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1.  How do surgeons decide to refer patients for adjuvant cancer treatment? Protocol for a qualitative study 
Background
Non-small cell lung cancer, breast cancer, and colorectal cancer are commonly diagnosed cancers in Canada. Patients diagnosed with early-stage non-small cell lung, breast, or colorectal cancer represent potentially curable populations. For these patients, surgery is the primary mode of treatment, with (neo)adjuvant therapies (e.g., chemotherapy, radiotherapy) recommended according to disease stage. Data from our research in Nova Scotia, as well as others’, demonstrate that a substantial proportion of non-small cell lung cancer and colorectal cancer patients, for whom practice guidelines recommend (neo)adjuvant therapy, are not referred for an oncologist consultation. Conversely, surveillance data and clinical experience suggest that breast cancer patients have much higher referral rates. Since surgery is the primary treatment, the surgeon plays a major role in referring patients to oncologists. Thus, an improved understanding of how surgeons make decisions related to oncology services is important to developing strategies to optimize referral rates. Few studies have examined decision making for (neo)adjuvant therapy from the perspective of the cancer surgeon. This study will use qualitative methods to examine decision-making processes related to referral to oncology services for individuals diagnosed with potentially curable non-small cell lung, breast, or colorectal cancer.
Methods
A qualitative study will be conducted, guided by the principles of grounded theory. The study design is informed by our ongoing research, as well as a model of access to health services. The method of data collection will be in-depth, semi structured interviews. We will attempt to recruit all lung, breast, and/or colorectal cancer surgeons in Nova Scotia (n ≈ 42), with the aim of interviewing a minimum of 34 surgeons. Interviews will be audiotaped and transcribed verbatim. Data will be collected and analyzed concurrently, with two investigators independently coding and analyzing the data. Analysis will involve an inductive, grounded approach using constant comparative analysis.
Discussion
The primary outcomes will be (1) identification of the patient, surgeon, institutional, and health-system factors that influence surgeons’ decisions to refer non-small cell lung, breast, and colorectal cancer patients to oncology services when consideration for (neo)adjuvant therapy is recommended and (2) identification of potential strategies that could optimize referral to oncology for appropriate individuals.
doi:10.1186/1748-5908-7-102
PMCID: PMC3503754  PMID: 23098262
Cancer; Surgeon; Referral rates; Qualitative methods; Grounded theory
2.  Overexpression of epithelial growth factor receptor (EGFR) predicts better response to neo-adjuvant chemotherapy in patients with triple-negative breast cancer 
Journal of Translational Medicine  2012;10(Suppl 1):S4.
Background
Triple negative breast cancer (TNBC) occurs in approximately 10% to 25% of all patients with breast cancer and is associated with poor prognosis. Neo-adjuvant chemotherapy has been reported to produce a higher pathologic complete response (pCR) rate in TNBC. If pCR is achieved, patients with TNBC had a similar survival with non-TNBC patients. The aim of our study was to investigate the protein expression of epithelial growth factor receptor (EGFR) and response to neo-adjuvant chemotherapy and clinical outcome in patients with TNBC compared with non-TNBC.
Methods
A total of 198 locally advanced breast cancer patients who received neo-adjuvant chemotherapy were studied. Immunohistochemistry (IHC) was carried out to detect the protein expression of EGFR in tumor samples. Clinical and pathological parameters, pCR rate and survival data were compared between 40 TNBCs and 158 non-TNBCs.
Results
In 198 cases who received neo-adjuvant chemotherapy, significant differences exist in surgical therapy (P=0.005) and pCR rate (P=0.012) between patients with TNBCs and non-TNBCs. Overexpression of EGFR was significantly associated with pCR rate in patients with TNBCs (P < 0.001). Survival analysis revealed that patients with TNBCs had worse DFS and OS than those with non-TNBCs (P = 0.001, P < 0.001 respectively). Furthermore, for patients with non-TNBCs, those who acheived pCR had better DFS and OS than those who acheived RD (both P < 0.001).
Conclusions
Our results suggested that patients with TNBCs had increased pCR rates compared with non-TNBC. Overexpression of EGFR predicted better response to neo-adjuvant chemotherapy in patients with TNBCs.
doi:10.1186/1479-5876-10-S1-S4
PMCID: PMC3445857  PMID: 23046633
3.  WSG ADAPT – adjuvant dynamic marker-adjusted personalized therapy trial optimizing risk assessment and therapy response prediction in early breast cancer: study protocol for a prospective, multi-center, controlled, non-blinded, randomized, investigator initiated phase II/III trial 
Trials  2013;14:261.
Background
Adjuvant treatment decision-making based on conventional clinical/pathological and prognostic single molecular markers or genomic signatures is a therapeutic area in which over-/under-treatment are still key clinical problems even though substantial and continuous improvement of outcome has been achieved over the past decades. Response to therapy is currently not considered in the decision-making procedure.
ADAPT is one of the first new generation (neo)adjuvant trials dealing with individualization of (neo)adjuvant decision-making in early breast cancer and aims to establish early predictive surrogate markers, e.g., Ki-67, for therapy response under a short induction treatment in order to maximally individualize therapy and avoid unnecessary toxicity by ineffective treatment.
