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Background Premenopausal women with high-risk hormone receptor (HR)-positive breast cancer often receive ovarian function suppression (OFS) with aromatase inhibitor therapy; however, abrupt menopause induction, together with further decrements in estrogen exposure through aromatase inhibition, may affect cardiovascular microcirculatory function. We examined adenosine-induced changes in left ventricular (LV) myocardial T1, a potential subclinical marker of LV microcirculatory function in premenopausal women undergoing treatment for breast cancer. Methods Twenty-one premenopausal women (14 with HR-positive breast cancer receiving OFS with an aromatase inhibitor and 7 comparator women with triple-negative breast cancer [TNBC] who had completed primary systemic therapy) underwent serial resting and adenosine cardiovascular magnetic resonance imaging measurements of LV myocardial T1 and LV volumes, mass, and ejection fraction. All statistical tests were 2-sided. Results After a median of 4.0 months (range = 3.1-5.7 months), the stress to resting ratio of LV myocardial T1 declined in women with HR-positive breast cancer (−1.3%, 95% confidence interval [CI] = −3.4% to 0.7%) relative to those with TNBC (3.2%, 95% CI = −1.2% to 7.6%, P = .02). After accounting for age, LV stroke volume, LV ejection fraction, diastolic blood pressure, and breast cancer subtype women with HR-positive breast cancer experienced a blunted T1 response after adenosine relative to women with TNBC (difference = −4.7%, 95% CI = −7.3% to −2.1%, Pdifference = .002). Conclusions Over the brief interval examined, women with HR-positive breast cancer receiving OFS with an aromatase inhibitor experienced reductions in adenosine-associated changes in LV myocardial T1 relative to women who received nonhormonal therapy for TNBC. These findings suggest a possible adverse impact on LV myocardial microcirculatory function in premenopausal women with breast cancer receiving hormone deprivation therapy.

Importance Indoleamine 2,3-dioxygenase 1 (IDO1) causes tumor immune suppression. The IDO1 pathway inhibitor indoximod combined with a taxane in patients with ERBB2-negative metastatic breast cancer was tested in a prospective clinical trial. Objective To assess clinical outcomes in patients with ERBB2-negative metastatic breast cancer treated with indoximod plus a taxane. Design, setting, and participants This phase 2 double-blinded randomized 1:1 placebo-controlled clinical trial enrolled patients at multiple international centers from August 26, 2013, to January 25, 2016. Eligibility criteria included ERBB2-negative metastatic breast cancer, ability to receive taxane therapy, good performance status, normal organ function, no previous immunotherapy use, and no autoimmune disease. The study was discontinued in June 2017 because of lack of efficacy. Data analysis was performed from February 2019 to April 2020. Interventions A taxane (paclitaxel [80 mg/m2] weekly 3 weeks on, 1 week off, or docetaxel [75 mg/m2] every 3 weeks) plus placebo or indoximod (1200 mg) orally twice daily as first-line treatment. Main outcomes and measures The primary end point was progression-free survival (PFS); secondary end points were median overall survival, objective response rate, and toxic effects. A sample size of 154 patients would detect a hazard ratio of 0.64 with 1-sided α = .1 and β = .2 after 95 events. Archival tumor tissue was stained with immunohistochemistry for IDO1 expression as an exploratory analysis. Results Of 209 patients enrolled, 169 were randomized and 164 were treated (85 in the indoximod arm; 79 in the placebo arm). The median (range) age was 58 (29-85) years; 166 (98.2%) were female, and 135 (79.9%) were White. The objective response rate was 40% and 37%, respectively (indoximod vs placebo) (P = .74). The median (range) follow-up time was 17.4 (0.1-39.4) months. The median PFS was 6.8 months (95% CI, 4.8-8.9) in the indoximod arm and 9.5 months (95% CI, 7.8-11.2) in the placebo arm (hazard ratio, 1.2; 95% CI, 0.8-1.8). Differences between the experimental and placebo arms in median PFS (6.8 vs 9.5 months) and overall survival (19.5 vs 20.6 months) were not statistically significant. Grade 3 or greater treatment-emergent adverse events occurred in 60% of patients in both arms. Conclusions and relevance This randomized clinical trial found that, among patients with ERBB2-negative metastatic breast cancer, addition of indoximod to a taxane did not improve PFS compared with a taxane alone. Trial registration ClinicalTrials.gov Identifier: NCT01792050.

