Long-term toxicity of an intraoperative radiotherapy boost using low energy X-rays during breast-conserving surgery

PURPOSE: Intraoperative radiotherapy (IORT) as a boost for breast cancer delivers a high single dose of radiation to a late-reacting tissue; therefore late toxicity is of particular interest, and long-term follow-up is warranted. To date there are only limited data available on breast cancer patients treated with IORT using low energy X-rays. We analyzed toxicity and cosmesis after IORT as a boost with a minimum follow-up of 18 months. METHODS AND MATERIALS: A total of 73 patients treated with IORT (20 Gy/50 kV X-rays; INTRABEAM [Carl Zeiss Surgical, Oberkochen, Germany]) to the tumor bed during breast-conserving surgery as a boost followed by whole-breast radiotherapy (WBRT, 46 Gy) underwent a prospective, predefined follow-up (median, 25 months; range 18-44 months), including clinical examination and breast ultrasound at 6-months and mammographies at 1-year intervals. Toxicities were documented using the common toxicity criteria (CTC)/European Organization for Research and Treatment of Cancer and the LENT-SOMA score. Cosmesis was evaluated with a score from 1 to 4. RESULTS: The IORT in combination with WBRT was well tolerated, with no Grade 3 or 4 skin toxicities and no telangiectasias. Fibrosis of the entire breast was observed in 5% of the patients. A circumscribed fibrosis around the tumor bed was palpable in up to 27% with a peak around 18 months after therapy and a decline thereafter. The observed toxicitiy rates were not influenced by age, tumor stage, or systemic therapy. The cosmetic outcome was good to excellent in>or=90% of cases. CONCLUSIONS: After IORT of the breast using low-energy X-rays, no unexpected toxicity rates were observed during long-term-follow-up.     

Clinical analysis of intraoperative radiotherapy during breast-conserving surgery of early breast cancer in the Chinese Han population

Purpose

While results of intraoperative radiotherapy (IORT) during breast-conserving surgery (BCS) have been reported when used either as a boost at the time of surgery or as the sole radiation treatment, the clinical safety and cosmetic outcome of IORT in the Chinese Han population has not. This report reviews oncologic and cosmetic outcomes for Chinese Han breast cancer patients who received IORT either as a boost or as their sole radiation treatment at our hospital.

Method

From July 2008 to December 2012, 50 early-stage Chinese Han breast cancer patients received BCS and IORT, either as boost or as their sole radiation treatment. Patients received adjuvant chemotherapy or hormonal therapy, according to our institution''s guidelines. Patients were followed to determine oncologic events, short-term toxicity and overall cosmesis.

Results

With a median follow-up of 51.8 months (range 22.6 months to 75.7 months), 2 patients (4.0%) developed local relapses and were salvaged by mastectomy. There were no metastases and no deaths. The average wound healing time was 17 days. Three patients (6.0%) developed postoperative infection, 5 patients (10.0%) had delayed wound healing, and 2 patients (4.0%) experienced wound edema. There were no lyponecrosis or hematomas observed. The evaluation of cosmetic outcome showed 44 patients (88.0%) graded as excellent or good while 6 patients (12.0%) were graded as fair or poor. No patients experienced radiotherapy related acute hematological toxicity, but 3 patients (6.0%), all IORT boost patients, developed skin pigmentation.

Conclusion

For early-stage breast cancer patients, intraoperative radiotherapy after breast-conserving surgery in the Chinese Han population is both safe and reliable and has resulted in very acceptable cosmetic outcomes.     

Late radiation toxicity after intraoperative radiotherapy (IORT) for breast cancer: results from the randomized phase III trial TARGIT A

