general, differences in toxicity, local control, and disease-free survival would probably be < 10%. However, since the results of this study suggest that patients with significantly tethered lesions may be better served with the higher dose and longer duration course of radiation, clinical degree of fixation should be included as a stratification parameter, and stopping criteria should be included for tethered lesions.

Advances in Lipidomics for Cancer Biomarkers Discovery

Lipids play critical functions in cellular survival, proliferation, interaction and death, since they are involved in chemical-energy storage, cellular signaling, cell membranes, and cell–cell interactions. These cellular processes are strongly related to carcinogenesis pathways, particularly to transformation, progression, and metastasis, suggesting the bioactive lipids are mediators of a number of oncogenic processes. The current review gives a synopsis of a lipidomic approach in tumor characterization; we provide an overview on potential lipid biomarkers in the oncology field and on the principal lipidomic methodologies applied. The novel lipidomic biomarkers are reviewed in an effort to underline their role in diagnosis, in prognostic characterization and in prediction of therapeutic outcomes. A lipidomic investigation through mass spectrometry highlights new insights on molecular mechanisms underlying cancer disease. This new understanding will promote clinical applications in drug discovery and personalized therapy.

Inter-observer variability of clinical target volume delineation in radiotherapy treatment of pancreatic cancer: a multi-institutional contouring experience

BackgroundAn observational multi-institutional study has been conducted aimed to evaluate the inter-observer variability in clinical target volume (CTV) delineation among different radiation oncologists in radiotherapy treatment of pancreatic cancer.MethodsA multi-institutional contouring dummy-run of two different cases of pancreatic cancer treated by postoperative and preoperative radiotherapy (RT) was performed. Clinical history, diagnostics, and planning CT imaging were available on AIRO website (http://www.radioterapiaitalia.it). Participants were requested to delineate CTVs according to their skills and knowledge. Aiming to quantify interobserver variability of CTVs delineations, the total volume, craniocaudal, laterolateral, and anteroposterior diameters were calculated. Descriptive statistic was calculated. The 95% Confidence Interval (95% CI) for coefficient of variation (CV) was estimated. The Dice Similarity Index (DSI) was used to evaluate the spatial overlap accuracy of the different CTVs compared with the CTVs of a national reference Centre considered as a benchmark. The mean DSI (mDSI) was calculated and reported.ResultsA total of 18 radiation oncologists from different Institutes submitted the targets. Less variability was observed for the Elective CTV rather than the Boost CTV, in both cases. The estimated CV were 28.8% (95% CI: 21.2 - 45.0%) and 20.0% (95% CI: 14.9 - 30.6%) for the Elective CTV, in adjuvant (Case 1) and neoadjuvant (Case 2) case, respectively. The mDSI value was 0.68 for the Elective CTVs in both cases (range 0.19 - 0.79 in postoperative vs range 0.35 - 0.79 in preoperative case). The mDSI was increased to 0.71 (Case 1) and 0.72 (Case 2) if the observers with a worse agreement have been excluded. On the other hand, a CV of 42.4% (95% CI: 30.1 - 72.4%) and 63.8% (95% CI: 43.9 - 119.2%) with a mDSI value of 0.44 and 0.52, were calculated for the Boost CTV in Case 1 and Case 2, respectively.ConclusionsThe CV and mDSI obtained values for Elective CTVs showed an acceptable agreement among participants either in postoperative as well in preoperative setting. Additional strategies to reduce the variability in Boost CTV delineation need to be found and promoted.

The Effect of Delaying Adjuvant Radiation Treatment after Conservative Surgery for Early Breast Cancer

Abstract:  We examined the effect of delaying radiation treatment after conservative surgery on the risk of breast cancer local recurrence (LR). From January 1997 to December 2001, 969 women with early‐stage breast cancer were treated at the Radiation Oncology Department in Chieti. We analyzed 802 of them who underwent conservative surgery followed by whole‐breast radiotherapy. The patients were divided into two groups: women who did not receive chemotherapy and women who received chemotherapy. The time intervals from surgery to breast irradiation used for the analysis were <16 or more weeks for no‐chemotherapy‐treated women, and <25 and 25 or more weeks for chemotherapy‐treated women. The relationship between LR and factors such as age, tumor size, margin status, and surgery‐radiotherapy time interval was evaluated. The 8‐year LR risk was estimated using the Kaplan–Meier method. LR was observed in 33 (4.1%) of the 802 patients. The overall 8‐year LR risk was 6.5% (±1.51). In the no‐chemotherapy group, the risk of LR was associated with a younger age and a positive margin status. In the chemotherapy group LR was associated with a younger age and a tumor size >3 cm. Surgery‐radiotherapy interval was not associated with LR in both groups of patients. Delay in the start of radiotherapy does not increase the risk of LR in patients with early breast cancer treated or not treated with chemotherapy.

Interobserver variability of clinical target volume delineation in supra-diaphragmatic Hodgkin’s disease

