Association between DPYD c.1129-5923 C>G/hapB3 and severe toxicity to 5-fluorouracil-based chemotherapy in stage III colon cancer patients: NCCTG N0147 (Alliance).

Severe (grade≥3) adverse events (AEs) to 5-fluorouracil (5-FU)-based chemotherapy regimens can result in treatment delays or cessation, and, in extreme cases, life-threatening complications. Current genetic biomarkers for 5-FU toxicity prediction, however, account for only a small proportion of toxic cases. In the current study, we assessed DPYD variants suggested to correlate with 5-FU toxicity, a deep intronic variant (c.1129-5923 C>G), and four variants within a haplotype (hapB3) in 1953 stage III colon cancer patients who received adjuvant FOLFOX±cetuximab. Logistic regression was used to assess multivariable associations between DPYD variant status and AEs common to 5-FU (5FU-AEs). In our study cohort, 1228 patients (62.9%) reported any grade≥3 AE (overall AE), with 638 patients (32.7%) reporting any grade≥3 5FU-AE. Only 32 of 78 (41.0%) patients carrying DPYD c.1129-5923 C>G and the completely linked hapB3 variants c.1236 C>G and c.959-51 T>C showed at least one grade≥3 5FU-AE, resulting in no statistically significant association (adjusted odds ratio=1.47, 95% confidence interval=0.90-2.43, P=0.1267). No significant associations were identified between c.1129-5923 C>G/hapB3 and overall grade≥3 AE rate. Our results suggest that c.1129-5923 C>G/hapB3 have limited predictive value for severe toxicity to 5-FU-based combination chemotherapy.

Relationship Between Metformin Use and Recurrence and Survival in Patients With Resected Stage III Colon Cancer Receiving Adjuvant Chemotherapy: Results From North Central Cancer Treatment Group N0147 (Alliance).

BACKGROUND: Preclinical and epidemiological data suggest that metformin might have antineoplastic properties against colon cancer (CC). However, the effect of metformin use on patient survival in stage III CC after curative resection is unknown. The survival outcomes were comparable regardless of the duration of metformin use. PATIENTS AND METHODS: Before randomization to FOLFOX (folinic acid, 5-fluorouracil, oxaliplatin) with or without cetuximab, 1,958 patients with stage III CC enrolled in the N0147 study completed a questionnaire with information on diabetes mellitus (DM) and metformin use. Cox models were used to assess the association between metformin use and disease-free survival (DFS), overall survival (OS), and the time to recurrence (TTR), adjusting for clinical and/or pathological factors. RESULTS: Of the 1,958 patients, 1,691 (86%) reported no history of DM, 115 reported DM with metformin use (6%), and 152 reported DM without metformin use (8%). The adjuvant treatment arms were pooled, because metformin use showed homogeneous effects on outcomes across the two arms. Among the patients with DM (n = 267), DFS (adjusted hazard ratio [aHR], 0.90; 95% confidence interval [CI], 0.59-1.35; p = .60), OS (aHR, 0.99; 95% CI, 0.65-1.49; p = .95), and TTR (aHR, 0.87; 95% CI, 0.56-1.35; p = .53) were not different for the metformin users compared with the nonusers after adjusting for tumor and patient factors. The survival outcomes were comparable regardless of the duration of metformin use (<1, 1-5, 6-10, ≥11 years) before randomization (ptrend = .64 for DFS, ptrend = .84 for OS, and ptrend = .87 for TTR). No interaction effects were observed between metformin use and KRAS, BRAF mutation status, tumor site, T/N stage, gender, or age. CONCLUSIONS: Patients with stage III CC undergoing adjuvant chemotherapy who used metformin before the diagnosis of CC experienced DFS, OS, and TTR similar to those for non-DM patients and DM patients without metformin use. IMPLICATIONS FOR PRACTICE: The present study did not find any relationship between metformin use or its duration and disease-free survival, time to recurrence, and overall survival in a large cohort of patients with resected stage III colon cancer receiving adjuvant FOLFOX (folinic acid, fluorouracil, oxaliplatin)-based chemotherapy. This relationship was not modified by KRAS or BRAF mutation or DNA mismatch repair status. Metformin use did not increase or decrease the likelihood of chemotherapy-related grade 3 or higher adverse events.

