Lawrence N. Shulman

Prognostic Value of Tumor-Infiltrating Lymphocytes in Triple-Negative Breast Cancers From Two Phase III Randomized Adjuvant Breast Cancer Trials: ECOG 2197 and ECOG 1199

PURPOSE Recent studies suggest that tumor-infiltrating lymphocytes (TILs) are associated with disease-free (DFS) and overall survival (OS) in operable triple-negative breast cancer (TNBC). We seek to validate the prognostic impact of TILs in primary TNBCs in two adjuvant phase III trials conducted by the Eastern Cooperative Oncology Group (ECOG). PATIENTS AND METHODS Full-face hematoxylin and eosin–stained sections of 506 tumors from ECOG trials E2197 and E1199 were evaluated for density of TILs in intraepithelial (iTILs) and stromal compartments (sTILs). Patient cases of TNBC from E2197 and E1199 were randomly selected based on availability of sections. For the primary end point of DFS, association with TIL scores was determined by fitting proportional hazards models stratified on study. Secondary end points were OS and distant recurrence–free interval (DRFI). Reporting recommendations for tumor marker prognostic studies criteria were followed, and all analyses were prespecified. RESULTS The majority of 481 evaluable cancers had TILs (sTILs, 80%; iTILs, 15%). With a median follow-up of 10.6 years, higher sTIL scores were associated with better prognosis; for every 10% increase in sTILs, a 14% reduction of risk of recurrence or death (P = .02), 18% reduction of risk of distant recurrence (P = .04), and 19% reduction of risk of death (P = .01) were observed. Multivariable analysis confirmed sTILs to be an independent prognostic marker of DFS, DRFI, and OS. CONCLUSION In two national randomized clinical trials using contemporary adjuvant chemotherapy, we confirm that stromal lymphocytic infiltration constitutes a robust prognostic factor in TNBCs. Studies assessing outcomes and therapeutic efficacies should consider stratification for this parameter.

The Sequencing of Chemotherapy and Radiation Therapy after Conservative Surgery for Early-Stage Breast Cancer

BACKGROUND Patients with early-stage breast cancer who are at substantial risk for systemic metastases are increasingly treated with breast-conserving therapy and adjuvant chemotherapy. However, the optimal sequencing of chemotherapy and radiation therapy is not clear. METHODS Two hundred forty-four patients with stage I or II breast cancer who were at substantial risk for distant metastases were randomly assigned to receive a 12-week course of chemotherapy either before or after radiation therapy. All had had breast-conserving surgery. The median length of follow-up in surviving patients was 58 months (range, 10 to 124). RESULTS The five-year actuarial rates of cancer recurrence at any site and of distant metastases in the radiotherapy-first group and the chemotherapy-first group were 38 percent and 31 percent (P = 0.17) and 36 percent and 25 percent (P = 0.05), respectively. Overall survival was 73 percent and 81 percent (P = 0.11), respectively. The five-year crude rates of first recurrence according to site in the radiotherapy-first and chemotherapy-first groups, respectively, were 5 percent and 14 percent for local recurrence and 32 percent and 20 percent for distant or regional recurrence or both. This difference in the pattern of recurrence was of borderline statistical significance (P = 0.07). CONCLUSIONS This study suggests that for patients ar substantial risk for systemic metastases, it is preferable to give a 12-week course of chemotherapy followed by radiation therapy, rather than radiation therapy followed by chemotherapy.

Expansion of cancer care and control in countries of low and middle income: a call to action

Substantial inequalities exist in cancer survival rates across countries. In addition to prevention of new cancers by reduction of risk factors, strategies are needed to close the gap between developed and developing countries in cancer survival and the effects of the disease on human suffering. We challenge the public health communitys assumption that cancers will remain untreated in poor countries, and note the analogy to similarly unfounded arguments from more than a decade ago against provision of HIV treatment. In resource-constrained countries without specialised services, experience has shown that much can be done to prevent and treat cancer by deployment of primary and secondary caregivers, use of off-patent drugs, and application of regional and global mechanisms for financing and procurement. Furthermore, several middle-income countries have included cancer treatment in national health insurance coverage with a focus on people living in poverty. These strategies can reduce costs, increase access to health services, and strengthen health systems to meet the challenge of cancer and other diseases. In 2009, we formed the Global Task Force on Expanded Access to Cancer Care and Control in Developing Countries, which is composed of leaders from the global health and cancer care communities, and is dedicated to proposal, implementation, and evaluation of strategies to advance this agenda.