Purpose: Low-dose tamoxifen reduces breast cancer risk, but remains untested in chest-irradiated cancer survivors—a population with breast cancer risk comparable with BRCA mutation carriers. We hypothesized that low-dose tamoxifen would be safe and efficacious in reducing radiation-related breast cancer risk. Patients and Methods: We conducted an investigator-initiated, randomized, phase IIb, double-blinded, placebo-controlled trial (FDA IND107367) between 2010 and 2016 at 15 U.S. sites. Eligibility included ≥12 Gy of chest radiation by age 40 years and age at enrollment ≥25 years. Patients were randomized 1:1 to low-dose tamoxifen (5 mg/day) or identical placebo tablets for 2 years. The primary endpoint was mammographic dense area at baseline, 1 and 2 years. IGF-1 plays a role in breast carcinogenesis; circulating IGF-1 and IGF-BP3 levels at baseline, 1 and 2 years served as secondary endpoints. Results: Seventy-two participants (low-dose tamoxifen: n = 34, placebo: n = 38) enrolled at a median age of 43.8 years (35–49) were evaluable. They had received chest radiation at a median dose of 30.3 Gy. Compared with the placebo arm, the low-dose tamoxifen arm participants had significantly lower mammographic dense area (P = 0.02) and IGF1 levels (P < 0.0001), and higher IGFBP-3 levels (P = 0.02). There was no difference in toxicity biomarkers (serum bone-specific alkaline phosphatase, lipids, and antithrombin III; urine N-telopeptide cross-links) between the treatment arms. We did not identify any grade 3–4 adverse events related to low-dose tamoxifen. Conclusions: In this randomized trial in chest-irradiated cancer survivors, we find that low-dose tamoxifen is effective in reducing established biomarkers of breast cancer risk and could serve as a risk-reduction strategy.

Background Young premenopausal women with breast cancer often experience more aggressive disease biology and poorer survival than older women. Diagnostic and therapeutic advances, including human epidermal growth factor receptor 2 (HER2)-directed therapy, may lessen treatment burden and improve survival for these young women, but contemporary incidence and survival data by HER2 status are limited. Patients and Methods We identified women aged 20-49 years (n = 68,530) diagnosed with stage I-III breast cancer during 2010-2016 from the United States Surveillance, Epidemiology, and End Results 18 registries database. Age-adjusted average annual percent changes in incidence (diagnosis 2010-2016) and 5-year Kaplan-Meier survival curves (diagnosis 2010-2015) were estimated by HER2 and hormone receptor (HR) status and stratified independently by cancer stage and race/ethnicity. Results With increasing age decade, proportions of HER2−/HR+ cancer increased, whereas proportions of HER2+/HR+, HER2+/HR−, and HER2−/HR− decreased. The greatest increases in incidence during 2010-2016 were observed for HER2+ among women aged 20-49 years and HER2−/HR− among women aged 20-29 years. Incidence decreased for HER2−/HR− among women aged 40-49 years. Five-year survival was lowest for HER2−/HR− status compared to other receptor-based subtypes among women aged 20-49 years. HER2+ status was more beneficial for 5-year survival than HR+ status among women aged 20-29 years, with the opposite observed among women aged 30-49 years, particularly those aged 40-49 years. Conclusion HER2+ breast cancer increased among premenopausal women and was also associated with higher early survival within each HR status. HER2−/HR− cancer also increased among women aged 20-29 years and was associated with lower early survival. Our contemporary data provide important insights to help inform preventive and therapeutic strategies for premenopausal women.

BACKGROUND: Our study aim was to evaluate neuromuscular ultrasound (NMUS) for the assessment of taxane chemotherapy-induced peripheral neuropathy (CIPN), the dose-limiting toxicity of this agent. METHODS: This cross-sectional study of breast cancer patients with taxane CIPN measured nerve cross-sectional area (CSA) by NMUS and compared with healthy historical controls. Correlations were determined between CSA and symptom scale, nerve conduction studies, and intraepidermal nerve fiber density (IENFD). RESULTS: A total of 20 participants reported moderate CIPN symptoms at a median of 3.8 months following the last taxane dose. Sural nerve CSA was 1.2 mm(2) smaller than healthy controls (P ≤ .01). Older age and time since taxane were associated with smaller sural nerve CSA. For each 1 mm(2) decrease in sural nerve CSA, distal IENFD decreased by 2.1 nerve/mm (R(2) 0.30; P = .04). CONCLUSIONS: These data support a sensory predominant taxane neuropathy or neuronopathy and warrant future research on longitudinal NMUS assessment of CIPN.

