18fluorodeoxyglucose positron emission tomography to detect mediastinal or internal mammary metastases in breast cancer.

PURPOSE: To determine the prevalence of suspected disease in the mediastinum and internal mammary (IM) node chain by 18fluorodeoxyglucose (FDG) positron emission tomography (PET), compared with conventional staging by computed tomography (CT) in patients with recurrent or metastatic breast cancer. PATIENTS AND METHODS: We retrospectively evaluated intrathoracic lymph nodes using FDG PET and CT data in 73 consecutive patients with recurrent or metastatic breast cancer who had both CT and FDG PET within 30 days of each other. In reviews of CT scans, mediastinal nodes measuring 1 cm or greater in the short axis were considered positive. PET was considered positive when there were one or more mediastinal foci of FDG uptake greater than the mediastinal blood pool. RESULTS: Overall, 40% of patients had abnormal mediastinal or IM FDG uptake consistent with metastases, compared with 23% of patients who had suspiciously enlarged mediastinal or IM nodes by CT. Both FDG PET and CT were positive in 22%. In the subset of 33 patients with assessable follow-up by CT or biopsy, the sensitivity, specificity, and accuracy for nodal disease was 85%, 90%, and 88%, respectively, by FDG PET; 54%, 85%, and 73%, respectively, by prospective interpretation of CT; and 50%, 83%, and 70%, respectively, by blinded observer interpretation of CT. Among patients suspected of having only locoregional disease recurrence (n = 33), 10 had unsuspected mediastinal or IM disease by FDG PET. CONCLUSION: FDG PET may uncover disease in these nodal regions not recognized by conventional staging methods. Future prospective studies using histopathology for confirmation are needed to validate the preliminary findings of this retrospective study.

Concurrent radiation therapy and paclitaxel or docetaxel chemotherapy in high-risk breast cancer.

PURPOSE: Evidence supports the inclusion of the taxanes in the treatment of breast cancer. A recent randomized trial has shown a survival advantage to the addition of paclitaxel in the adjuvant treatment of node-positive patients. Several studies have suggested diminished local control if adjuvant radiation is delayed, while in vitro and in vivo studies have demonstrated a benefit of concurrent administration of taxanes with radiation. For these reasons, we began in 1995 to administer radiation therapy concurrently with the taxanes in advanced breast cancer. This retrospective review examines the feasibility of such treatment. METHODS AND MATERIALS: Forty-four patients were treated with concurrent radiation and either paclitaxel (29 patients) or docetaxel (15 patients). One patient received both paclitaxel and docetaxel. Eighteen patients were treated for recurrent disease, 9 had received prior radiation. Toxicity was assessed by the RTOG scale for acute and late effects. RESULTS: Concurrent radiation and taxane chemotherapy was well tolerated. Nine patients (20%) experienced Grade 3 acute skin toxicity. This was more likely with docetaxel than paclitaxel (p = 0. 04). Among patients undergoing breast conservation, there were no Grade 3 toxicities. With a median follow-up of 11 months, 1 patient has developed breast fibrosis. CONCLUSION: Concurrent administration of both paclitaxel and docetaxel with radiation resulted in acceptable toxicity. Overall, the acute skin toxicity seen with docetaxel was more pronounced. However, among patients undergoing breast conservation the taxanes were both well tolerated. Further study is necessary to assess the impact of concurrent treatment on long-term outcome.

'Neo-FAC' (5-fluorouracil, doxorubicin, and cyclophosphamide) for poor-prognosis stage IV breast cancer: a Southwest Oncology Group Phase II Study.

