New Treatment Strategies for the Inflammatory Breast Cancer.

OPINION STATEMENT: Inflammatory breast cancer (IBC) remains the most aggressive type of breast cancer. During the past decade, enormous progress has been made to refine diagnostic criteria and establish multimodality treatment strategies as keys for the improvement of survival outcomes. Multiple genomic studies enabled a better understanding of underlying tumor biology, which is responsible for the complex and aggressive nature of IBC. Despite these important achievements, outcomes for this subgroup of patients remain unsatisfactory compared to locally advanced non-IBC counterparts. Global efforts are now focused on identifying novel strategies that will improve treatment response, prolong survival for metastatic patients, achieve superior local control, and possibly increase the cure rate for locally advanced disease. Genomic technologies constitute the most important tool that will support future clinical progress. Gene-expressing profiling of the tumor tissue and liquid biopsy are important parts of the everyday clinical practice aiming to guide treatment decisions by providing information on tumor molecular drivers or primary and acquired resistance to treatment. The International IBC expert panel and IBC International Consortium made a tremendous effort to define IBC as a distinct entity of BC, and they will continue to lead and support the research for this rare and very aggressive disease. Finally, a uniform platform is now required to develop and lead large, multi-arm, proof-of-concept clinical trials that perform rapid, focused, and cost-effective evaluations of potential novel therapeutics in IBC.

Does residual microscopic disease after chemoradiotherapy for locally advanced rectal cancer translate into a good clinical outcome?

AIM: This study aimed to assess the progression-free and overall survival of patients with residual microscopic disease following neoadjuvant chemoradiotherapy and rectal resection for locally advanced rectal cancer. METHOD: Two-hundred and thirty-four consecutive rectal cancer patients who had neoadjuvant chemoradiotherapy followed by radical resection (from May 2000 to April 2012) were divided according to pathological tumour response: residual microscopic disease (MIC), complete response (pCR) and partial/no response (non-CR). Data on the neoadjuvant regime, treatment-to-surgery interval, final pathology, type of operation, operative time, postoperative complications, length of hospital stay, disease recurrence and mortality were compared between the groups. RESULTS: There were 13 (5.5%) MIC patients, 48 (20.5%) with pCR and 173 (73.9%) with non-CR group. The groups were demographically comparable. MIC patients had more retrieved lymph nodes compared with the non-CR and pCR patients (median 13 compared with 8 and 10, respectively, P = 0.0086). The 5-year overall survival rates were 93.4% for the pCR and MIC patients vs 82.1% for the non-CR patients (P = 0.0324). The 5-year progression-free survival was 85.2% for the pCR and MIC patients vs 73.8% for the non-CR patients (P = 0.086). CONCLUSION: We have identified and assessed a new pathological subgroup of rectal cancer patients who had residual microscopic disease after neoadjuvant therapy. The survival analysis aligned them closely with pCR patients.

The interference between oxaliplatin & anti-EGFR therapies: a different hypothesis to explain the 'unexplainable'.

This paper has been written because we have a differing idea concerning the suspected negative interference between oxaliplatin and anti-EGFR therapies in cancer patients. Several multicenter, randomized, controlled clinical trials investigated whether the efficacy of oxaliplatin-based chemotherapy is improved by the addition of anti-EGFR therapies in patients affected by KRAS wild-type advanced colorectal cancer. Results of these trials have produced puzzling findings, with some studies demonstrating improved survival and other studies showing no differences in overall survival between experimental and control arms. Moreover, a detrimental effect has been demonstrated in some settings. Nevertheless, the extent of this interaction remains uncertain. Some physicians proposed personal interpretations. This paper describes our hypothesis.

Dosimetric Analysis of Microscopic Disease in SBRT for Lung Cancers.