Background Evidence-based medicine (EBM) is a key aspect of medical training that can be challenging for trainees to learn. Tumour boards (TBs) are multidisciplinary meetings that are often opportunities for trainees to deliver patient case presentations, which is another integral part of medical education; however, TBs are time intensive, typically lack academic structure and may fail to emphasise EBM. Objective To design a systematic approach to improve both trainee satisfaction and the level of evidence cited at typical academic TBs. Methods From 2017 to 2018, Plan-Do-Study-Act (PDSA) methodology was used to develop a systematic approach for medical oncology trainees towards TBs. Statistical testing was used to assess which characteristics of a patient case made it more difficult to apply EBM. Anonymous surveys were distributed to trainees before and after the intervention to assess the educational utility. Results We developed a shared voluntary case database, so that references with higher levels of evidence could be rapidly recalled and applied to similar cases. We then developed EBM-focused review sessions to highlight database trends. Both the database and the review sessions had high participation rates (>90% cases had voluntary data entry), and each were reported to have educational value by trainees. Conclusions A two-step implementation of an easy-to-use case database followed by review sessions focused on high-yield sources of evidence improved trainee satisfaction for TBs, but did not significantly improve the strength of the evidence cited.

Purpose The risk of scalp metastases in patients using scalp cooling for preservation of hair during chemotherapy has been a concern but is poorly described. Methods A systematic review and meta-analysis of longitudinal studies was undertaken to evaluate the effect of scalp cooling versus no scalp cooling on the risk of scalp metastasis in patients treated for breast cancer with chemotherapy. Electronic databases, journal specific, and hand searches of articles identified were searched. Patients were matched based on disease, treatment, lack of metastatic disease, and sex. Results A total of 24 full-text articles were identified for review. Of these articles, ten quantified the incidence of scalp metastasis with scalp cooling over time. For scalp cooling, 1959 patients were evaluated over an estimated mean time frame of 43.1 months. For no scalp cooling, 1238 patients were evaluated over an estimated mean time frame of 87.4 months. The incidence rate of scalp metastasis in the scalp cooling group versus the no scalp cooling group was 0.61% (95% CI 0.32–1.1%) versus 0.41% (95% CI 0.13–0.94%); P = 0.43. Conclusion The incidence of scalp metastases was low regardless of scalp cooling. This analysis suggests that scalp cooling does not increase the incidence of scalp metastases. Electronic supplementary material The online version of this article (doi:10.1007/s10549-017-4185-9) contains supplementary material, which is available to authorized users.

The vitamin D hormone, [1,25(OH) 2D, calcitriol], inhibits proliferation and angiogenesis in breast cancer but its therapeutic use is limited by hypercalcemia. Synthetic analogs of 1,25(OH) 2D that are less calcemic, such as paricalcitol (19-nor-1,25-Dihydroxyvitamin D 2), are used to treat hyperparathyroidism associated with chronic kidney disease. We sought to determine the safety and feasibility of taking oral paricalcitol with taxane-based chemotherapy in women with metastatic breast cancer (MBC). Oral paricalcitol was considered safe if it did not result in excessive toxicity, defined as grade 3 or higher serum calcium levels. It was considered feasible if the majority of women could take eight weeks of continuous therapy in the first three months. Serum calcium was monitored weekly and the paricalcitol dose was adjusted based on its calcemic effect. Intact parathyroid hormone (iPTH) was monitored as a marker of paricalcitol activity. Twenty-four women with MBC were enrolled. Twenty women (83%) received eight weeks of continuous therapy. Paricalcitol was well-tolerated with no instances of hypercalcemia grade 2 or greater. Fourteen women (54%) were able to escalate the dose. The dose range of paricalcitol in the first 3 mo was 2-7 ug/day. Serum iPTH levels at baseline were significantly higher in women with serum 25-Hydroxyvitamin D (25-OHD) levels less than 30 ng/ml (96.4 ± 40.9 pg/ml) vs. 46.2 ± 20.3 pg/ml (p = 0 0.001) (iPTH reference 12-72 pg/ml). We conclude that paricalcitol is safe and feasible in women with MBC who are receiving chemotherapy.