Clinical Activity of Trastuzumab and Vinorelbine in Women With HER2-Overexpressing Metastatic Breast Cancer

PURPOSE To determine the response rate and toxicity profile of trastuzumab administered concurrently with weekly vinorelbine in women with HER2-overexpressing advanced breast cancer. PATIENTS AND METHODS Forty women with HER2-positive (+3 by immunohistochemistry, n = 30; +2 or positive, n = 10) breast cancer were enrolled onto a study of trastuzumab (4 mg/kg x 1, 2 mg/kg weekly thereafter) and vinorelbine (25 mg/m2 weekly, with dose adjusted each week for neutrophil count). Eighty-two percent of women had received prior chemotherapy as part of adjuvant (30%), metastatic (25%), or both (28%) treatment, including substantial portions of patients who had previously received either anthracyclines (20%), taxanes (15%), or both types (38%) of chemotherapy. RESULTS Responses were observed in 30 of 40 patients (overall response rate, 75%, conditional corrected 95% confidence interval, 57% to 89%). The response rate was 84% in patients treated with trastuzumab and vinorelbine as first-line therapy for metastatic disease, and 80% among HER2 +3 positive patients. High response rates were also seen in women treated with second- or third-line therapy, and among patients previously treated with anthracyclines and/or taxanes. Combination therapy was feasible; patients received concurrent trastuzumab and vinorelbine in 93% of treatment weeks. Neutropenia was the only grade 4 toxicity. No patients had symptomatic heart failure. Grade 2 cardiac toxicity was observed in three patients. Prior cumulative doxorubicin dose in excess of 240 mg/m2 and borderline pre-existing cardiac function were associated with grade 2 cardiac toxicity. CONCLUSION Trastuzumab in combination with vinorelbine is highly active in women with HER2-overexpressing advanced breast cancer and is well tolerated.

Prognostic Utility of the 21-Gene Assay in Hormone Receptor–Positive Operable Breast Cancer Compared With Classical Clinicopathologic Features

PURPOSE Adjuvant! is a standardized validated decision aid that projects outcomes in operable breast cancer based on classical clinicopathologic features and therapy. Genomic classifiers offer the potential to more accurately identify individuals who benefit from chemotherapy than clinicopathologic features. PATIENTS AND METHODS A sample of 465 patients with hormone receptor (HR) -positive breast cancer with zero to three positive axillary nodes who did (n = 99) or did not have recurrence after chemohormonal therapy had tumor tissue evaluated using a 21-gene assay. Histologic grade and HR expression were evaluated locally and in a central laboratory. RESULTS Recurrence Score (RS) was a highly significant predictor of recurrence, including node-negative and node-positive disease (P < .001 for both) and when adjusted for other clinical variables. RS also predicted recurrence more accurately than clinical variables when integrated by an algorithm modeled after Adjuvant! that was adjusted to 5-year outcomes. The 5-year recurrence rate was only 5% or less for the estimated 46% of patients who have a low RS (< 18). CONCLUSION The 21-gene assay was a more accurate predictor of relapse than standard clinical features for individual patients with HR-positive operable breast cancer treated with chemohormonal therapy and provides information that is complementary to features typically used in anatomic staging, such as tumor size and lymph node involvement. The 21-gene assay may be used to select low-risk patients for abbreviated chemotherapy regimens similar to those used in our study or high-risk patients for more aggressive regimens or clinical trials evaluating novel treatments.