Effect of oxaliplatin, fluorouracil, and leucovorin with or without cetuximab on survival among patients with resected stage III colon cancer: a randomized trial.

CONTEXT: Leucovorin, fluorouracil, and oxaliplatin (FOLFOX) is the standard adjuvant therapy for resected stage III colon cancer. Adding cetuximab to FOLFOX benefits patients with metastatic wild-type KRAS but not mutated KRAS colon cancer. OBJECTIVE: To assess the potential benefit of cetuximab added to the modified sixth version of the FOLFOX regimen (mFOLFOX6) in patients with resected stage III wild-type KRAS colon cancer. DESIGN, SETTING, AND PARTICIPANTS: A randomized trial of 2686 patients aged 18 years or older at multiple institutions across North America enrolled following resection and informed consent between February 10, 2004, and November 25, 2009. The primary randomized comparison was 12 biweekly cycles of mFOLFOX6 with and without cetuximab. KRAS mutation status was centrally determined. The trial was halted after a planned interim analysis of 48% of predicted events (246/515) occurring in 1863 (of 2070 planned) patients with tumors having wild-type KRAS. A total of 717 patients with mutated KRAS and 106 with indeterminate KRAS were accrued. The 2070 patients with wild-type KRAS provided 90% power to detect a hazard ratio (HR) of 1.33 (2-sided α = .05), with planned interim efficacy analyses after 25%, 50%, and 75% of expected relapses. MAIN OUTCOME MEASURES: Disease-free survival in patients with wild-type KRAS mutations. Secondary end points included overall survival and toxicity. RESULTS: Median (range) follow-up was 28 (0-68) months. The trial demonstrated no benefit when adding cetuximab. Three-year disease-free survival for mFOLFOX6 alone was 74.6% vs 71.5% with the addition of cetuximab (HR, 1.21; 95% CI, 0.98-1.49; P = .08) in patients with wild-type KRAS, and 67.1% vs 65.0% (HR, 1.12; 95% CI, 0.86-1.46; P = .38) in patients with mutated KRAS, with no significant benefit in any subgroups assessed. Among all patients, grade 3 or higher adverse events (72.5% vs 52.3%; odds ratio [OR], 2.4; 95% CI, 2.1-2.8; P < .001) and failure to complete 12 cycles (33% vs 23%; OR, 1.6; 95% CI, 1.4-1.9; P < .001) were significantly higher with cetuximab. Increased toxicity and greater detrimental differences in all outcomes were observed in patients aged 70 years or older. CONCLUSION: Among patients with stage III resected colon cancer, the use of cetuximab with adjuvant mFOLFOX6 compared with mFOLFOX6 alone did not result in improved disease-free survival. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00079274.

Immunoscore Is Prognostic in Low-Risk and High-Risk Stage III Colon Carcinomas Treated With Adjuvant Infusional Fluorouracil, Leucovorin, and Oxaliplatin in a Phase III Trial.

