Statins and Left Ventricular Ejection Fraction Following Doxorubicin Treatment.

BACKGROUND: Statins taken for cardiovascular indications by patients with breast cancer and lymphoma during doxorubicin treatment may attenuate left ventricular ejection fraction (LVEF) decline, but the effect of statins on LVEF among patients with no cardiovascular indications is unknown. METHODS: A double-blind, placebo-controlled, 24-month randomized trial of 40 mg of atorvastatin per day administered to patients with breast cancer and lymphoma receiving doxorubicin was conducted within the National Cancer Institute Community Oncology Research Program across 31 sites in the United States. At pretreatment and then 6 and 24 months after initiating doxorubicin, we assessed left ventricular (LV) volumes, strain, mass, and LVEF through cardiac magnetic resonance imaging, along with cognitive function and serum markers of inflammation. The primary outcome was the difference in 24-month LVEF between placebo and treatment groups, adjusted for pretreatment LVEF. RESULTS: A total of 279 participants were enrolled in the trial. Participants had a mean (±SD) age of 49±12 years; 92% were women; and 83% were White. The mean (±SD) LVEF values were 61.7±5.5% before treatment and 57.4±6.8% at 24 months in the placebo group and 62.6±6.4% before treatment and 57.7±5.6% at 24 months in the atorvastatin group. On the basis of a multiple imputed data set for missing data and adjusted for each individual's pretreatment LVEF, 24-month declines in LVEF averaged 3.3±0.6 percentage points and 3.2±0.7 percentage points, for those randomly assigned to placebo versus statins, respectively (P=0.93). Across both treatment arms, similar percentages of individuals experienced changes of more than 10 percentage points in LVEF, LV strain, LV mass, cognition, and inflammation biomarkers, including among those with greater than 90% drug compliance. CONCLUSIONS: In patients with breast cancer and lymphoma with no existing indication for statin therapy, prospective statin administration did not affect LVEF declines 2 years after doxorubicin. (Funded by the National Institutes of Health; ClinicalTrials.gov number, NCT01988571.).

A Randomized Phase IIb Study of Low-dose Tamoxifen in Chest-irradiated Cancer Survivors at Risk for Breast Cancer.

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.

Incidence and Survival by Human Epidermal Growth Factor Receptor 2 Status in Young Women With Stage I-III Breast Cancer: SEER, 2010-2016.

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.

Neuromuscular ultrasound for taxane peripheral neuropathy in breast cancer.

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 mm2 smaller than healthy controls (P ≤ .01). Older age and time since taxane were associated with smaller sural nerve CSA. For each 1 mm2 decrease in sural nerve CSA, distal IENFD decreased by 2.1 nerve/mm (R2 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.

Increasing Adherence to Adjuvant Hormone Therapy Among Patients With Breast Cancer: A Smart Phone App-Based Pilot Study.

PURPOSE: This study tested the feasibility and efficacy of using a text-based intervention to increase initiation, decrease discontinuation, and improve adherence as prescribed to adjuvant hormone therapy (AHT) among hyphenate post-menopausal breast cancer survivors. METHODS: The 3-month intervention consisted of daily text message reminders to take medication, coupled with a dynamic (eg, feedback on progress) tailored intervention using weekly interactive surveys delivered by a smartphone app. Five clinic sites within the Alliance for Clinical Trials in Oncology participated. Hormone levels were measured prior to AHT initiation and at study exit. RESULTS: Of the 39 patients recruited to the pilot study, 27 (69.2%) completed all study requirements (completed both the baseline and the exit surveys, both blood draws, and did not miss more than 2 weekly surveys). Significant improvements were observed pre- to postintervention for self-reported medication adherence (P = .015), mental health functioning (P = .007), and perceived stress (P = .04). Significant decreases in estradiol, estrogen, and estrone hormone levels were observed from baseline to study exit (P < .001), indicating the accuracy of self-reported AHT adherence. Participants (91.9%) and physicians (100%) agreed that participant participation in the intervention was beneficial. CONCLUSIONS: The results of this pilot study established the general feasibility and efficacy of an app-based intervention to support patient AHT adherence. Larger controlled, randomized trials are needed to examine the effectiveness of the app-based intervention in improving AHT and quality of life among breast cancer survivors.

