Increasing the Rates of Complete Response to Neoadjuvant Chemoradiotherapy for Distal Rectal Cancer: Results of a Prospective Study Using Additional Chemotherapy During the Resting Period

OBJECTIVES: Addition of chemotherapy in the resting period between radiotherapy completion and response assessment during neoadjuvant treatment for distal rectal cancer could potentially increase rates of complete tumor regression. The purpose of this study was to evaluate toxicity rates and the impact of an extended neoadjuvant chemoradiation regimen on complete response rates. METHODS: Thirty-four consecutive patients with nonmetastatic distal rectal cancer were prospectively included. Patients were managed by 5,400 Gy of radiation and 5-fluorouracil/leucovorin-based chemotherapy given for three consecutive days every 21 days for six cycles (three cycles concomitant with radiotherapy). Tumor response assessment was performed at ten weeks from radiation completion. Patients with complete clinical response were strictly monitored and were not immediately operated on. Patients with incomplete clinical response were referred to surgery. RESULTS: Twenty-nine patients had completed 12 months of follow-up and were included in this preliminary analysis. Twenty-eight (97%) successfully completed treatment. Fifteen of 16 patients had Grade III toxicities that were skin-related (93%). Median follow-up was 23 months. Fourteen patients (48%) were considered as complete clinical responders sustained for at least 12 months (median, 24 months) after chemoradiation completion by clinical assessment alone. An additional five patients (17%) were considered as complete responders with ypT0 results after full-thickness local excision. Overall, the complete response rate was 65%. CONCLUSIONS: The addition of chemotherapy during the resting period after neoadjuvant chemoradiation is associated with acceptable toxicity and high tolerability rates. The considerably high rates of complete response in this preliminary series requires further follow-up, but they may provide valuable information for future prospective, randomized trials.

Pathological complete response after neoadjuvant chemotherapy is an independent predictive factor irrespective of simplified breast cancer intrinsic subtypes: a landmark and two-step approach analyses from the EORTC 10994/BIG 1-00 phase III trial.

BACKGROUND: Pathological complete response (pCR) following chemotherapy is strongly associated with both breast cancer subtype and long-term survival. Within a phase III neoadjuvant chemotherapy trial, we sought to determine whether the prognostic implications of pCR, TP53 status and treatment arm (taxane versus non-taxane) differed between intrinsic subtypes. PATIENTS AND METHODS: Patients were randomized to receive either six cycles of anthracycline-based chemotherapy or three cycles of docetaxel then three cycles of eprirubicin/docetaxel (T-ET). pCR was defined as no evidence of residual invasive cancer (or very few scattered tumour cells) in primary tumour and lymph nodes. We used a simplified intrinsic subtypes classification, as suggested by the 2011 St Gallen consensus. Interactions between pCR, TP53 status, treatment arm and intrinsic subtype on event-free survival (EFS), distant metastasis-free survival (DMFS) and overall survival (OS) were studied using a landmark and a two-step approach multivariate analyses. RESULTS: Sufficient data for pCR analyses were available in 1212 (65%) of 1856 patients randomized. pCR occurred in 222 of 1212 (18%) patients: 37 of 496 (7.5%) luminal A, 22 of 147 (15%) luminal B/HER2 negative, 51 of 230 (22%) luminal B/HER2 positive, 43 of 118 (36%) HER2 positive/non-luminal, 69 of 221(31%) triple negative (TN). The prognostic effect of pCR on EFS did not differ between subtypes and was an independent predictor for better EFS [hazard ratio (HR) = 0.40, P < 0.001 in favour of pCR], DMFS (HR = 0.32, P < 0.001) and OS (HR = 0.32, P < 0.001). Chemotherapy arm was an independent predictor only for EFS (HR = 0.73, P = 0.004 in favour of T-ET). The interaction between TP53, intrinsic subtypes and survival outcomes only approached statistical significance for EFS (P = 0.1). CONCLUSIONS: pCR is an independent predictor of favourable clinical outcomes in all molecular subtypes in a two-step multivariate analysis. CLINICALTRIALSGOV: EORTC 10994/BIG 1-00 Trial registration number NCT00017095.