The randomized phase III trial TARGIT A showed non-inferiority regarding local control after intraoperative radiotherapy (IORT 20 Gy which was followed by whole breast radiotherapy (WBRT) in patients with risk factors only) in comparison to standard WBRT (50–56 Gy) after breast-conserving surgery in selected patients. This is the first analysis of long-term toxicities in the setting of TARGIT. Between 02/2002 and 12/2008, 305 patients were treated within TARGIT A (Arm A: n = 34 IORT, n = 20 IORT + WBRT for risk factors; Arm B WBRT: n = 55) or received IORT as a planned boost (control group: n = 196) at a single center. Toxicity was assessed according to the LENT SOMA scales. No significant differences were seen between Arm A and Arm B regarding fibrosis, breast edema, retraction, ulceration, lymphedema, hyperpigmentation, and pain. Arm A had significantly less telangiectases compared to Arm B (p = 0.049). In the subanalysis (Arm A IORT vs. Arm A IORT + WBRT vs. Arm B), fibrosis had a cumulative rate of 5.9 versus 37.5 versus 18.4 %, respectively (38.2 % IORT boost control group), at 3 years. No telangiectases were seen after IORT alone (0 % Arm A IORT vs. 17.5 % Arm A IORT + WBRT vs. 17.7 % Arm B). The hazard ratio of higher grade toxicity as first event was 0.46 (95 % CI, 0.26–0.83) for Arm A IORT as compared to Arm B (p = 0.010). No recurrences were seen after a median follow-up of 40 months (Arm A) and 42 months (Arm B). With its very low chronic skin toxicity rates and outstanding long-term results regarding toxicity and local control, IORT with 50 kV X-rays is a safe and effective method for treatment of selected breast cancer patients.     

Intraoperative radiotherapy given as a boost after breast-conserving surgery in breast cancer patients

Conventional radiotherapy after breast-conserving therapy is confined to 50-55 Gy external beam radiation therapy (EBRT) to the whole breast and 10-16 Gy external boost radiation to the tumour bed or brachytherapy to the tumour bed. Local recurrence rate after breast-conserving surgery varies between 5 and 18%. External boost radiation can partially miss the tumour bed and therefore can result in local failure. Intra-operative radiotherapy (IORT) as a high precision boost can prevent a 'geographical miss'. From October 1998 to December 2000, 156 patients with stage I and stage II breast cancer were operated upon in a dedicated IORT facility. After local excision of the tumour, the tumour bed was temporarily approximated by sutures to bring the tissue in the radiation planning target volume. A single dose of 9 Gy was applied to the 90% reference isodose with energies ranging from 4 to 15 MeV, using round applicator tubes 4-8 cm in diameter. After wound healing, the patients received additional 51-56 Gy EBRT to the whole breast. No acute complications associated with IORT were observed. In 5 patients, a secondary mastectomy had to be performed because of tumour multicentricity in the final pathological report or excessive intraductal component. 2 patients developed rib necroses. In 7 patients, wound healing problems occurred. After a mean follow-up of 18 months, no local recurrences were observed. Cosmesis of the breast was very good and comparable to patients without IORT. Preliminary data suggest that IORT given as a boost after breast-conserving surgery could be a reliable alternative to conventional postoperative fractionated boost radiation by accurate dose delivery and avoiding geographical misses, by enabling smaller treatment volumes and complete skin-sparing and by reducing postoperative radiation time by 7-14 days.     

Ten-year results of accelerated hypofractionated adjuvant whole-breast radiation with concomitant boost to the lumpectomy cavity after conserving surgery for early breast cancer

Accelerated hypofractionated whole-breast radiotherapy (WBRT) is considered a standard therapeutic option for early breast cancer (EBC) in the postoperative setting after breast conservation (BCS). A boost to the lumpectomy cavity may further increase local control. We herein report on the 10-year results of a series of EBC patients treated after BCS with hypofractionated WBRT with a concomitant photon boost to the surgical bed over 4 weeks. Between 2005 and 2007, 178 EBC patients were treated with a basic course of radiotherapy consisting of 45 Gy to the whole breast in 20 fractions (2.25 Gy daily) with an additional boost dose of 0.25 Gy delivered concomitantly to the lumpectomy cavity, for an additional dose of 5 Gy. Median follow-up period was 117 months. At 10-year, overall, cancer-specific, disease-free survival and local control were 92.2% (95% CI 88.7–93.4%), 99.2% (95% CI 96.7–99.7%), 95.5% (95% CI 91.2–97.2%) and 97.3% (95% CI 94.5–98.9%), respectively. Only eight patients recurred. Four in-breast recurrences, two axillary node relapses and two metastatic localizations were observed. Fourteen patients died during the observation period due to other causes while breast cancer-related deaths were eight. At last follow-up, ≥G2 fibrosis and telangiectasia were seen in 7% and 5% of patients. No major lung and heart toxicities were observed. Cosmetic results were excellent/good in 87.8% of patients and fair/poor in 12.2%. Hypofractionated WBRT with concomitant boost to the lumpectomy cavity after BCS in EBC led to consistent clinical results at 10 years. Hence, it can be considered a valid treatment option in this setting.     