The authors report a phase II pilot investigation in the Southwest Oncology Group examining a combination of 5-fluorouracil, doxorubicin, and cyclophosphamide (FAC) incorporating modulated 5-FU in patients with poor-prognosis stage IV breast cancer. Patients with poor-prognosis stage IV breast cancer were treated with this "neo-FAC" as front-line therapy. The regimen consisted of 5-fluorouracil by continuous ambulatory infusion pump at 200 mg/m2/day for 42 days, repeated at 56-day intervals; doxorubicin at 20 mg/m2/week intravenously to a maximum cumulative total dose (including adjuvant therapy, if any) of 500 mg/m2; cyclophosphamide 60 mg/m2/day taken orally; methotrexate 15 mg/m2/week intravenously beginning 1 week after termination of doxorubicin; and oral prednisone decreasing from 60 mg/day on a tapering schedule for a total of 7 weeks of treatment. Treatment was continued until progression, unacceptable toxicity, or patient refusal. Twenty-four patients were accrued to this study. Of these, two were ineligible, and the remaining 22 were evaluable for response. Ten patients experienced grade 3 toxicity, and six had grade 4. There were no treatment-associated deaths. Best responses were a complete response in one patient (5%) and partial responses in 6, for an overall response rate of 32% (7/22 evaluable patients). Overall survival in five pilot studies in the Southwest Oncology Group in this poor-prognosis population are relatively superimposable. The present regimen, with its relatively poor outcome and the expense and inconvenience of administering chemotherapy by ambulatory infusion pump, will not be pursued further.

Monitoring the response of patients with locally advanced breast carcinoma to neoadjuvant chemotherapy using [technetium 99m]-sestamibi scintimammography.

BACKGROUND: Mammographic and physical examination assessments of the response of locally advanced breast carcinoma (LABC) to neoadjuvant therapy have been shown to be inaccurate. The authors studied the feasibility and accuracy of [technetium 99m]-sestamibi (MIBI) for monitoring the response of patients with LABC to neoadjuvant chemotherapy. METHODS: Patients receiving neoadjuvant chemotherapy for LABC underwent prone lateral scintimammography before therapy, after 2 months of therapy, and close to the completion of chemotherapy (presurgery) if chemotherapy continued for >3 months. Images were analyzed both qualitatively and quantitatively using the lesion-to-normal breast MIBI uptake ratio (L:N). Imaging results were compared with the clinical response and the pathologic response as determined from the posttherapy surgical specimen. RESULTS: A total of 32 patients (29 who were assessable for primary tumor response and 28 who were assessable for lymph node response) were included in the study. The mean change in the primary tumor L:N MIBI uptake ratio after 2 months of chemotherapy was -35% for clinical responders and +17% for nonresponders (P<0.001). Patients achieving a pathologic primary tumor macroscopic complete response (CR) had a mean change in uptake on the presurgical scan of -58% versus -18% for patients with a partial response (P<0.005). A decrease of > or =40% in the MIBI uptake ratio identified CRs with 100% sensitivity and 89% specificity. Pretherapy imaging predicted axillary lymph node metastases in 85% of patients ultimately found to have > or =1 positive lymph nodes at surgery, but was less accurate in identifying residual lymph node disease after therapy (55% sensitivity and 75% specificity). CONCLUSIONS: MIBI imaging accurately assessed the response to neoadjuvant chemotherapy in patients with LABC. Further studies are needed to determine the role of MIBI in this group of patients.

Infusional paclitaxel and weekly vinorelbine chemotherapy with concurrent filgrastim for metastatic breast cancer: high complete response rate in a phase I-II study of doxorubicin-treated patients.

PURPOSE: We investigated 96-hour paclitaxel infusion combined with weekly (days eight and 15) vinorelbine as salvage therapy for metastatic breast cancer in anthracycline-exposed patients. All patients received scheduled support with granulocyte colony-stimulating factor (G-CSF; filgrastim). Tumor response, toxicity, time to progression (TTP), and survival were assessed. PATIENTS AND METHODS: This single-center nonrandomized trial enrolled 32 patients. Anthracycline exposure and subsequent progression were common to all patients. Paclitaxel and vinorelbine were escalated over three dosing levels, stratified by liver function. RESULTS: Seven patients (22%) achieved a complete response and nine patients achieved a partial response for an overall response rate of 50%. The median TTP was 6.1 months, and median survival time was 14.1 months. Dose-limiting toxicity was neutropenia, with dose delay or reduction in seven of 32 patients. Febrile neutropenia requiring hospitalization was uncommon (three of 32 patients; 9%). There were no treatment-related deaths. Grade 3/4 thrombocytopenia occurred in two patients (6%), and 13 patients (41%) required RBC transfusions for anemia. Grade 3 nausea and vomiting was seen in one patient, who was found to be Addisonian. Despite potentially overlapping neurologic toxicities of the two agents, only two patients (6%) were removed from the study because of progressive peripheral neuropathy. CONCLUSION: Administration of 96-hour paclitaxel infusion and subsequent weekly vinorelbine with G-CSF support is well tolerated. The response rate, TTP, and survival data are encouraging for therapy given to anthracycline pretreated patients with metastatic breast cancer. If these results can be verified in multi-institution trials, this or a similar combination of drugs would merit investigation as first-line therapy in this patient population.

