Breast-conserving treatment for ductal carcinoma in situ: Impact of boost and tamoxifen on local recurrences.

PURPOSE: Ductal carcinoma in situ represents 15 to 20% of all breast cancers. Breast-conserving surgery and whole breast irradiation was performed in about 60% of the cases. This study reports local recurrence rates in patients with ductal carcinoma in situ treated by breast-conserving surgery and whole breast irradiation with or without boost and/or tamoxifen and compares different therapeutic options in two European countries. PATIENTS AND METHODS: From 1998 to 2007, 819 patients with pure ductal carcinoma in situ were collected, both in France (266) and Italy (553). Median age was 56. All underwent breast-conserving surgery and whole breast irradiation; 391 (48%) received a boost (55% in France and 45% in Italy, P=0.017) and 173 (22.5%) tamoxifen (4.5% in France and 32% in Italy, P<0.0001). RESULTS: With a 90-month median follow-up, there were 51 local recurrences (6.2%), including 27 invasive (53%). The 5- and 10-year local recurrence rates were 4% and 8.6%. Two patients developed axillary recurrence and 12 (1.5%) metastases (seven after invasive local recurrence); 41 (5%) patients had contralateral breast cancer. In the multivariate analysis, high nuclear grade and lack of tamoxifen are the most powerful predictors of local recurrence, with 2.6 (95% confidence interval [95% CI]: 1.74-3.89, P=0.0012) and 2.85 (95% CI: 1.42-5.72, P=0.04) odds ratio (OR) estimates, respectively. Age, margin status and boost did not influence local recurrence rates. CONCLUSIONS: This study confirms the ductal carcinoma in situ treatment heterogeneity among countries and the unfavourable prognostic role of nuclear grade. Tamoxifen reduces local recurrence rates and might be considered for some subgroups of patients, but further confirmation is required. The boost usefulness still remains unclear.

In vivo cell kinetics in head and neck squamous cell carcinomas predicts local control and helps guide radiotherapy regimen.

PURPOSE: To determine whether pretherapy cell kinetics can predict local control for patients affected by head and neck squamous cell carcinomas (HN-SCCs) to be treated by primary radiotherapy and, moreover, guide to a choice between conventional and accelerated radiotherapy. PATIENTS AND METHODS: Between 1989 and 1993, 83 patients with stage II to IV HN-SCC entered the study. Multiple primary tumor biopsies were obtained 6 hours after in vivo infusion of bromodeoxyuridine (BrdUrd). In vivo S-phase fraction labeling index (LI), duration of S phase (Ts), and potential doubling time (Tpot) were obtained by analysis of multivariate flow-cytometric data. Between April 1989 and January 1991, 49 patients were treated by conventional radiotherapy (70 Gy in 35 fractions over 7 weeks), whereas, afterwards, 34 patients entered an accelerated radiotherapy regimen with the concomitant boost technique (75 Gy in 40 fractions over 6 weeks). RESULTS: Univariate analysis showed that, among patients treated by conventional radiotherapy, local control probability was affected by tumor stage (P = .02), Tpot (P < .001), and LI (P = .04). Similarly, among patients treated with accelerated radiotherapy, we found that local control probability was related to tumor stage (P = .03) and primary tumor site (P = .05). For the subgroup of patients with tumors characterized by fast growth (Tpot < or = 5 days), accelerated radiotherapy gave a better local control rate than conventional radiotherapy (P = .02). Cox multivariate analysis of the total number of patients showed that the only significant independent prognostic factors related to local control were tumor stage (P = .002) and Tpot (P = .004). Moreover, when the Cox analysis was restricted to the subgroup of patients treated with conventional radiotherapy, Tpot was the most significant factor to predict local outcome (P < .01). CONCLUSION: Pretreatment tumor Tpot appears to be an important independent prognostic factor for local control of HN-SCC treated by primary radiotherapy.

Helical Tomotherapy of the breast: can thermoplastic immobilization improve the reproducibility of the treatment setup and the accuracy of the delivered dose?