Hypofractionated Radiotherapy for Breast Cancers - Preliminary Results from a Tertiary Care Center in Eastern India

Background: The standard radiotherapy (RT) fractionation practiced in India and worldwide is 50Gyin 25 fractions over 5 weeks to the chest wall or whole breast followed by tumour bed boost in case of breastconservation (BCS). A body of validated data exists regarding hypofractionation in breast cancer. We herereport initial results for 135 patients treated at our center with the START-B type of fractionation. Materials andMethods: From May 2011 till July 2012, women with all stages of breast cancer (excluding metastatic), who hadundergone BCS or mastectomy were planned for 40Gy in 15 fractions over 3weeks to chest wall/whole breastand supraclavicular fossa (where indicated) followed by tumour bed boost in BCS patients. Planning was doneusing Casebow’s technique. The primary end point was to assess the acute toxicity and the cosmetic outcomes.Using cosmetic scales; patients were assessed during radiotherapy and at subsequent follow up visits with theradiation oncologist. Results: Of the 135 patients, 62 had undergone BCS and 73 mastectomy. Median age ofthe population was 52 years. Some 80% were T1&T2 tumours in BCS whereas most patients in mastectomygroup were T3&T4 tumours (60%). 45% were node negative in BCS group whilst it was 23% in the mastectomygroup. Average NPI scores were 3.9 and 4.9, respectively. Most frequently reported histopathology report wasinfiltrating ductal carcinoma (87%), grade III being most common (58%), and 69% were ER positive tumours,and 30% were Her 2 Neu positive. Triple negative tumours accounted for 13% and their mean age was young(43 yrs.) The maximum acute skin toxicity at the end of treatment was Grade 1 in 94% of the mastectomygrouppatients and 71% in BCS patients. Grade 2 toxicity was 6% in mast group and 23% in BCS group. Grade3 was 6% in BCS group, no grade 3 toxicity in mastectomy patients and there was no grade 4 skin toxicity inany case. Post RT at 1 month; 39% of BCS patients had persisting Grade I skin reaction which was only 2% inmastectomy patients. At 3 months post RT, 18% patients had persisting hyperpigmentation. At 6 months 8%patients had persisting erythema in the BCS group only. Some 3% BCS and 8% mastectomy patients had lymphedema till the date of evaluation. Cosmetic outcome in BCS patients remained good to excellent 6 months postsurgery and radiotherapy. 1 patient of BCS and 3 patients of mast had developed metastatic disease at the timeof evaluation. Conclusions: Hypofractionated RT is well tolerated in Indian population with reduced acute skintoxicity and good cosmetic outcome. Regimens such as these should be encouraged in other centers to increasemachine output time. The study is on-going to assess long term results.     

Intraoperative radiotherapy (IORT) for breast cancer using the Intrabeam system

INTRODUCTION: Intraoperative radiotherapy (IORT) with low-energy X-rays (30-50 KV) is an innovative technique that can be used both for accelerated partial breast irradiation (APBI) and intraoperative boosting in patients affected by breast cancer. Immediately after tumor resection the tumor bed can be treated with low-distance X-rays by a single high dose. Whereas often a geographic miss in covering the boost target occurs with external beam boost radiotherapy (EBRT), the purpose of IORT is to cover the tumor bed safely. This report will focus on the feasibility and technical aspects of the Intrabeam device and will summarize our experience with side effects and local control. MATERIALS AND METHODS: Between February 2002 and June 2003 57 breast cancer patients, all eligible for breast conserving surgery (BCS), were treated at the Mannheim Medical Center with IORT using the mobile X-ray system Intrabeam. The patient population in this feasibility study was not homogeneous consisting of 49 patients with primary stage I or II breast cancer, seven with local recurrence after previous EBRT and one with a second primary in a previously irradiated breast. The selection criteria for referral for IORT included tumor size, tumor cavity size, margin status and absence of an extensive intraductal component. The previously irradiated patients with local recurrences and 16 others received IORT as single modality. In all other cases IORT was followed by EBRT with a total dose of 46 Gy in 2-Gy fractions. The intraoperatively delivered dose after tumor resection was 20 Gy prescribed to the applicator surface. EBRT was delivered with a standard two-tangential-field technique using linear accelerators with 6- or 18-MV photons. Patients were assessed every three months by their radiation oncologist or surgeon during the first year after treatment and every six months thereafter. Breast ultrasound for follow-up was done every six months and mammographies once yearly. Acute side effects were scored according to the CTC/EORTC score and late side effects according to the Lent-Soma classification. RESULTS: Twenty-four patients received IORT only; eight patients because they had received previous radiotherapy, 16 because of a very favorable risk profile or their own preference. Thirty-three patients with tumor sizes between 1 and 30 mm and no risk factors were treated by IORT as a boost followed by EBRT. The Intrabeam system was used for IORT. The Intrabeam source produces 30-50 KV X-rays and the prescribed dose is delivered in an isotropic dose distribution around spherical applicators. Treatment time ranged between 20 and 48 minutes. No severe acute side effects or complications were observed during the first postoperative days or after 12 months. One local recurrence occurred 10 months after surgery plus IORT followed by EBRT. In two patients distant metastases were diagnosed shortly after BCS. DISCUSSION: IORT with the Intrabeam system is a feasible method to deliver a single high radiation dose to breast cancer patients. As a preliminary boost it has the advantage of reducing the EBRT course by 1.5 weeks, and as APBI it might be a promising tool for patients with a low risk of recurrence. The treatment is well tolerated and does not cause greater damage than the expected late reaction in normal tissue.     