Methods/design
The prospective, multi-center, controlled, non-blinded, randomized, investigator initiated phase II/III ADAPT trial has an innovative “umbrella” protocol design. The “umbrella” is common for all patients, consisting of dynamic testing of early therapy response. ADAPT will recruit 4,936 patients according to their respective breast cancer subtype in four distinct sub-trials at 80 trial sites in Germany; 4,000 patients with hormone receptor positive (HR+) and HER2 negative disease will be included in the ADAPT HR+/HER2- sub-trial, where treatment decision is based on risk assessment and therapy response to induction therapy, and 380 patients will be included in ADAPT HER2+/HR+. A further 220 patients will be included in ADAPT HER2+/HR- and 336 patients will be recruited for ADAPT Triple Negative. These three sub-trials focus on identification of early surrogate markers for therapy success in the neoadjuvant setting. Patients will be allocated to the respective sub-trial according to the result of their diagnostic core biopsy, as reported by local/central pathology for HR and HER2 status.
Discussion
Recent trials, such as the GeparTrio, have shown that response-guided therapy using clinical response may improve outcome. For chemotherapy or HER2-targeted treatment, pathologic complete response in a neoadjuvant setting is an excellent predictor of outcome. For endocrine therapy, response to short induction treatment – as defined by decrease in tumor cell proliferation – strongly correlates with outcome. ADAPT now aims to combine static prognostic and dynamic predictive markers, focusing not just on single therapeutic targets, but also on general markers of proliferation and cell death. Biomarker analysis will help to optimize selection of subtype-specific treatment.
Trial registration
ClinicalTrials.gov: ADAPT Umbrella: NCT01781338; ADAPT HR+/HER2-: NCT01779206; ADAPT HER2+/HR+: NCT01745965; ADAPT HER2+/HR-: NCT01817452; ADAPT TN:NCT01815242.
doi:10.1186/1745-6215-14-261
PMCID: PMC3765940  PMID: 23958221
ADAPT; Biomarker; Early breast cancer; Investigator initiated trial
4.  Benefit risk assessment and update on the use of docetaxel in the management of breast cancer 
The objective of this paper is to review the data supporting the use of docetaxel in the treatment of breast cancer, focusing on pharmacokinetics, efficacy in adjuvant and metastatic trials alone and in combination with chemotherapeutic and targeted agents, and the toxicity of docetaxel in comparison to paclitaxel. Docetaxel is a semisynthetic product derived from the European yew tree Taxus baccata L. It promotes the assembly of microtubules, stabilizes them, and thereby prevents their depolymerization. Docetaxel has been incorporated into neo-adjuvant chemotherapy regimens, both with and without anthracyclines. The inclusion of taxanes such as docetaxel in polychemotherapy regimens in early breast cancer is associated with a statistically significant reduction in mortality. As a single agent, docetaxel is highly active in the treatment of metastatic breast cancer. In first-line treatment of metastatic breast cancer, the combination of docetaxel and capecitabine was associated with an improvement in overall survival; however, toxicity was higher. The toxicity profile of docetaxel has been well documented and is predictable; the most frequent adverse effects are neutropenia and febrile neutropenia. Taxane-specific adverse effects, such as peripheral neuropathy, are also expected but are manageable with appropriate dosing and scheduling.
doi:10.2147/CMAR.S49321
PMCID: PMC3798099  PMID: 24143122
taxanes; docetaxel; clinical trial; adverse effects; peripheral neuropathy; neutropenia
5.  Randomized Trial Using Gonadotropin-Releasing Hormone Agonist Triptorelin for the Preservation of Ovarian Function During (Neo)Adjuvant Chemotherapy for Breast Cancer 
Journal of Clinical Oncology  2012;30(5):533-538.
Purpose
Chemotherapy-induced amenorrhea is a serious concern for women undergoing cancer therapy. This prospective randomized trial evaluated the use of gonadotropin-releasing hormone (GnRH) analog triptorelin to preserve ovarian function in women treated with chemotherapy for early-stage breast cancer.
Patients and Methods
Premenopausal women age 44 years or younger were randomly assigned to receive either triptorelin or no triptorelin during (neo)adjuvant chemotherapy and were further stratified by age (< 35, 35 to 39, > 39 years), estrogen receptor status, and chemotherapy regimen. Objectives included the resumption of menses and serial monitoring of follicle-stimulating hormone (FSH) and inhibin A and B levels.
Results
Targeted for 124 patients with a planned 5-year follow-up, the trial was stopped for futility after 49 patients were enrolled (median age, 39 years; range, 21 to 43 years); 47 patients were treated according to assigned groups with four cycles of adriamycin plus cyclophosphamide alone or followed by four cycles of paclitaxel or six cycles of fluorouracil, epirubicin, and cyclophosphamide. Menstruation resumed in 19 (90%) of 21 patients in the control group and in 23 (88%) of 26 in the triptorelin group (P= .36). Menses returned after a median of 5.8 months (range, 1 to 19 months) after completion of chemotherapy in the triptorelin versus 5.0 months (range, 0 to 28 months) in the control arm (P= .58). Two patients (age 26 and 35 years at random assignment) in the control group had spontaneous pregnancies with term deliveries. FSH and inhibin B levels correlated with menstrual status.
