Faculty Bibliography

The extent of tumor reduction from neoadjuvant chemotherapy for breast cancer correlates with outcome. We investigated whether the initial cellular responses to paclitaxel are related to the extent of tumor reduction. Eleven women with breast cancer received paclitaxel (every 2 weeks for 4 cycles) as neoadjuvant treatment. Serial fine-needle aspirations (FNA; 25-gauge, 1 pass) were obtained before treatment and at 24, 48, 72, and 96 h after the first paclitaxel dose. Microscopic counts of apoptotic and mitotic indices were performed. The change in cancer volume from treatment was determined using radiological measurements with allowance for change in the histopathological amount of cancer. Apoptotic and mitotic responses usually subsided within 4 days. The duration of the initial apoptotic response was different for women with different treatment results. Cumulative apoptotic response for the first 4 days inversely correlated with the proportion of residual cancer after neoadjuvant treatment. FNA is a versatile clinical method to obtain breast cancer cells for therapy response studies. Apoptotic response to the first dose of paclitaxel is almost complete within 4 days, implying that more frequent (weekly) paclitaxel dosing might be beneficial. The apoptotic response to the first dose of paclitaxel appeared to predict the amount of cancer reduction from this treatment. This is a promising start toward the development of an early chemopredictive assay for paclitaxel treatment of breast cancer

A phase I study was performed to determine the maximum tolerated doses of intravenous etoposide and paclitaxel for women with previously treated persistent or recurrent ovarian cancer. Starting doses were paclitaxel 135 mg/m2 during 24 hours and etoposide 50 mg/m2/day for 3 consecutive days. The study was designed to escalate first the dose of etoposide, and then the dose of paclitaxel, in successive cohorts of patients. In an attempt to determine whether toxicity was affected by sequence of the drugs, the order of administration of the two drugs was reversed on alternate cycles. The starting doses of paclitaxel (135 mg/m2/24 hours) and etoposide (50 mg/m2/day x 3) caused severe neutropenia even with the addition of granulocyte colony-stimulating factor, and the trial was amended to administer the paclitaxel during 3 hours. However, this also proved too myelosuppressive without growth factor support. Twenty-one women were treated. A complete response was observed in one of nine patients with measurable disease, and a major decrease in CA-125 was noted in two patients who did not have measurable disease. Because of the severe myelosuppression observed in most patients, dose reduction was often required after the first cycle. The power to detect sequence-dependent variation in toxicity was minimal; however, no large differences were observed. A combination of the usual doses of these drugs will be difficult to administer in patients who have received previous chemotherapy for ovarian cancer.

OBJECTIVE: Pegylated liposomal doxorubicin (Doxil) may have enhanced therapeutic efficacy and reduced toxicity compared with the parent compound. This phase II study further evaluates the activity of Doxil in patients with ovarian cancer and explores activity in other gynecologic cancers. METHODS: Sixty-three patients were treated with Doxil 50 mg/m(2) infused over 1 h; 44 were evaluable. Forty-eight had epithelial ovarian cancer and all received prior treatment with cisplatin and paclitaxel: 27 received two to six prior regimens, 44 were platinum resistant, 21 patients had measurable disease, and 27 had evaluable disease only. RESULTS: The overall survival of these patients was 10 months (range, 0.25-33); progression-free survival was 3 months (range, 0.25-18). The response rate among those with measurable disease was 19%, with a median duration of 4.5 months (range, 3-12). The response rate of 22 patients with elevated CA-125 was 59%; median duration was 3.5 months (range, 1-12). Also, 27% achieved prolonged stabilization of disease for a median of 7 months (range, 5-18). Overall, treatment was well tolerated in this heavily pretreated population. Grade 3 and 4 toxic effects were: 5 grade 3 stomatitis, 3 grade 3 skin, 1 each grade 4 neutropenia and thrombocytopenia, 5 admits for infection, and no neutropenic fever; nausea and vomiting were uncommon in 204 cycles to ovarian cancer patients. CONCLUSION: This study demonstrates the activity of Doxil in heavily pretreated patients with ovarian cancer and poor prognostic features and confirms the prolonged responses and favorable toxicity profile. Encouraging findings were also observed in the patients with nonovarian gynecologic cancers.