Induction Chemoradiation and Surgical Resection for Superior Sulcus Non–Small-Cell Lung Carcinomas: Long-Term Results of Southwest Oncology Group Trial 9416 (Intergroup Trial 0160)

PURPOSE Traditional treatment for superior sulcus non-small-cell lung cancers (SS NSCLC), radiation plus surgery, yields a 50% rate of complete resection and a 30% 5-year survival. On the basis of improved outcomes in other subsets of stage III NSCLC, this trial tested the feasibility of induction chemoradiotherapy for SS NSCLC. PATIENTS AND METHODS Patients with T3-4, N0-1 SS NSCLC received two cycles of cisplatin and etoposide concurrently with radiation (45 Gy). Patients with stable or responding disease underwent thoracotomy. All patients received two more cycles of chemotherapy. Survival was calculated by the Kaplan-Meier method and prognostic factors were assessed by Cox regression analysis. RESULTS From April 1995 to November 1999, 110 eligible patients (76 men, 34 women) were entered onto the study (78 T3, 32 T4 tumors). Induction therapy was completed by 104 (95%) patients. Of 95 patients eligible for surgery, 88 (80%) underwent thoracotomy, two (1.8%) died postoperatively, and 83 (76%) had complete resection. Pathologic complete response (CR) or minimal microscopic disease was seen in 61 (56%) resection specimens. Five-year survival was 44% for all patients and 54% after complete resection, with no difference between T3 and T4 tumors. Pathologic CR led to better survival than when any residual disease was present (P = .02). Disease progression occurred mainly in distant sites. CONCLUSION This combined-modality approach is feasible and is associated with high rates of complete resection and pathologic CR in both T3 and T4 tumors. Local control and overall survival seem markedly improved relative to previous studies of radiation plus resection.

Docetaxel Administered on a Weekly Basis for Metastatic Breast Cancer

PURPOSE To evaluate the safety and efficacy of weekly docetaxel in women with metastatic breast cancer. PATIENTS AND METHODS Twenty-nine women were enrolled onto a study of weekly docetaxel given at 40 mg/m(2)/wk. Each cycle consisted of 6 weeks of therapy followed by a 2-week treatment break, repeated until disease progression or removal from study for toxicity or patient preference. Fifty-two percent of patients had been previously treated with adjuvant chemotherapy; 21% had received prior chemotherapy for metastatic breast cancer, and 31% had previously received anthracyclines. All patients were assessable for toxicity; two patients were not assessable for response but are included in an intent-to-treat analysis. RESULTS Patients received a median of 18 infusions, with a median cumulative docetaxel dose of 720 mg/m(2). There were no complete responses. Twelve patients had partial responses (overall response rate, 41%; 95% confidence interval, 24% to 61%), all occurring within the first two cycles. Similar response rates were observed among subgroups of patients previously treated either with any prior chemotherapy or with anthracyclines. An additional 17% of patients had stable disease for at least 6 months. The regimen was generally well tolerated. There was no grade 4 toxicity. Only 28% of patients had any grade 3 toxicity, most commonly neutropenia and fatigue. Acute toxicity, including myelosuppression, was mild. Fatigue, fluid retention, and eye tearing/conjunctivitis became more common with repetitive dosing, although these side effects rarely exceeded grade 2. Dose reductions were made for eight of 29 patients, most often because of fatigue (n = 5). CONCLUSION Weekly docetaxel is active in treating patients with metastatic breast cancer, with a side effect profile that differs from every-3-weeks therapy.

Phase I Clinical Trial of Recombinant Human Endostatin Administered as a Short Intravenous Infusion Repeated Daily

PURPOSE To perform a phase I trial of recombinant human endostatin (rhEndostatin; EntreMed, Rockville, MD) given as a daily 20-minute intravenous (IV) injection in adult patients with refractory solid tumors. PATIENTS AND METHODS The daily dose was increased from 15 to 240 mg/m(2) by a factor of 100% in cohorts of three patients. In the absence of dose-limiting toxicity, uninterrupted treatment was continued until the tumor burden increased by more than 50% from baseline. Correlative studies included dynamic contrast-enhanced magnetic resonance imaging of tumor blood flow, urinary vascular endothelial growth factor and basic fibroblast growth factor levels, rhEndostatin serum pharmacokinetics, and monitoring of circulating antibodies to rhEndostatin. RESULTS There were no notable treatment related toxicities among 15 patients receiving a total of 50 monthly cycles of rhEndostatin. One patient with a pancreatic neuroendocrine tumor had a minor response and two patients showed disease stabilization. Linearity in the pharmacokinetics of rhEndostatin was indicated by dose-proportionate increases in the area under the curve for the first dose and the peak serum concentration at steady state. Daily systemic exposure to rhEndostatin in patients receiving 240 mg/m(2)/d was approximately 50% lower than that provided by the therapeutically optimal dose in preclinical studies. CONCLUSION rhEndostatin administered as a 20-minute daily IV injection at doses up to 240 mg/m(2) showed no significant toxicities. Evidence of clinical benefit was observed in three patients. Due to high variability between the peak and trough serum concentrations associated with the repeated short IV infusion schedule, daily serum drug levels only briefly exceeded concentrations necessary for in vitro antiangiogenic effects.