Milataxel is a novel taxane analog, with evidence of enhanced preclinical activity compared to paclitaxel and docetaxel, especially in cell lines that over express P-glycoprotein. Based on preclinical data that milataxel may be active in colorectal cancer (CRC), a phase II study was performed in patients with advanced previously treated CRC.Forty-four eligible patients were entered. Milataxel was administered intravenously every 3 weeks at the dose of 35 mg/m(2). No objective responses were noted, stable disease was seen in three patients. The median time to progression was 1.4 months (95% CI of 1.2-2.4 months). Three subjects developed neutropenic sepsis and two died. The most frequent grade 3/4 adverse events were neutropenia (57%), leukopenia (27%), dehydration (14%), neuropathy (16%), diarrhea (14%) and thrombocytopenia (14%). The pharmacokinetics of milataxel was assessed in five subjects. The mean milataxel elimination half-life was 64 h and the mean area under the plasma concentration-time curve was 1,708 ng h/ml.A syndrome of neutropenic sepsis and diarrhea can be life threatening and close surveillance is needed in patients treated with milataxel at the dose of 35 mg/m(2) every 3 weeks. Clinical activity was not demonstrated in patients with advanced previously treated CRC.

Background The primary objectives of this phase I study were to define a tolerable dose and to describe the toxicity of lenalidomide administered as a daily oral dose for 4 weeks followed by a 2-week rest period (6-week cycle) in patients with solid tumors that were refractory to standard treatment. The secondary objective was to document any antitumor activity. Methods Key eligibility criteria included a performance status of 0–2 and acceptable hematologic, hepatic, and renal function. The dose was escalated from 5 to 10 to 25 mg/day. Nine cycles (54 weeks) were planned unless the patient developed intolerable toxicity or experienced tumor progression. Dose-limiting toxicity was defined as nonhematologic toxicity of grade 3 or higher and hematologic toxicity of grade 4 or higher occurring in cycle 1. Results Overall, 20 patients were enrolled. One patient was ineligible due to a thromboembolic event within the preceding 6 months, but this was not known at enrollment and this patient was included in the analysis. Three, five, and 12 patients were treated with 5, 10, and 25 mg/day, respectively. One patient on 25 mg/day developed grade 3 motor neuropathy in cycle 1, and this was the only dose-limiting toxicity. Moderate dose-dependent and reversible hematologic toxicity was observed. The nonhematologic toxicities were otherwise mild to moderate over multiple cycles of lenalidomide. One patient had a partial response, and three patients had stable disease; three of these patients had non-small cell lung cancer. Conclusion The recommended dose of lenalidomide for further studies in patients with solid tumors is 25 mg/day for 4 weeks followed by a 2-week rest period.

Purpose: Women with metastatic triple negative breast cancer (TNBC) can have a poor prognosis with treatment limited to cytotoxic chemotherapy. The identification of effective therapies that may limit exposure to cytotoxic chemotherapy and lead to prolonged survival is an unmet medical need. We tested an inhibitor of the epidermal growth factor receptor, panitumumab in combination with chemotherapy. Methods: We conducted a single arm clinical trial in women with metastatic or locally advanced TNBC to paclitaxel 80 mg/m2 and carboplatin AUC of 2 on days 1, 8, and 15 and panitumumab 6 mg/kg on days 1 and 15 for a cycle length of 28 days. The objectives were to evaluate the response rate and safety of the combination in comparison to historical controls. Results: Fourteen patients with TNBC were enrolled with a median age of 53 years. The majority of women were African American (64.3%) with visceral metastasis (64.2%). Hematologic toxicities, particularly neutropenia and thrombocytopenia, were a major cause of missed chemotherapy and delayed treatment in this study. The overall response rate (complete and partial response) of the 13 evaluable patients was 46%. The median time to best response was 2.4 months and the median time to disease progression was 3.6 months. We were able to perform the PAM50 analysis on tumors from 7 of our subjects. All the samples tested clustered within the basal-like subtype. Conclusions: In our experience the response rate of carboplatin, paclitaxel and panitumumab was consistent with other reports of response for cytotoxic chemotherapy in metastatic TNBC.