PURPOSE: To evaluate the impact of thermoplastic mask immobilization in the setup reproducibility and delivered dose for Helical Tomotherapy (HT) of the breast/chest wall. METHODS: 16 patients treated with Accuray Hi-Art HT for breast-cancer were considered. Patients were positioned supine with arms extended above the head using Civco Wing Board (WB) system. In 50% of patients an Orfit thermoplastic mask was added in order to improve immobilization. Before each treatment fraction a megavoltage CT (MVCT) scan was taken and registered to the planning CT by experienced medical staff. The impact of thermoplastic mask was investigated analysing MVCT shift-roll data and MVCT dose distribution using Planned Adaptive software. RESULTS: In the analysed cases, the addition of thermoplastic mask had minor impact on the lateral, longitudinal and roll data distribution. Variance of vertical shifts was significantly reduced in the WB + Orfit group. Van Herk's margins were not affected by addition of thermoplastic immobilization. In both groups, target coverage (V95) and maximum dose (D1) were almost identical to planned values. D1 of organs at risk were not significantly different in the two groups. CONCLUSIONS: Analysis of shift-roll data shows no improvement in the group of patients immobilized with the addition of thermoplastic mask. Van Herk's margin is quite large (7-10 mm) in both groups evidencing the need to perform daily setup correction. The adapted dose distribution complies well with the planned one, showing that if MVCT is used before each treatment fraction, a 3 mm margin (setup component) for CTVs expansion could be adequate.

Locally advanced non-metastatic breast cancer: analysis of prognostic factors in 125 patients homogeneously treated with a combined modality approach.

125 stage III breast cancer patients, including 51 cases of inflammatory carcinoma, were treated with the following combined modality approach: three courses of primary 5-fluorouracil, doxorubicin, cyclophosphamide (FAC) chemotherapy followed by locoregional treatment and subsequent adjuvant chemotherapy consisting of three courses of FAC alternating with three courses of cyclophosphamide, methotrexate, 5-fluorouracil (CMF). Clinical response to primary FAC was 65% (complete 10%). Residual tumour mass in the mastectomy specimen was > 1 and < or = 1 cm in 82 and 18% of cases, respectively. Complete pathological response following primary chemotherapy was achieved in only 3.5% of cases. After primary FAC and local treatment, 97% of patients were disease-free. Overall survival (S) and progression-free survival (PFS) at 5 years were 56 and 34%, respectively. Univariate analysis showed that age, receptor status and clinical and pathological response to primary chemotherapy did not appear to influence treatment outcome significantly, whereas stage, presence of inflammatory disease and number of involved nodes had a significant impact on both S and PFS.

A pilot study of accelerated cyclophosphamide, epirubicin and 5-fluorouracil plus granulocyte colony stimulating factor as adjuvant therapy in early breast cancer.

32 consecutive early breast cancer patients were treated to evaluate the feasibility of an accelerated CEF regimen (cyclophosphamide 600 mg/m2, epirubicin 60 mg/m2 and 5-fluorouracil 600 mg/m2) given intravenously every 2 weeks for six cycles together with granulocyte colony stimulating factor, 5 micrograms/kg/day subcutaneously from day 4 to day 11. One hundred and eighty two out of 192 planned cycles (95%) were administered. Toxicity was mild: no cases of grade IV non-haematological toxicity and only one episode of grade IV granulocytopenia were observed. Delays or dose reductions of anti-neoplastic drugs occurred in 14 cycles (7.7%). The mean duration of six cycles of treatment was 71 days (planned 70) and 93% of average planned dose intensity was actually administered. The short course CEF therapy is a feasible, well tolerated outpatient chemotherapy regimen, allowing a 46% increase in dose intensity compared with a standard CEF regimen given every 3 weeks. A randomised study comparing this regimen to a standard CEF regimen is now in progress in early breast cancer patients.

Total body irradiation in acute myeloid leukemia and chronic myelogenous leukemia: influence of dose and dose-rate on leukemia relapse.

From June 1981 to March 1987, 106 patients--59 with acute myeloid leukemia (AML) and 47 with chronic myelogenous leukemia (CML)--were treated with Cyclophosphamide 60 mg/kg X 2 d and total body irradiation (TBI-990 cGy/3fr/3d described dose) before allogeneic bone marrow transplantation. Seventy-nine patients are evaluable for risk of relapse: 32 with chronic myelogenous leukemia (23 in first chronic phase, 9 in accelerated phase) and 47 with acute myeloid leukemia (38 in first complete remission, 9 in subsequent phases). Actual TBI doses delivered to these patients varied between 839 and 1250 cGy (mean 956 +/- 101)/3 fr/3d, with dose rates between 2.7 and 7.25 cGy/min (mean 4.2 +/- 1.8). Patients receiving high (greater than 990 cGy) and low (less than or equal to 990) dose and/or dose rate (greater than 4 cGy/min and less than or equal to 4, respectively) have been evaluated overall and stratified by type of leukemia and phase of disease. When the patients are considered altogether, high total dose is significantly correlated with decreased risk of relapse (p = 0.0005) as well as high dose rate (p = 0.03). When considering specific subgroups, the influence of total dose on relapse rate is evident both for "early" and "advanced" leukemias, while an impact of dose rate appears only for chronic myelogenous leukemia in 1st chronic phase. Pertinent radiobiological and clinical literature is reviewed, and a possible role of dose fractionation and dose rate in leukemic control rate is evidenced; in this TBI setting, total dose not less than 990 cGy/3fr/3d and dose rate not less than 4 cGy/min have to be guaranteed.

