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The aim of this study was to evaluate the activity and safety of pegylated liposomal doxorubicin (PLD) and oxaliplatin (LOHP) as salvage chemotherapy in patients with metastatic gastric cancer (MGC) who had earlier been treated with docetaxel, capecitabine, 5-fluorouracil, and leucovorin. Treatment consisted of PLD (40 mg/m(2)) and LOHP (120 mg/m(2)) administered over 2 days, every 3 weeks. Response to therapy was assessed using the Response Evaluation Criteria In Solid Tumors; toxicity was evaluated by the National Cancer Institute common toxicity criteria (version 2.0). Thirty-six patients with pretreated MGC and a mean age of 66 years were recruited for the study. After a median follow-up of 11 months and 202 courses of chemotherapy administered (median, five courses per patient), the overall response rate in the 36 evaluable patients was estimated to be 28%. Grades 3 and 4 hematological toxicities were neutropenia in 44% of patients, grade 2-3 diarrhea in 14% of patients, and grade 2 neuropathy in 12 patients. Median progression-free survival and overall survival were 5.8 and 9.2 months, respectively, with 1-year survival rate of 36%, [95% confidence interval (CI): 21-54%]. Median survival time from the diagnosis of metastatic disease was 31.5 months. Seventy-two percent of patients (n=26) (95% CI: 58-88%) obtained a clinical benefit from this chemotherapy regimen. PLD and LOHP is an active regimen, able to give palliation in a substantial percentage of MCG patients who have been pretreated with taxanes.

Objectives: The antitumor activity and toxicity of a multi-step treatment were evaluated in patients with locally advanced, inoperable, or incompletely resected pancreatic (Pa) and biliary tree (Bt) adenocarcinomas (ADKs)., Methods: Fifty-four patients, 63% with Pa and 37% with Bt ADK, received 3 courses of cisplatin-gemcitabine induction chemotherapy. Progression-free (PF) patients were given consolidation radiotherapy with concurrent capecitabine. PF patients had, as maintenance immunotherapy (MI), interleukin 2 (1.8x10 IU) and 13-cis-retinoic acid (0.5 mg/kg) [DOSAGE ERROR CORRECTED]., Results: Thirty-eight patients, 27 with Pa and 11 with Bt ADKs, PF after cisplatin/gemcitabine, were treated with consolidation radiotherapy with concurrent capecitabine. Fourteen PF patients, 7 with Pa and 7 with Bt ADK, received MI. Median PF and overall survivals (OS) for all 54 patients were 6.8 and 12.1 months, respectively. Patients treated with MI had a median PF survival of 16.2 months, whereas median OS had not been reached yet, after a median follow-up of 27.5 months., Toxicity: Grades 3 and 4 hematological and gastrointestinal in 30% and 37% of patients, respectively; grades 1 and 2 autoimmune reactions in 28% of patients., Conclusions: These results support the efficacy and safety of a multi-step sequential treatment in patients with locally advanced, inoperable or incompletely resected Pa and Bt ADKs.

Background: To evaluate the antitumor activity and toxicity of 5-fluorouracil (FU)/leucovorin (LV) and capecitabine (C) given with either oxaliplatin (OX) or camptothecin (CPT-11) in the treatment of chemotherapy naive patients with metastatic colorectal cancer., Materials and Methods: The outpatient treatment, consisted of 2 consecutive days of LV, 200 mg/m(2), 5-FU 400 mg/m(2), and C 2000 mg/m(2) that, in one cycle, was preceded by 2 days of OX 50 mg/m(2), and, in the subsequent cycle, by CPT-11, 90 mg/m(2)., Results: All 54 patients were assessable for toxicity and response. Thirty-two patients responded, giving an overall response rate of 59.3%. Median progression-free survival was 12.3 months and median survival was 20.5 months. Toxicity included grade 3 to 4 neutropenia in 43% of patients, grade 3 diarrhea in 7% of patients, and grade 2 neurotoxicity in 6% of patients., Conclusions: The alternating, bimonthly schedule of OX and CPT-11 plus 5-FU/LV/C has substantial antitumor activity and is well tolerated.

