Tumor Bed Boost Radiotherapy in the Conservative Treatment of Breast Cancer: A Review of Intra-Operative Techniques and Outcomes.

Conservative surgery is the preferred treatment in the management of breast cancer followed by adjuvant whole-breast irradiation. Since the tumor bed is the main site of relapse, boost doses are conveniently administered according to risk factors for local relapse to increase the efficacy of the treatment. The benefit of a radiation boost is well established and it can be performed by several techniques like brachytherapy, external radiation or intraoperative radiotherapy. Greater precision in localizing the tumor cavity, immediacy and increased biological response are the main advantages of intraoperative boost irradiation. This modality of treatment can be performed by means of mobile electron accelerators or low-photon X-ray devices. There is a lot of research and some published series analyzing the results of the use of an intraoperative boost as an adjuvant treatment, after neoadjuvant systemic therapy and in combination with some reconstructive surgeries. This review discusses advantages of intraoperative radiotherapy and presents the main results of a boost in terms of local control, survival, tolerance and cosmesis.

Clinical Validation of Siemens' Syngo.via Automatic Contouring System.

Purpose: The manual delineation of organs at risk is a process that requires a great deal of time both for the technician and for the physician. Availability of validated software tools assisted by artificial intelligence would be of great benefit, as it would significantly improve the radiation therapy workflow, reducing the time required for segmentation. The purpose of this article is to validate the deep learning-based autocontouring solution integrated in syngo.via RT Image Suite VB40 (Siemens Healthineers, Forchheim, Germany). Methods and Materials: For this purpose, we have used our own specific qualitative classification system, RANK, to evaluate more than 600 contours corresponding to 18 different automatically delineated organs at risk. Computed tomography data sets of 95 different patients were included: 30 patients with lung, 30 patients with breast, and 35 male patients with pelvic cancer. The automatically generated structures were reviewed in the Eclipse Contouring module independently by 3 observers: an expert physician, an expert technician, and a junior physician. Results: There is a statistically significant difference between the Dice coefficient associated with RANK 4 compared with the coefficient associated with RANKs 2 and 3 (P < .001). In total, 64% of the evaluated structures received the maximum score, 4. Only 1% of the structures were classified with the lowest score, 1. The time savings for breast, thorax, and pelvis were 87.6%, 93.5%, and 82.2%, respectively. Conclusions: Siemens' syngo.via RT Image Suite offers good autocontouring results and significant time savings.

Accuracy of sentinel node mapping in patients with biopsy-proven metastatic axillary lymph nodes and upfront surgery: preliminary results of the Multimodal Targeted Axillary Surgery (MUTAS) trial.

Background: Some studies suggested that the patients included in the Z0011 trial may represent patients with ultrasound-negative axillary nodes and axillary invasion diagnosed by sentinel node (SN) biopsy. Nevertheless, the National Comprehensive Cancer Network (NCCN) guidelines recommend SN mapping if 1 or 2 suspicious lymph nodes are identified on axillary ultrasound (AU). The aim of this preliminary phase of the Multimodal Targeted Axillary Surgery (MUTAS) trial was to establish the accuracy of SN mapping in patients with axillary involvement undergoing upfront surgery. Methods: Between September 2019 and March 2022, we recruited patients with biopsy-proven metastatic axillary nodes and upfront surgery from a single center. We performed SN mapping in these patients before the surgical intervention, which included axillary lymph node dissection. The biopsy-proven metastatic node, SNs and the remaining axillary nodes were excised separately. SN status was considered representative of the status of the remaining axillary nodes. We calculated the sensitivity, specificity, negative predictive value and positive predictive value of the SN, overall and in patients with palpable nodes, in those with non-palpable nodes and an AU leading to diagnosis of axillary involvement, in those with 1 or 2 suspicious nodes on AU, and in patients with a single suspicious node on AU. We evaluated clinical, imaging and pathology features as predictors of the status of the remaining axillary nodes, false-negatives, and false-positives. Results: We included 25 patients in this phase. The false-negative rate of SN mapping was 28% overall, 21.42% for patients with palpable nodes, 36.36% for patients with non-palpable nodes and an AU diagnosis of axillary involvement, 28.75% for those with 1 or 2 suspicious nodes on AU, and 15.38% in patients with a single suspicious node on AU. The negative predictive value was highest in patients with a single suspicious node on AU (75%). The only significant predictive factor was that FN showed a higher Ki67 index score. Conclusions: In this study, SN mapping was not reliable in patients with biopsy-proven metastatic axillary nodes and upfront surgery for any of the subgroups studied. Further research should elucidate the best staging pathways in these patients to avoid premature de-escalation.