Hypofractionated stereotactic radiotherapy in combination with whole brain radiotherapy for brain metastases

BACKGROUND: The efficacy and toxicity of hypofractionated stereotactic radiotherapy (HSRT) in combination with whole brain radiotherapy (WBRT), for the treatment of 1-4 brain metastases, using a non invasive fixation of the skull, was investigated. METHODS: Between 04/2001 and 01/2006 30 patients with 44 brain metastases underwent irradiation. Every patient received WBRT (10 x 3 Gy); 41/44 lesions received HSRT boost with a median dose fraction of 6 Gy, the fractionation schemes were 3 x 6 Gy and 4 x 8 Gy; a median total dose of 18 Gy was delivered to the tumor isocenter. RESULTS: The median survival period was 9.15 months, the actuarial 1-year overall survival and freedom from new brain metastases were 36.6% and 87.9%, respectively; at univariate analysis Karnofsky Performance Status (KPS) was statistically significant (P = 0.05); the actuarial 1-year local control for the 41/44 lesions was 86.1%. No patient had acute or late complications. CONCLUSIONS: HSRT as a concomitant boost during WBRT is a safe and well tolerated treatment for selected patients with brain metastases.     

Hypofractionated conformal stereotactic radiotherapy alone or in combination with whole-brain radiotherapy in patients with cerebral metastases

PURPOSE: The aim was to evaluate treatment of cerebral metastases with hypofractionated conformal stereotactic radiotherapy (HCSRT) or whole-brain radiotherapy (WBRT) in combination with a stereotactic boost. METHODS AND MATERIALS: Forty-seven patients were treated with HCSRT and 14 patients with WBRT in combination with a stereotactic boost. Radiation doses were 40 Gy (5 fractions) in HCSRT or 30 Gy (WBRT) combined with a mean dose of 17 Gy stereotactically (1-3 fractions). RESULTS: The median survival time in the HCSRT as well as the WBRT group was 5.0 months, and 87% died of extracranial disease. Radiologic follow-up (mean, 3.7 months after treatment) showed local control in the HCSRT group in 84% and in the WBRT group in 100%. Patients treated with HCSRT developed new brain metastases distant from the irradiated area in 25%. Two patients treated with HCSRT deteriorated neurologically during treatment, and in 2 patients radionecrosis developed. CONCLUSIONS: Although there may be a higher risk of distant new metastases, HCSRT as a treatment for brain metastases seems to be as effective as WBRT in combination with a stereotactic boost. Complications are in the range of what has been reported previously.     

A phase Ⅱ trial of comprehensive treatment based on radiotherapy in leptomeningeal metastasis