PURPOSE: The recommended duration of adjuvant fluoropyrimidine and oxaliplatin chemotherapy for patients with stage III colon cancer is based on tumor classification into clinically low-risk (T1-3 N1) and high-risk (T4 or N2) groups. We determined whether Immunoscore can enhance prognostication within these risk groups. MATERIALS AND METHODS: Patients with stage III colon carcinomas (N = 600) were randomly selected from the infusional fluorouracil, leucovorin, and oxaliplatin arm of adjuvant trial NCCTG N0147 (Alliance for Clinical Trials in Oncology). Tumors were evaluated for Immunoscore that quantifies CD3+ and CD8+ T-cell densities in the tumor center and invasive margin by digital image analysis. Disease-free survival (DFS) by Immunoscore was analyzed using a multivariable Cox regression model in each risk group with adjustment for covariates including KRAS, BRAFV600E, and mismatch repair status. RESULTS: Of 559 cancers with Immunoscore data, 299 (53.5%) were classified as clinically low-risk (T1-3 N1) and 260 (46.5%) as clinically high-risk (T4 and/or N2). Among patients with low-risk tumors, those with Immunoscore-Low versus Immunoscore-High tumors had significantly worse 5-year DFS rates (77.5% v 91.8%; hazard ratio, 1.70; 95% CI, 1.03 to 2.79; P = .037). Among patients with high-risk tumors, those with Immunoscore-Low versus Immunoscore-High tumors also had significantly worse DFS (55.3% v 70.3%; hazard ratio, 1.65; 95% CI, 1.11 to 2.47; P = .013). Tumors that were low-risk/Immunoscore-Low had similar outcomes as did tumors that were high-risk/Immunoscore-High (P = .174). Prognostication was significantly improved in multivariable models where Immunoscore was added to clinical risk parameters and limited biomarkers (likelihood ratio test P = .0003). CONCLUSION: Immunoscore can refine patient prognosis beyond clinical risk group classification, suggesting its potential utility for adjuvant decision making.

Association of Adiponectin and Vitamin D With Tumor Infiltrating Lymphocytes and Survival in Stage III Colon Cancer.

Background: Adipocyte-derived adiponectin may play a role in the host inflammatory response to cancer. We examined the association of plasma adiponectin with the density of tumor-infiltrating lymphocytes (TILs) in colon cancers and with vitamin D, clinicopathological features, and patient survival. Methods: Plasma adiponectin and 25-hydroxyvitamin D [25(OH)D] were analyzed by radioimmunoassay in 600 patients with stage III colon cancer who received FOLFOX-based adjuvant chemotherapy (NCCTG N0147 [Alliance]). TIL densities were determined in histopathological sections. Associations with disease-free survival (DFS), time to recurrence, and overall survival were evaluated by multivariable Cox regression adjusting for potential confounders (ie, body mass index, race, TILs, and N stage). All statistical tests were 2-sided. Results: We found a statistically significant reduction in adiponectin, but not 25(OH)D, levels in tumors with high vs low TIL densities (median = 6845 vs 8984 ng/mL; P = .04). A statistically significant reduction in adiponectin was also observed in obese (body mass index >30 kg/m2) vs nonobese patients (median = 6608 vs 12 351 ng/mL; P < .001), in men vs women (median = 8185 vs 11 567 ng/mL; P < .001), in Blacks vs Whites or Asians (median = 6412 vs 8847 vs 7858 ng/mL; P < .03), and in those with fewer lymph node metastases (N1 vs N2: median = 7768 vs 9253 ng/mL; P = .01). Insufficiency of 25(OH)D (<30 ng/mL) was detected in 291 (48.5%) patients. In multivariable analyses, neither adiponectin nor 25(OH)D were associated with a statistically significant difference in DFS, overall survival , or time to recurrence in models adjusted for potential confounders. We found a statistically significant association of TILs with prognosis, yet no such interaction was observed for the association of adiponectin with TILs for DFS. Conclusions: Lower circulating adiponectin levels were associated with a statistically significant increase in TIL densities in colon cancers, indicating an enhanced antitumor immune response. In contrast to TILs, neither adiponectin nor 25(OH)D was independently prognostic.

Contribution of Immunoscore and Molecular Features to Survival Prediction in Stage III Colon Cancer.