An evidence-based medicine approach for case presentations by trainees.

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.

Scalp cooling with adjuvant/neoadjuvant chemotherapy for breast cancer and the risk of scalp metastases: systematic review and meta-analysis.

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.

Oral paricalcitol (19-nor-1,25-dihydroxyvitamin D2) in women receiving chemotherapy for metastatic breast cancer: a feasibility trial.

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.

Low to moderate dose anthracycline-based chemotherapy is associated with early noninvasive imaging evidence of subclinical cardiovascular disease.

OBJECTIVES: The goal of this study was to determine if low to moderate doses of anthracycline-based chemotherapy (Anth-bC) are associated with subclinical cardiovascular (CV) injury. BACKGROUND: Cancer survivors who receive Anth-bC experience premature CV events. It is unknown whether low to moderate doses of anthracyclines promote early subclinical CV disease manifested by deteriorations in left ventricular ejection fraction (LVEF) or increases in aortic stiffness, or if these doses are associated with changes in quality of life (QOL). METHODS: In 53 men and women with breast cancer, leukemia, or lymphoma, we assessed left ventricular volumes, LVEF, circumferential strain, aortic pulse wave velocity, late gadolinium enhancement, serum B-type natriuretic peptide, troponin I, and the impact of treatment on QOL before and 1, 3, and 6 months after receipt of Anth-bC. RESULTS: Participants averaged 50 ± 2 (range 19 to 80) years in age, 58% were women, 17% were black, and they each received a range of 50 to 375 mg/m(2) of doxorubicin-equivalent chemotherapy. Left ventricular end-systolic volume (48 ± 3 ml to 54 ± 3 ml; p = 0.02), left ventricular strain (-17.7 ± 0.4 to -15.1 ± 0.4; p = 0.0003), pulse wave velocity (6.7 ± 0.5 m/s to 10.1 ± 1 m/s; p = 0.0006), and QOL deterioration (15.4 ± 3.3 to 28.5 ± 3.9; p = 0.008) increased, whereas LVEF (58 ± 1% to 53 ± 1%; p = 0.0002) decreased within 6 months after low to moderate doses of Anth-bC. All findings persisted after accounting for age, gender, race (white/black), doxorubicin-equivalent dose, doxorubicin administration technique, comorbidities associated with CV events, and cancer diagnosis (p = 0.02 to 0.0001 for all). There were no new late gadolinium enhancement findings after 6 months. CONCLUSIONS: In these study patients, low to moderate doses of Anth-bC were associated with the early development of subclinical abnormalities of cardiac and vascular function that in other populations are associated with the future occurrence of CV events.

Race and recurrence in women who undergo neoadjuvant chemotherapy for breast cancer.

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 = .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 = .05). The 5-year overall survival was similar (P = .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.

Aortic stiffness increases upon receipt of anthracycline chemotherapy.

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.

Phase I study of lenalidomide in solid tumors.

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.

Predictive value of 18-fluoro-deoxy-glucose-positron emission tomography (18F-FDG-PET) in the identification of responders to chemoradiation therapy for the treatment of locally advanced esophageal cancer.

OBJECTIVE: To evaluate the utility of F-FDG-PET in predicting response to concomitant chemoradiation in locally-advanced esophageal cancer. SUMMARY BACKGROUND DATA: 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. METHODS: 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. RESULTS: 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 SUVmax1hour < 15 (P = 0.005). Significant response was observed in 71.4% of patients with a decrease in SUVmax1hour > or = 10 compared with 33.3% when the SUVmax1hour decreased <10 (P = 0.004). CONCLUSIONS: 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.

A prospective evaluation of the impact of 18-F-fluoro-deoxy-D-glucose positron emission tomography staging on survival for patients with locally advanced esophageal cancer.

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.

Pathologic complete response may not represent the optimal surrogate for survival after preoperative therapy for esophageal cancer.

BACKGROUND: 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). AIM OF STUDY: The pathologic complete response (pCR) was the primary endpoint to estimate efficacy. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Irinotecan/gemcitabine followed by twice-weekly gemcitabine/radiation in locally advanced pancreatic cancer.

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]).

Schedule-selective biochemical modulation of 5-fluorouracil in advanced colorectal cancer--a phase II study.

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.