Jacqueline Benedetti

Disease-Free Survival Versus Overall Survival As a Primary End Point for Adjuvant Colon Cancer Studies: Individual Patient Data From 20,898 Patients on 18 Randomized Trials

PURPOSE A traditional end point for colon adjuvant clinical trials is overall survival (OS), with 5 years demonstrating adequate follow-up. A shorter-term end point providing convincing evidence to allow treatment comparisons could significantly speed the translation of advances into practice. METHODS Individual patient data were pooled from 18 randomized phase III colon cancer adjuvant clinical trials. Trials included 43 arms, with a pooled sample size of 20,898 patients. The primary hypothesis was that disease-free survival (DFS), with 3 years of follow-up, is an appropriate primary end point to replace OS with 5 years of follow-up. RESULTS The recurrence rates for years 1 through 5 were 12%, 14%, 8%, 5%, and 3%, respectively. Median time from recurrence to death was 12 months. Eighty percent of recurrences were in the first 3 years; 91% of patients with recurrence by 3 years died before 5 years. Correlation between 3-year DFS and 5-year OS was 0.89. Comparing control versus experimental arms within each trial, the correlation between hazard ratios for DFS and OS was 0.92. Within-trial log-rank testing using both DFS and OS provided the same conclusion in 23 (92%) of 25 cases. Formal measures of surrogacy were satisfied. CONCLUSION In patients treated on phase III adjuvant colon clinical trials, DFS and OS are highly correlated, both within patients and across trials. These results suggest that DFS after 3 years of median follow-up is an appropriate end point for adjuvant colon cancer clinical trials of fluorouracil-based regimens, although marginally significant DFS improvements may not translate into significant OS benefits.

Phase III Study Comparing Gemcitabine Plus Cetuximab Versus Gemcitabine in Patients With Advanced Pancreatic Adenocarcinoma: Southwest Oncology Group–Directed Intergroup Trial S0205

PURPOSE Patients with advanced pancreas cancer present with disease that is poorly responsive to conventional therapies. Preclinical and early clinical evidence has supported targeting the epidermal growth factor receptor (EGFR) signaling pathway in patients with pancreas cancer. This trial was conducted to evaluate the contribution of an EGFR-targeted agent to standard gemcitabine therapy. Cetuximab is a monoclonal antibody against the ligand-binding domain of the receptor. PATIENTS AND METHODS Patients with unresectable locally advanced or metastatic pancreatic adenocarcinoma were randomly assigned to receive gemcitabine alone or gemcitabine plus cetuximab. The primary end point was overall survival. Secondary end points included progression-free survival, time to treatment failure, objective response, and toxicity. RESULTS A total of 745 eligible patients were accrued. No significant difference was seen between the two arms of the study with respect to the median survival time (6.3 months for the gemcitabine plus cetuximab arm v 5.9 months for the gemcitabine alone arm; hazard ratio = 1.06; 95% CI, 0.91 to 1.23; P = .23, one-sided). Objective responses and progression-free survival were similar in both arms of the study. Although time to treatment failure was longer in patients on gemcitabine plus cetuximab (P = .006), the difference in length of treatment was only 2 weeks longer in the combination arm. Among patients who were studied for tumoral EGFR expression, 90% were positive, with no treatment benefit detected in this patient subset. CONCLUSION In patients with advanced pancreas cancer, the anti-EGFR monoclonal antibody cetuximab did not improve the outcome compared with patients treated with gemcitabine alone. Alternate targets other than EGFR should be evaluated for new drug development.