BACKGROUND: The American Joint Committee on Cancer staging and other prognostic tools fail to account for stage-independent variability in outcome. We developed a prognostic classifier adding Immunoscore to clinicopathological and molecular features in patients with stage III colon cancer. METHODS: Patient (n = 559) data from the FOLFOX arm of adjuvant trial NCCTG N0147 were used to construct Cox models for predicting disease-free survival (DFS). Variables included age, sex, T stage, positive lymph nodes (+LNs), N stage, performance status, histologic grade, sidedness, KRAS/BRAF, mismatch repair, and Immunoscore (CD3+, CD8+ T-cell densities). After determining optimal functional form (continuous or categorical) and within Cox models, backward selection was performed to analyze all variables as candidate predictors. All statistical tests were two-sided. RESULTS: Poorer DFS was found for tumors that were T4 vs T3 (hazard ratio [HR] = 1.76, 95% confidence interval [CI] = 1.19 to 2.60; P = .004), right- vs left-sided (HR = 1.52, 95% CI = 1.14 to 2.04; P = .005), BRAF V600E (HR = 1.74, 95% CI = 1.26 to 2.40; P < .001), mutant KRAS (HR = 1.66, 95% CI = 1.08 to 2.55; P = .02), and low vs high Immunoscore (HR = 1.69, 95% CI = 1.22 to 2.33; P = .001) (all P < .02). Increasing numbers of +LNs and lower continuous Immunoscore were associated with poorer DFS that achieved significance (both Ps< .0001). After number of +LNs, T stage, and BRAF/KRAS, Immunoscore was the most informative predictor of DFS shown multivariately. Among T1-3 N1 tumors, Immunoscore was the only variable associated with DFS that achieved statistical significance. A nomogram was generated to determine the likelihood of being recurrence-free at 3 years. CONCLUSIONS: The Immunoscore can enhance the accuracy of survival prediction among patients with stage III colon cancer.

Hereditary colorectal cancer syndromes and the role of the surgical oncologist.

The expanding understanding of the genetic basis to hereditary colon cancer syndromes is dismantling previously conceived categorizations and shedding light on why those schemes often failed in past. This review highlights evolving concepts regarding the genetic diagnosis and clinical management of the more commonly inherited colorectal cancer syndromes, including a discussion of recently described familial syndromes. This review also addresses clinician responsibilities in recognition of familial syndromes and provision of counseling.

Neoplastic conversion of human colon smooth muscle cells: No requirement for telomerase.

The role of telomerase as an essential requirement for the neoplastic conversion of human cells has been controversial. In the model of conversion of normal human cells to cancer cells by the combination of simian virus 40 (SV40) early region genes and oncogenic Ras (H-Ras(G12V)), telomerase (hTERT) was originally described as essential in conjunction with these other genes. Here we used primary cultures of colon smooth muscle cells isolated from surgical specimens. SV40 large T antigen (TAg) and oncogenic Ras(G12V) were introduced into the cells by retroviral transduction and cells were rapidly transplanted into the subrenal capsule space in immunodeficient mice, without selection in culture. Malignant tumors were formed from transduced cells. Extensive invasion into the kidney occurred even when tumors were small; in contrast, at the same tumor size, oncogene-expressing fibroblasts did not show much invasion. Increased invasiveness was also observed in vitro. However, cells in these cancers showed morphological evidence of crisis, consistent with their lack of telomerase. These experiments on human colon smooth muscle cells support the concept that Ras(G12V) and SV40 TAg form a minimal set of genes that can convert normal human cells to cancer cells without a requirement for hTERT.

Squamous cell carcinoma of the anal canal.

Squamous cell carcinoma (SCC) of the anal canal is a rare condition with increasing incidence rates in the United States population in the past several decades. This review article provides a complete overview of the etiology, anatomy and the approach to the multidisciplinary management of the patient with anal SCC. Chemoradiation therapy for the treatment of SCC of the anal canal provides excellent disease control and survival while preserving anal sphincter function in the majority of patients. The surgeon plays a key role in the diagnosis and follow-up of this disease. Surgical salvage with APR for disease persistence or recurrence in carefully selected patients can result in reasonable 5-year survivals.

Safety and efficacy of metallic stents in the management of colorectal obstruction.