Value of combined FDG PET and MR imaging in the evaluation of suspected recurrent local-regional breast cancer: preliminary experience.

PURPOSE: To assess the performance and potential clinical effects of combined 2-[fluorine 18]fluoro-2-deoxy-D-glucose (FDG) positron emission tomography (PET) and magnetic resonance (MR) imaging of the axilla and brachial plexus in patients suspected of having local-regional breast cancer metastases. MATERIALS AND METHODS: Upper-body FDG PET and axillary and supraclavicular MR imaging were performed in 10 patients (age range, 45-71 years) with clinical findings suggestive of breast cancer metastases. Medical records were reviewed retrospectively. Imaging findings were correlated with clinical data and follow-up findings in all patients. Surgical findings were available in four patients. RESULTS: Nine patients had local-regional breast cancer metastases. MR imaging was diagnostic for tumor in five patients and was indeterminate in four patients with axillary or chest wall metastases. With FDG PET, metastatic tumor was positively identified in all nine patients. MR imaging was useful for determining the relationship of metastatic tumor to axillary and supraclavicular neurovascular structures. FDG PET helped confirm metastases in patients with indeterminate MR imaging findings and depicted unsuspected metastases outside the axilla. CONCLUSION: MR imaging and FDG PET are complementary in detecting and characterizing local-regional breast cancer metastases. Combined FDG PET and MR imaging provide useful treatment-planning data for patients clinically suspected of having recurrent axillary or supraclavicular breast cancer.

Dose-intensive vinorelbine with concurrent granulocyte colony-stimulating factor support in paclitaxel-refractory metastatic breast cancer.

PURPOSE: We evaluated weekly single-agent intravenous (IV) vinorelbine as salvage therapy for metastatic breast cancer. After the first five patients, all received elective growth factor support with granulocyte colony-stimulating factor (G-CSF; filgrastim) in an attempt to maximize delivered dose-intensity (DDI). Objective tumor response, DDI, and toxicity were assessed, as well as time to progression (TTP) and survival. PATIENTS AND METHODS: This single-center nonrandomized trial enrolled 40 patients. Anthracycline exposure and subsequent progression were common to all patients, and 38 of 40 were paclitaxel-refractory. Vinorelbine was given initially at 30 mg/m2/wk, then at 35 mg/m2/wk in a phase I/II design, which involved first intermittent (6 days of 7) and then continuous (daily) administration of G-CSF at 5 micrograms/kg. RESULTS: The maximum-tolerated starting dose was 35 mg/m2/wk with continuous G-CSF support. The mean DDI was 27.7 mg/m2/wk for all patients. There were two complete responses (CRs) and eight partial responses (PRs) in 40 assessable patients for an overall response rate of 25% (95% confidence interval [CI], 13% to 41%). The median TTP was 13 weeks and median survival time 33 weeks. The dose-limiting toxicity was neutropenia, with dose delay or reduction required in 14 of 27 patients entered at 35 mg/m2. Febrile neutropenia that required hospitalization was unusual (three of 40 patients, 8%). There were no treatment-related deaths. Grade 3/4 thrombocytopenia occurred in nine patients (23%) and 26 patients (65%) required RBC transfusions for anemia. Seven patients (18%) had reversible grade 3/4 nonhematologic complications, primarily related to neurotoxicity. Grade > or = 3 mucositis was absent. CONCLUSION: Concurrent administration of weekly vinoralbine and daily G-CSF is feasible and permits an increase in DDI for vinorelbine of 43% to 76% over that reported in series without growth factor support. The response rate, TTP, and survival data are encouraging for therapy given to heavily pretreated patients with metastatic breast cancer. Vinorelbine is not cross-resistant with paclitaxel and should be considered for further trials in the dose-intensified mode made possible by G-CSF, alone or combined with other agents.