Phase I Trial of Intraperitoneal Injection of the E1B-55-kd-Gene–Deleted Adenovirus ONYX-015 (dl1520) Given on Days 1 Through 5 Every 3 Weeks in Patients With Recurrent/Refractory Epithelial Ovarian Cancer

PURPOSE Resistance to chemotherapy in ovarian cancer is frequently associated with mutations in the p53 gene. The adenovirus dl1520 (ONYX-015) with the E1B 55-kd gene deleted, allowing selective replication in and lysis of p53-deficient tumor cells, has shown preclinical efficacy against p53-deficient nude mouse-human ovarian carcinomatosis xenografts. PATIENTS AND METHODS We undertook a phase I trial of intraperitoneal dl1520 in patients with recurrent ovarian cancer. Sixteen women with recurrent/refractory ovarian cancer received 35 cycles (median, two cycles) of dl1520 delivered on days 1 through 5 in four dose cohorts: 1 x 10(9) plaque forming units (pfu), 1 x 10(10) pfu, 3 x 10(10) pfu, and 1 x 10(11) pfu. RESULTS The most common significant toxicities related to virus administration were flu-like symptoms, emesis, and abdominal pain. One patient receiving 1 x 10(10) pfu developed common toxicity criteria grade 3 abdominal pain and diarrhea, which was dose-limiting. The maximum-tolerated dose was not reached at 10(11) pfu, and at this dose level patients did not experience significant toxicity. There was no clear-cut evidence of clinical or radiologic response in any patient. Blood samples were taken for adenovirus DNA and neutralizing antibodies. Polymerase chain reaction data indicating presence of virus up to 10 days after the final (day 5) infusion of dl1520 are suggestive of continuing viral replication. CONCLUSION This article therefore describes the first clinical experience with the intraperitoneal delivery of any replication-competent/-selective virus in cancer patients.

Association of Sleep-Disordered Breathing With Postoperative Complications

BACKGROUND Obstructive sleep apnea (OSA) is associated with increased perioperative risk, but the incidence of postoperative complications and the severity of OSA associated with increased risk have not been established. We investigated the relationship between intermittent hypoxemia measured by home nocturnal oximetry with the occurrence of postoperative complications in patients with clinical signs of OSA identified during preoperative assessment for elective surgery. METHODS This study was performed at a tertiary care hospital. Home nocturnal oximetry was performed on elective surgical patients with clinical features of OSA. The number of episodes per hour of oxygen desaturation (or oxygen desaturation index) of > or = 4% (ODI4%) was determined. Subjects with five or more desaturations per hour (ODI4% > or = 5) were compared to those with less than five desaturations per hour (ODI4% < 5). Hospital records were reviewed to assess the incidence and type of postoperative complications. RESULTS A total of 172 patients were investigated as part of this study. No significant differences were observed between groups in terms of age, body mass index, number of medical comorbidities, or smoking history. Patients with an ODI4% > or = 5 had a significantly higher rate of postoperative complications than those with ODI4% < 5 (15.3% vs 2.7%, respectively [p < 0.01]; adjusted odds ratio, 7.2; 95% confidence interval, 1.5 to 33.3 [p = 0.012]). The complication rate also increased with increasing ODI severity (patients with an ODI4% of 5 to 15 events per hour, 13.8%; patients with an ODI4% of > or = 15 events per hour, 17.5%; p = 0.01) Complications were respiratory (nine patients), cardiovascular (five patients), GI (one patient), and bleeding (two patients). The hospital length of stay was similar in both groups. CONCLUSION An ODI4%> or = 5, determined by home nocturnal oximetry, in patients with clinical features of OSA is associated with an increased rate of postoperative complications.