Chemo-radiotherapy and autologous bone marrow transplantation in poor prognosis neuroblastoma.

In Genoa, 39 patients affected by disseminated neuroblastoma, one to twelve years old, were treated with intensive chemotherapy (Vincristine 4 mg/sqm c.i. over 5 days, Melphalan 140 mg/sqm), total body irradiation (TBI) (3.3 Gy for 3 days), and unpurged autologous bone marrow transplantation (ABMT) since October 1984 until November 1987. Thirty-two patients were in complete response (first group) and 7 had residual disease (second group) after an intensive chemotherapeutic induction regimen. Actuarial overall survival at 38 months is 52% and disease free survival at 30 months is 28% for the first group. Actuarial overall survival at 25 months is instead 14% for the second group related treatment toxicity has not been too high (3 deaths).

Total body irradiation before allogeneic and autologous bone marrow transplantation: a ten year Genoa experience.

Since 1976 in Genoa, 291 TBI treatments were performed. Before allogeneic BMT, 1000 cGy/1 fx were prescribed in the first 22 patients, and then 990 cGy/3 fx/3 d in AML and CML, and the same or 1200 cGy/6 fx/3 d in ALL. Survival (S) and probability of remaining in remission (PRR) were 54% and 69% at 80 months in 80 AML; in 62 CML 45% and 60% at 60 months; in 69 ALL, 32% and 45% at 82 months. Differences in favour of higher doses and dose rates were observed and are presented. Before autologous BMT, 1000 cGy/1 fx were prescribed to AML and NHL, and 1200 cGy/3 fx/3 d to ALL patients. Disease free survival (DFS) was 71% and 13% at 82 months in 21 AML treated in first R and 9 ALL, respectively; 81% at 32 months in 11 NHL treated in R.

Merkel cell carcinoma of the skin. Treatment of primary, recurrent, and metastatic disease: review of clinical cases.

The clinical features of 10 cases with the adjunct of a literature review of primary neuroendocrine carcinoma of the skin (Merkel cell tumor) are reported. This cancer arises in the dermis and subcutaneous tissue of elderly individuals. Natural history is characterized by local recurrences (40%), regional lymph-nodes metastases (50%), and distant metastases (60%). Surgery is the elective treatment of primary and locoregional disease and subsequent radiotherapy prevents local recurrences and prolong disease-free survival in literature reports. Chemotherapy and radiotherary resulted in only a short-term palliative response in the metastatic setting.

Merkel cell carcinoma of the skin. Treatment of primary, recurrent and metastatic disease: review of clinical cases.

The clinical features of 10 cases of primary neuroendocrine carcinoma of the skin (Merker cell tumor) are reported. This cancer arises in the dermis and subcutaneous tissues of elderly individuals. Natural history is characterized by local recurrences (30%), regional lymph node metastases (65%) and distant metastases (40%). Surgery is elective treatment, chemotherapy and radiotherapy resulted only to short-term palliative response.

Impact of irradiation of residual breast on adjuvant chemotherapy dose intensity.

The chemotherapy dose intensity for breast cancer has been recently considered to be an important factor in determining clinical outcome. Many trials have shown routine postoperative irradiation to have a detrimental effect on the delivered dose of adjuvant chemotherapy. In this paper the impact of radiotherapy on the dose intensity of adjuvant chemo- or hormonotherapy was evaluated in 237 breast cancer patients. 177 patients had radical mastectomy and 60 quadrantectomy followed by radiotherapy. Chemotherapy comprised 6 cycles of FEC (5-fluorouracil, epidoxorubicin, cyclophosphamide) alternated to 6 cycles of CMF (cyclophosphamide, methotrexate, 5-fluorouracil)+tamoxifen for 5 years. There were no significant differences in the adjuvant chemotherapy dose intensity in the mastectomy group compared to the radiotherapy group.

Management of acute radiodermatitis. Pharmacological or nonpharmacological remedies?