The purpose of this study was to determine the efficacy and safety of a maintenance immunotherapy regimen administered to patients with recurrent/metastatic squamous cell carcinoma of the head and neck (RMHN) who showed clinical benefit from docetaxel, ifosfamide, and cisplatin chemotherapy (DIP). Every 4 weeks, patients with RMHN received 60 mg/m docetaxel on day 1, and 1200 mg/m ifosfamide and 20 mg/m cisplatin on days 1 to 4. Low-dose subcutaneous interleukin-2 and oral 13-cis-retinoic acid were administered as maintenance immunotherapy to patients who showed a clinical benefit (complete or partial response, disease stability). The primary end point was response; secondary end points were progression-free survival, overall survival, toxicity, and evaluations of lymphocytes, natural killer cells, and serum vascular endothelial growth factor (VEGF). After a median follow-up of 22 months, 263 courses of chemotherapy were administered to the 54 patients. The overall response rate was 59%. Forty-two patients (78%) had a clinical benefit and received 185 courses of maintenance immunotherapy. Median progression-free survival and overall survival were 11.1 and 21.8 months, respectively. Statistically significant, progressive increases in lymphocytes and natural killer cells and a decrease in VEGF were observed in patients treated with maintenance immunotherapy. The toxicity was relatively well tolerated and caused no death. Outpatient administration of DIP, followed by low-dose interleukin-2 and 13-cis-retinoic acid, was generally well tolerated and showed promising activity against RMHN. Longitudinal changes in lymphocytes, natural killer cells, and VEGF might be useful biomarkers for response and survival.

Combining chemotherapy and immunotherapeutic agents such as interleukin-2 and interferon alpha-2b might improve treatment results in metastatic melanoma (MM) patients compared with chemotherapy alone. This prospective study evaluated the potential efficacy of a biochemotherapy regimen followed by maintenance biotherapy for the treatment of MM. Twenty-two patients with stage IV melanoma were treated for 5 consecutive days with cisplatin at 20 mg/m, vinblastine at 1.6 mg/m, and dacarbazine at 160 mg/m. Pegylated interferon alpha-2b at a dose of 50 microg every week, subcutaneous interleukin-2, 1.8 MIU, and oral 13-cis-retinoic acid (13-cis-RA) at 0.5 mg/kg were given 5 days/week for 3 weeks each month during the period of chemotherapy administration. Maintenance biotherapy was continued in patients who had a complete or partial response or disease stability (clinical benefit) after six courses of biochemotherapy. The primary endpoint was response; secondary endpoints were the evaluation of the immunologic parameters, toxicity, progression-free survival, and overall survival. Twelve patients (54.5%) achieved a response, and seven (31.8%) maintained stable disease for at least 6 months with maintenance biotherapy. The median progression-free survival and overall survival were 23.3 and 45.7 months, respectively. The most important toxicities from chemotherapy were grades 3 and 4 neutropenia and thrombocytopenia in 41 and 18% of patients, respectively, whereas grade 2 autoimmune reactions were observed in 21% of patients after maintenance biotherapy. A prolonged enhancement of immunologic function was observed in the 19 patients treated with maintenance therapy. A regimen of six cycles of biochemotherapy followed by maintenance immunotherapy is well tolerated, and shows significant activity in patients with MM.

Docetaxel, capecitabine and 5-fluorouracil have been shown to be active in the treatment of metastatic gastric adenocarcinoma. Consistent with this finding, the aim of this study was to test this combination in a clinical trial. Forty-one patients with metastatic gastric adenocarcinoma and a median age of 64 years were recruited for the study. The treatment was based on the administration of docetaxel 60 mg/m2 every 4 weeks, leucovorin 200 mg/m2, 5-fluorouracil 400 mg/m2 bolus, and capecitabine 1000 mg/m2 twice daily on days 1 and 2 every 2 weeks. Patients achieving a clinical benefit were treated, as maintenance immunotherapy, with low-dose interleukin-2 and 13-cis-retinoic acid. The primary end point of this phase II study was the response rate. The secondary end points relied on the evaluation of the immunological parameters, toxicity, and progression-free survival and overall survival. The overall response rate in the 41 evaluable patients was estimated to be 49%. Median progression-free and overall survival was 9.5 and 21.1 months, respectively. Grade 3 and 4 hematological toxicities were neutropenia and thrombocytopenia in 44 and 5% of patients, respectively. A sustained improvement of evaluated immunological parameters with a negligible toxicity profile was observed in the 27 patients treated with interleukin 1-2/13-cis-retinoic acid. Docetaxel in combination with leucovorin, 5-fluorouracil and capecitabine followed by low-dose interleukin 1-2 and 13-cis-retinoic acid is well tolerated, and shows a significant activity in patients with metastatic gastric adenocarcinoma.