Pathological complete response and residual DCIS following neoadjuvant chemotherapy for breast carcinoma

Patients who have no residual invasive cancer following neoadjuvant chemotherapy for breast carcinoma have a better overall survival than those with residual disease. Many classification systems assessing pathological response to neoadjuvant chemotherapy include residual ductal carcinoma in situ (DCIS) only in the definition of pathological complete response. The purpose of this study was to investigate whether patients with residual DCIS only have the same prognosis as those with no residual invasive or in situ disease. A retrospective analysis of a prospectively maintained database identified 435 patients, who received neoadjuvant chemotherapy for operable breast cancer between February 1985 and February 2003. Of these, 30 (7%; 95% CI 5-9%) had no residual invasive disease or DCIS and 20 (5%; CI 3-7%) had residual DCIS only. With a median follow-up of 61 months, there was no statistical difference in disease-free survival, 80% (95% CI 60-90%) in those with no residual invasive or in situ disease and 61% (95% CI 35-80%) in those with DCIS only (P = 0.4). No significant difference in 5-year overall survival was observed, 93% (95% CI 75-98%) in those with no residual invasive or in situ disease and 82% (95% CI 52-94%) in those with DCIS only (P = 0.3). Due to the small number of patients and limited number of events in each group, it is not possible to draw definitive conclusions from this study. Further analyses of other databases are required to confirm our finding of no difference in disease-free and overall survival between patients with residual DCIS and those with no invasive or in situ disease following neoadjuvant chemotherapy for breast cancer.

Complete Clinical Response After Neoadjuvant Chemoradiation Therapy for Distal Rectal Cancer: Characterization of Clinical and Endoscopic Findings for Standardization

BACKGROUND: Complete tumor regression may develop after neoadjuvant chemoradiation therapy for distal rectal cancer. Studies have suggested that selected patients with complete clinical response may avoid radical surgery and close surveillance may provide good outcomes with no oncologic compromise. However, definition of complete clinical response is often imprecise and may vary between different studies. The aim of this study is to provide a clear definition for a complete clinical response after neoadjuvant chemoradiation therapy in patients with distal rectal cancer in addition to actual endoscopic videos from patients managed nonoperatively. METHODS: Patients with nonmetastatic distal rectal cancer treated by neoadjuvant chemoradiation therapy, including 50.4 Gy and concomitant 5-fluorouracil and leucovorin, were assessed for tumor response at least 8 weeks after chemoradiation therapy completion. Complete and incomplete clinical responses were defined based on clinical and endoscopic findings. Patients with complete clinical response were not immediately operated on and were closely followed. Early and late endoscopic findings were recorded. RESULTS: Definition of a complete clinical response should be based on very strict clinical and endoscopic criteria. The finding of any residual superficial ulceration, irregularity, or nodule should prompt surgical attention, including transanal full-thickness excision or even a radical resection with total mesorectal excision. Standard or incisional biopsies should be avoided in this setting. Complete clinical responders should harbor no more than whitening of the mucosa, teleangiectasia with mucosal integrity to be considered for a nonoperative approach. In the presence of these findings, regularly scheduled reassessments may provide a safe alternative to these patients with early detection of recurrent disease. CONCLUSION: Strict definition of the clinical and endoscopic findings of patients experiencing complete clinical response after neoadjuvant chemoradiation therapy may provide a useful tool for the understanding of outcomes of patients managed with no immediate surgery allowing standardization of classifications and comparison between the experiences of different institutions.