False positive tumor markers: elevation in patients with breast cancer on FAC-type chemotherapy and correlation with the development of hand-foot syndrome.

Breast cancer patients on dose-intensive chemotherapy often have elevated tumor markers during the course of treatment. Our objective was to estimate the incidence of a "false positive" tumor marker screen and to determine whether hand-foot epithelial damage was correlated. Data from 53 patients with high risk primary breast cancer who had undergone adjuvant or neoadjuvant 5FU-containing chemotherapy (FAC or FAC plus G-CSF) for 3 to 12 months were reviewed. The relationship between tumor marker elevation and disease recurrence, regimen intensity, and the occurrence of hand-foot syndrome was examined. Thirty-three of the 53 patients had elevated tumor markers in the absence of recurrent disease. The false positive rate was higher in patients who underwent FAC plus G-CSF chemotherapy than in patients who underwent FAC chemotherapy (92% vs 55%, p = .01). A false positive marker screen was associated with the occurrence of hand-foot syndrome even when the effect of regimen was accounted for by stratification (p = .01). Tumor marker screening of breast cancer patients on this type of adjuvant chemotherapy has poor specificity for recurrent malignancy. These data suggest tumor marker elevation may be an indicator of epithelial toxicity during chemotherapy, manifested clinically as hand-foot syndrome.

Effect of delay in radiation in the combined modality treatment of breast cancer.

PURPOSE: To study how the timing of radiation influences local control, overall survival, and disease-free survival in patients being treated with chemotherapy and radiation for a local-regional carcinoma of the breast. METHODS AND MATERIALS: Over a ten year period, 105 patients received chemotherapy and radiation treatments for a local-regional breast cancer. The population was divided into two groups based on the timing of their radiation treatments. Forty-eight patients began their radiation within 6 months of their diagnosis (early radiation group). Fifty-seven patients had a delay in their radiation for 6 or greater months in order to first maximize chemotherapy treatments (delayed radiation group). There were no significant differences between the two groups with respect to nodal status, stage of the primary, estrogen receptor status, patient age, or type of surgery performed. The only prognostic parameter that was imbalanced was that of a greater percentage of patients with close or positive margins in the early radiation group compared to the delayed radiation group (69% versus 38%, p < 0.02). RESULTS: Comparisons of local control, overall survival, and disease-free survival between the early radiation patients and delayed radiation patients all favored the early radiation group. Respective 8-year actuarial rates were: local control--98% vs. 76%, p = 0.004; overall survival--80% vs. 52%, p = 0.016; disease-free survival--71% vs. 48%, p = 0.008. The differences continued to be significant in a multivariate Cox regression model comparison: p = 0.011, p = 0.050, p = 0.009. There was only one death from intercurrent disease, so that overall survival approximated cause-specific survival to an accurate degree. CONCLUSIONS: In patients requiring chemotherapy and radiation treatments for a local-regional breast cancer, a delay in the initiation of radiation for a period of 6 months or greater from diagnosis resulted in a higher local failure rate. Furthermore, this higher local failure rate was associated with an increased rate of distant metastases and a decreased overall survival rate.

Alternating weekly doxorubicin and 5-fluorouracil/leucovorin followed by weekly doxorubicin and daily cyclophosphamide in stage IV breast cancer. A Southwest Oncology Group study.