BACKGROUND: The use of self-expandable metallic stents in the management of obstructing colorectal cancer has been described with increasing frequency in the literature. Our goal was to evaluate the efficacy and associated morbidity of the use of self-expandable metallic stents to relieve colorectal obstruction at our institution. METHODS: A retrospective chart review of patients who underwent colorectal stent placement between December 2001 and December 2003 in a tertiary referral center was performed. RESULTS: Stents were placed successfully in 17 of 21 patients (81%) with colorectal obstruction. Placement was achieved endoscopically in 13 patients and radiologically in 4. Ten self-expandable metallic stents were used as a bridge to surgery, and 7 were used for palliation. The obstructions were located in the sigmoid colon (11 patients), the rectosigmoid (3), the splenic flexure, the hepatic flexure, and the rectum. Malignant obstruction was noted in 14 patients. One patient with malignancy experienced a sigmoid perforation, and 2 patients with benign disease had complications (1 stent migration and 1 re-obstruction). Stent patency in obstruction secondary to colonic adenocarcinoma was 100% in our follow-up period (range, 5 to 15 months). CONCLUSIONS: The use of stents as a bridge to surgery is associated with low morbidity, allows for bowel preparation, and thus avoids the need for a temporary colostomy. Long-term patency suggests that stents may allow for the avoidance of an operation in patients with metastatic disease and further defines their role in the palliation of malignant obstruction. Further prospective randomized studies are necessary to fully elucidate the use of stents in the management of colorectal cancer.

Molecular prognostics in colorectal cancer.

Conventional staging of colorectal cancer does not account for the marked variability in outcome that exists within each stage. Certain populations of patients with early recurrence, resistance to chemotherapy and decreased survival cannot be predicted utilizing common histopathologic criteria. As the molecular mechanisms underlying colorectal carcinogenesis are elucidated, putative molecular prognostic factors are identified. A comprehensive review of various molecular markers and their roles as prognostic factors in colorectal cancer is presented.

Contemporary management of benign liver tumors.

Benign lesions of the liver represent diagnostic dilemmas, clinically and radiographically; however, certain clues can help the extensive differential diagnosis of both benign and malignant processes. Hemangiomas and simple cysts have very distinct and very specific radiographic characteristics, and if diagnosed, no further work-up is necessary. The remaining benign lesions have significant overlap, even though there are some more common characteristics to each of the entities. Still, differentiation of any particular lesion outside simple cysts or hemangioma may be difficult. It is reasonable and relatively simple, with minimal invasiveness, to perform US- or CT-guided, percutaneous core-needle biopsies. It is recommended that core biopsies be performed, because many of the benign entities have some overlapping histologic features, and if fine-needle aspirations are performed, a definitive diagnosis may be difficult to obtain. A definitive pathological diagnosis still cannot be made in some cases, even after needle biopsy. Therefore, a surgical resection or wedge resection may be necessary if a benign process cannot be definitively ruled out.

Overview of anal cancer for the surgeon.

Cancers of the anal canal represent a diverse group of pathology and require a multidisciplinary approach for treatment. For the most common anal canal cancer, anal SCC, the primary therapy is CMT with systemic chemotherapy and radiation. The surgeon plays a key role in the diagnosis and follow-up after treatment, with surgical intervention reserved for residual or recurrent disease. The overall prognosis for this disease is favorable. For anal adenocarcinoma, aggressive surgical resection remains the mainstay of therapy, with radiation therapy and chemotherapy used to aid in local disease control and for treatment of metastatic disease. A high rate of distant failure in this disease is responsible for the poor long-term prognosis. Anorectal melanoma has a high rate of distant failure and a poor overall survival rate. Surgical intervention is focused on local disease control with preservation of sphincter function. The biggest improvements in survival for this disease will come with more effective systemic therapy.

The etiology and epidemiology of anal cancer.