Risk Factors for the Sexual Transmission of Genital Herpes

OBJECTIVE To determine the risk of sexual transmission of genital herpes simplex virus (HSV) in heterosexual couples. DESIGN Prospective study of couples who were participants in a clinical trial. Each source partner had symptomatic, recurrent genital HSV, and each susceptible partner was without serologic or clinical evidence of genital herpes. Couples were followed for a median of 334 days. SETTING Two university-based research clinics. PATIENTS One hundred forty-four heterosexual couples were studied out of an initial enrollment of 214 couples. MAIN OUTCOME MEASURES Development of culture-proven HSV infection or type-specific antibodies in the susceptible partner. MAIN RESULTS Transmission occurred in 14 (9.7%) couples, including 11 (16.9%) of 65 couples with male and 3 (3.8%) of 79 with female source partners (P = 0.05). The annual rate of acquisition was higher (31.8%) in susceptible female partners who lacked antibodies to either HSV type 1 or 2 at entry compared with females with HSV type 1 antibodies at entry (9.1%). Couples avoiding transmission of HSV reported fewer days with genital lesions in source partners. Detailed histories were available at the time of transmission in 13 couples. In nine couples, transmission occurred when the source partner was reported to be asymptomatic and in four, it resulted from sexual contact at the time of prodrome (1 case) or within hours before lesions were first noticed by the source partner (3 cases). CONCLUSIONS Despite clear recognition of genital herpes in source partners, there was substantial risk for transmission; in 70% of patients, transmission appeared to result from sexual contact during periods of asymptomatic viral shedding. The risk for acquisition of HSV was higher in women than men, and previous HSV type 1 infection appeared to reduce the risk for acquisition of HSV type 2 infection among women.

Updated Analysis of SWOG-Directed Intergroup Study 0116: A Phase III Trial of Adjuvant Radiochemotherapy Versus Observation After Curative Gastric Cancer Resection

PURPOSE Surgical resection of gastric cancer has produced suboptimal survival despite multiple randomized trials that used postoperative chemotherapy or more aggressive surgical procedures. We performed a randomized phase III trial of postoperative radiochemotherapy in those at moderate risk of locoregional failure (LRF) following surgery. We originally reported results with 4-year median follow-up. This update, with a more than 10-year median follow-up, presents data on failure patterns and second malignancies and explores selected subset analyses. PATIENTS AND METHODS In all, 559 patients with primaries ≥ T3 and/or node-positive gastric cancer were randomly assigned to observation versus radiochemotherapy after R0 resection. Fluorouracil and leucovorin were administered before, during, and after radiotherapy. Radiotherapy was given to all LRF sites to a dose of 45 Gy. RESULTS Overall survival (OS) and relapse-free survival (RFS) data demonstrate continued strong benefit from postoperative radiochemotherapy. The hazard ratio (HR) for OS is 1.32 (95% CI, 1.10 to 1.60; P = .0046). The HR for RFS is 1.51 (95% CI, 1.25 to 1.83; P < .001). Adjuvant radiochemotherapy produced substantial reduction in both overall relapse and locoregional relapse. Second malignancies were observed in 21 patients with radiotherapy versus eight with observation (P = .21). Subset analyses show robust treatment benefit in most subsets, with the exception of patients with diffuse histology who exhibited minimal nonsignificant treatment effect. CONCLUSION Intergroup 0116 (INT-0116) demonstrates strong persistent benefit from adjuvant radiochemotherapy. Toxicities, including second malignancies, appear acceptable, given the magnitude of RFS and OS improvement. LRF reduction may account for the majority of overall relapse reduction. Adjuvant radiochemotherapy remains a rational standard therapy for curatively resected gastric cancer with primaries T3 or greater and/or positive nodes.

Neonatal herpes simplex virus infection in relation to asymptomatic maternal infection at the time of labor.

Abstract Background and Methods. To define the risk factors associated with neonatal acquisition of herpes simplex virus (HSV) infection, we prospectively obtained HSV cultures from the cervix and external genitalia of 15,923 pregnant women in early labor who were without symptoms or signs of genital HSV infection. Follow-up of the women with positive cultures for HSV and their HSV-exposed infants included serologic tests and serial cultures for HSV. Results. HSV was isolated from 56 of the women (0.35 percent), 18 of whom (35 percent) had serologic evidence of a recently acquired, subclinical first episode of genital HSV infection, and 34 of whom (65 percent) had reactivation of HSV. Neonatal HSV developed in 6 of 18 infants (33 percent) born to the women with a first episode of genital HSV, and in 1 of 34 infants (3 percent) born to the women with reactivation of HSV (P<0.01); neonatal HSV also occurred in three of the infants born to the 15,867 women with negative cultures. Neonatal HSV-2 occurred in 1...