Objective To evaluate the efficacy and safety of comprehensive treatment based on radiotherapy for patients with leptomeningeal metastases (LM) in this prospective study. Methods A total of 93 patients diagnosed with LM admitted to our hospital undergoing whole brain radiotherapy (WBRT) or craniospinal irradiation (CSI) with or without simultaneous boost from 2014 to 2017 were enrolled. The dynamic changes of clinical signs and symptoms, enhanced magnetic resonance imaging (MRI), cerebrospinal fluid cytology and liquid biopsy detection were recorded. The primary endpoint was overall survival (OS),the secondary endpoints were local control (LC), intracranial progress-free survival (IPFS), brain metastasis specific survival (BMSS) and toxicity. Results The major primary disease was non-small cell lung cancer. The whole cohort received WBRT with boost (40 Gy in 20 fractions (f) for WBRT and 60Gy in 20 f for boost), focal radiation to LM, WBRT and CSI (40 Gy in 20 f or 50Gy in 25 f for WBRT and 36 Gy in 20 f for CSI). For 20 patients, tumor cells were identified and intrathecal chemotherapy was performed. Sixty-three patients received target therapy. The median follow-up time was 33.8 months. The 1-year OS, LC and IPFS was 62.4%, 77.2% and 52.6%, respectively. The median survival time was 15.9 months, and the median BMSS was 42.2 months.Treatment-related grade 3–4 adverse events were rare and only 8 cases was observed to have grade 3 hematological toxicity. Conclusion Reasonable comprehensive treatment including precise radiotherapy, intrathecal chemotherapy and targeted therapy can be well tolerated and prolong the survival time of LM patients.     

放疗为主的综合方案治疗脑膜转移瘤Ⅱ期临床研究

目的 前瞻性分析脑膜转移瘤以放疗为主的综合治疗方案的有效性及安全性。方法 纳入2014-2017年中国医学科学院肿瘤医院收治的93例脑膜转移瘤患者,接受螺旋断层放疗技术实施的全脑放疗、局部推量和/或全脊髓照射为基础的综合治疗,记录临床症状、磁共振检查、脑脊液细胞学、液体活检变化情况及不良反应。主要研究终点为总生存(OS),次要研究终点为局部控制(LC)、颅内无进展生存(IPFS)及脑转移专项生存(BMSS)及不良反应。结果 主要原发病为非小细胞肺癌。全组接受全脑放疗±局部推量(中位剂量分别为40Gy分20次、60Gy分20次)或全脑、全脊髓照射(中位剂量分别为40Gy分20次或50Gy分25次、36Gy分20次)。20例找到肿瘤细胞并行鞘注化疗;63例接受靶向治疗。中位随访时间33.8个月,1年OS、LC及IPFS分别为62%、77%及53%。中位生存时间15.9个月,中位BMSS时间42.2个月。3-4级不良反应少见,仅观察到8例3级血液学不良反应。结论 精准放疗结合鞘注化疗或靶向治疗的综合治疗方法,可有效延长脑膜转移瘤患者的生存时间,且不良反应可耐受。     

Intraoperative radiotherapy given as a boost for early breast cancer: long-term clinical and cosmetic results

PURPOSE: The standard radiotherapy (RT) of breast cancer consists of 50 Gy external beam RT (EBRT) to the whole breast followed by an electron boost of 10-16 Gy to the tumor bed, but this has several cosmetic disadvantages. Intraoperative radiotherapy (IORT) could be an alternative to overcome these. METHODS AND MATERIALS: We evaluated 50 women with early breast cancer operated on in a dedicated IORT facility. Median dose of 10 Gy was delivered using 9-MeV electron beams. All patients received postoperative EBRT (50 Gy in 2 Gy fractions). Late toxicity and cosmetic results were assessed independently by two physicians according to the Common Terminology Criteria for Adverse Event v3.0 grading system and the European Organization for Research and Treatment of Cancer questionnaires. RESULTS: After a median follow-up of 9.1 years (range, 5-15 years), two local recurrences were observed within the primary tumor bed. At the time of analysis, 45 patients are alive with (n = 1) or without disease. Among the 42 disease-free remaining patients, 6 experienced Grade 2 late subcutaneous fibrosis within the boost area. Overall, the scores indicated a very good quality of life and cosmesis was good to excellent in the evaluated patients. CONCLUSION: Our results confirm that IORT given as a boost after breast-conserving surgery is a reliable alternative to conventional postoperative fractionated boost radiation.     

Hypofractionation with no boost after breast conservation in early-stage breast cancer patients