Machine learning-based automated planning for hippocampal avoidance prophylactic cranial irradiation.

PURPOSE: Design and evaluate a knowledge-based model using commercially available artificial intelligence tools for automated treatment planning to efficiently generate clinically acceptable hippocampal avoidance prophylactic cranial irradiation (HA-PCI) plans in patients with small-cell lung cancer. MATERIALS AND METHODS: Data from 44 patients with different grades of head flexion (range 45°) were used as the training datasets. A Rapid Plan knowledge-based planning (KB) routine was applied for a prescription of 25 Gy in 10 fractions using two volumetric modulated arc therapy (VMAT) arcs. The 9 plans used to validate the initial model were added to generate a second version of the RP model (Hippo-MARv2). Automated plans (AP) were compared with manual plans (MP) according to the dose-volume objectives of the PREMER trial. Optimization time and model quality were assessed using 10 patients who were not included in the first 44 datasets. RESULTS: A 55% reduction in average optimization time was observed for AP compared to MP. (15 vs 33 min; p = 0.001).Statistically significant differences in favor of AP were found for D98% (22.6 vs 20.9 Gy), Homogeneity Index (17.6 vs 23.0) and Hippocampus D mean (11.0 vs 11.7 Gy). The AP met the proposed objectives without significant deviations, while in the case of the MP, significant deviations from the proposed target values were found in 2 cases. CONCLUSION: The KB model allows automated planning for HA-PCI. Automation of radiotherapy planning improves efficiency, safety, and quality and could facilitate access to new techniques.

OPTimizing Irradiation through Molecular Assessment of Lymph node (OPTIMAL): a randomized clinical trial.

BACKGROUND AND PURPOSE: In breast cancer (BC) patients, the involvement of four or more lymph nodes (LN) is an indication of regional irradiation. The optimal treatment strategy remains unclear when fewer nodes are involved and lymphadenectomy is not performed. We designed a clinical trial to show the non-inferiority of Incidental (INC) compared to intentional (INT) irradiation of axillary nodes in patients with early-stage BC and low burden LN involvement. MATERIALS AND METHODS: BC patients, cN0 (n = 487) undergoing breast conservation surgery and sentinel node biopsy, with total tumor load assessed by OSNA (One-Step Nucleic Acid Amplification) of 250-15,000 copies mRNA CK19/µL in sentinel LN were randomized to receive INC or INT nodal irradiation. The primary endpoint was 5-year disease-free survival (DFS). Secondary endpoints were locoregional recurrence (LRR), distant recurrence (DR), and acute and chronic toxicity (CT). RESULTS: Five-years DFS were 93.7% (INC) and 93.8% (INT) (difference 0.1% [one-sided 95% CI < 5.7%]; non-inferiority p = 0.075). Cumulative Incidences of LRR were 3.5% (INC) and 3.4% (INT) (difference of 0.1% [<4.8%]; p = 0.021), and 5% (INC) and 3.5% (INT) (difference 1.4% [<6.0%]; non-inferiority p = 0.101) for DR. CT was more Incident with INT (26.9%) than with INC (19.2%), though the difference was not statistically significant (HR 1.39 [95% CI: 0.92, 2.10]; p = 0.11). CONCLUSION: Intentional does not outperform incidental irradiation by more than 5.7% in terms of 5-year DFS, 4.8% for LRR, and 6% for DR. REGISTRATION NUMBER: ClinicalTrials.gov Identifier: NCT02335957.