The anatomic definitions for anal cancer (canal versus margin) are made based on the relationship of the tumor to the anal verge. This method had led to confusion for some providers. A modification in the terminology is proposed that includes intra-anal, perianal, and skin as categories. The cause of anal carcinoma remains to be fully elucidated, and HPV seems to play a central role in this process. The incidence of anal cancers has increased, which is related to the evolution of HIV and AIDS, and their treatment. The accurate pathologic analysis of anal tumors is complex and is significantly aided by close communication between clinician and pathologist.

Uncommon anal neoplasms.

The neoplasms of the anus discussed in this article are uncommon, and therefore lack a consistent diagnostic and treatment algorithm derived from prospective clinical trial datasets. There may be an opportunity to design prospective Phase II clinical trials, with established uniform surgical pathology, surgical technique guidelines, and endpoints. The American College of Surgeons Oncology Group may have an opportunity to design and carry out controlled clinical trials for select rare anal neoplasms. Such an effort may yield modern benchmarks with which to base subsequent patient care algorithms.

Intraoperative hepatic lymphatic mapping in patients with liver metastases from colorectal carcinoma.

The survival of patients undergoing liver resection for colorectal metastases is poor in the presence of extrahepatic disease. Therefore identification of periportal and celiac lymph node metastases is central to proper patient selection. In this study we examined the technique of intraoperative hepatic lymphatic mapping with isosulfan blue dye in humans. Intrahepatic dye injection was performed in patients undergoing surgical exploration for colorectal liver metastases. The location of all blue-stained lymphatics and lymph nodes was recorded. All stained and unstained lymph nodes were biopsied for pathologic examination. Thirteen intraoperative lymphatic mapping procedures were performed in 11 patients. A blue-stained lymphatic was visualized in 11 of 13 injections (85%). A blue lymph node was visualized in seven of 13 injections (54%). Three of the seven blue nodes (43%) were not detected by the surgeon before the mapping procedure. There were no complications associated with the intrahepatic dye injections. All biopsied lymph nodes were negative for metastatic tumor. We conclude that intraoperative hepatic lymphatic mapping with isosulfan blue dye is a simple, rapid, and safe technique in humans. It may serve as an adjunct to random lymph node biopsy for the identification of periportal and celiac nodal metastases before liver resection in patients with metastatic colorectal carcinoma.

Comparison of FOLFIRI with or without cetuximab in patients with resected stage III colon cancer; NCCTG (Alliance) intergroup trial N0147.

BACKGROUND: Two arms with FOLFIRI, with or without cetuximab, were initially included in the randomized phase III intergroup clinical trial NCCTG (North Central Cancer Treatment Group) N0147. When other contemporary trials demonstrated no benefit to using irinotecan as adjuvant therapy, the FOLFIRI-containing arms were discontinued. We report the clinical outcomes for patients randomized to FOLFIRI with or without cetuximab. PATIENTS AND METHODS: After resection, patients were randomized to 12 biweekly cycles of FOLFIRI, with or without cetuximab. KRAS (Kirsten rat sarcoma viral oncogene homolog) mutation status was retrospectively determined in a central lab. The primary end point was disease-free survival (DFS). Secondary end points included overall survival (OS) and toxicity. RESULTS: One hundred and six patients received FOLFIRI and 40 received FOLFIRI plus cetuximab. Median follow-up was 5.95 years (range, 0.1-7.0 years). The addition of cetuximab showed a trend toward improved DFS (hazard ratio [HR], 0.53; 95% CI, 0.26-1.1; P = .09) and OS (HR, 0.45; 95% CI, 0.17-1.16; P = .10) in the overall group, regardless of KRAS status, and in patients with wild type KRAS. Grade ≥ 3 nonhematologic adverse effects were significantly increased in the cetuximab versus FOLFIRI-alone arm (68% vs. 46%; P = .02). Adjuvant FOLFIRI resulted in a 3-year DFS less than that expected for FOLFOX. CONCLUSION: In this small randomized subset of patients with resected stage III colon cancer, the addition of cetuximab to FOLFIRI was associated with a nonsignificant trend toward improved DFS and OS. Nevertheless, considering the limitations of this analysis, FOLFOX without the addition of a biologic agent remains the standard of care for adjuvant therapy in resected stage III colon cancer.