The aim of this study was to evaluate local control, survival and toxicity profile of a consecutive cohort of early-stage breast cancer (EBC) patients treated with adjuvant hypofractionated radiotherapy (HF) with no boost delivered to the lumpectomy cavity, after breast-conserving surgery (BCS). Between 2005 and 2015, a total of 493 women affected with EBC were treated with HF (46 Gy/20 fractions or 40.05 Gy/15 fractions) to the whole breast without boost to tumor bed, because of age and/or favorable tumor characteristics. The primary endpoint was 5-year actuarial local control (LC); secondary endpoints included survival, toxicity profile and cosmesis. Median follow-up was 57 months (range 6–124). Actuarial 5-year overall, cancer-specific, disease-free survival and LC were 96.3, 98.9, 97.8 and 98.6 %, respectively. On multivariate analysis, tumor stage (T1 vs. T2) and hormonal status (positive vs. negative estrogen receptors) were significantly correlated with LC. Only 2 % of patients experienced ≥G3 acute skin toxicity. Late toxicity was mild with only 1 case of G3 fibrosis. Most of the patients (95 %) had good–excellent cosmetic results. HF to the whole breast with no boost delivered to the tumor bed is a safe and effective option for a population of low-risk breast cancer patients after BCS, with excellent 5-year LC, mild toxicity profile and promising cosmetic outcome. A subgroup of patients with larger tumors and/or with no estrogen receptor expression may potentially benefit from treatment intensification with a boost dose to the lumpectomy cavity.     

A study of radiotherapy modalities combined with continuous 5-FU infusion for locally advanced gastrointestinal malignancies.

AIM: We describe the feasibility of combining infusional 5-fluorouracil (5-FU) with intraoperative radiation therapy (IORT). METHODS: Patients with surgically resectable locally advanced gastrointestinal cancers were treated concurrently during surgery with IORT and a 72 h infusion of 5-FU. Patients without previous external beam radiation therapy (EBRT) were subsequently treated with EBRT (40-50Gy) concurrent with a 21-day continuous infusion of 5-FU. Pancreatic, gastric, duodenal, ampullary, recurrent colorectal, and recurrent anal cancer were included. RESULTS: During IORT/5-FU, no chemotherapy-related grade III or IV hematologic or gastrointestinal toxicity was noted. Post-surgical recovery or wound healing was not affected. One of nine patients who received post-operative radiation required a treatment break. During follow-up, there were more complications in patients with pelvic tumours, especially those with previous radiation. Nine patients have had local and/or local regional recurrences, two of these in the IORT field. CONCLUSIONS: Treatment with a combination of IORT and 5-FU followed by EBRT and 5-FU is feasible. However, long-term complications may be increased in previously irradiated recurrent pelvic tumours.     

An accelerated radiotherapy scheme using a concomitant boost technique for the treatment of unresectable stage III non-small cell lung cancer

BACKGROUND: We designed a phase II trial for evaluation of the efficacy and tolerability of an accelerated concomitant boost radiotherapy scheme for the treatment of the patients with non-small cell lung cancer (NSCLC). METHODS: Thirty patients with unresectable stage IIIA/IIIB NSCLC were prospectively enrolled in this protocol. All patients were scheduled to receive 15 fractions of conventional radiotherapy in doses of 1.8 Gy, to a total of 27 Gy. For the last 10 treatment days, an accelerated concomitant boost schedule was started that was composed of 1.8 Gy/fraction/day, 5 days/week to the large field and 1.8 Gy/fraction/day to the boost field 6 h apart, to a total dose of 63 Gy/35 fractions/5 weeks. RESULTS: Median follow-up time was 13 months (range, 5-50 months; 3-year overall, disease-free, loco-regional disease-free and metastasis-free survivals were 23%, 19%, 19% and 23%, respectively). The most common acute toxicity was esophagitis in 31% of patients with the Radiation Therapy Oncology Group and the European Organization for Research and Treatment of Cancer (RTOG/EORTC) criteria grade 1, and in 54% with grade 2. Radiation pneumonitis developed in 16% of patients with RTOG/EORTC grade 1. Three-year actuarial rate of late pulmonary and skin-subcutaneous toxicity were 12% and 16%, respectively. No late radiotherapy complications of spinal cord or esophagus were recorded. CONCLUSION: Overall survival, local control and freedom from local progression were comparable with the results reported with pure hyperfractionated radiotherapy. The overall rate of acute and late toxicity was acceptable.     

Raltitrexed and radiotherapy as adjuvant treatment for stage II-III rectal cancer: a feasibility study