The medical and nursing literature suggests a wide variety of pharmacological and nonpharmacological approaches to treatment of acute radiation skin damages (erythema, dry and moist desquamation, ulceration), but no specific and standardized therapy. The incidence of radiodermatitis has decreased with mega-voltage instruments, but it can nevertheless influence the therapeutic program and impair quality of life of patients. A study has been conducted to evaluate the tolerability and effectiveness of a nonpharmacological remedy, a mixture of hydrophobic (stearic acid) and hydrophilic (propylene glycol, glycerol, and polyunsaturated alcohols) components in a foam emulsion for the treatment of acute skin injuries following radiotherapy. Thirty-eight of 42 initial patients were evaluable: we observed a complete response in 22 (57.9%), improvement in 14 (36.8%), and failure in only two (5.3%).

Introducing quality assurance in radiotherapy.

Introducing a Quality Assurance methodology appears particularly useful in Radiation Oncology due to the complexity of the procedures involved and the heterogeneity of the standards adopted, if any, in the great majority of the Centers. There are two possible ways of evaluating quality in the Health Environment: a formal, Institutional certification, or a voluntary one obtained through a mechanism of peer review. The European Society for Therapeutic Radiology and Oncology (ESTRO) started in 1994 with the publication of a methodological Report intended to be adopted by the individual national Societies, and this paper is an invitation to do it.

Radiotherapy after high-dose chemotherapy followed by autologous bone marrow transplantation in patients with intermediate or high-grade non-Hodgkin's lymphoma.

Patients with intermediate or high-grade non-Hodgkin's lymphoma are rarely cured of their disease after the failure of conventional therapy. Autologous bone marrow transplantation (ABMT) offers such patients a new possibility of cure. Our purpose was to evaluate the usefulness of radiotherapy. In these patients who did not achieve complete remission of disease after high-dose chemotherapy (HDCT) followed by ABMT or who had previous bulky disease. In this study we examined 10 patients: after HDCT+ABMT, 9 patients had persistent disease and 1 patient with previous bulky disease was in complete remission. All patients underwent involved-field radiotherapy administered by a 6-18 MV linear accelerator, total mean dose 4000 cGy (range, 3200-5000 cGy). At the end of radiotherapy we observed 6 complete responses and 4 progressions of disease outside the radiotherapy field. No serious side effects were observed. To date, of the 6 complete responses 2 have relapsed (after 9 and 11 months) and 4 are alive and disease free at 24 months (range, 8-39 months) after radiotherapy. In our opinion, radiotherapy is an effective treatment after HDCT+ABMT and may have a role in a prospective multidisciplinary approach.

Radio-hyperthermia in post-surgical recurrence of melanoma.

AIMS AND BACKGROUND: Malignant melanoma is one of the most radioresistant tumors. It can be treated with combinated hyperthermia and radiation therapy. METHODS: From January 1991 through June 1992, 7 patients, 1 male and 6 female, aged 40-88 years (mean 75), with skin and nodal post-surgical recurrences of melanoma, were treated with a combination of radiation therapy and hyperthermia. Two patients presented systemic disease when they reached our observation, but all of them were without symptoms. None of them underwent surgical excision of the recurrence before or during thermoradiotherapy. None received chemotherapy for these recurrences or had received radiotherapy in the past. They were irradiated with electron beams, with electron energies selected according to the depth of the lesions. The total dose was 40 Gy in 10 fractions in 5 weeks. Hyperthermia was administered for 10 minutes to 1 hour after irradiation. An inductive method of radiofrequency heating at 434 of 915 MHz was used depending on the depth of the lesions. In all of these treatments a ionized water bolus was used. The prescribed hyperthermic dose was 42 degrees C for half a hour. The treatments were carried out twice a week for 5 weeks. A fiberoptic multichannel thermometer was used for thermometry. RESULTS: Four patients (57%) achieved a complete response, 2 patients (29%) a partial response, and 1 patient (14%) stabilization. We found no correlation between tumor volume and response rate. Site effects and complications of the treatment were minimal (moderate erythema). CONCLUSIONS: Our results are in the wide range of values reported in the literature.

A risk score model predictive of the presence of additional disease in the axilla in early-breast cancer patients with one or two metastatic sentinel lymph nodes.

BACKGROUND: Axillary lymph node dissection (ALND) in early-breast cancer patients with positive sentinel node (SLN+) may not always be necessary. AIMS: To predict the finding of ≥1 metastatic axillary node in addition to SLN+(s); to discriminate between patients who would or not benefit from ALND. METHODS: Records of 397 consecutive patients with 1-2 SLN+s receiving ALND were reviewed. Clinico-pathological features were used in univariate and multivariate analyses to develop a logistic regression model predictive of the risk of ≥1 additional axillary node involved. The discrimination power of the model was quantified by the area under the receiver operating characteristic curve (AUC) and validated using an independent set of 83 patients. RESULTS: In univariate analyses, the risk of ≥1 additional node involved was correlated with tumor size, grade, HER-2 and Ki-67 over-expression, number of SLN+s. All factors, but Ki-67, retained in multivariate regressions were used to generate a predictive model with good discriminating power on both the training and the validation sets (AUC 0.73 and 0.75, respectively). Three patient groups were defined based on their risk to present additional axillary burden. CONCLUSIONS: The model identifies SLN+-patients at low risk (≤15%) who could reasonably be spared ALND and those at high risk (>75%) who should receive ALND. For patients at intermediate risk, ALND appropriateness could be individually evaluated based on other clinico-pathological parameters.