Preoperative multimodality therapy improves disease-free survival in patients with carcinoma of the rectum: NSABP R-03.

PURPOSE: Although chemoradiotherapy plus resection is considered standard treatment for operable rectal carcinoma, the optimal time to administer this therapy is not clear. The NSABP R-03 (National Surgical Adjuvant Breast and Bowel Project R-03) trial compared neoadjuvant versus adjuvant chemoradiotherapy in the treatment of locally advanced rectal carcinoma. PATIENTS AND METHODS: Patients with clinical T3 or T4 or node-positive rectal cancer were randomly assigned to preoperative or postoperative chemoradiotherapy. Chemotherapy consisted of fluorouracil and leucovorin with 45 Gy in 25 fractions with a 5.40-Gy boost within the original margins of treatment. In the preoperative group, surgery was performed within 8 weeks after completion of radiotherapy. In the postoperative group, chemotherapy began after recovery from surgery but no later than 4 weeks after surgery. The primary end points were disease-free survival (DFS) and overall survival (OS). RESULTS: From August 1993 to June 1999, 267 patients were randomly assigned to NSABP R-03. The intended sample size was 900 patients. Excluding 11 ineligible and two eligible patients without follow-up data, the analysis used data on 123 patients randomly assigned to preoperative and 131 to postoperative chemoradiotherapy. Surviving patients were observed for a median of 8.4 years. The 5-year DFS for preoperative patients was 64.7% v 53.4% for postoperative patients (P = .011). The 5-year OS for preoperative patients was 74.5% v 65.6% for postoperative patients (P = .065). A complete pathologic response was achieved in 15% of preoperative patients. No preoperative patient with a complete pathologic response has had a recurrence. CONCLUSION: Preoperative chemoradiotherapy, compared with postoperative chemoradiotherapy, significantly improved DFS and showed a trend toward improved OS.

Preoperative chemotherapy: updates of National Surgical Adjuvant Breast and Bowel Project Protocols B-18 and B-27.

PURPOSE: National Surgical Adjuvant Breast and Bowel Project (NSABP) Protocol B-18 was designed to determine whether four cycles of doxorubicin and cyclophosphamide (AC) administered preoperatively improved breast cancer disease-free survival (DFS) and overall survival (OS) compared with AC administered postoperatively. Protocol B-27 was designed to determine the effect of adding docetaxel (T) to preoperative AC on tumor response rates, DFS, and OS. PATIENTS AND METHODS: Analyses were limited to eligible patients. In B-18, 751 patients were assigned to receive preoperative AC, and 742 patients were assigned to receive postoperative AC. In B-27, 784 patients were assigned to receive preoperative AC followed by surgery, 783 patients were assigned to AC followed by T and surgery, and 777 patients were assigned to AC followed by surgery and then T. RESULTS: Results from B-18 show no statistically significant differences in DFS and OS between the two groups. However, there were trends in favor of preoperative chemotherapy for DFS and OS in women less than 50 years old (hazard ratio [HR] = 0.85, P = .09 for DFS; HR = 0.81, P = .06 for OS). DFS conditional on being event free for 5 years also demonstrated a strong trend in favor of the preoperative group (HR = 0.81, P = .053). Protocol B-27 results demonstrated that the addition of T to AC did not significantly impact DFS or OS. Preoperative T added to AC significantly increased the proportion of patients having pathologic complete responses (pCRs) compared with preoperative AC alone (26% v 13%, respectively; P < .0001). In both studies, patients who achieved a pCR continue to have significantly superior DFS and OS outcomes compared with patients who did not. CONCLUSION: B-18 and B-27 demonstrate that preoperative therapy is equivalent to adjuvant therapy. B-27 also showed that the addition of preoperative taxanes to AC improves response.