The safety and efficacy of gemcitabine and concurrent radiation to the upper abdomen followed by weekly gemcitabine in patients with resected pancreatic cancer was determined. Patients with resected adenocarcinoma of the pancreas were treated with intravenous gemcitabine administered twice-weekly (40 mg m(-2)) for 5 weeks concurrent with upper abdominal radiation (50.4 Gy in 5(1/2) weeks). At the completion of the chemoradiation, patients without disease progression were given gemcitabine (1000 mg m(-2)) weekly for two cycles. Each cycle consisted of 3 weeks of treatment followed by 1 week without treatment. Forty-seven patients were entered, 46 of whom are included in this analysis. Characteristics: median age 61 years (range 35-79); 24 females (58%); 73% stage T3/T4; and 70% lymph node positive. Grade III/IV gastrointestinal or haematologic toxicities were infrequent. The median survival was 18.3 months, while the median time to disease recurrence was 10.3 months. Twenty-four percent of patients were alive at 3 years. Only six of 34 patients with progression experienced local regional relapse as a component of the first site of failure. These results confirm the feasibility of delivering adjuvant concurrent gemcitabine and radiation to the upper abdomen. This strategy produced good local regional tumour control.

To evaluate the utility of F-FDG-PET in predicting response to concomitant chemoradiation in locally-advanced esophageal cancer.Approximately 25% of esophageal cancer patients experience a pathologic complete response (pCR) to preoperative chemoradiation therapy. Computed tomography, endoscopy, and endoscopic ultrasound are unable to identify patients experiencing a pCR. Growing evidence supports the use of F-FDG-PET in the staging of esophageal cancer in its ability to detect occult metastatic and lymph nodal disease. The identification of patients with a pCR to chemoradiation could potentially spare those patients the morbidity associated with a resection.Eligibility criteria included T3-T4N0M0 or T1-T4N1M0 esophageal cancer. Patients underwent an initial F-FDG-PET before treatment and then repeated 4 to 6 weeks after chemoradiation, prior to the esophagectomy. Chemoradiation consisted of: cisplatinum, 5-fluorouracil, and radiation to a median dose of 50.4 Gy. Pathologic response was determined from a systematic review of the esophagectomy specimens.Sixty-four patients have completed therapy to date. Response was as follows: pCR 27%, pathologic residual microscopic (pCRmicro) 14.5%, partial response 19%, and stable or progressive disease 39.5%. A pretreatment standardized uptake value (SUVmax1hour)or = 15 was associated with an observed 77.8% significant response (pCR + pCRmicro) compared with 24.2% for patients with a pretreatment SUVmax1hour15 (P = 0.005). Significant response was observed in 71.4% of patients with a decrease in SUVmax1houror = 10 compared with 33.3% when the SUVmax1hour decreased10 (P = 0.004).Pretreatment and posttreatment F-FDG-PET can be useful for predicting significant response to chemoradiation in esophageal cancer. These data should be considered in evaluation of patients for esophagectomy after chemoradiation.

Purpose: To determine the impact of 18-F-fluoro-deoxy-D-glucose positron emission tomography (FDG-PET) in the staging and prognosis of patients with locally advanced esophageal cancer (LAEC). Methods and Materials: Between January 2000 and October 2004, all patients with LAEC evaluated in the Department of Radiation Oncology were considered for enrollment into a Phase II trial of preoperative chemoradiation. Entry required a staging whole-body FDG-PET scan. Results: One hundred ten consecutive patients were evaluated; 38 were ineligible for reasons including treatment elsewhere, prior malignancy, or refusal of treatment. After conventional staging (clinical examination, endoscopic ultrasound, and chest/abdominal computerized tomography), 33 patients were ineligible because of metastatic disease or poor performance status. Of the remaining 39 patients, 23 were confirmed to have LAEC after FDG-PET staging and were treated in the Phase II trial (Cohort I). Sixteen patients, however, had FDG-PET findings consistent with occult metastatic disease and were deemed ineligible for the trial but were treated with curative intent (Cohort II). The 2-year survival rate for the 23 patients in Cohort I was 64%, compared with 17% ( p = 0.003) for patients in Cohort II (FDG-PET positive). Conclusions: More than one-third of patients determined to have LAEC with conventional staging were upstaged with the use of FDG-PET. Despite comparable therapy, upstaging with FDG-PET predicts poor 2-year survival.