Conclusion
When stratified for age, estrogen receptor status, and treatment regimen, amenorrhea rates on triptorelin were comparable to those seen in the control group.
doi:10.1200/JCO.2011.34.6890
PMCID: PMC3295555  PMID: 22231041
6.  Sentinel lymph node biopsy using dye alone method is reliable and accurate even after neo-adjuvant chemotherapy in locally advanced breast cancer - a prospective study 
Background
Sentinel lymph node biopsy (SLNB) is now considered a standard of care in early breast cancers with N0 axillae; however, its role in locally advanced breast cancer (LABC) after neo-adjuvant chemotherapy (NACT) is still being debated. The present study assessed the feasibility, efficacy and accuracy of sentinel lymph node biopsy (SLNB) using "dye alone" (methylene blue) method in patients with LABC following NACT.
Materials and methods
Thirty, biopsy proven cases of LABC that had received three cycles of neo-adjuvant chemotherapy (cyclophosphamide, adriamycin, 5-fluorouracil) were subjected to SLNB (using methylene blue dye) followed by complete axillary lymph node dissection (levels I-III). The sentinel node(s) was/were and the axilla were individually assessed histologically. The SLN accuracy parameters were calculated employing standard definitions. The SLN identification rate in the present study was 100%. The sensitivity of SLNB was 86.6% while the accuracy was 93.3%, which were comparable with other studies done using dual lymphatic mapping method. The SLN was found at level I in all cases and no untoward reaction to methylene blue dye was observed.
Conclusions
This study confirms that SLNB using methylene blue dye as a sole mapping agent is reasonably safe and almost as accurate as dual agent mapping method. It is likely that in the near future, SLNB may become the standard of care and provide a less morbid alternative to routine axillary lymph node dissection even in patients with LABC that have received NACT.
doi:10.1186/1477-7819-9-19
PMCID: PMC3041688  PMID: 21396137
7.  Inflammatory breast cancer: is it really a separate entity? 
ecancermedicalscience  2012;6:250.
Background
Inflammatory breast cancer (IBC) is the most aggressive form of primary breast carcinoma and is associated with a dismal outcome despite the availability of multi-modality treatment options.
Patients and methods
This is a prospective case control study comparing two groups of newly diagnosed patients; the first with inflammatory breast cancer (IBC) and the second with locally advanced non inflammatory breast cancer (LABC). In both groups MIB1, ER, PR, Her2neu were assessed. Neo-adjuvant chemotherapy consisted of four cycles of FEC100 followed by modified radical mastectomy according to clinical response, postoperative chemotherapy with two courses of the same regimen followed by radiotherapy. Tamoxifen 20 mg po daily for 5 years in ER and/or PR positive tumours, starting after the completion of radiotherapy. Primary end points were a) comparison of MIB-1 score in both groups, b) comparison of clinical and pathological responses in both groups. Secondary endpoints were comparison of progression free survival and overall survival.
Results
From a total of 42 patients, 21 were stage III B (T4d, N0-2 M0) IBC and 21 were stage III B (T4a-c, N0-2, M0) LABC. Patients in the age range from 28 to 68 were included and followed from November 2007 until February 2010 with a median follow-up period of 22.5 months. Toxicity of both arms, mainly haematologic, nausea and vomiting, was in general acceptable with no treatment-related deaths. Of the patients with IBC 81.3% had a high MIB-1 score as compared with 43.8% of patients with LABC (P-value = 0.028). Objective clinical response to neo-adjuvant chemotherapy in the IBC arm was 57.1% (4.8% complete response (CR)) as compared with 81% (9.5% CR) in LABC (P-value = 0.09). Overall pathological response (complete pathological response (pCR)+partial pathological response (pPR)) was 35.3% in the IBC arm compared with 40% in LABC arm (P-value = 0.618). One year, 2 year and median progression free survival (PFS) were 55.87%, 37.71% and 21.7 months, respectively in the IBC arm compared with 85.71%, 66.67% in LABC (median PFS was not reached) (P-value = 0.072). One and 2 year overall survival (OS) were 69.82% and 51.20%, respectively in the IBC arm compared with 95.24% and 95.24% in LABC arm (P-value = 0.0038).
Conclusions
IBC should be considered as a separate entity. A high MIB-1 score is a potential molecular marker for IBC.
doi:10.3332/ecancer.2012.250
PMCID: PMC3345939  PMID: 22570674
8.  Neo-adjuvant chemotherapy in early stage non-small cell lung cancer 
Journal of Thoracic Disease  2013;5(Suppl 4):S446-S448.
Lung cancer treatment has evolved during the last decade from the non-specific cytotoxic drugs to targeted therapy. New diagnostic equipment such as the endobronchial ultrasound bronchoscopy and positron emission tomography has enhanced early lung cancer diagnosis. However; we still need additional novel biomarkers to assist the already used diagnostic techniques. Surgery is the still the best treatment for early lung cancer treatment. Several surgical techniques are being used based on the tumour location and cardiothoracic centre’s experienced. There are however marginal situations where neo-adjuvant chemotherapy provides a “pre-step” for the patient. In the current work we will provide current data for the patients needing neo-adjuvant chemotherapy before proceeding to curative surgery.
doi:10.3978/j.issn.2072-1439.2013.07.36
PMCID: PMC3791501  PMID: 24102019
Lung cancer; neo-adjuvant; early stage
9.  Neoadjuvant chemotherapy in breast cancer: early response prediction with quantitative MR imaging and spectroscopy 
British Journal of Cancer  2006;94(3):427-435.