Laparoscopic omega-loop gastric bypass for the conversion of failed sleeve gastrectomy: early experience.

OBJECTIVES: Despite the initial effectiveness of sleeve gastrectomy (SG), some patients who undergo this purely restrictive technique have inadequate weight loss or renewed weight gain and persistent obesity-related co-morbidities with their potentially lethal complications. In such patients, the conversion of SG by the addition of a malabsorptive technique may then be necessary. PATIENTS AND METHODS: Conversion of SG to a mini gastric bypass (MGBP) was evaluated for failure of weight loss. An ante-colic end-to-side stapled gastro-jejunal anastomosis was performed laparoscopically, connecting the long narrow gastric tube to the jejunum at a point 200cm downstream from the ligament of Treitz. RESULTS: Between October 2006 and February 2012, 651 laparoscopic MGBP were performed for morbid obesity. Twenty-three of these patients (3.5%) had previously undergone SG. The conversion from SG to MGPB was performed laparoscopically in 19 of the 23 patients (81%) at a mean interval of 26.3months (8.2-63.7). The 30-day postoperative mortality rate was zero and the morbidity rate was 9.5%. The mean BMI before MGBP was 44±7.7kg (35.8-55.4). Conversion of SG to MGBP resulted in additional weight loss, achieving a mean BMI of 39.9 with a 26.8% loss of excess BMI (EBL) at 3months, mean BMI of 36.5 with 37.2% EBL at 12months, mean BMI of 36.2 with 48.6% EBL at 18months, and mean BMI of 35.7 with EBL of 51.6% at 24months. The overall mean EBL was 57.3±19.5% (range: 25-82%) at 42.3months (range 16.7-60.8months). CONCLUSION: Conversion of SG to MGBP is feasible, safe and effective, and results in significant additional weight loss. Definitive results at 2 and 5years are awaited for the long-term procedure validation.

A two-step selection of breast cancer patients candidates for exclusive IORT with electrons: a mono-institutional experience.

AIM: To assess the impact of a two-step multiparameter selection on the actual enrollment of women with breast cancer into a prospective intraoperative radiotherapy (IORT) trial. PATIENTS AND METHODS: From September 2009, a prospective clinical trial was started in order to deliver adjuvant exclusive single -fraction IORT to patients with early breast cancer. To select patients meeting suitable eligibility criteria for the clinical trial, a two-step decision process was developed: at pre-surgical examination (first step) and during surgery (second step). RESULTS: A series of 464 patients with breast cancer was analysed: at the first step, out of 464 patients, 333 (71%) were considered eligible for the IORT protocol; at the second step, out of 333 patients, 199 (60%) met the eligibility criteria and received the IORT fraction according to the criteria of the controlled trial. CONCLUSION: In our experience, the ultimate rate of patients who enrolled in the IORT clinical trial after the two-step decision process was 43%.

[A proposal for the treatment technique for the breast and regional lymph nodes in patients with conservatively operated neoplasms]. / Una proposta tecnica per il trattamento della mammella e dei linfonodi regionali in pazienti affette da neoplasia operate conservativamente.

Adequate irradiation of regional lymph-nodes in selected patients seems to improve disease-free and over-all survival rates. Technically, regional lymph-nodes are generally treated separately (supra-infra clavicular, apex of axilla and internal mammary chain-IMC). About the treatment of the IMC nodes, there are two main problems: the identification of the individual target volume, and its correct irradiation. For the latter problem, the most employed solutions are: the inclusion of IMC in the tangential fields, the use of the direct or oblique electron beam for IMC alone. None of them is optimal regarding to the tolerance of adjacent critical organs and from a geometric and dosimetric point of view. In this paper we propose and discuss a modified method. The IMC nodes together with the breast are irradiated by a three field technique (two tangential photon beams and one oblique electron beam). Their arrangement allows to treat every part of the target by two fields, reducing the risk of hot and cold spots. This is obtained by extending the internal tangential photon beams to cover the electron beam. Wedges and different weights must be used to achieve an uniform dose distribution.