Evidence-based guidelines for hypofractionated radiation in breast cancer: conclusions of the Catalan expert working group.

INTRODUCTION: Daily, moderate hypofractionation has become standard treatment for breast cancer following breast-conserving surgery, although substantial variation exists in its use. This paper describes the generation of consensus-based recommendations for the utilisation of this therapy at the healthcare system level and compares these to American Society for Radiation Oncology (ASTRO) guidelines. MATERIALS AND METHODS: Consensus-based guidelines were developed in three steps, including a systematic literature review and involvement of radiation oncologists specialising in breast cancer in Catalonia: (a) creation of a working group and evidence review; (b) consideration of the levels of evidence and agreement on the formulation of survey questions; and (c) performance of survey and development of consensus-based recommendations. Results were compared to the ASTRO recommendations. RESULTS: Consensus was above 80% for 10 of the 14 survey items. Experts supported hypofractionated radiotherapy for all breast cancer patients aged 40 years or more; with invasive carcinoma and breast-conserving surgery; without radiation of lymph nodes; and regardless of the tumour size, histological grade, molecular subtype, breast size, laterality, other treatment characteristics, or need for a boost. Over half favoured its use in all situations, even where available scientific evidence is insufficient. The resulting recommendations and the quality of the evidence are comparable to those from ASTRO, despite some differences in the degree of consensus. CONCLUSION: Specialists agree that hypofractionation is the standard treatment for breast cancer following breast-conserving surgery, but some specific areas require a higher level of evidence before unequivocally extending indications.

DNA Damage Protection for Enhanced Bacterial Survival Under Simulated Low Earth Orbit Environmental Conditions in Escherichia coli.

Some organisms have shown the ability to naturally survive in extreme environments, even outer space. Some of these have natural mechanisms to resist severe DNA damage from conditions such as ionizing and non-ionizing radiation, extreme temperatures, and low pressures or vacuum. A good example can be found in Deinococcus radiodurans, which was exposed to severe conditions such as those listed in the Exposure Facility of the International Space Station (ISS) for up to three years. Another example are tardigrades (Ramazzottius varieornatus) which are some of the most resilient animals known. In this study, the survival under simulated Low earth Orbit (LEO) environmental conditions was tested in Escherichia coli. The radiation resistance of this bacteria was enhanced using the Dsup gene from R. varieornatus, and two more genes from D. radiodurans involved in DNA damage repair, RecA and uvrD. The enhanced survival to wide ranges of temperatures and low pressures was then tested in the new strains. This research constitutes a first step in the creation of new bacterial strains engineered to survive severe conditions and adapting existing species for their survival in remote environments, including extra-terrestrial habitats. These strains could be key for the development of environments hospitable to life and could be of use for ecological restoration and space exploration. In addition, studying the efficacy and the functioning of the DNA repair mechanisms used in this study could be beneficial for medical and life sciences engineering.

Validation of 3D printing materials for high dose-rate brachytherapy using ionisation chamber and custom phantom.

