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.

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.

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%.

Impact of chemotherapy dose-density on radiotherapy dose-intensity after breast conserving surgery.

PURPOSE: To evaluate if chemotherapy (CT) dose-intensification jeopardizes radiotherapy (RT) dose-intensity (DI). PATIENTS AND METHODS: From 1992 to 1997, 247 stage I-II breast cancer patients, treated with conserving surgery, were treated at the National Cancer Institute of Genoa in a randomized study comparing the same CEF regimen delivered every two weeks (CEF14) or three weeks (CEF21). RT was applied to the residual breast at a total dose of 50 Gy in five weeks. Allowance was made for treatment at 2.3 Gy per fraction in order to compensate for gaps (hypofractionation). Radiotherapy DI was expressed as the average total dose received each week, i.e., 'weekly dose-rate' (WDR). The effect of various tumour, treatment and patient-related factors on the endpoint (a delivered WDR of RT < 9.5 Gy) was investigated by univariate analysis. Factors found to have P-value < or = 0.20 were entered in multivariate analysis. RESULTS: All but three patients (244 of 247, 98.8%) received a cumulative total dose of RT within +/- 10% of that planned. Moreover, most of them (197 of 247, 79.8%) received an average WDR of > or = 9.5 Gy/wk. With univariate analysis the probability of WDR < 9.5 Gy/wk significantly correlated with age, menopausal status, concomitant administration of RT and CT, and white blood cell toxicity. Moreover, a positive effect on WDR was found in patients treated at 2.3 Gy per fraction. The type of treatment (CEF14 vs. CEF21) did not affect the probability of WDR < 9.5 Gy/wk. With multivariate analysis, age (< or = 55 vs. > 55 years, RR = 3.99, 95% CI: 1.89-8.42, P = 0.0003), RT fractionation (conventional vs. hypofractionation, RR = 0.32, 95% CI: 0.15-0.68, P = 0.017) and WBC toxicity (none vs. some, RR = 1.54, 95% CI: 1.06-2.22, P = 0.027) were independent predictors of WDR < 9.5 Gy. Regarding the CT-RT overlap, patients receiving more than two cycles of chemotherapy during radiotherapy had an increased risk of RT delay compared to other patients (RR = 3.74, 95% CI: 1.44-9.48, P = 0.0063). CONCLUSIONS: There is no evidence of a direct effect of CT dose-density on dose-intensity of RT. However, the concomitant use of CT and RT reduces the possibility of giving a full dose-intensity of RT.

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.

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.

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.

[Hodgkin's lymphoma: problems in the treatment of the early stages]. / Linfoma di Hodgkin: problematiche nel trattamento degli stadi iniziali.

The prognosis for Hodgkin's disease patients has improved markedly in the past 3 decades, thanks to improved staging techniques and therapeutic advances in both radiation and chemotherapy. Yet, individual treatment schedules continue to evolve: in particular, the extent of irradiation fields, the allocation of Hodgkin's patients to prognostic groups using information from clinical staging techniques and the choice of radiotherapy alone versus combined modalities are still controversial in the early stages of this disease. To try to eliminate the need for staging laparotomy, the EORTC investigated the role of clinical staging in different studies and found that favorable clinical stage I/II patients do not need laparotomy and that irradiation alone yields satisfactory results. Current treatment goals include maximizing the cure rate while minimizing toxicity, late side-effects in particular. An approach is to reduce irradiation fields and combine irradiation with chemotherapy. There is no doubt that various organ sites can be cumulatively damaged by this combined approach, but new protocols seem to yield better results. Several literature findings are reviewed in this paper. The allocation of stage IA and IIA Hodgkin's disease patients to prognostic groups using information from clinical staging procedures appears to be a very important step. The combined approach seems to be useful in patients at intermediate risk of relapse. We conclude that excellent results and very little toxicity and morbidity can be achieved through respect and collaboration between the chemotherapist and the radiotherapist.

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.

[Single-dose palliative radiotherapy in inoperable non-small-cell lung carcinoma]. / Radioterapia palliativa con dose singola nel carcinoma polmonare inoperabile non a piccole cellule.

The treatment of choice for advanced inoperable non-small cell lung cancer (NSCLC) is radiation therapy. Palliative radiotherapy schedules vary considerably in different centers, but a 30-Gy dose given in ten fractions over two weeks is a typical standard schedule. Our study was aimed at investigating whether a shorter course of only one 10-Gy fraction allows good palliation in the treatment of inoperable NSCLC patients whose main symptoms are related to an intrathoracic lesion. Patients of both sexes and any age, untreated with radiotherapy, with inoperable and histologically or cytologically proved NSCLC were examined. Seventeen patients, too advanced for radical "curative" radiotherapy and whose main symptoms were related to primary intrathoracic lesions, entered the study even though they had metastases. On admission, 76% (13/17) of patients had cough 76% (13/17) dyspnea, 70.7% (12/17) chest pain and 23.6% (4/17) hemoptysis. They received a single dose of 10 Gy, delivered with an 18-Mv linear accelerator via anteroposteriorly opposing portals without spinal cord shielding. Treatment volume usually included the macroscopically detected lesion identified with a CT simulator. Palliation of symptoms was achieved in high rates of patients: 46% for cough, 69% for dyspnea, 83% for pain and 75% for hemoptysis. These results were obtained within one month of treatment. Unfortunately, palliation of symptoms did not last long, decreasing to 42% within two months of the end of treatment and to 32% at three months. Four patients were retreated, one patient three months and three patients two months after the end of radiotherapy. Ten Gy to the target volume were administered as retreatment with spinal cord shielding. Side-effects were mild: nausea in 3 patients (17%), vomiting in one patient (5%) and grade-II dysphagia in two patients were observed and classified according to WHO criteria. Pain increased 24 hours after radiotherapy in five patients. We can conclude that single dose radiotherapy yields good, but short, palliation of symptoms with acceptable side-effects.

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.

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.

Angiosarcoma of the residual breast after conservative surgery and radiotherapy for primary carcinoma.

BACKGROUND: Angiosarcoma of residual breast, arising after conservative surgery and radiotherapy for early breast cancer, is a rare tumor, with only 14 cases having so far been documented. The first was observed in 1987 and 7 of the 14 were reported in 1992 alone. METHODS: Here, we present an additional case developing in residual breast 3.3 years after lumpectomy and radiotherapy. The other fourteen are reviewed. RESULTS: Review of data from this series of patients reveals a higher incidence of breast oedema (67%) than that reported in the literature (4%). Another unusual finding is the shorter mean latency period (time interval from radiotherapy to onset of angiosarcoma) noted here (6 years) compared to the more than 10 years reported for other secondary angiosarcomas. CONCLUSIONS: In view of the widespread use of radiotherapy after breast-conserving surgery, and also its lack of benefit in terms of overall survival, every novel complication should be investigated. Given the apparent rise in incidence of this rare tumor over the last few years, doctors should be aware of the phenomenon in order to recognize and define it.

Radiotherapy and hyperthermia in the treatment of primary Merkel cell carcinoma of the skin: a case report.

We report a case of a large Merkel cell skin tumor (left cheek) in an 83 year-old woman treated by a combination of radiotherapy and hyperthermia. A complete response to the treatment was observed and without side effects. The patient has now been followed for 12 months without signs of recurrence, nodal disease, or distant metastasis.

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.

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.

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%).