The purpose of this study was to evaluate the potential efficacy of a chemo-immunotherapy regimen for the treatment of metastatic renal cell carcinoma (MRCC). Forty-one patients with progressing MRCC and with a median age of 63 years were recruited. Planned treatment consisted of 6 courses of capecitabine 1000 mg/m twice daily on days 1 to 14 every 4 weeks, pegylated alpha-interferon 2b 50 microg every week, interleukin-2 1.8 M IU subcutaneously, and oral 13-cis-retinoic acid 0.5 mg/kg, all given 5 days/wk, 3 weeks of each month. After 6 courses of concomitant biochemotherapy, biotherapy was continued in patients who had a clinical benefit. The primary end point was response; secondary end points were the evaluation of the immunologic parameters, toxicity, progression-free, and overall survival. The treatment was well-tolerated. Grade 3 and 4 neutropenia and thrombocytopenia occurred in 5% and 7% of patients, respectively. The overall response rate in the 41 evaluable patients was 53.6% (95% confidence interval 37%-69%). Median progression-free and overall survivals were 14.7 and 27.8 months, respectively. A sustained improvement in all evaluated immunologic parameters was observed in the 36 patients treated with maintenance biotherapy. Six cycles of biochemotherapy, being followed by maintenance immunotherapy is well-tolerated and shows significant activity in patients with MRCC.

High serum levels of vascular endothelial growth factor (VEGF) are a poor prognostic factor for patients with advanced non-small-cell lung cancer (NSCLC). We have previously shown that low-dose interleukin (IL)-2 and 13-cis retinoic acid (RA) decreased VEGF and improved the immune function of patients with advanced tumors treated with chemotherapy. The primary end point of this study was to verify whether IL-2 and RA decreased serum VEGF in NSCLC patients showing a clinical benefit from chemotherapy. The secondary end point was the evaluation of clinical outcome. We treated 38 patients with advanced NSCLC who had a complete or partial response or disease stability to chemotherapy and had a median serum VEGF level of 508 ng/mL; as maintenance therapy, they received subcutaneous IL-2 (1.8 x 10(6) IU) and oral RA. Matched controls (n = 87) were selected from a large cohort of patients with a similar disease status, including clinical benefit from chemotherapy. The most common adverse events were mild cutaneous skin rash and fever. Serum VEGF decreased to a mean level of 152 ng/mL (P = 0.0002). A statistically significant improvement in immune function was observed (lymphocyte and natural killer cell numbers and CD4+/CD8+ ratio) with respect to baseline values and controls. An improvement in the clinical outcome was also observed compared with controls. These data show that the administration of low-dose subcutaneous IL-2 and oral RA to patients with advanced NSCLC showing a clinical benefit from chemotherapy is feasible with a low-toxicity profile, decreases VEGF, and seems to improve progression-free and overall survival.

Oxaliplatin (L-OHP) and stealth pegylated liposomal doxorubicin (PLD) have been shown to be active in pre-treated advanced ovarian cancer (PAOC). The aim of this phase I study was to determine the maximum tolerated dose (MTD) of L-OHP, combined with fixed doses of PLD as salvage treatment of PAOC. Twenty patients with recurrent ovarian cancer previously treated with two (30%) or three lines (70%) of chemotherapy were entered into the trial. Patients had a median age of 64 years (52-77) and a median platinum-free interval of 13 months (range 6-35). Patients received a fixed dose of PLD 40 mg/m2, combined with escalating doses of L-OHP from 80 to 130 mg/m2 administered in 1 day, every 3 weeks. Dose escalation was interrupted if 30% or more patients of a given cohort (three patients) exhibited dose-limiting toxicity in the first treatment cycle. The MTD of L-OHP was 130 mg/m2 as two out of three patients of this cohort showed dose-limiting thrombocytopenia and/or neutropenia during the first cycle of treatment. Amongst 20 evaluable patients, we observed an overall response rate of 55% (95% confidence interval 31.5-76.9%). With a median follow-up of 12 months (3.4+/-19.2), median time to progression was 9.7 months, while median survival was not reached yet. We conclude that a combination of PLD and L-OHP has a manageable toxicity profile, and can be safely administered as outpatient chemotherapy for heavily pre-treated patients with relapsed ovarian cancer. Promising anti-tumor activity was observed.