AIMS AND BACKGROUND: Adjuvant 5-FU chemotherapy plus radiotherapy represents the standard treatment for radically resected rectal cancer at high risk of relapse according to the NIH Consensus Conference. The therapeutic gain was obtained with a high rate of severe treatment-related toxicity and a suboptimal patient compliance with this regimen. Raltitrexed is a specific thymidylate synthase inhibitor with a convenient administration schedule, acceptable toxicity and radiosensitizing properties, as the published phase I trials in combination with radiotherapy have shown. The aim of this prospective multicenter phase II study was to evaluate the feasibility, gastrointestinal and hematological acute toxicity of raltitrexed in combination with radiotherapy in rectal cancer patients. METHODS: From September 2000 to June 2004, 50 patients with radically resected stage II-III rectal adenocarcinoma were treated. All patients were evaluable for compliance and acute toxicity. Within 45-60 days of surgery, each patient underwent concomitant adjuvant radiochemotherapy. Radiotherapy was administered to the pelvis (plus perineum after abdominoperineal resection) with photon beam energy exceeding 5 MV, 3-4 fields, 45 Gy/25 fractions/5 weeks plus a boost delivered to the site of resected disease with 3-4 fields, 9 Gy/5 fractions/1 week to a total dose of 54 Gy. The boost dose was administered after complete exclusion of the small bowel from the treatment volumes; if this was not possible a total dose of 50.4 Gy was given. Raltitrexed was administered intravenously at a dose of 3 mg/m2 as a bolus injection on days 1 and 22 of radiotherapy one hour before treatment, for a total of two cycles. Each patient underwent weekly clinical evaluation and laboratory tests. Toxicity was assessed by the WHO scale. RESULTS: Forty-five (90%) patients completed the established treatment. Acute severe toxicity included grade III proctitis in 4/50 (8%), grade III-IV diarrhea in 4/50 (8%), grade III perineal dermatitis in 4/50 (8%) and grade III leukopenia in 2/50 (4%) patients; five patients (10%) experienced a transient grade Ill increase in their liver biochemistry values. CONCLUSIONS: Our data related to acute toxicity and patient compliance proved the feasibility of this adjuvant radiochemotherapy treatment. A longer follow-up is necessary to evaluate the effectiveness of this new regimen in terms of disease-free and overall survival.     

Predictive Factors Increasing the Risk of Radiation Toxicity in Patients with Early Breast Cancer

Objectives: Radiation induces adverse events on healthy tissues which may be augmented by certain factors. This study aimed to assess patients; tumor and treatment-related factors which increase the risk of radiation-induced toxicity in breast cancer patients. Methods: This prospective study included postmenopausal early breast cancer patients treated at the clinical oncology department, Assiut University, Egypt between January 2015 and December 2018. Patients treated with mastectomy followed by conventional radiotherapy (25x 2 Gy) and either concurrent or sequential letrozole. Acute and late radiation toxicity was scored according to EORTC/RTOG and risk factors were analyzed. Results: A total of 75 patients were included in the study. After a median follow-up of 24 months, 12 patients had > grade 2 acute dermatitis, 5 patients had > grade 2 cardiac toxicity and 3 patients had > grade 2 lung toxicity. Multivariate analysis revealed that trastuzumab use was associated with a decrease risk of acute dermatitis (p= 0.01) but boost irradiation was significantly associated with increased risk of acute dermatitis (p= 0.01). Late toxicity > grade 2 was observed in 6 patients, 14 patients, and 2 patients for skin, heart, and lung respectively. Conclusion: The use of boost irradiation was associated with increased risk of acute dermatitis, in the contrary; the use of trastuzumab seemed to be protective as observed in this study.     

Dose Escalation by Intensity-modulated Radiotherapy Boost after Whole Pelvic Radiotherapy in Postoperative Patients of Carcinoma Cervix with Residual Disease

AimsExternal beam radiotherapy followed by brachytherapy is the standard treatment for patients with carcinoma cervix. However, for patients who come from peripheral hospitals after incomplete surgery, whole pelvic radiotherapy (WPRT) followed by boost with either vaginal vault brachytherapy if suitable or further external beam radiotherapy is recommended. This study was conducted to evaluate if it was possible to give a higher tumour dose using intensity-modulated radiotherapy for that group of patients who were not suitable for high dose rate vaginal vault brachytherapy because of gross disease after WPRT.Materials and methodsA prospective study was carried out from 2005 to 2010 in which 25 postoperative patients of cervical carcinoma with gross residual disease after WPRT of 46 Gy/23 fractions/4.5 weeks were included. Nine patients were treated with 20 Gy to the planning target volume and 30 Gy to the clinical target volume in 10 fractions; 16 patients were treated with 30 Gy to the planning target volume and 35 Gy to the clinical target volume in 15 fractions. The end points of this study were local control, survival and treatment-related toxicity.ResultsThe median follow-up was 38 months. The 3 year local control, progression-free survival and overall survival rates were 76, 74 and 67%, respectively. Late grade 2 rectal toxicity was seen in 11 patients. Grade 2 bladder toxicity occurred in two patients and grade 3 bowel toxicity in two patients. No other grade 3 or higher toxicity was seen.ConclusionInadequate and inappropriate surgery in invasive cervical cancer with resulting gross residual disease is common in India. It is possible to escalate the tumour dose by intensity-modulated radiotherapy boost after WPRT in postoperative cervical carcinoma patients with gross residual disease with low incidence of severe toxicity and excellent local control.     