The need for effective radiosentitizing agents: experience in patients with complete pathological response

Chemoradiation therapy is now considered the preferred initial treatment strategy for distal rectal cancer because of the observation of better local disease control and significant tumor downstaging. Downstaging has become an important clinical outcome as patients with complete pathological response are associated with improved survival. Even though radiation alone may result in low local recurrence rates, the use of additional radiosensitizing agents may provide an increase in local disease control in addition to improved tumor regression rates. Several compounds have been investigated in the setting of neoadjuvant multimodality treatment of rectal cancer with variable rates of treatment-related toxicity and complete pathological response. The balance between complete pathological response and toxicity should aid in the management decision for the use of radiosensitizing agents in the neoadjuvant setting for the treatment of rectal cancer. Anti-Cancer Drugs 22: 308-310 (C) 2011 Wolters Kluwer Health | Lippincott Williams & Wilkins.

Complete Clinical Response after Neoadjuvant Chemoradiation for Distal Rectal Cancer

Multimodality treatment of rectal cancer, with the combination of radiation therapy, chemotherapy, and surgery has become the preferred approach to locally advanced rectal cancer The use of neoadjuvant chemoradiation therapy (CRT) has resulted in reduced toxicity rates, significant tumor down-sizing and downstaging, better chance of sphincter preservation, and improved functional results A proportion of patients treated with neoadjuvant CRT may ultimately develop complete clinical response Management of these patients with complete clinical response remains controversial and approaches including radical resection, transanal local excision, and observation alone without immediate surgery have been proposed The use of strict selection criteria of patients after neoadjuvant CRT has resulted in excellent long-term results with no oncological compromise after observation alone in patients with complete clinical response Recurrences are detectable by clinical assessment and frequently amenable to salvage procedures

Uveitis in celiac disease with an excellent response to gluten-free diet: third case described

To describe the case of a patient with celiac disease who achieved a complete response to a gluten-free diet. A 28-year-old woman presented with diarrhea, oral ulcers, and refractory uveitis of 2.5-years duration. She was treated with prednisone, mydriatic drops, and infliximab with no response. She was referred to our hospital at which point her previous diagnosis of uveitis was confirmed; she was also diagnosed with right-sided sacro-iliitis. The patient did not have arthritis or any skin conditions. Three tests for fecal parasites and a fecal leukocyte were negative. Endoscopy revealed atrophic appearance of the duodenal mucosa. Biopsy showed atrophy of the duodenal villi with intra-epithelial lymphocytes, hyperplasia of the crypts, and chronic inflammatory infiltrate. The search for antiendomysial antibody was > 1/1,280. The patient was started on a gluten-free diet and after 3 months demonstrated significant improvement of gastrointestinal symptoms and uveitis, as well as a reduction of antiendomysial antibodies (1/80). After 6 months, there was complete remission of gastrointestinal symptoms and total control of uveitis. The antiendomysial antibody was negative at that time. Clinical uveitis as a manifestation of celiac disease has been described in only two cases in the literature. This case study is the third to demonstrate that uveitis is a clinical symptom that can be addressed in patients with celiac disease.

Durable Complete Responses in Metastatic Colorectal Cancer Treated with Chemotherapy Alone

Background/Purpose: The median survival for patients with metastatic colorectal cancer (mCRC) has progressively increased over the past decades. Since the introduction of 5-fluorouracil (5-FU)-based chemotherapy, followed by hepatic resection of metastases, and more recently the adoption of newer chemotherapeutic regimens associated with targeted therapy, the gains are getting more substantial. Despite the recognition of the potential for long-term survival after surgical resection of metastatic disease, long-term survival data to determine the potential curative role of chemotherapy alone is lacking. Methods: We performed a retrospective review of 2751 patients who presented with mCRC at The MD Anderson Cancer Center from 1990 through 2003. Patients alive at 5 years who achieved complete response with chemotherapy and were not submitted to any surgical or interventional procedures directed to the metastatic sites were included in the analysis. Results: The 5-year overall survival rate for all patients with mCRC during this period was 10.8%. Among these long-term survivors, 2.2% achieved a sustained complete response after chemotherapy (all 6 with fluoropyrimidines and 2 with irinotecan) as the only treatment modality and were without evidence of disease until the last follow-up visit (median of 10.3 years). This number corresponds to 0.24% (6 of 2541) of all patients with mCRC included in this review. Conclusion: Cure with chemotherapy alone is possible for a very small number of patients with metastatic colorectal cancer. Improved therapies are increasing complete response rates, but the impact of modern chemotherapy on durable complete responses will require additional follow up.