The aim of the present trial was to investigate the protective effects on ovarian function, and the efficacy and tolerability of goserelin added to adjuvant chemotherapy for early breast cancer. Following surgical treatment, 64 premenopausal patients with early breast cancer received goserelin 3.6 mg (every 28 days for 1 year) and an adjuvant treatment which was chosen according to the patient's prognosis. Median age was 42 years (range 27-50). ECOG performance status was 0-1 in all patients. Twenty-eight patients (44%) had estrogen receptor (ER)+ tumors and 36 (56%) patients had ER- tumors. Fifty-two (81%) patients had stage II disease and 12 (19%) had stage III disease. Eighteen patients received cyclophosphamide, methotrexate and 5-fluorouracil chemotherapy, 46 patients received an anthracycline-based regimen, and nine of them received high-dose chemotherapy and autologous peripheral blood progenitor cell transplantation. Fifty-one patients (80%) were irradiated. ER+ patients also received tamoxifen for 5 years. Serum estradiol was suppressed to values below 40 pg/ml in all patients. After a median follow-up of 55 months, 86% of patients had resumed normal menses, 84% of patients were disease-free and 94% were alive. The 1-, 3- and 5-year projected recurrence-free survival rates were 100, 81 and 75%, respectively. Five years after treatment one patient had a pregnancy that ended with a normal childbirth. No unexpected adverse events were reported. These data show that the addition of goserelin to adjuvant therapy of premenopausal patients with early breast cancer is well tolerated and protects long-term ovarian function.

5-Fluorouracil (5-FU) given by continuous infusion (c.i.) allows higher dose delivery, causes less myelosuppression, and may interfere with repair of DNA damage caused by epirubicin and cyclophosphamide. With this rationale, we conducted a phase II study to test the activity and toxicity of 5-FU c.i., epirubicin, and cyclophosphamide in patients with metastatic breast cancer (MBC). Twenty-eight patients with MBC were entered in the trial. 5-FU (200 mg/m(2)) was administered by c.i. from day 1 to day 20. Epirubicin (35 mg/m(2)) and cyclophosphamide (400 mg/m(2)) were administered from day 2 to day 4, every 4 weeks. All patients were evaluable for response and toxicity. A total of 125 courses of chemotherapy were administered, with a median of 4 per patient (range: 2--6). Toxicity, assessed using World Health Organization criteria, was as follows: nausea and vomiting grade III--IV occurred in 36%, alopecia (grade III) in 86%, neutropenia (grade III--IV) in 50%, and cardiac toxicity grade I--II in 11% of patients. Five patients (17.9%) had a complete response to therapy, and 16 (57.1%) had a partial response (response rate 75%, 95% CI 55--89%). Disease stability and progression occurred in 4 (14.3%) and 3 (10.7%) patients, respectively. Median time to progression was 13.1 months (range: 3.4--66.9+), and median survival time was 27.7 months (range: 5.4--67.1+). Outpatient treatment with combined 5-FU c.i., epirubicin, and cyclophosphamide shows high activity in advanced breast cancer and gives prolonged remission with acceptable toxicity.

Management of metastatic prostatic carcinoma when it becomes refractory to hormonal therapy is controversial, and no standard treatment exists. Nevertheless, chemotherapy for hormone-refractory prostatic carcinoma (HRPC) has shown some advantages compared with the best supportive care. In a prospective phase II study, we evaluated the combination of epirubicin (E), mitomycin C (MMC), and 5-fluorouracil (5-FU) in patients with HRPC. Twenty-eight patients with HRPC were treated with a combination of E (30 mg/m2), 5-FU (750 mg/m2), and MMC (5 mg/m2) day 1 and 2, every 4 weeks. Treatment was continued until evidence of disease progression or excessive toxicity. Patients were monitored with serial measurements of prostate-specific antigen (PSA). Forty-seven percent of the patients exhibited a reduction of serum PSA concentration and an objective response; 38% exhibited disease stability, and 15% had disease progression. Toxicity was substantial. The median time to progression was 7.3 months (range, 1.7-16.8 months) and median survival was 14.5 months (range, 1.6-38.4 months). Performance status improved in 80% of patients, and bone pain was relieved in 70%. Thus the combination of E, MMC, and 5-FU shows activity in the treatment of HRPC, giving substantial palliation of symptoms. In one patient, PSA values remained low even when the tumor had progressed.