Methods.Measurements were taken with the Exradin A20 (Standard Imaging) ionisation chamber, and the 'homemade' MARM phantom was made with the 3D Ultimaker 2+ printer using PLA material. The material used for validation was ABS Medical from Smart Materials 3D. The irradiation was undertaken with a192Ir source by means of Varian's GammaMed Plus iX HDR equipment. EBT3 films were used to run additional tests. We compared different measurements for PLA, ABS Medical, and water. Additional validation methods, described in the bibliography, were also compared.Results.The measurements with the ionisation chamber that we obtained using the MARM phantom with PLA and ABS within the clinically relevant range (0.5-1.5 cm) differ with respect to the measures in the water reference, by 2.3% and 0.94%, respectively.Discussion.The literature describes highly heterogeneous validation methods, complicating the performance of systematic reviews and comparisons between materials. Thus, creating a phantom represents a single effort that will quickly pay off. This system enables comparisons, ensuring that geometric conditions remain stable-something that is not always possible with radiochromic films. The use of a calibrated ionisation chamber in the corresponding energy range, combined with the 'homemade' MARM phantom applied according to the proposed methodology, allows a differentiation between the attenuation of the material itself and the drop in the dose due to distance.Conclusion.The validation method for 3D printing materials, using an ionisation chamber and the MARM PLA phantom, represents an accessible, standardisable solution for manufacturing brachytherapy applicators.

Once-Weekly Hypofractionated Radiotherapy for Breast Cancer in Elderly Patients: Efficacy and Tolerance in 486 Patients.

PURPOSE: Radiation therapy is a key treatment of breast cancer. Elderly patients with associated diseases that modify their performance status do not tolerate long periods of daily irradiation. The objective of this study is to analyze the results of weekly hypofractionated treatment in these patients. MATERIAL AND METHODS: Between 1992 and 2016, we included 486 elderly patients presenting concomitant pathology or sociofamilial problems in which it was not feasible to propose conventional treatment. They were treated with conservative surgery or mastectomy and then adjuvant hypofractionated irradiation, administering 5 Gy or 6.25 Gy in 6 fractions, once a week (total dose 30-37.5 Gy) over 6 weeks. RESULTS: Breast cancer overall survival according to the Kaplan-Meier method at 5 years was 74.2% ± 2.3%; breast cancer disease-free survival was 90% ± 1.6%; local relapse-free survival was 96.5% ± 1% showing that patients die more from other causes and not from their neoplasia. Acute dermatitis was mild (75.6% of the patients grades I-III) and 30.6% had moderate chronic fibrosis. CONCLUSIONS: The once-weekly hypofractionated radiotherapy is a feasible and convenient option for elderly patients with breast cancer. It is a safe treatment modality with similar survival and local control results compared to standard fractionation, while the side effects are acceptable.

Relationship between radiation-induced apoptosis of T lymphocytes and chronic toxicity in patients with prostate cancer treated by radiation therapy: a prospective study.

PURPOSE: To assess the correlation of radiation-induced apoptosis in vitro of CD4 and CD8 T lymphocytes with late toxicity of prostate cancer patients treated with radiation therapy. METHODS AND MATERIALS: 214 patients were prospectively included in the study. Peripheral blood was drawn from patients before treatment and irradiated with 8 Gy. The percentage of CD4+ and CD8+ T lymphocytes that underwent radiation-induced apoptosis was assessed by flow cytometry. Toxicity and mortality were correlated in 198 cases with pretreatment apoptosis and clinical and biological variables by use of a Cox proportional hazards model. RESULTS: The mean percentage of CD4+ and CD8+ T lymphocyte radiation-induced apoptosis was 28.58% (±14.23) and 50.76% (±18.9), respectively. Genitourinary (GU) toxicity was experienced by 39.9% of patients, while gastrointestinal (GI) toxicity was experienced by 19.7%. The probability of development of GU toxicity was nearly doubled (hazard ratio [HR] 1.99, P=.014) in those patients in whom the percentage of in vitro radiation-induced apoptosis of CD4+ T-lymphocytes was ≤28.58%. It was also almost double in patients who received doses ≥50 Gy in 65% of the bladder volume (V65 ≥50) (HR 1.92, P=.048). No correlation was found between GI toxicity and any of the variables studied. The probability of death during follow-up, after adjustment for different variables, was 2.7 times higher in patients with a percentage of CD8+ T lymphocyte apoptosis ≤50.76% (P=.022). CONCLUSIONS: In conclusion, our study shows, in the largest prospective cohort of prostate cancer patients undergoing radiation therapy, that in vitro radiation-induced apoptosis of CD4+ T lymphocytes assessed before radiation therapy was associated with the probability of developing chronic GU toxicity. In addition, the radiation dose received in the urinary bladder (V65 ≥50) affected the occurrence of GU toxicity. Finally, we also demonstrate that radiation-induced apoptosis of CD8+ T lymphocytes was associated with overall survival, although larger series are needed to confirm this finding.