Late radiation toxicity after whole brain radiotherapy: the influence of antiepileptic drugs

This retrospective study had the following aims: (a) calculation of actuarial rate of late radiation toxicity after whole-brain radiotherapy (WBRT), (b) correlation of clinical symptoms with changes of computed tomography (CT) scans, and (c) analysis of potentially predictive factors with special regard to concomitant treatment with antiepileptic drugs. We analyzed 49 adult patients, selected from a preexisting data base. Inclusion criteria were as follows: no previous brain irradiation; WBRT without boost; CT, clinical, and neurologic examination before and more than 3 months after completion of WBRT. Uni- and multivariate tests of various patient- and treatment-related parameters as possible predictive factors for clinical symptoms of late radiation toxicity (scored according to the RTOG/EORTC system) as well as cerebral atrophy and white matter abnormalities were performed. Median age was 54 years. Patients were treated for brain metastases (n = 37), primary cerebral lymphoma (n = 2), primary brain tumors (n = 7), or with prophylactic intention (n = 3). Carbamazepine was given to 15 patients, phenytoin to 12, and barbiturate to 7, respectively; 42 patients also received corticosteroids. The median dose of WBRT was 30 Gy (range 27-66 Gy). Median fraction size was 3 Gy (1-3 Gy). Nine patients received two fractions per day. The biologically effective dose (BED) according to the linear-quadratic model ranged between 90 and 141 Gy (median, 120 Gy; alpha/beta value, 1 Gy). Median follow-up was 10 months (range, 4-130 months). In 16 cases, symptoms of late radiation toxicity grade I-III appeared. Actuarial rates were 32% after 1 year, 49% after 2 years, and 83% after 5 years. Actuarial rates of cerebral atrophy were 50% after 1 year and 84% after 2 years (white matter abnormalities: 25% and 85%, respectively). There was a significant correlation between atrophy and white matter abnormalities, but not between CT changes and clinical symptoms. CT changes were dependent on BED, absence of barbiturate use, and preexisting cerebral atrophy. Clinical symptoms usually were dependent on BED too, but treatment with carbamazepine was more important in the multivariate model. Neither other drugs nor other factors influenced late radiation toxicity. A detailed analysis showed that most carbamazepine-treated symptomatic patients took the drug during WBRT as well as during follow-up. Actuarial rates of grade I-III symptoms were 18% versus 50% after 1 year with or without carbamazepine. Even after exclusion of carbamazepine-treated patients, CT changes and clinical symptoms did not correlate. In conclusion, a BED <120 Gy was associated with a lower rate of late radiation toxicity after WBRT. The anticonvulsant drug carbamazepine showed a surprisingly clear influence on clinical symptoms of late radiation toxicity; that might be explained by the fact that the side effects of long-term drug treatment are indistinguishable from mild or moderate true radiation sequelae, rather than that it has a role in the pathogenesis of radiation-induced changes.     

Surgical management of retroperitoneal sarcomas associated with external and intraoperative electron beam radiotherapy.

AIMS: To report outcomes of adults with retroperitoneal sarcoma (RS) treated by surgery, external beam radiotherapy (EBRT) and intraoperative electron beam radiotherapy (IORT). METHODS: From July 1988 to February 2001; 24 patients with primary and recurrent RS were diagnosed and treated. The median dose and energy of IORT delivered was 15 Gy/9meV. EBRT dose varies between 45-50 Gy. RESULTS: There were five primary and 19 recurrent tumours. One primary and five recurrent tumours underwent R0 resection. There were 12 liposarcomas and 19 grade I tumours; 13 patients developed local recurrence and three developed distant metastases.Twenty-two patients received IORT associated with EBRT: 11 developed recurrences. Six patients developed Neurotoxicity (4 grade II and 2 grade III). Disease free survival and overall survival at 5 years was 28 and 56% respectively. CONCLUSIONS: EBRT with IORT treatment is a promising technique for local control. Lower recurrence rates are associated with radical (R0) surgical procedures.