The authors evaluated the efficacy and toxicity of the combination of carboplatin, ifosfamide, and vinorelbine in the treatment of advanced non-small-cell lung cancer. From March 1994 through March 1996, 56 previously untreated patients with stage IIIB or stage IV non-small-cell lung cancer with measurable lesions and good performance status were entered in the study. The chemotherapy schedule was as follows: carboplatin 100 mg/m2 and ifosfamide 1,500 mg/m2 with mesna on days 1, 2, and 3; vinorelbine 25 mg/m2 on days 1 and 8, every 21 days; for a total of six courses. Among 55 evaluable patients there were three complete responses (5%) and 22 partial responses (40%), for a response rate of 45% (95% confidence interval, 32-59%). The median response duration was 10.3 months (range, 2.5-27.7 months), and median survival time was 11.3 months (range, 1.1-28.1 months). The survival rate at 1 year was 48%. Toxicity included hematologic toxicity in 60% of the 247 treatment cycles administered, nausea, alopecia, and neuropathy. One pathologic complete response was observed in a patient with stage IIIB disease who became operable after four courses of chemotherapy. The outpatient treatment with carboplatin, ifosfamide, and vinorelbine shows activity in advanced non-small-cell lung cancer. The toxicity was well tolerated by patients with a good performance status.

Because of the poor response of pancreatic cancer to conventional therapy, the authors performed a phase II pilot study to evaluate whether beta-interferon and retinoids, added to active chemotherapeutic agents, could increase response rate and survival in a group of patients who had metastatic disease. Twenty-three chemotherapy-naive patients were treated as follows: epirubicin, 60 mg/m2, and mitomycin C, 10 mg/m2, intravenously on day 1; folinic acid, 200 mg/m2, and 5-fluorouracil (5-FU), 370 mg/m2, intravenously for 5 consecutive days. beta-Interferon, 1 x 10(6) IU/m2, subcutaneously three times a week, and retinol palmitate, 50,000 IU orally twice a day, were given between chemotherapy cycles. Patients having responses and disease stabilization were maintained with the same dose of beta-interferon and retinol palmitate. Treatment was given every 4 weeks for four courses or until onset of progression. A median of three courses of chemotherapy was delivered to each patient. All patients were evaluable. Eight patients responded (35%) and 8 (35%) had stable disease. Median time to progression and survival for all patients were, respectively, 6.1 months and 11 months. Toxicity was severe: 60% of patients had hematologic toxicity, 40% had gastrointestinal toxicity, 13% had cardiac toxicity, and 1 patient had a hemolitic-uremic syndrome. The combination of chemotherapy, beta-interferon, and retinoids shows activity in metastatic pancreatic carcinoma. Toxicity was high but patients who had responses and disease stabilization had prolonged symptom palliation.

This phase I randomized study was designed in order to verify if the sequential administration of filgrastim, a granulocyte colony-stimulating factor (G-CSF), and molgramostim, a granulocyte-macrophage colony-stimulating factor (GM-CSF), was superior to filgrastim alone in improving tolerance of dose-intensified carboplatin (CBDCA), cyclophosphamide (CTX), and etoposide (VP-16). A group of 10 heavily pretreated patients with stage IV disease and no therapeutic option were enrolled into the study. They received two courses of the same chemotherapy with CTX and VP-16 at doses of 1,500 mg/m2 and 400 mg/m2, respectively. CBDCA doses were escalated from 450 to 600 mg/m2. After chemotherapy each patient was allocated randomly to receive either 14 days of G-CSF (arm A) or 7 days of G-CSF followed by 7 days of GM-CSF (arm B). Crossover in the second chemotherapy course was accomplished. Both G-CSF and GM-CSF were given 5 microg/kg/day, subcutaneously. Twenty chemotherapy courses are evaluable, 10 in each arm. Absolute neutrophil count < 1 x 10(3)/microl was observed for 54 days in arm A vs. 68 days in arm B (P < 0.02); platelet (PLT) count < 20 x 10(3)/microl, 57 days vs. 30 days (P < 0.01); days of hospitalization 35 vs. 16 (P < 0.38); PLT transfusion, 107 vs. 58 (P < 0.01); packed red blood cell unit transfusions, 15 vs. 5 (P < 0.13). Seven patients had responses. These data indicate that dose-intensified chemotherapy may be delivered without bone marrow or peripheral stem cell support, with acceptable toxicity, and that, while G-CSF alone shortens days of neutropenia, the combination of the two cytokines shortens the time of thrombocytopenia and decreases the number of PLT transfusions.