The Role of Carcinoembriogenic Antigen in Predicting Response and Survival to Neoadjuvant Chemoradiotherapy for Distal Rectal Cancer

PURPOSE: Carcinoembriogenic antigen (CEA) is the most frequently used tumor marker in rectal cancer. A decrease in carcinoembriogenic antigen after radical surgery is associated with survival in these patients. Neoadjuvant chemoradiotherapy may lead to significant primary tumor downstaging, including complete tumor regression in selected patients. Therefore, we hypothesized that a decrease in CEA after neoadjuvant chemoradiotherapy could reflect tumor response to chemoradiotherapy, affecting final disease stage and ultimately survival. METHODS: Patients with distal rectal cancer managed by neoadjuvant chemoradiotherapy and available pretreatment and postchemoradiotherapy levels of CEA were eligible for the study. Outcomes studied included final disease stage, relapse, and survival, and these were compared according to initial CEA level, postchemoradiotherapy CEA level, and the reduction in CEA. RESULTS: Overall 170 patients were included. Postchemoradiotherapy CEA levels < 5 ng/ml were associated with increased rates of complete clinical response and pathologic response. Additionally, postchemoradiotherapy CEA levels < 5 ng/ml were associated with increased overall and disease-free survival (P = 0.01 and P = 0.03). There was no correlation between initial CEA level or reduction in CEA and complete response or survival. CONCLUSION: A postchemoradiotherapy CEA level < 5 ng/ml is a favorable prognostic factor for rectal cancer and is associated with increased rates of earlier disease staging and complete tumor regression. Postchemoradiotherapy CEA levels may be useful in decision making for patients who may be candidates for alterative treatment strategies.

Saturable dose-response relationships for melphalan in melanoma treatment by isolated limb infusion in the nude rat

Nude rats bearing melanomas on their hindlimbs were treated by isolated limb infusion (ILI) with increasing doses (7.5-400 mug/ml) of melphalan. The response of tumours to treatment at the end of the observation period was graded, according to diameter, as complete response (CR), partial response (PR), no change (NC) or progressive disease (PD). No linear relationship between the dose of melphalan and the tumour response was observed. All doses above a threshold of 15 mug/ml achieved a PR or CR. The achievement of CR was not related to increased dose. Two major implications arise from this work. Firstly, the typically two-to three-fold increase in cytotoxic drug concentration given in high dose chemotherapy compared with standard drug concentration may not be sufficient to produce the expected increase in tumour response and possibly survival, and the controversial results of high dose chemotherapy in different studies may thus be explained. Secondly, since an increase in melphalan dose above a certain threshold does not greatly increase tumour response, the use of combination therapies would seem to be more likely to be effective than increased chemotherapeutic drug doses in achieving better tumour responses.

Microdialysis and response during regional chemotherapy by isolated limb infusion of melphalan for limb malignancies