A prospective study was undertaken in women undergoing neoadjuvant chemotherapy for locally advanced breast cancer in order to determine the ability of quantitative magnetic resonance imaging (MRI) and proton spectroscopy (MRS) to predict ultimate tumour response (percentage decrease in volume) or to detect early response. Magnetic resonance imaging and MRS were carried out before treatment and after the second of six treatment cycles. Pharmacokinetic parameters were derived from T1-weighted dynamic contrast-enhanced MRI, water apparent diffusion coefficient (ADC) was measured, and tissue water : fat peak area ratios and water T2 were measured using unsuppressed one-dimensional proton spectroscopic imaging (30 and 135 ms echo times). Pharmacokinetic parameters and ADC did not detect early response; however, early changes in water : fat ratios and water T2 (after cycle two) demonstrated substantial prognostic efficacy. Larger decreases in water T2 accurately predicted final volume response in 69% of cases (11/16) while maintaining 100% specificity and positive predictive value. Small/absent decreases in water : fat ratios accurately predicted final volume non-response in 50% of cases (3/6) while maintaining 100% sensitivity and negative predictive value. This level of accuracy might permit clinical application where early, accurate prediction of non-response would permit an early change to second-line treatment, thus sparing patients unnecessary toxicity, psychological morbidity and delay of initiation of effective treatment.
doi:10.1038/sj.bjc.6602948
PMCID: PMC2361138  PMID: 16465174
breast neoplasms; chemotherapy; magnetic resonance; MR; spectroscopy; contrast enhancement; diffusion study
10.  Comparing Efficacy of Preoperative neo-Adjuvant Chemotherapy and Surgery versus Surgery Alone in Patients with Resectable Gastroesophageal Cancer 
Background
Recent researches have led to find strategies to prevent relapse and to improve survival for gastric cancer patients, including preoperative neo-adjuvant approaches. However, the efficacy of some neo-adjuvant regimens including 5-fluorouracil, cisplatin, and docetaxel have been less investigated. The present study evaluated the outcome and mid-term survival of patients with gastric cancer who undergoing this regimen.
Methods
In a randomized double-blinded controlled trial performed at the Firoozgar hospital in Tehran in 2011-12, 61 patients were randomly assigned to treatment (32 to neo-adjuvant chemotherapy with docetaxel, cisplatin and 5-fluorouracil (5-FU) before surgery and 27 to surgery alone). The present study tried to assess the efficacy of neoadjuvant chemotherapy regarding improvement of mid-term survival, complications, and R0 resection status.
Results
The two groups were matched in terms of gender, mean age, cancer location, and TNM staging. However, R0 resection in the former group was 85.7%; while this indicator in the isolated surgery group was significantly lower (61.5%). Regarding WHO performance, no significant difference was observed across the two groups. Patients in neo-adjuvant chemotherapy group were followed for mean follow-up time 10.32 months and those who categorized in isolated surgery group were followed for mean follow-up time 10.88 months. Mid-term mortality rate in the two groups was 14.3% and 15.4%, respectively (p = 0.866). In this regard, 3-, 6-, and 9-month survival rate in neo-adjuvant chemotherapy group was 96.4%, 89.3%, and 85.7%, respectively. These survival rates in the surgery group were 92.3%, 88.5%, and 84.6%, respectively. Multivariable logistic regression analysis showed that among all study variables, only R0 resection status could predict mid-term mortality.
Conclusion
Neo-adjuvant chemotherapy and surgery compare to surgery alone more improve R0 resection status, but mid-term survival rate is similar in the two regiments. R0 resection status can effectively predict appropriate mid-term survival in undertreated patients.
PMCID: PMC3915424  PMID: 24505539
Gastroesophageal junction; Mortality; Chemotherapy; Surgery
11.  Innovations in chemotherapy and radiation therapy: Implications and opportunities for the Asia-Pacific Rim 
New cases of invasive cancer in the United States occur among nearly 1.5 million people annually. In 2007, more than 1,500 people died per day with this diagnosis. Cancer is responsible for nearly one in every four deaths reported in the country. Enormous amounts of money and research have been, and are being spent, in an attempt to improve these numbers. While prevention and early detection remain the key to long-term success, treatment in the neo-adjuvant, adjuvant and metastatic settings still centre around two main treatment modalities – radiation therapy and chemotherapy. This article will review the advances that have been made in both areas that are making these treatments more precise and convenient, as well as less toxic, for the patient. In the field of radiation therapy this involves the development of new therapy planning and delivery systems, such as intensity-modulated radiation therapy (IMRT), and positron emission and computed tomography, PET-CT. Chemotherapy has also evolved with the development of targeted chemotherapy for the treatment of specific malignancies as well as improved supportive care agents which allow for the administration of dose-dense chemotherapy when appropriate.
doi:10.2349/biij.4.3.e40
PMCID: PMC3097728  PMID: 21611006
Cancer; radiation therapy; chemotherapy; supportive care
12.  Patients' preferences for adjuvant chemotherapy in early-stage breast cancer: is treatment worthwhile? 
British Journal of Cancer  2001;84(12):1577-1585.