Benefit of adjuvant chemotherapy for resectable gastric cancer: A meta-analysis

CONTEXT Despite potentially curative resection of stomach cancer, 50% to 90% of patients die of disease relapse. Numerous randomized clinical trials (RCTs) have compared surgery alone with adjuvant chemotherapy, but definitive evidence is lacking. OBJECTIVES To perform an individual patient-level meta-analysis of all RCTs to quantify the potential benefit of chemotherapy after complete resection over surgery alone in terms of overall survival and disease-free survival, and to further study the role of regimens, including monochemotherapy; combined chemotherapy with fluorouracil derivatives, mitomycin C, and other therapies but no anthracyclines; combined chemotherapy with fluorouracil derivatives, mitomycin C, and anthracyclines; and other treatments. DATA SOURCES Data from all RCTs comparing adjuvant chemotherapy with surgery alone in patients with resectable gastric cancer. We searched MEDLINE (up to 2009), the Cochrane Central Register of Controlled Trials, the National Institutes of Health trial registry, and published proceedings from major oncologic and gastrointestinal cancer meetings. STUDY SELECTION All RCTs closed to patient recruitment before 2004 were eligible. Trials testing radiotherapy; neoadjuvant, perioperative, or intraperitoneal chemotherapy; or immunotherapy were excluded. Thirty-one eligible trials (6390 patients) were identified. DATA EXTRACTION As of 2010, individual patient data were available from 17 trials (3838 patients representing 60% of the targeted data) with a median follow-up exceeding 7 years. RESULTS There were 1000 deaths among 1924 patients assigned to chemotherapy groups and 1067 deaths among 1857 patients assigned to surgery-only groups. Adjuvant chemotherapy was associated with a statistically significant benefit in terms of overall survival (hazard ratio [HR], 0.82; 95% confidence interval [CI], 0.76-0.90; P < .001) and disease-free survival (HR, 0.82; 95% CI, 0.75-0.90; P < .001). There was no significant heterogeneity for overall survival across RCTs (P = .52) or the 4 regimen groups (P = .13). Five-year overall survival increased from 49.6% to 55.3% with chemotherapy. CONCLUSION Among the RCTs included, postoperative adjuvant chemotherapy based on fluorouracil regimens was associated with reduced risk of death in gastric cancer compared with surgery alone.

Recurrences after oral and genital herpes simplex virus infection. Influence of site of infection and viral type

We prospectively followed 39 adults with concurrent primary herpes simplex virus (HSV) infection (12 with HSV type 1 and 27 with HSV type 2) of the oropharynx and genitalia, caused by the same virus in each person, to evaluate the influence of viral type (HSV-1 vs. HSV-2) and site of infection (oropharyngeal vs. genital) on the frequency of recurrence. The subsequent recurrence patterns of HSV infection differed markedly according to viral type and anatomical site. Oral-labial recurrences developed in 5 of 12 patients with HSV-1 and 1 of 27 patients with HSV-2 (P less than 0.001). Conversely, genital recurrences developed in 24 of 27 patients with HSV-2 and 3 of 12 patients with HSV-1 (P less than 0.01). The mean rate of subsequent genital recurrences (due to HSV-1 and HSV-2) was 0.23 per month, whereas the mean rate of oral-labial recurrences was only 0.04 per month (P less than 0.001). The mean monthly frequencies of recurrence were, in order, genital HSV-2 infections, 0.33 per month; oral-labial HSV-1 infections, 0.12 per month; genital HSV-1 infections, 0.020 per month; and oral HSV-2 infections, 0.001 per month (P less than 0.01 for each comparison). We conclude that the likelihood of reactivation of HSV infection differs between HSV-1 and HSV-2 infections and between the sacral and trigeminal anatomical sites. The sixfold more frequent clinical recurrence rate of genital HSV infections as compared with oral-labial HSV infections may account for the relatively rapid increase in the prevalence of clinically recognized genital herpes in recent years.