Purpose: This phase II trial of induction irinotecan/gemcitabine followed by twice-weekly gemcitabine and upper abdominal radiation was initiated to determine the activity of this regimen in patients with unresectable pancreatic cancer. Methods: Patients with locally advanced, nonmetastatic adenocarcinoma of the pancreas received 2 cycles of induction irinotecan (100 mg/m 2 IV) and gemcitabine (1000 mg/m 2 IV) on days 1 and 8 of each 3-week cycle. Following the induction, patients without disease progression received gemcitabine administered twice weekly (40 mg/m 2 /day) for 5 weeks concurrent with upper abdominal radiation (50.4 Gy over 5.5 weeks). Results: From April 2000 to August 2003, 20 patients were entered into this study, 17 of whom were evaluable for treatment response. Characteristics included a median age of 67 years (range, 44-87 years) and 14 men (70%). Grades III and IV hematologic toxicity occurred in 25% and 5% of patients respectively and was primarily thrombocytopenia. No grade IV gastrointestinal toxicities or deaths due to therapy were observed. All therapy was completed in 8 patients, 7 patients were removed due to progression, 2 due to toxicity, 2 refused further treatment, and 1 was removed per the treating physician. The median time to progression and median survival was 5.1 months (95% CI, 3.2-6.7) and 8.8 months (95% CI, 6.4-10.1) respectively. Four patients (20%) were alive at 12 and 18 months. Conclusion: Induction irinotecan/gemcitabine followed by twice-weekly gemcitabine and upper abdominal radiation is feasible in patients with locally advanced pancreatic cancer. This regimen, however, has only modest activity and should not be explored further.

ImportanceChemotherapy-induced alopecia is a common and distressing adverse effect. In previous studies of scalp cooling to prevent chemotherapy-induced alopecia, conclusions have been limited.ObjectivesTo evaluate whether use of a scalp cooling system is associated with a lower amount of hair loss among women receiving specific chemotherapy regimens for early-stage breast cancer and to assess related changes in quality of life.Design, setting, and participantsA prospective cohort study conducted at 5 US medical centers of women with stage I or II breast cancer receiving adjuvant or neoadjuvant chemotherapy regimens excluding sequential or combination anthracycline and taxane (106 patients in the scalp cooling group and 16 in the control group; 14 matched by both age and chemotherapy regimen). The study was conducted between August 2013 and October 2014 with ongoing annual follow-up for 5 years.ExposuresUse of a scalp cooling system. Scalp cooling was initiated 30 minutes prior to each chemotherapy cycle, with scalp temperature maintained at 3°C (37°F) throughout chemotherapy and for 90 minutes to 120 minutes afterward.Main outcomes and measuresSelf-estimated hair loss using the Dean scale was assessed 4 weeks after the last dose of chemotherapy by unblinded patient review of 5 photographs. A Dean scale score of 0 to 2 (≤50% hair loss) was defined as treatment success. A positive association between scalp cooling and reduced risk of hair loss would be demonstrated if 50% or more of patients in the scalp cooling group achieved treatment success, with the lower bound of the 95% CI greater than 40% of the success proportion. Quality of life was assessed at baseline, at the start of the last chemotherapy cycle, and 1 month later. Median follow-up was 29.5 months.ResultsAmong the 122 patients in the study, the mean age was 53 years (range, 28-77 years); 77.0% were white, 9.0% were black, and 10.7% were Asian; and the mean duration of chemotherapy was 2.3 months (median, 2.1 months). No participants in the scalp cooling group received anthracyclines. Hair loss of 50% or less (Dean score of 0-2) was seen in 67 of 101 patients (66.3%; 95% CI, 56.2%-75.4%) evaluable for alopecia in the scalp cooling group vs 0 of 16 patients (0%) in the control group (P