This study sought to use a microdialysis technique to relate clinical and biochemical responses to the time course of melphalan concentrations in the subcutaneous interstitial space and in tumour tissue (melanoma, malignant fibrous histiocytoma, Merkel cell tumour and osteosarcoma) in patients undergoing regional chemotherapy by Isolated Limb Infusion (ILI). 19 patients undergoing ILI for treatment of various limb malignancies were monitored for intra-operative melphalan concentrations in plasma and, using microdialysis, in subcutaneous and tumour tissues. Peak and mean concentrations of melphalan were significantly higher in plasma than in subcutaneous or tumour microdialysate. There was no significant difference between drug peak and mean concentrations in interstitial and tumour tissue, indicating that there was no preferential uptake of melphalan into the tumours. The time course of melphalan in the microdialysate could be described by a pharmacokinetic model which assumed melphalan distributed from the plasma into the interstitial space. The model also accounted for the vascular dispersion of melphalan in the limb. Tumour response in the whole group to treatment was partial response: 53.8% (n = 7); complete response: 33.3% (n = 5); no responses 6.7% (n = 1). There was a significant association between tumour response and melphalan concentrations measured over time in subcutaneous microdialysate (P < 0.01). No significant relationship existed between the severity of toxic reactions in the limb or peak plasma creatine phosphokinase levels and peak melphalan microdialysate or plasma concentrations. It is concluded that microdialysis is a technique well suited for measuring concentrations of cytotoxic drug during ILI. The possibility of predicting actual concentrations of cytotoxic drug in the limb during ILI using our model opens an opportunity for improved drug dose calculation. The combination of predicting tissue concentrations and monitoring in microdialysate of subcutaneous tissue could help optimise ILI with regard to post-operative limb morbidity and tumour response. (C) 2001 Cancer Research Campaign http:,//www.bjcancer.com.

The value of metabolic imaging to predict tumour response after chemoradiation in locally advanced rectal cancer

Background: We aim to investigate the possibility of using 18F-positron emission tomography/computer tomography (PET-CT) to predict the histopathologic response in locally advanced rectal cancer (LARC) treated with preoperative chemoradiation (CRT). Methods: The study included 50 patients with LARC treated with preoperative CRT. All patients were evaluated by PET-CT before and after CRT, and results were compared to histopathologic response quantified by tumour regression grade (patients with TRG 1-2 being defined as responders and patients with grade 3-5 as non-responders). Furthermore, the predictive value of metabolic imaging for pathologic complete response (ypCR) was investigated. Results: Responders and non-responders showed statistically significant differences according to Mandard's criteria for maximum standardized uptake value (SUVmax) before and after CRT with a specificity of 76,6% and a positive predictive value of 66,7%. Furthermore, SUVmax values after CRT were able to differentiate patients with ypCR with a sensitivity of 63% and a specificity of 74,4% (positive predictive value 41,2% and negative predictive value 87,9%); This rather low sensitivity and specificity determined that PET-CT was only able to distinguish 7 cases of ypCR from a total of 11 patients. Conclusions: We conclude that 18-F PET-CT performed five to seven weeks after the end of CRT can visualise functional tumour response in LARC. In contrast, metabolic imaging with 18-F PET-CT is not able to predict patients with ypCR accurately

Predicting response and survival in chemotherapy-treated triple-negative breast cancer.

BACKGROUND In this study, we evaluated the ability of gene expression profiles to predict chemotherapy response and survival in triple-negative breast cancer (TNBC). METHODS Gene expression and clinical-pathological data were evaluated in five independent cohorts, including three randomised clinical trials for a total of 1055 patients with TNBC, basal-like disease (BLBC) or both. Previously defined intrinsic molecular subtype and a proliferation signature were determined and tested. Each signature was tested using multivariable logistic regression models (for pCR (pathological complete response)) and Cox models (for survival). Within TNBC, interactions between each signature and the basal-like subtype (vs other subtypes) for predicting either pCR or survival were investigated. RESULTS Within TNBC, all intrinsic subtypes were identified but BLBC predominated (55-81%). Significant associations between genomic signatures and response and survival after chemotherapy were only identified within BLBC and not within TNBC as a whole. In particular, high expression of a previously identified proliferation signature, or low expression of the luminal A signature, was found independently associated with pCR and improved survival following chemotherapy across different cohorts. Significant interaction tests were only obtained between each signature and the BLBC subtype for prediction of chemotherapy response or survival. CONCLUSIONS The proliferation signature predicts response and improved survival after chemotherapy, but only within BLBC. This highlights the clinical implications of TNBC heterogeneity, and suggests that future clinical trials focused on this phenotypic subtype should consider stratifying patients as having BLBC or not.