Five-year outcomes, cosmesis, and toxicity with 3-dimensional conformal external beam radiation therapy to deliver accelerated partial breast irradiation.

PURPOSE: To report the interim results from a study comparing the efficacy, toxicity, and cosmesis of breast-conserving treatment with accelerated partial breast irradiation (APBI) or whole breast irradiation (WBI) using 3-dimensional conformal external beam radiation therapy (3D-CRT). METHODS AND MATERIALS: 102 patients with early-stage breast cancer who underwent breast-conserving surgery were randomized to receive either WBI (n=51) or APBI (n=51). In the WBI arm, 48 Gy was delivered to the whole breast in daily fractions of 2 Gy, with or without additional 10 Gy to the tumor bed. In the APBI arm, patients received 37.5 Gy in 3.75 Gy per fraction delivered twice daily. Toxicity results were scored according to the Radiation Therapy Oncology Group Common Toxicity Criteria. Skin elasticity was measured using a dedicated device (Multi-Skin-Test-Center MC-750-B2, CKelectronic-GmbH). Cosmetic results were assessed by the physician and the patients as good/excellent, regular, or poor. RESULTS: The median follow-up time was 5 years. No local recurrences were observed. No significant differences in survival rates were found. APBI reduced acute side effects and radiation doses to healthy tissues compared with WBI (P<.01). Late skin toxicity was no worse than grade 2 in either group, without significant differences between the 2 groups. In the ipsilateral breast, the areas that received the highest doses (ie, the boost or quadrant) showed the greatest loss of elasticity. WBI resulted in a greater loss of elasticity in the high-dose area compared with APBI (P<.05). Physician assessment showed that >75% of patients in the APBI arm had excellent or good cosmesis, and these outcomes appear to be stable over time. The percentage of patients with excellent/good cosmetic results was similar in both groups. CONCLUSIONS: APBI delivered by 3D-CRT to the tumor bed for a selected group of early-stage breast cancer patients produces 5-year results similar to those achieved with conventional WBI.

Clinical and technological transition in breast cancer.

This article is a summary of the conference "Clinical and technological transition in breast cancer" that took place in the Congress of the Spanish Society of Radiation Oncology, placed in Vigo (Spain) on June 21, 2013. Hugo Marsiglia and Philip Poortmanns were the speakers, the first discussed about "Clinical and technological transition" and the second about "EORTC clinical trials and protocols".

Radiation techniques used in patients with breast cancer: Results of a survey in Spain.

AIM: To evaluate the resources and techniques used in the irradiation of patients with breast cancer after lumpectomy or mastectomy and the status of implementation of new techniques and therapeutic schedules in our country. BACKGROUND: The demand for cancer care has increased among the Spanish population, as long as cancer treatment innovations have proliferated. Radiation therapy in breast cancer has evolved exponentially in recent years with the implementation of three-dimensional conformal radiotherapy, intensity modulated radiotherapy, image guided radiotherapy and hypofractionation. MATERIAL AND METHODS: An original survey questionnaire was sent to institutions participating in the SEOR-Mama group (GEORM). In total, the standards of practice in 969 patients with breast cancer after surgery were evaluated. RESULTS: The response rate was 70% (28/40 centers). In 98.5% of cases 3D conformal treatment was used. All the institutions employed CT-based planning treatment. Boost was performed in 56.4% of patients: electrons in 59.8%, photons in 23.7% and HDR brachytherapy in 8.8%. Fractionation was standard in 93.1% of patients. Supine position was the most frequent. Only 3 centers used prone position. The common organs of risk delimited were: homolateral lung (80.8%) and heart (80.8%). In 84% histograms were used. An 80.8% of the centers used isocentric technique. In 62.5% asymmetric fields were employed. CTV was delimited in 46.2%, PTV in 65% and both in 38.5%. A 65% of the centers checked with portal films. IMRT and hypofractionation were used in 1% and in 5.5% respectively. CONCLUSION: In most of centers, 3D conformal treatment and CT-based planning treatment were used. IMRT and hypofractionation are currently poorly implemented in Spain.