BACKGROUND: Black women can have worse outcomes than white women with breast cancer. We examined survival in black and white women who received neoadjuvant chemotherapy. METHODS: We identified 98 women with stage II or III breast cancer who underwent neoadjuvant chemotherapy. Women with inflammatory breast cancer, T4 disease, or metastases were excluded. Data were analyzed using the Fisher exact test and Kaplan-Meier method. RESULTS: From the cohort, 69 women were included. The median follow-up was 6.2 years. The estrogen receptor status was similar. White women tended to overexpress human epidermal growth factor receptor 2 (HER2) (P 5.091). The pretreatment T stage was T3. All women received similar neoadjuvant chemotherapy. The 5-year progression-free survival was better for white women compared with black women (78% vs 58%, P 5 .05). The 5-year overall survival was similar (P 5 .095). CONCLUSIONS: The pretreatment characteristics of women receiving neoadjuvant chemotherapy were similar. Black women had a worse disease-free survival. The overall survival was the same.

• Fifty-eight patients with either advanced or unresectable squamous cell carcinoma of the head and neck were randomly selected to receive either twice daily radiation alone or twice daily radiation plus concomitant chemotherapy with cisplatin and fluorouracil (5-fluorouracil). There was no advantage in survival or time to progression with the addition of chemotherapy to twice daily radiation for patients with advanced resectable cancers. In the group of patients with unresectable cancers, however, there was a statistically significant advantage to the addition of chemotherapy, both in terms of disease-free survival and date to progression. ( Arch Otolaryngol Head Neck Surg . 1992;118:806-810)

Purpose Cancer survivors exposed to anthracyclines experience an increased risk of cardiovascular (CV) events. We hypothesized that anthracycline use may increase aortic stiffness, a known predictor of CV events. Patients and Methods We performed a prospective, case-control study involving 53 patients: 40 individuals who received an anthracycline for the treatment of breast cancer, lymphoma, or leukemia (cases), and 13 age- and sex-matched controls. Each participant underwent phase-contrast cardiovascular magnetic resonance measures of pulse wave velocity (PWV) and aortic distensibility (AoD) in the thoracic aorta at baseline, and 4 months after initiation of chemotherapy. Four one-way analyses of covariance models were fit in which factors known to influence thoracic aortic stiffness were included as covariates in the models. Results At the 4-month follow-up visit, aortic stiffness remained similar to baseline in the control participants. However, in the participants receiving anthracyclines, aortic stiffness increased markedly (relative to baseline), as evidenced by a decrease in AoD (P < .0001) and an increase in PWV (P < .0001). These changes in aortic stiffness persisted after accounting for age, sex, cardiac output, administered cardioactive medications, and underlying clinical conditions known to influence aortic stiffness, such as hypertension or diabetes (P < .0001). Conclusion A significant increase in aortic stiffness occurs within 4 months of exposure to an anthracycline which was not seen in an untreated control group. These results indicate that previously regarded cardiotoxic cancer therapy adversely increases thoracic aortic stiffness, a known independent predictor of adverse cardiovascular events.

Early clinical studies combining irinotecan (CPT-11, Camptosar) and gemcitabine (Gemzar) have yielded encouraging results. Gemcitabine administered via a twice-weekly schedule results in an enhanced radiation-sensitizing effect. This multi-institution phase II trial of induction irinotecan/gemcitabine followed by twice-weekly gemcitabine and upper abdominal radiation has been initiated to determine the activity of this regimen in patients with unresectable pancreatic cancer. Patients received two cycles of induction irinotecan (100 mg/ m2 IV) and gemcitabine (1,000 mg/m2 IV) on days 1 and 8 of each 3-week cycle. Following the induction therapy, patients without disease progression received twice-weekly gemcitabine at 40 mg/m2 and radiation. Nine patients have been enrolled in the study to date. Median patient age was 71 years (range: 65-85 years). The major toxicity observed thus far was grade 3/4 neutropenia. Grade 3/4 nonhematologic toxicity was rarely observed and included dehydration (12%) and diarrhea (12%), which were likely related to the irinotecan. No treatment-related deaths have occurred. These preliminary data suggest that this regimen is well tolerated. Although the data are limited, tumor progression during the induction chemotherapy has not been observed thus far (radiographically or biochemically [CA-19-9]).