Twenty-seven women with metastatic breast cancer were treated with doxorubicin (Adriamycin, Adria Laboratories, Columbus, OH) every other week, alternating with 5-fluorouracil (5FU) and high-dose calcium leucovorin, for a 12-week induction regimen, followed by weekly doxorubicin and oral daily cyclophosphamide. Twenty-five women were eligible and evaluable. Of these, complete response occurred in two patients (8%) and partial response in six patients (24%), for a total response rate of 32%. Toxicity was similar to that seen in previous Southwest Oncology Group (SWOG) trials in this patient population. Response rates in this study were inferior, with comparable median survivals to those of previous SWOG studies that are reviewed. Additional, more dose-intensive approaches incorporating newer approaches to the administration of cancer chemotherapeutic agents are planned.

Cisplatin and novobiocin in the treatment of non-small cell lung cancer. A Southwest Oncology Group study.

Novobiocin, a commercially available oral antibiotic, inhibits DNA topoisomerase II in a manner shown in cell culture to enhance the cytotoxicity of alkylating agents and cisplatin. Thirty-six patients were entered on a Phase II trial using high-dose cisplatin (100 mg/m2 on days 1 and 8 for four cycles) after steady-state dosing with novobiocin (1000 mg or four 250-mg capsules every 12 hours for six doses, four of which were administered before each dose of cisplatin). One patient remains on study and cannot be evaluated for response. No complete responses were seen. Three patients (8%) had partial responses and an additional patient had an unconfirmed partial response. The median survival time of all patients was just less than 7 months. These results are comparable with those of other concurrent Southwest Oncology Group (SWOG) Phase II and III trials of high-dose cisplatin in non-small cell lung cancer (NSCLC). Novobiocin plasma levels were obtained for three patients and were approximately 50% of the optimal concentration as reported in cell culture for potentiation of cytotoxicity. It was concluded that an optimum test of novobiocin as a modulator of cytotoxicity may require the availability of an intravenous preparation.

Bone marrow involvement in epithelial ovarian cancer by immunocytochemical assessment.

The incidence of bone marrow involvement with epithelial ovarian cancer has been evaluated as a continuation of interest in autologous bone marrow support. Fifty-eight aspirates were obtained on 50 patients and 53 aspirates were evaluable. Immunocytochemistry with the monoclonal cytokeratin antibodies 35 beta H11 and 34 beta E12 was performed. There have been no complications. Twelve (23%) were positive and three were indeterminate. Stage, grade, and CA-125 level were not different in the two groups. No patient had a positive biopsy at the time of initial diagnosis. The majority of patients were drawn from second-look procedures; of these, 7 of 19 were positive. Five of twelve with positive aspirates died from disease versus 5 of 38 with negative aspirates, and patients with a positive aspirate had a longer overall survival time until death from disease. We can confirm the presence of epithelial ovarian cancer in 23% of patients at varying times in the course of their disease. We cannot identify risk factors for the development of this finding nor the viability of those cells when found in this data set.

Combination chemotherapy and high-dose cyclophosphamide intensification for poor prognosis breast cancer. A Southwest Oncology Group Study.

Thirty-seven patients with poor prognosis, metastatic breast cancer were treated with 5-fluorouracil, vinblastine, and Adriamycin (doxorubicin; Adria Laboratories, Columbus, OH) (FUVA) induction chemotherapy. All 26 patients (74%) with responsive or stable disease after induction chemotherapy received intensification with high-dose cyclophosphamide (120 mg/kg). Continued responders received additional FUVA as consolidation. The response rate to induction therapy was 54% (with complete response [CR] in 11%). With intensification, three patients (11%) showed improved response (partial response [PR] in one, PR to complete response [CR] in two); however, six patients (23%) progressed within 2 months of cyclophosphamide intensification, three within 1 month. The overall response rate to all three phases of the study was 69%, with CR in 23%. The median survival of all patients entered in this study was 15 months. For cyclophosphamide intensification, major toxicity consisted of leukopenia with fever requiring broad-spectrum antibiotics in 27%. The authors conclude that a single cycle of high-dose cyclophosphamide intensification in metastatic breast cancer does not result in significantly improved responses or prolonged survival.