When making decisions about adjuvant chemotherapy for early-stage breast cancer, costs and benefits of treatment should be carefully weighed. In this process, patients' preferences are of major importance. The objectives of the present study were: (1) to determine the minimum benefits that patients need to find chemotherapy acceptable, and (2) to explore potential preference determinants, namely: positive experience of the treatment, reconciliation with the treatment decision, and demographic variables. Preferences were elicited from patients scheduled for adjuvant chemotherapy (chemotherapy group: n = 38) before (T 1), during (T 2), and 1 month after chemotherapy (T 3), and were compared to responses from patients not scheduled for chemotherapy (no-chemotherapy group: n = 38). The patients were asked, for a hypothetical situation, to indicate the minimum benefit (in terms of improved 5-year disease-free survival) to find adjuvant chemotherapy acceptable. In the chemotherapy group, the median benefit was 1% at all 3 measurement points. In the no-chemotherapy group the attitude towards chemotherapy became more negative over time, although not statistically significantly so (T 1: 12%, T 2: 15%, T 3: 15%;P = 0.10). At all measurement points, the patients in the chemotherapy group indicated that they would accept chemotherapy for significantly (P< 0.01) less benefit than the patients in the no-chemotherapy group. Of the demographic variables, age was related to preferences, but only at T 2 and only in the no-chemotherapy group. The more positive attitude towards chemotherapy and the stability of preferences in the chemotherapy group indicated that reconciliation with the treatment decision was a more important determinant of patients' preferences than positive experience of the treatment. © 2001 Cancer Research Campaign http://www.bjcancer.com
doi:10.1054/bjoc.2001.1836
PMCID: PMC2363690  PMID: 11401308
preferences; breast cancer; chemotherapy; cognitive dissonance reduction; shared decision-making
13.  Breast cancer in the elderly—Should it be treated differently? 
Breast cancer risk increases with age and about a third of female breast cancers are diagnosed in patients aged older than 70. Breast cancer in the elderly has, however, poorer outcome with lower survival rate compared to younger subjects. This may be partly explained by the delay in diagnosis and the ‘under-treatment’ of elderly breast cancer patients. In this review I try to provide recommendations for screening, surgery, radiotherapy, (neo)adjuvant hormone treatment and chemotherapy, and also the treatment of metastatic disease. Since large randomised trials usually exclude elderly patients with breast cancer, there is still an insufficient evidence for the treatment of such patients.
doi:10.1016/j.rpor.2012.05.005
PMCID: PMC3863252  PMID: 24381744
Breast cancer; Cancer treatment; Elderly; Old age
14.  Clinical and immunological assessment in breast cancer patients receiving anticancer therapy and bovine dialyzable leukocyte extract as an adjuvant 
Dialyzable leukocyte extract (DLE) is one of the immunological agents used as an adjuvant in cancer therapy; it has been associated with improved quality of life during cancer chemotherapy. Based on these previous findings and on the observed clinical benefits attributed to DLE in other types of cancer, we investigated its clinical and immunological effects as a therapy adjuvant on breast cancer patients who received only chemotherapy, as compared to patients administered bovine DLE (bDLE) as an adjuvant. This study included 43 breast cancer patients who were about to begin chemotherapy. This group was divided as follows: 25 received chemotherapy and bDLE as an adjuvant therapy, and 18 received only chemotherapy without the adjuvant. All patient clinical and immunological responses were monitored. Among patients in the group that received bDLE as adjuvant, 60% showed a complete response, 32% showed a partial response and 8% did not respond. By contrast, in the group without the adjuvant, 39% showed a complete response, 50% displayed a partial response and 11% were non-responders. In addition, bDLE treatment in combination with chemotherapy resulted in the enhancement of the Karnofsky performance scale during chemotherapy. Even though patients underwent several cycles of chemotherapy without bDLE, the lymphocyte population dropped to below the reference value. On the other hand, in patients with bDLE as adjuvant, the CD4+ and CD8+ lymphocytes and the B lymphocytes were maintained within the median range of the reference value. The number of natural killer cells also increased after chemotherapy treatment with bDLE as an adjuvant. In conclusion, bDLE treatment contributes to significant immunological recovery in patients that have undergone heavy chemotherapy, increasing the clinical response and quality of life during chemotherapy.
doi:10.3892/etm_00000066
PMCID: PMC3445885  PMID: 22993557
dialyzable leukocyte extract; immunotherapy agent; clinical response; Karnofsky performance scale
15.  Predicting the response of localised oesophageal cancer to neo-adjuvant chemoradiation 
Background
A complete pathological response to neo-adjuvant chemo-radiation for oesophageal cancer is associated with favourable survival. However, such a benefit is seen in the minority. If one could identify, at diagnosis, those patients who were unlikely to respond unnecessary toxicity could be avoided and alternative treatment can be considered. The aim of this review was to highlight predictive markers currently assessed and evaluate their clinical utility.