OBJECTIVE: The objective of this study is to theoretically and experimentally evaluate the dosimetry in the microscopic disease regions surrounding the tumor under stereotactic body radiation therapy of lung cancer. METHODS: For simplicity, the tumor was considered moving along 1 dimension with a periodic function. The probability distribution function of the tumor position was generated according to the motion pattern and was used to estimate the delivered dose in the microscopic disease region. An experimental measurement was conducted to validate both the estimated dose with a probability function and the calculated dose from 4-dimensional computed tomography data using a dynamic thorax phantom. Four tumor motion patterns were simulated with cos4(x) and sin(x), each with 2 different amplitudes: 10 mm and 5 mm. A 7-field conformal plan was created for treatment delivery. Both films (EBT2) and optically stimulated luminescence detectors were inserted in and around the target of the phantom to measure the delivered doses. Dose differences were evaluated using gamma analysis with 3%/3 mm. RESULTS: The average gamma index between measured doses using film and calculated doses using average intensity projection simulation computed tomography was 80.8% ± 0.9%. In contrast, between measured doses using film and calculated doses accumulated from 10 sets of 4-dimensional computed tomography data, it was 98.7% ± 0.6%. The measured doses using optically stimulated luminescence detectors matched very well (within 5% of the measurement uncertainty) with the theoretically calculated doses using probability distribution function at the corresponding position. Respiratory movement caused inadvertent irradiation exposure, with 70% to 80% of the dose line wrapped around the 10 mm region outside the target. CONCLUSION: The use of static dose calculation in the treatment planning system could substantially underestimate the actual delivered dose in the microscopic disease region for a moving target. The margin for microscopic disease may be substantially reduced or even eliminated for lung stereotactic body radiation therapy.

Impact of microscopic disease extension, extra-CTV tumour islets, incidental dose and dose conformity on tumour control probability.

The impact of microscopic disease extension (MDE), extra-CTV tumour islets (TIs), incidental dose and dose conformity on tumour control probability (TCP) is analyzed using insilico simulations in this study. MDE in the region in between GTV and CTV is simulated inclusive of geometric uncertainties (GE) using spherical targets and spherical dose distribution. To study the effect of incidental dose on TIs and the effect of dose-response curve (DRC) on tumour control, islets were randomly distributed and TCP was calculated for various dose levels by rescaling the dose. Further, the impact of dose conformity on required PTV margins is also studied. The required PTV margins are ~2 mm lesser than assuming a uniform clonogen density if an exponential clonogen density fall off in the GTV-CTV is assumed. However, margins are almost equal if GE is higher in both cases. This shows that GE has a profound impact on margins. The effect of TIs showed a bi-phasic relation with increasing dose, indicating that patients with islets not in the beam paths do not benefit from dose escalation. Increasing dose conformity is also found to have considerable effect on TCP loss especially for larger GE. Further, smaller margins in IGRT should be used with caution where uncertainty in CTV definition is of concern.

The effect of age in breast conserving therapy: a retrospective analysis on pathology and clinical outcome data.

BACKGROUND AND PROPOSE: Age is an important prognostic marker of patient outcome after breast conserving therapy; however, it is not clear how age affects the outcome. This study aimed to explore the relationship between age with the cell quantity and the radiosensitivity of microscopic disease (MSD) in relation to treatment outcome. MATERIALS AND METHODS: We employed a treatment simulation framework which contains mathematic models for describing the load and spread of MSD based on a retrospective cohort of breast pathology specimens, a surgery simulation model for estimating the remaining MSD quantity and a tumor control probability model for predicting the risk of local recurrence following radiotherapy. RESULTS: The average MSD cell quantities around the primary tumor in younger (age⩽50years) and older patients were estimated at 1.9∗10(8)cells and 8.4∗10(7)cells, respectively (P<0.01). Following surgical simulation, these numbers decreased to 2.0∗10(7)cells and 1.3∗10(7)cells (P<0.01). Younger patients had smaller average surgical resection volume (118.9cm(3)) than older patients (162.9cm(3), P<0.01) but larger estimated radiosensitivity of MSD cells (0.111Gy(-1) versus 0.071Gy(-1), P<0.01). CONCLUSION: The higher local recurrence rate in younger patients could be explained by larger clonogenic microscopic disease cell quantity, even though the microscopic disease cells were found to be more radiosensitive.