Long-term results and prognostic factors of patients with cervical carcinoma treated with concurrent chemoradiotherapy.

AIMS AND BACKGROUND: To evaluate the predictive factors of recurrence in cervical cancer treated with radical radiochemotherapy. METHODS: A retrospective analysis of 56 women was performed. Response was assessed using the RECIST response. Overall survival and disease-free survival curves were estimated by the Kaplan-Meier method and the Cox proportional hazards model was used to analyse predictors of recurrence. RESULTS: Local recurrence was documented in 16 patients and distant metastases in 15. The Kaplan-Meier survival probabilities were 95.1 ± 6.4% at 3 years and 80.4 ± 13.1% at 5 years and the Kaplan-Meier curve values for disease-free survival were 60.3 ± 14.3% at 3 years and 53.0 ± 15.7% at 5 years. Thirty-five patients were alive and 21 patients died, 19 from metastatic disease and 2 from other causes. Complete response after chemoradiation therapy, squamous cell carcinoma and tumour size ≤ 4 cm were significantly associated with outcome. In the Cox regression model, tumour size > 4 cm (hazard ratio 7.48; 95% CI 2.71-20.6; p < 0.001) and partial response (hazard ratio 7.09; 95% CI 2.82-17.8; p < 0.001) were predictive factors for disease-free survival and partial response (hazard ratio 3.7; 95% CI 1.3-10.1; p < 0.001) and non-squamous cell carcinoma (hazard ratio 3.5; 95% CI 1.2-9.7; p < 0.001) were predictive factors for overall survival. CONCLUSIONS: Non-squamous histology and partial response were independent prognostic factors for overall survival and tumour size and partial response were independent prognostic variables for 5-year disease survival.

Acute motor axonal neuropathy associated with anal carcinoma: Paraneoplastic neurological syndrome or coincidence?

AIM: Assessment of the association of an acute motor axonal neuropathy with a squamous cell anal carcinoma. BACKGROUND: Paraneoplastic neurologic syndromes are not a direct consequence of neither primary tumor nor its metastasis. They often parallel the course of the malignancy but may be the presenting sign of an occult cancer. Sometimes it is very difficult to distinguish if it is a paraneoplastic syndrome or just a coincidence. MATERIALS AND METHODS: We report a 60-year-old man that presented with an acute motor deficit of the four limbs. Clinical examination found a pure and severe motor deficit in the four limbs. No sensory abnormality was found and all motor nerves were unexcitable. Electromyography suggested the diagnosis of acute motor axonal neuropathy (AMAN). Four months after developing the AMAN, blood in the stool revealed anal carcinoma. The patient was treated with concurrent chemoradiotherapy. Radiation was given to the tumor and to the pelvis, including inguinal nodes, over a five-week period plus fluorouracil and mitomycin. We investigated the presence of antiganglioside antibodies as studies suggest that carcinomas can express antigens shared with Schwann cells. RESULTS: Anti-GM1 IgG antibodies were detected by an enzyme-linked immunosorbent assay method. Other antibodies, including antinuclear nucleoprotein antibody (anti-Hu), anti-Tr, anti-Ri, anti-CV2, anti-amphiphysin and anti-Yo, were negative. Clinical improvement of the motor state was observed at the fourth week of oncologic treatment. CONCLUSION: The presence of anti-GM1 IgG antibodies and the clinical improvement of the motor state after concurrent chemoradiotherapy lead us to believe there is an association between anal carcinoma and this severe impairment.