Methods
A systematic search of Pubmed and Google Scholar was performed using the following keywords; "neo-adjuvant", "oesophageal", "trimodality", "chemotherapy", "radiotherapy", "chemoradiation" and "predict". The original manuscripts were sourced for further articles of relevance.
Results
Conventional indices including tumour stage and grade seem unable to predict histological response. Immuno-histochemical markers have been extensively studied, but none has made its way into routine clinical practice. Global gene expression from fresh pre-treatment tissue using cDNA microarray has only recently been assessed, but shows considerable promise. Molecular imaging using FDG-PET seems to be able to predict response after neo-adjuvant chemoradiation has finished, but there is a paucity of data when such imaging is performed earlier.
Conclusion
Currently there are no clinically useful predictors of response based on standard pathological assessment and immunohistochemistry. Genomics, proteomics and molecular imaging may hold promise.
doi:10.1186/1477-7819-5-97
PMCID: PMC1999497  PMID: 17716369
16.  Clinical efficacy of local targeted chemotherapy for triple-negative breast cancer 
Radiology and Oncology  2011;45(2):123-128.
Background
The aim of the study was to evaluate the clinical efficacy of superselective intra-arterial targeted neo-adjuvant chemotherapy in the treatment of estrogen receptor (ER)-negative, progesterone receptor (PR)-negative, and human epidermal growth factor receptor 2 (HER2)-negative (triple-negative) breast cancer.
Patients and methods.
A total of 47 triple-negative breast cancer patients (29 at stage II, 13 at stage III and 5 at stage IV) were randomly assigned to two groups: targeted chemotherapy group (n=24) and control group (n=23). Patients in the targeted chemotherapy group received preoperative superselective intra-arterial chemotherapy with CEF regimen (C: cyclophosphamide [600 mg/m2]; E: epirubicin [90 mg/m2]; F: 5-fluorouracil [600 mg/m2]), and those in the control group received routine neoadjuvant chemotherapy with CEF. The duration of the treatment, changes in lesions and the prognosis were determined.
Results
The average course of the treatment was 15 days in the targeted chemotherapy group which was significantly shorter than that in the control group (31 days) (P<0.01). The remission rate of lesions was 91.6% in the targeted chemotherapy group and 60.9% in the control group, respectively. Among these patients, 9 died within two years, including 2 (both at IV stage) in the targeted chemotherapy group and 7 (2 at stage II, 4 at stage III and 1 at stage IV) in the control group.
Conclusions
As an neoadjuvant therapy, the superselective intra-arterial chemotherapy is effective for triple-negative breast cancer, with advantages of the short treatment course and favourable remission rates as well as prognoses.
doi:10.2478/v10019-011-0014-7
PMCID: PMC3423732  PMID: 22933945
triple-negative breast cancer; targeted chemotherapy; prognosis
17.  A central review of histopathology reports after breast cancer neoadjuvant chemotherapy in the neo-tango trial 
British Journal of Cancer  2013;108(4):866-872.
Background:
Neo-tAnGo, a National Cancer Research Network (NCRN) multicentre randomised neoadjuvant chemotherapy trial in early breast cancer, enroled 831 patients in the United Kingdom. We report a central review of post-chemotherapy histopathology reports on the surgical specimens, to assess the presence and degree of response.
Methods:
A central independent two-reader review (EP and HME) of histopathology reports from post-treatment surgical specimens was performed. The quality and completeness of pathology reporting across all centres was assessed. The reviews included pathological response to chemotherapy (pathological complete response (pCR); minimal residual disease (MRD); and lesser degrees of response), laterality, the number of axillary metastases and axillary nodes, and the type of surgery. A consensus was reached after discussion.
Results:
In all, 825 surgical reports from 816 patients were available for review. Out of 4125 data items there were 347 discrepant results (8.4% of classifications), which involved 281 patients. These involved grading of breast response (169 but only 9 involving pCR vs MRD); laterality (6); presence of axillary metastasis (35); lymph node counts (108); and type of axillary surgery (29). Excluding cases with pCR, only 45% of reports included any comment regarding response in the breast and 30% in the axillary lymph nodes.
Conclusion:
We found considerable variability in the completeness of reporting of surgical specimens within this national neoadjuvant breast cancer trial. This highlights the need for consensus guidelines among trial groups on histopathology reporting, and the participation of histopathologists throughout the development and analysis of neoadjuvant trials.
doi:10.1038/bjc.2012.547
PMCID: PMC3590651  PMID: 23299526
breast cancer; neoadjuvant chemotherapy; clinical trials; histopathology
18.  Response Prediction to Neoadjuvant Chemotherapy: Comparison between Pre-Therapeutic Gene Expression Profiles and In Vitro Chemosensitivity Assay 
PLoS ONE  2013;8(6):e66573.