A simulation framework for modeling tumor control probability in breast conserving therapy.

BACKGROUND AND PURPOSE: Microscopic disease (MSD) left after tumorectomy is a major cause of local recurrence in breast conserving therapy (BCT). However, the effect of microscopic disease and RT dose on tumor control probability (TCP) was seldom studied quantitatively. A simulation framework was therefore constructed to explore the relationship between tumor load, radiation dose and TCP. MATERIALS AND METHODS: First, we modeled total disease load and microscopic spread with a pathology dataset. Then we estimated the remaining disease load after tumorectomy through surgery simulation. The Webb-Nahum TCP model was extended by clonogenic cell fraction to model the risk of local recurrence. The model parameters were estimated by fitting the simulated results to the observations in two clinical trials. RESULTS: Higher histopathology grade has a strong correlation with larger MSD cell quantity. On average 12.5% of the MSD cells remained in the patient's breast after surgery but varied considerably among patients (0-100%); illustrating the role of radiotherapy. A small clonogenic cell fraction was optimal in our model (one in every 2.7*10(6)cells). The mean radiosensitivity was estimated at 0.067Gy(-1) with standard deviation of 0.022Gy(-1). CONCLUSION: A relationship between radiation dose and TCP was established in a newly designed simulation framework with detailed disease load, surgery and radiotherapy models.

Microscopic disease extensions as a risk factor for loco-regional recurrence of NSCLC after SBRT.

PURPOSE: Stereotactic body radiotherapy (SBRT) is a highly conformal technique that allows a more accurate irradiation of lung tumors. However, a highly conformal dose distribution may underdose undetected microscopic disease extensions (MDE) near the tumor leading to loco-regional failure in tumor control. The purpose of the current work is to assess the risk of loco-regional failure in SBRT by analyzing pre-treatment scans. METHODS AND MATERIALS: A model to predict the risk of occurrence of MDE from pretreatment images was developed based on pathology samples of 47 lung cancer patients. This model was used to assess the outcome of 238 SBRT treatments. RESULTS: Patients with high risk of MDE presence showed significantly lower 2-year loco-regional control (82.0% vs. 91.8%) and shorter time to loco-regional failure (8.4 months vs. 20.7 months) than low risk patients. The minimum dose delivered in the volume surrounding the GTV affected the model predictive power. The model remained predictive for patients who received less than 31 Gy in that volume. For patients who received larger doses, the MDE risk classification was not significant. CONCLUSIONS: The results show that MDEs are, at least partially, responsible of loco-regional failure in highly conformal radiotherapy. This information could be used to optimize dose distributions.

Effect of respiratory motion on radiation dose to the margin of target volume in stereotactic body radiotherapy for lung cancer / 中华放射肿瘤学杂志

Objective To investigate the effect of respiratory motion on inadvertent irradiation dose (ⅡD)to the microscopic disease(MD)and expanding margin of target volume in stereotactic body radiotherapy for lung cancer. Methods Based on the pattern of respiration-induced tumor motion during lung radiotherapy, a probability model of MD entry into or exit from internal target volume(ITV)was established and the theoretical dose to MD was calculated according to the static dose distribution by four-dimensional computed tomography. The experimental dose to MD during respiratory motion was measured using a respiration simulation phantom and optically stimulated luminescence(OSL)and then compared with the theoretical value for model validation.Results For the target volume in periodic motion,the deviation of the theoretical dose to MD from the experimental value measured by OSL was less than 5%. A 10-mm margin around ITV received a biological dose higher than 80 Gy. Conclusions The dose model established in this study can accurately predict the irradiation dose to MD in the target volume in periodic motion. Respiratory motion increases ⅡD to MD and there is no need to expand clinical target volume.