BACKGROUND: The indications for pegylated liposomal doxorubicin (doxil) are expanding. We, therefore, wished to assess the safety of delivering doses exceeding 500 mg/m2 of doxil to patients with solid tumors. PATIENTS AND METHODS: Subjects accrued to eight phase I and II protocol studies conducted at two institutions, were assessed for cardiac function at baseline and at specified intervals by MUGA scans. In this retrospective analysis, the findings of 42 patients, from the total of 237 entered, who had reached or exceeded cumulative doses of 500 mg/m2 (range 500-1500 mg/m2) were reviewed. Changes in left ventricular ejection fraction (LVEF), and in clinical cardiac status were analyzed. Six patients, three who had received prior doxorubicin, also underwent endomyocardial biopsies after cumulative doses of 490-1320 mg/m2. RESULTS: None of the 42 patients had clinical congestive heart failure (CHF) secondary to cardiomyopathy. Post doxil MUGA scans were available for 41 of the 42 patients. Five had a drop of 10% or more in LVEF; three of these had received prior doxorubicin. Billingham endomyocardial biopsy scores ranged from 0-1 in five patients, while the sixth had a score of 1.5 after both 900 mg/m2 and 1320 mg/m2 doxil. Of a remaining 195 patients, 1 episode of CHF was recorded in a patient who had received 312 mg/m2 doxil over 120 mg/m2 of mitoxantrone and chest radiation. CONCLUSIONS: Cumulative doses in excess of 500 mg/m2 of doxil appear to carry a considerably lesser risk of cardiomyopathy as judged by serial LVEF's and clinical follow-up, than is generally associated with free doxorubicin. Heart biopsies have provided reassuring data in a small number of patients, even if pretreated with doxorubicin. However, since three doxorubicin pretreated patients were among the five experiencing drops in LVEF, more data are warranted on such patients.

Effects of variations in agent, dose, and route of treatment administration on patient reported quality of life (QOL) were examined for 279 patients enrolled on a seven-arm randomized clinical trial (S8905) of 5-FU and its modulation for advanced colorectal cancer. Patients completed QOL questionnaires at randomization and weeks 6, 11, and 21 post-randomization with five QOL endpoints considered primary: three treatment-specific symptoms (stomatitis, diarrhea, and hand/foot sensitivity); physical functioning; and emotional functioning. Patient compliance with the QOL assessment schedule was good, supporting the feasibility of including QOL measures in cooperative group trials. However, death and deteriorating health produced substantial missing data. Cross-sectional analyses indicated that the seven therapeutic arms did not differ in their impact on QOL. Unfortunately, longitudinal analyses of the QOL data were inappropriate given non-random missing data. Graphical presentation of non-random missing data identified the seriousness of this problem and its effect on potential conclusions about QOL during treatment. This problem appears to be particularly challenging in the context of advanced-stage disease. Failure to recognize the presence of non-random missing data can lead to serious overestimates of patient QOL over time.

BACKGROUND: The work-up of adenocarcinoma of unknown primary usually includes history, physical examination, radiographic imaging, tumor markers, and more recently molecular and genetic information. We report here on how the suggestion by family history of a BRCA1 mutation guided the diagnostic and therapeutic approach in a patient with metastatic carcinoma of unknown primary. METHODS: BRCA1 mutation was screened for by polymerase chain reaction (PCR) and single-strand conformational polymorphism analysis. Primers for PCR amplification included selected BRCA1 exons 2, 110, 11L, 13, and 20. The PCR product was cloned into a PCRII vector and sequenced with a Sequenase Version 2.0 Sequencing Kit. RESULTS: Single-strand conformational polymorphism analysis suggested a mutation in the region of exon 20 and sequencing confirmed the presence of a germline mutation 5382insC. CONCLUSIONS: This case illustrates an unusual presentation of adenocarcinoma of unknown primary in a patient with a germline BRCA1 mutation, the use of a suspected germline mutation to guide the work-up and treatment, and finally the value of positron emission tomography scanning in the work-up of an unknown primary.