Although the use of (neo-)adjuvant chemotherapy in breast cancer patients has resulted in improved outcome, not all patients benefit equally. We have evaluated the utility of an in vitro chemosensitivity assay in predicting response to neoadjuvant chemotherapy. Pre-therapeutic biopsies were obtained from 30 breast cancer patients assigned to neoadjuvant epirubicin 75 mg/m2 and docetaxel 75 mg/m2 (Epi/Doc) in a prospectively randomized clinical trial. Biopsies were subjected to a standardized ATP-based Epi/Doc chemosensitivity assay, and to gene expression profiling. Patients then received 3 cycles of chemotherapy, and response was evaluated by changes in tumor diameter and Ki67 expression. The efficacy of Epi/Doc in vitro was correlated with differential changes in tumor cell proliferation in response to Epi/Doc in vivo (p = 0.0011; r = 0.73670, Spearmańs rho), but did not predict for changes in tumor size. While a pre-therapeutic gene expression signature identified tumors with a clinical response to Epi/Doc, no such signature could be found for tumors that responded to Epi/Doc in vitro, or tumors in which Epi/Doc exerted an antiproliferative effect in vivo. This is the first prospective clinical trial to demonstrate the utility of a standardized in vitro chemosensitivity assay in predicting the individual biological response to chemotherapy in breast cancer.
doi:10.1371/journal.pone.0066573
PMCID: PMC3691196  PMID: 23826101
19.  Hormone receptor status and pathologic response of HER2-positive breast cancer treated with neoadjuvant chemotherapy and trastuzumab 
Annals of Oncology  2008;19(12):2020-2025.
Background: The aim of this study was to compare the extent of pathologic response in patients with HER2-positive (HER2+) breast cancer treated with standard neoadjuvant chemotherapy, with or without trastuzumab (H), according to hormone receptor (HR) status.
Patients and methods: We included 199 patients with HER2+ breast cancer from three successive cohorts of neo-adjuvant chemotherapy on the basis of paclitaxel (Taxol) (P) administered weekly (w) or three weekly (3-w), followed by 5-fluorouracil (F), doxorubicin (A) or epirubicin (E), and cyclophosphamide (C). Residual cancer burden (RCB) was determined from pathologic review of the primary tumor and lymph nodes and was classified as pathologic complete response (pCR) or minimal (RCB-I), moderate (RCB-II), or extensive (RCB-III) residual disease.
Results: In HR-positive (HR+) cancers, a higher rate of pathologic response (pCR/RCB-I) was observed with concurrent H + 3-wP/FEC (73%) than with 3-wP/FEC (34%, P = 0.002) or wP/FAC (47%; P = 0.02) chemotherapy alone. In HR-negative (HR−) cancers, there were no significant differences in the rate of pathologic response (pCR/RCB-I) from 3-wP/FAC (50%), wP/FAC (68%), or concurrent H + 3-wP/FEC (72%).
Conclusions: Patients with HR+/HER2+ breast cancer obtained significant benefit from addition of trastuzumab to P/FEC chemotherapy; pathologic response rate was similar to that seen in HR−/HER2+ breast cancers.
doi:10.1093/annonc/mdn427
PMCID: PMC2733116  PMID: 18667396
breast cancer; HER2; hormone receptor status; neoadjuvant chemotherapy; trastuzumab
20.  Mammography Screening and Treatment of Breast Cancer in the Elderly 
Breast Care  2008;3(3):177-182.
Summary
Breast cancer patients of an advanced age will suffer from ailments related to both senescence and cancer. Some will have been denied access to screening programmes and will present with an advanced disease. Many will need the expertise of the geriatrician and the oncologist who will participate in specific case discussions to look at social and medical issues that will affect the treatment plan (with questions regarding surgery, radiation, drug therapy, rehabilitation, supportive care, and palliative care often intertwined). This paper reviews recommendations by the International Society of Geriatric Oncology (SIOG) task force which recently assessed the available evidence on breast cancer in elderly individuals, and provided evidence-based recommendations for the diagnosis and treatment of breast cancer in such individuals. Recommendations on the topics of screening, surgery, radiotherapy, (neo)adjuvant hormone treatment, and chemotherapy, and on metastatic disease have been given. Oncologists are now learning to take into account the physiological age of their patient, which is the reflection of a normal and sometimes abnormally accelerated loss of body reserves which is certainly related to chronological age but not precisely dictated by it. Understanding the biology of breast cancer will allow to optimally adapt the treatment of the elderly patient.
doi:10.1159/000137627
PMCID: PMC2931114  PMID: 20824036
Breast cancer; Elderly; Geriatric assessment; Creatinine clearance; Comorbidity
21.  Neutropenia Prediction Based on First-Cycle Blood Counts Using a FOS-3NN Classifier 
Advances in Bioinformatics  2012;2011:172615.