Background:To determine interobserver variability in clinical target volume (CTV) of supra-diaphragmatic Hodgkin’s lymphoma.Materials and Methods:At the 2008 AIRO (Italian Society of Radiation Oncology) Meeting, the Radiation Oncology Department of Chieti proposed a multi-institutional contouring dummy-run of two cases of early stage supra-diaphragmatic Hodgkin’s lymphoma after chemotherapy. Clinical history, diagnostics, and planning CT imaging were available on Chieti’s radiotherapy website (www.radioterapia.unich.it). Participating centers were requested to delineate the CTV and submit it to the coordinating center. To quantify interobserver variability of CTV delineations, the total volume, craniocaudal, laterolateral, and anteroposterior diameters were calculated.Results:A total of 18 institutions for case A and 15 institutions for case B submitted the targets. Case A presented significant variability in total volume (range: 74.1–1,157.1 cc), craniocaudal (range: 6.5–22.5 cm; median: 16.25 cm), anteroposterior (range: 5.04–14.82 cm; median: 10.28 cm), and laterolateral diameters (range: 8.23–22.88 cm; median: 15.5 cm). Mean CTV was 464.8 cc (standard deviation: 280.5 cc). Case B presented significant variability in total volume (range: 341.8–1,662 cc), cranio-caudal (range: 8.0–28.5 cm; median: 23 cm), anteroposterior (range: 7.9–1.8 cm; median: 11.1 cm), and laterolateral diameters (range: 12.9–24.0 cm; median: 18.8 cm). Mean CTV was 926.0 cc (standard deviation: 445.7 cc).Conclusion:This significant variability confirms the need to apply specific guidelines to improve contouring uniformity in Hodgkin’s lymphoma.Ziel:Diese Studie wurde durchgeführt, um die Inter-Beobachter-Variabilität des klinischen Zielvolumens bei supradiaphragmatischem Hodgkin-Lymphom festzustellen.Methodik:Beim 18. Treffen der AIRO (Italienischen Gesellschaft für Radioonkologie) in Mailand (November 2008) schlug die Abteilung für Strahlentherapie/Radioonkologie von Chieti eine multiinstitutionelle Zielvolumen-Konturierung („Dummy-run“) von zwei Fällen supradiaphragmatischer Hodgkin-Lymphome im frühen Stadium nach der Chemotherapie vor. Informationen über den klinischer Verlauf, die diagnostischen Befunde und die Planungs-CT-Bildgebung standen auf der Website (www.radioterapia.unich.it) der Abteilung für Strahlentherapie/Radioonkologie der Universität Chieti zur Verfügung. Die teilnehmenden Zentren wurden gebeten, die klinischen Zielvolumina zu definieren und ihre Ergebnisse bei der Koordinierungsstelle einzureichen. Um die Inter-Beobachter-Variabilität bei der Konturierung des klinischen Zielvolumens zu quantifizieren, wurden das Gesamtvolumen (cc), die kraniokaudalen, laterolateralen und die anteroposterioren Durchmesser (cm) berechnet.Ergebnisse:18 Zentren bezüglich des Falls A und 15 Zentren bezüglich des Falls B haben Zielvolumen-Definitionen eingereicht. Dabei wurden signifikante Variationen bei der Konturierung des klinischen Zielvolumens festgestellt. Der Range der Volumendefinition im Fall A reichte von 74,1 bis zu 1157,1 cc (Abbildung 1). Diese Variationen wurden bei der Messung der kraniokaudalen (durchschnittlich 16,25 cm; Range 6,5–22,5 cm) (Abbildung 2), anteroposterioren (durchschnittlich 10,28 cm; Range 5,04–14,82 cm) (Abbildung 3) und laterolateralen Durchmesser (durchschnittlich 15,5 cm; Range 8,23–22,88 cm) (Abbildung 4) bestätigt (Tabelle 1). Der Durchschnitt der klinischen Zielvolumina war 464,8 cc mit einer Standardabweichung von 280,5 cc. Der Range der Volumendefinition im Fall B reichte von 341,8 bis zu 1662 cc (Abbildung 1); und diese Variationen wurden bei der Messung der kraniokaudalen (durchschnittlich 23 cm; Range 8,0–28,5 cm) (Abbildung 5), anteroposterioren (durchschnittlich 11,1 cm; Range 7,9–14,8 cm) (Abbildung 6) und laterolateralen Durchmesser (durchschnittlich 18,8 cm; Range 12,9–24,0 cm) (Abbildung 7) bestätigt (Tabelle 2). Der Durchschnitt der klinischen Zielvolumina war 926,0 cc mit einer Standardabweichung von 445,7 cc.Schlussfolgerung:Diese signifikante Variabilität bestätigt die Notwendigkeit der Anwendung von spezifischen Guidelines, um die Uniformität der Konturierung bei Hodgkin-Lymphomen zu verbessern.

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.

Interval Between Breast-Conserving Surgery and Start of Radiation Therapy in Early-Stage Breast Cancer is Not Predictive of Local Recurrence: A Single-Institution Experience

BACKGROUND The aim of this study was to evaluate if the interval between breast-conserving surgery and the start of radiotherapy has an effect on local relapse risk. MATERIALS AND METHODS Between January 2000 and December 2006 a total of 387 patients with T1-2N0+ breast cancer were treated with breast-conserving surgery and radiotherapy, with and without hormone therapy and chemotherapy. Adjuvant radiotherapy was administered to a total dose of 60 to 66 Gy in 30 to 33 fractions. The time intervals between breast-conserving surgery and the start of radiotherapy were < 60, 61 to 120, 121 to 180 and > 180 days. The Kaplan-Meier method was used to calculate local relapse-free survival rates, and the Cox regression method was used to identify predictive factors of local relapse. Evaluated variables were age, tumor location, tumor histologic type, tumor size, surgical margin status, axillary node status, estrogen receptors, tumor grading, adjuvant therapy, adjuvant chemotherapy, radiation therapy, boost dose, and interval between breast-preserving surgery and start of radiation therapy. RESULTS Five-year local relapse-free survival rates were 97.3% ± 1.5% for patients who did not receive chemotherapy and 94.5% ± 1.9% for patients who received chemotherapy (P = .71). There was no significant difference in local relapse among the 4 interval groups (P = .9). Multivariate Cox regression analysis showed that intervals between breast-conserving surgery and radiotherapy were not associated with higher local relapse risk. CONCLUSION In our study a delay in administering radiotherapy after breast-conserving surgery was not associated with an increased risk of local relapse. Taking into account contrasting results of many published studies, a larger evaluation of this issue is warranted.