Recurrence Rates in Genital Herpes after Symptomatic First-Episode Infection

Genital herpes continues to be epidemic throughout most sexually active populations [1-4]. A recent serosurvey indicated that 21.7% of the U.S. population have HSV-2 antibodies, which represents a 31% increase in prevalence in the last decade [5, 6]. The seroprevalence of HSV-2 averages 30% in most family practice and obstetrics clinics and 30% to 50% among sexually transmitted disease clinic attendees. Seroprevalence is consistently higher in women than in men [7, 8]. The natural history of HSV infection includes acute or subclinical first-episode mucocutaneous infection, establishment of neuronal latency, and intermittent virus reactivation with or without associated recurrent symptoms [9, 10]. Although this sequence of events has been recognized for more than five decades, little is known about the long-term natural history of genital herpes. In the late 1970s, supported by the National Institutes of Health, we began a prospective study of a large cohort of persons with recently acquired symptomatic genital HSV infection in order to define more precisely the natural history of genital herpes. Clinical, demographic, and recurrence data were collected for 457 patients who presented with virologically, serologically, and clinically confirmed first-episode genital infection. More than half of these patients did not receive antiviral therapy during their primary episode, providing a population not likely to be replicated in the future. We summarize the natural history of symptomatic recurrences in the complete population and in the subset of untreated patients. Methods In 1974, a research clinic dedicated to the study of genital herpes infection was established at Harborview Medical Center, a King Countyfunded hospital affiliated with the University of Washington. Patients were referred by their private physicians or by the sexually transmitted disease clinic at Harborview, or responded to advertisements for participation in clinical studies of HSV infection. Only patients willing to participate in prospective studies with long-term follow-up or in therapeutic trials were enrolled. Between 1974 and 1988, we registered 457 patients with serologically and virologically proven first-episode infection who were followed for at least 60 days from the onset of infection. At the initial clinic visit, genital lesions were cultured and described by anatomic site, stage, and area. Patients were then generally followed at 2- to 3-day intervals until their lesions had healed. The median number of visits and genital examinations during the initial disease episode was 5 (range, 3 to 14 visits). After resolution of the first clinical episode, patients were instructed to return to the clinic during each recurrence or for routine visits at least every 2 to 3 months. Patients who were unable to return for each recurrence were instructed to maintain a diary of onset and resolution dates for each recurrence. These data were collected at the following clinic visit. In general, we insisted that patients return for recurrences until they were able to recognize the signs and symptoms of genital herpes reactivation and to fill out patient diaries about onset and healing of reactivations. We defined a recurrence of genital herpes as the presence of genital ulcerations. We defined duration of a recurrence as the number of days from the first appearance of genital lesions to the reepithelialization of all lesions. If new lesions appeared before complete healing of other lesions, all were considered part of the same episode. We report only recognized symptomatic (lesional) recurrences and do not address subclinical shedding of HSV in the genital tract. Serum specimens from both the acute and convalescent phases were obtained from all patients and tested for HSV-specific antibodies by Western blot; all patients showed seroconversion to HSV-1 or HSV-2 [11, 12]. Some had antibodies to HSV-1 in their acute-phase specimen and antibodies to both HSV-1 and HSV-2 in their convalescent-phase specimens. Patients were categorized as having primary first-episode disease if their acute-phase serum specimen showed absence of antibodies to HSV by Western blot. Based on Western blot profiles of convalescent-phase specimens and the subtype of the HSV isolates from lesions, patients were categorized as having primary HSV-1 or primary HSV-2 infection. Patients who had HSV-1 antibodies in acute-phase specimens and antibodies to HSV-2 in convalescent-phase specimens were classified as having nonprimary first-episode HSV-2 disease [11, 13]. Patients with detectable antibodies to the homologous viral type isolated in initial specimens were classified as having recurrent disease [13]. Forty-two patients had serologic evidence of HSV-2 antibodies in acute- and convalescent-phase serum specimens, and 19 patients with HSV-1 antibodies in both their acute- and convalescent-phase specimens were classified as having reactivation