We designed a phase II trial to examine the benefit of preoperative hyperfractionated radiation therapy (XRT) and concurrent chemotherapy for patients with locally advanced esophageal cancer (LAEC).The pathologic complete response (pCR) was the primary endpoint to estimate efficacy.Twenty-three patients with LAEC received twice-daily XRT during wk 1 and 5 and once-daily XRT during wk 2-4 (59 Gy). Cisplatin (100 mg/m(2)) was given on d 1, while 5-fluorouracil (1000 mg/m(2)) was given by continuous infusion the first and fifth weeks of the XRT.The pCR for the 19 patients undergoing esophagectomy was 16%. The study was closed at the interim analysis having not met the required minimum pCR rate of 20%. Hematologic toxicities consisted of grades III and IV neutropenia observed in 33% and 14% of patients, respectively. Grade III nausea and vomiting was seen in 38% of patients. One grade V pulmonary toxicity occurred. The median survival was 44.6 mo with 65% of patients alive at 2 yr.The pCR rate in this trial did not meet the predetermined statistical minimum. With the encouraging 2-yr survival, it is not clear that pCR is a reliable surrogate endpoint to discern treatment efficacy.

Background 5-fluorouracil remains the standard therapy for patients with advanced/metastatic colorectal cancer. Pre-clinical studies have demonstrated the biological modulation of 5-fluorouracil by methotrexate and leucovorin. This phase II study was initiated to determine the activity and toxicity of sequential methotrexate – leucovorin and 5-fluorouracil chemotherapy in patients with advanced colorectal cancer. Methods Ninety-seven patients with metastatic colorectal cancer were enrolled onto the study. Methotrexate – 30 mg/m2 was administered every 6 hours for 6 doses followed by a 2 hour infusion of LV – 500 mg/m2. Midway through the leucovorin infusion, patients received 5-fluorouracil – 600 mg/m2. This constituted a cycle of therapy and was repeated every 2 weeks until progression. Results The median age was 64 yrs (34–84) and the Eastern Cooperative Group Oncology performance score was 0 in 37%, 1 in 55% and 2 in 8% of patients. Partial and complete responses were seen in 31% of patients with a median duration of response of 6.4 months. The overall median survival was 13.0 months. The estimated 1-year survival was 53.7%. Grade III and IV toxic effects were modest and included mucositis, nausea and vomiting. Conclusions This phase II study supports previously reported data demonstrating the modest clinical benefit of 5-FU modulation utilizing methotrexate and leucovorin in patients with metastatic colorectal cancer. Ongoing studies evaluating 5-fluorouracil modulation with more novel agents (Irinotecan and/or oxaliplatin) are in progress and may prove encouraging.

Monolayer cultures can be established from human endometrial tissue after enzymatic dispersal into isolated glands or single cells. Three cell types that have distinct morphology by light and electron microscopy are observed in the resulting primary cultures. One cell type, an elongated spindle cell, is similar in appearance to fibroblasts derived from other tissues. A second cell type forms colonies of tightly cohesive cells, ranging in shape from oval to polygonal. These cells have typical organelles and junctional complexes characteristic of epithelial cells from the endometrium. The third cell type assumes a pavement-like appearance composed of polygonal cells when viewed by phase contrast microscopy, but lacks distinctive ultrastructural features of epithelial cells. These cells in culture resemble the endometrial stromal cell, the predominant cell type of the human endometrium in vivo. The epithelial cell does not survive subculturing but the other two cell types can be passaged through several generations and can be stored in liquid nitrogen and subsequently returned to culture.

Propagable cell cultures derived from human endometrial tissue were determined to contain cells predominantly of stromal cell origin based on their morphologic resemblance to endometrial stromal cells. These features included nexi, solitary cilia, and predecidual cytology. In addition to morphology the cell cultures retained a normal karyotype and responded to steroid hormones as evidenced by cellular aggregation. The stromal cells were evaluated for a variety of characteristics associated with transformed cells and seemed to be biologically normal without neoplastic phenotypes. Growth potential of the stromal cell cultures was also characterized in normal maintenance medium, in nutritionally depleted medium with reduced levels of calcium or serum, and in medium with increased levels of serum. The prolonged survival of the stromal cells in vitro coupled with the retention of in vivo characteristics and an absence of neoplastic phenotype provides a human cell system that is amenable to a variety of long-term experimental analyses.