18F-FDG PET definition of gross tumor volume for radiotherapy of lung cancer: is the tumor uptake value-based approach appropriate for lymph node delineation?

PURPOSE: Positron emission tomography (PET) with the glucose analogue [18F] fluoro-2-deoxy-D-glucose ((18)F-FDG-PET) has been used in radiation treatment planning for non-small-cell carcinoma. To date, lymph nodes have been contoured according to the uptake of the tumor. This prospective study was performed to evaluate if nodal volume delineates according to FDG uptake within the primary tumor (PET-GTVnt) is suitable for nodal target volume delineation or if individualized nodal FDG uptake measure (PET-GTVnn) is necessary to better nodal target definition. METHODS AND MATERIALS: Forty cases, who underwent a diagnostic (18)F-FDG PET/computed tomography (CT) scan, were included. Two PET-based GTVs for each lymph node were contoured and compared. First, we used an isocontour of 40% of the maximum tumor uptake (PET-GTVnt). Second, an isocontour of 40% of the maximum uptake of each node (PET-GTVnn) was employed. To avoid interobserver variability, this was carried out by the same radiation oncologist. Afterwards, the difference between both lymph node volumes was plotted against the ratio of the maximum uptakes (I(n)/I(t)) in a linear regression analysis. RESULTS: Compared with CT-based lymph node volume (CT-GTVn), the intraclass correlation coefficient of PET-GTVnn was higher than the coefficient of PET-GTVnt (p < 0.001). All cases could be divided into four groups: undetected (17.5%), detected but overestimated (10%), detected but underestimated (35%), and correctly detected (37.5%). CONCLUSIONS: If a method of automatic delineation shall be applied, this method must be applied to every lesion separately. However, to facilitate the delineation in daily practice, when I(n)/I(t) is ≤25%, lymph nodes could be delineated in accordance with tumor uptake, keeping an absolute difference in radii <5 mm.

Predictors of acute esophagitis in lung cancer patients treated with concurrent three-dimensional conformal radiotherapy and chemotherapy.

PURPOSE: To evaluate the risk factors for acute esophagitis (AET) in lung cancer patients treated with concurrent 3D-CRT and chemotherapy. METHODS AND MATERIALS: Data from 100 patients treated with concurrent chemoradiotherapy with a mean dose of 62.05 +/- 4.64 Gy were prospectively evaluated. Esophageal toxicity was graded according to criteria of the Radiation Therapy Oncology Group. The following dosimetric parameters were analyzed: length and volume of esophagus in treatment field, percentage of esophagus volume treated to >or=10, >or=20, >or=30, >or=35, >or=40, >or=45, >or=50, >or=55, and >or=60 Gy, and the maximum (D(max)) and mean doses (D(mean)) delivered to the esophagus. Also, we developed an esophagitis index (EI) to account the esophagitis grades over treatment time. RESULTS: A total of 59 patients developed AET (Grade 1, 26 patients; Grade 2, 29 patients; and Grade 3, 4 patients). V50 was associated with AET duration (p = 0.017), AET Grade 1 duration (p = 0.016), maximum analgesia (p = 0.019), esophagitis index score (p = 0.024), and AET Grade >or=1 (p = 0.058). If V50 is <30% there is a 47.3% risk of AET Grade >or=1, which increases to 73.3% if V50 is >or=30% (p = 0.008). The predictive abilities of models (sensitivity and specificity) were calculated by receiver operating characeristic curves. CONCLUSIONS: According to the receiver operating characeristic curve analysis, the 30% of esophageal volume receiving >or=50 Gy was the most statistically significant factor associated with AET Grade >or=1 and maximum analgesia (A(max)). There was an association with AET Grade >or=2 but it did not achieve statistical significance (p = 0.076).