infection and were not included in this study even though they claimed to be experiencing their first episode. We also excluded 64 patients seen between 1974 and 1985 whose serum specimens were analyzed by microneutralization but whose enrollment specimens could not be retrospectively retrieved for confirmation by Western blot [14]. In this study, we compared baseline patient characteristics and severity of primary infection with the subsequent recurrence experience of the patient. Patient characteristics included sex, race, age, and measures of past sexual activity, such as number of partners and history of sexually transmitted diseases. Clinical characteristics included pain, itch, discharge, fever, headache, photophobia, and stiff neck. Because many patients were participants in our early randomized trials of acyclovir, treatment status was also recorded [15-17]. Statistical Methods Monthly recurrence rates for each patient were estimated by dividing the number of recorded recurrences by the number of months the patient was followed. Comparisons of recurrence rates were made using the Wilcoxon rank-sum test or, for comparisons between more than two groups, the Kruskal-Wallis test. The Kaplan-Meier estimate was used to compute time to first recurrence, and appropriate comparisons were made using the Cox model [18]. Recursive partitioning was used as an exploratory technique to identify potential subsets of patients at higher risk for subsequent recurrence. Classification and regression trees were used for recursive partitioning of recurrence rates and a modification of this technique by LeBlanc and Crowley was used to establish time to first recurrence [19, 20]. These techniques identify the variable (and cutpoint, for continuous variables) most closely related to the recurrence pattern. Within each of these two splits, or nodes, of the data, the data are split again. This process is repeated within each node until no further splits appear to be important in predicting recurrences. This partitioning of the data can be represented as a tree that shows the splits of the variables into disjoint patient subsets. Because our previous placebo-controlled treatment trials failed to detect an effect of antiviral therapy on subsequent recurrences, most of our analyses are reported for the entire patient population. However, because treatment is known to affect the duration of primary symptoms, analyses to assess the potential effect of symptoms on subsequent recurrences were also done in the subset of untreated patients. Results Viral Type and Clinical Classification of Persons with First-Episode Genital Herpes Of the 457 patients presenting with first-episode genital herpes, 399 (87%) had primary genital HSV infection; 73 (16% of the total cohort) were infected with HSV-1 and 326 (71% of the total cohort) were infected with HSV-2. Fifty-eight (13%) patients were classified as having nonprimary HSV-2 infection. The median age of the patients was 24 years; 92% were single and 91% were white. Demographic characteristics were similar among those presenting with primary HSV-1, primary HSV-2, and nonprimary HSV-2 infection and were identical to those reported previously [10, 15-17, 21]. Frequencies of the major clinical signs and symptoms of the initial episode of genital herpes are shown in Figure 1. Patients with true primary genital herpes infection, regardless of infecting viral type, tended to have more severe disease than did patients with previous HSV-1 infection. This was most evident with respect to constitutional symptoms: Seventy-nine percent of those with primary HSV-1 or HSV-2 infection reported at least one constitutional symptom (fever, headache, photophobia, or stiff neck) during their first episode, compared with only 43% of those with nonprimary infection. Seventy-seven percent of those with primary episodes had inguinal adenopathy compared with 52% of those with nonprimary genital herpes (P = 0.001). Frequencies of symptoms and signs were similar between those with primary genital HSV-1 and primary genital HSV-2 infections, except in the case of nuchal rigidity, which was reported by 42% of patients with primary HSV-2 infection and 12% of those with primary HSV-1 infection (P = 0.005). Figure 1. Frequency of clinical signs and symptoms of first-episode genital herpes by viral type and evidence of previous herpes simplex virus type 1 (HSV-1) exposure. P Overall Recurrence Rates after Resolution of the Initial Episode Follow-up was defined as the time from enrollment to the date of the last clinic visit or to the date that a patient initiated long-term suppressive oral acyclovir therapy. The median follow-up was 418 days (range, 61 to 4897 days) and was similar in all subsets of patients whether segregated according to viral type, sex, or severity of clinical episode. The median numbers of clinic visits per patient in the first 90, 91 to 180, 181 to 365, and 366 to 720 days of follow-up were 10, 2, 2, and 1, respectively. The large numbers o