Background. Delivery of full doses of adjuvant chemotherapy on schedule is key to optimal breast cancer outcomes. Neutropenia is a serious complication of chemotherapy and a common barrier to this goal, leading to dose reductions or delays in treatment. While past research has observed correlations between complete blood count data and neutropenic events, a reliable method of classifying breast cancer patients into low- and high-risk groups remains elusive. Patients and Methods. Thirty-five patients receiving adjuvant chemotherapy for early-stage breast cancer under the care of a single oncologist are examined in this study. FOS-3NN stratifies patient risk based on complete blood count data after the first cycle of treatment. All classifications are independent of breast cancer subtype and clinical markers, with risk level determined by the kinetics of patient blood count response to the first cycle of treatment. Results. In an independent test set of patients unseen by FOS-3NN, 19 out of 21 patients were correctly classified (Fisher's exact test probability P < 0.00023 [2 tailed], Matthews' correlation coefficient +0.83). Conclusions. We have developed a model that accurately predicts neutropenic events in a population treated with adjuvant chemotherapy in the first cycle of a 6-cycle treatment.
doi:10.1155/2011/172615
PMCID: PMC3290820  PMID: 22454638
22.  Adjuvant Chemotherapy for Breast Cancer in a Patient with Primary Autoimmune Neutropenia 
We report an extremely rare and complex case of a 44-year-old woman diagnosed with an early stage triple negative breast cancer in the setting of primary autoimmune neutropenia with a pre-existing severe neutropenia. This case-report demonstrates that adjuvant chemotherapy for breast cancer can be administered in a patient with severe neutropenia. The management is however complicated and requires careful monitoring of side-effects related to both chemotherapy and treatment of autoimmune neutropenia. The role of chemotherapy in the treatment of triple negative breast cancer, the approach to autoimmune neutropenia and potential interactions are reviewed. To our knowledge, this is the first case reporting on the use of chemotherapy in a patient with severe pre-existing primary autoimmune neutropenia.
doi:10.4137/BCBCR.S10767
PMCID: PMC3572877  PMID: 23440399
breast cancer; autoimmune neutropenia; chemotherapy
23.  In vivo proton magnetic resonance spectroscopy of breast cancer: a review of the literature 
An emerging clinical modality called proton magnetic resonance spectroscopy (1H-MRS) enables the non-invasive in vivo assessment of tissue metabolism and is demonstrating applications in improving the specificity of MR breast lesion diagnosis and monitoring tumour responsiveness to neoadjuvant chemotherapies. Variations in the concentration of choline-based cellular metabolites, detectable with 1H-MRS, have shown an association with malignant transformation of tissue in in vivo and in vitro studies. 1H-MRS exists as an adjunct to the current routine clinical breast MR examination. This review serves as an introduction to the field of breast 1H-MRS, discusses modern high-field strength and quantitative approaches and technical considerations, and reviews the literature with respect to the application of 1H-MRS for breast cancer.
doi:10.1186/bcr3132
PMCID: PMC3446370  PMID: 22515594
24.  The presence and prognostic impact of apoptotic and nonapoptotic disseminated tumor cells in the bone marrow of primary breast cancer patients after neoadjuvant chemotherapy 
Introduction
Neoadjuvant systemic therapy of primary breast cancer (PBC) patients offers the possibility to monitor treatment response. However, patients might have metastatic relapse despite achieving a pathologic complete response (pCR). This indicates that local response to therapy must not be representative for systemic treatment efficacy. Therefore, the aim of this study was to compare local response with systemic tumor cell dissemination by determining the presence of disseminated tumor cells (DTCs), including apoptotic tumor cells, in the bone marrow (BM) of PBC patients after neoadjuvant chemotherapy (NACT).
Methods
DTCs were detected by immunocytochemistry (pancytokeratin antibody A45-B/B3) and cytomorphology (DTC status). The presence of apoptotic tumor cells was determined by using the M30 antibody (M30 status). This antibody detects a neo-epitope that is expressed only during early apoptosis.
Results
BM aspirates from 400 PBC patients that had completed NACT were eligible for this study. Of these, 167 (42%) patients were DTC positive (DTC status). The M30 status was investigated in 308 patients. Apoptotic (M30-positive) tumor cells were detected in 89 (29%) of these. Whereas the DTC status was not correlated (P = 0.557) to local treatment response (that is, pCR or a clinical complete/partial response), the presence of M30-positive tumor cells was significantly higher in patients that responded to therapy (P = 0.026). Additionally, DTC-positive patients were at an increased risk for disease relapse (hazard ratio, 1.87; 95% CI, 1.11 to 3.15; P = 0.019).
Conclusion
The presence of DTC is independent of therapy response of the primary tumor. As patients that are DTC positive after NACT have an unfavorable outcome, they might benefit from additional systemic treatment.
doi:10.1186/bcr3496
PMCID: PMC3978634  PMID: 24099325
25.  Use of Oncotype DX in Women with Node-Positive Breast Cancer 
PLoS Currents  2011;3:RRN1249.
Women with early stage breast cancer frequently receive adjuvant chemotherapy to prevent recurrence; however, not all patients benefit. Recently, gene expression marker panels, such as Oncotype DX, that may better predict risk of breast cancer recurrence have become commercially available and are being used to guide treatment decisions. Oncotype DX analyzes the expression of 21 genes within a tumor to determine a recurrence score that corresponds to a specific likelihood of breast cancer recurrence within 10 years of the initial diagnosis, as well as response to adjuvant treatment. We examined the published literature on the analytic validity, clinical validity, and clinical utility of Oncotype DX in guiding adjuvant treatment decisions in women with lymph node-positive breast cancer.
doi:10.1371/currents.RRN1249
PMCID: PMC3145540  PMID: 21984342

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