Induction chemotherapy with cisplatin and gemcitabine followed by concurrent chemoradiation with twice-weekly gemcitabine in unresectable stage III non-small cell lung cancer: final results of a phase II study.

Concurrent chemoradiotherapy (CCR) followed or preceded by full-dose chemotherapy seems to be a standard treatment for unresectable non-small cell lung cancer (NSCLC). Gemcitabine is a strong radiosensitizer, and a phase I study confirmed the feasibility of CCR with low-dose gemcitabine administered twice-weekly in NSCLC patients. Consequently, we designed a prospective, multicentric, phase II trial to evaluate the efficacy and toxicity of this approach, following induction chemotherapy with cisplatin and gemcitabine. We included patients with unresectable stage III NSCLC, no pleural effusion, adequate pulmonary, renal, liver and hematological functions, Karnofsky index >70 and planned treated volume (PTV) <2200cm3. Treatment consisted of 3 cycles of cisplatin (100mg/m2, d1) and gemcitabine (1250mg/m2, d1 and 8) q3w, followed by CCR (gemcitabine 50mg/m2 on Mondays and Thursdays and radiotherapy 68.4Gy, 1.8Gyqd). After the inclusion of 22 patients (group A), an unacceptable toxicity was detected. Thus, cisplatin dose was reduced to 70mg/m2, and gemcitabine dose was adjusted to 35mg/m2 during CCR. Another 34 patients (33 eligible, group B) were included. Five patients in group A and 6 patients in group B discontinued the study treatment during induction. Thus, 17 and 27 patients, respectively initiated CCR. Hematological toxicity (grades III and IV) was particularly relevant in group A during this phase, with 35 and 23% of thrombopenia and neutropenia, respectively. Nonhematological grades III-IV toxicity of chemoradiation was significant and similar in groups A and B: esophagitis 35.2 and 33.3% and pneumonitis 23.5 and 25.9%, respectively. 40.9% of patients in group A vs. 57.5% in group B completed treatment. Overall response (intention-to-treat analysis) was 68.1% in group A and 63.5% in group B. Median survival was 17.7 months for the whole group with a mean follow-up of 41.2 months. 20% of patients were alive at 3 years. Long-term results of this schedule are encouraging. However, nonhematological toxicity of chemoradiation is substantial and different strategies should be tested to minimize it.

Prevention of radiochemotherapy-induced esophagitis with glutamine: results of a pilot study.

PURPOSE: To assess the usefulness of oral glutamine to prevent radiochemotherapy-induced esophagitis in patients with lung cancer, and to determine the dosimetric parameter predictive of esophagitis. METHODS AND MATERIALS: Seventy-five patients were enrolled; 34.7% received sequential radiochemotherapy, and 65.3% received concomitant radiochemotherapy. Every patient received prophylactic glutamine powder in doses of 10 g/8 h. Prescribed radiation doses were 45-50 Gy to planning target volume (PTV)1 (gross tumor volume plus wide margins) and 65-70 Gy to PTV2 (reduced margins). The primary endpoint was the incidence of Grade 2 or greater acute esophagitis. RESULTS: No patient experienced glutamine intolerance or glutamine-related toxicity. Seventy-three percent of patients who received sequential chemotherapy and 49% of those who received concomitant chemotherapy did not present any form of esophagitis. V50 was the dosimetric parameter with better correlation between esophagitis and its duration. A V50 of or=2, which increased to 71% with a V50 of >30% (p = 0.0009). CONCLUSIONS: The use of oral glutamine may have an important role in the prevention of esophageal complications of concomitant radiochemotherapy in lung cancer patients. However, randomized trials are needed to corroborate that effect. V50 is the dosimetric parameter with better correlation with esophagitis grade and duration.