A Double-Blind Study of Oral Acyclovir for Suppression of Recurrences of Genital Herpes Simplex Virus Infection

Patients with frequently recurring genital herpes were enrolled in a double-blind placebo-controlled trial comparing 200-mg acyclovir capsules, given five or two times daily, with placebo. Of 47 placebo recipients, 44 (94 per cent) had recurrences during the 120-day treatment period, compared with 13 (29 per cent) of 45 patients treated with acyclovir five times daily and 18 of 51 (35 per cent) treated with acyclovir twice daily (P less than 0.001 for each regimen compared with placebo). The median time to the first clinical recurrence was 18 days in placebo recipients, compared with over 120 days in both acyclovir-treated groups (P less than 0.001 for both groups compared with placebo). The mean monthly recurrence rate during the medication period was 0.86 in placebo recipients, compared with 0.13 in patients treated with acyclovir five times daily and 0.14 in patients treated with acyclovir twice daily (P less than 0.001 for both groups compared with placebo). While receiving therapy, 86 of 96 acyclovir-treated patients had over a 50 per cent reduction in their pretreatment recurrence rate. Breakthrough recurrences in acyclovir recipients were of shorter duration and associated with a lower frequency of viral shedding than recurrences in placebo recipients. After medication was discontinued, the subsequent recurrence rate returned to pretreatment frequencies. Daily oral acyclovir was well tolerated. We conclude that oral acyclovir given for four months markedly reduces but does not completely prevent recurrences of genital herpes and does not influence the long-term natural history of the disease.

Phase II Trial of Erlotinib in Gastroesophageal Junction and Gastric Adenocarcinomas: SWOG 0127

PURPOSE A phase II trial of the oral epidermal growth factor receptor (EGFR) inhibitor erlotinib in patients with gastroesophageal adenocarcinomas stratified according to primary tumor location into two groups: gastroesophageal junction (GEJ)/cardia and distal gastric adenocarcinomas. PATIENTS AND METHODS Patients with a histologically proven diagnosis of adenocarcinoma of the GEJ or stomach (ST) that was unresectable or metastatic; presence of measurable disease; no prior chemotherapy for advanced or metastatic cancer; Zubrod performance status (PS) of 0 to 1; and adequate renal, hepatic, and hematologic function were treated with erlotinib 150 mg/d orally. Patient characteristics were median age, GEJ-63 years, ST-64 years; sex, GEJ-84% male and 16% female, ST-60 male and 40 female; Zubrod PS, GEJ-25 had a PS of 0 and 18 had a PS 1, ST-13 had a PS of 0 and 12 had a PS of 1. RESULTS Percentage of common toxicities were skin rash, 86% and 72%; fatigue, 51% and 44%; and AST/ALT elevation, 28% and 28%, respectively for GEJ and ST. There has been one confirmed complete response, three confirmed partial responses (PRs) and one unconfirmed PR for an overall response probability of 9% confirmed (95% CI, 3% to 22%), all occurring in GEJ stratum. No responses were observed in ST stratum. The median survival was 6.7 months in GEJ and 3.5 months in ST stratum. Neither intratumoral EGFR, transforming growth factor-alpha or phosphorylated Akt kinase expression nor plasma proteomic analyses were predictive of clinical outcome. No somatic mutations of the EGFR exons 18, 19, or 21 were detected and there was no gross amplification of EGFR by fluorescence in situ hybridization. CONCLUSION Erlotinib is active in patients with GEJ adenocarcinomas, but appears inactive in gastric cancers. The molecular correlates examined were not predictive of the patient therapeutic response.