The prognosis for patients with metastatic breast cancer, progressing after anthracycline-based cytotoxic therapy, is poor, and new treatment strategies are needed. Carboplatin (CBDCA), etoposide (VP-16), and cyclophosphamide (CTX) combination therapy has proved activity against a wide variety of tumors. This study was undertaken to evaluate the activity and toxicity of standard doses of CBDCA, VP-16, and CTX administered as salvage chemotherapy in a group of patients with metastatic breast cancer previously treated with two chemotherapy regimens, including anthracyclines. Thirty patients received an average 3.5 courses of the following treatment: CBDCA, 300 mg/m2, and CTX, 500 mg/m2, on day 1; VP-16, 60 mg/m2, on days 2, 3, and 4. Thirteen patients (43%) achieved an objective response, seven (23%) stabilized, while 10 (34%) progressed. The median response duration was 11.5 months (range, 1-19); the median overall survival from protocol entry was 9.1 months (range, 1.5-26). Gastrointestinal toxicity was noted in six patients, and hematologic toxicity of grade 3-4 was found in 11 patients. The combination of CTX, CBDCA, and VP-16 at this dose and schedule is active as salvage treatment of patients with breast cancer. Even when the toxicity was severe, responders had good symptom palliation with a substantial improvement in performance status.

We evaluated the role of low-dose alpha-2b interferon, added to chemotherapy, for advanced colorectal cancer; we randomized patients, to either a combination chemotherapy of 5-fluorouracil (5-FU) and high-dose folinic acid (HDFA) or the same regimen plus interferon. Between January 1990 and March 1992, 100 untreated patients (PTS) with advanced colorectal cancer, 53 men and 47 women, with an ECOG performance status (PS) of < or = 3, were randomized to either HDFA 200 mg/m2 iv bolus and 5FU 370 mg/m2 in 15-min iv infusion days 1-5 every 4 weeks (arm A), or the same chemotherapy plus IFN 3 x 10(6) IU subcutaneously three times a week in chemotherapy intervals (arm B). A total of 97 PTS are evaluable for response, toxicity, and survival; 3 PTS are not evaluable in arm B for major protocol violations. PTS characteristics were well balanced in both arms for age (median, 64 years), disease-free survival, and disease site. ECOG PS was 0 in 28% of PTS in arm A and in 13% in arm B. Response rates were as follows: arm A, 40%; and arm B, 23%. Median time to failure was as follows: 10.2 months arm A versus 9 months arm B. Median survival was as follows: 13.3 months arm A versus 10.9 months arm B. Grade 3 haematological toxicity was 9% of PTS in both arms. Gastrointestinal toxicity was as follows: 17% arm A versus 22% arm B. The cost of drugs expressed per m2/month was $60 in arm A and $390 in arm B. The results show that IFN at the schedule and doses employed adds no benefit to the combination of 5FU/HDFA.

Interferons (IFNs) have been shown to enhance both in vitro and in vivo the antiproliferative activity of some hormones and anti-hormones which mainly act via steroid receptors. We discuss some of the mechanisms which could be involved in determining this effect in breast, endometrial and prostatic cancer cells, with a particular emphasis on steroid receptor modulation, reduction of the expression of epidermal growth factor receptors and, finally, down-regulation of some oncogenes. It seems that under appropriate conditions IFN might produce changes in cancer cells that enhance or restore hormone sensitivity. Nevertheless, available clinical data are too few to allow any conclusion to be drawn and this problem merits further investigations.

Age-related arterial stiffening and widening of the pulse pressure elevates ventricular systolic wall stress while it lowers diastolic coronary perfusion pressure. These changes are thought to adversely alter the balance between myocardial work load and blood supply. To test this hypothesis, the native compliant thoracic aorta was surgically bypassed by a stiff tube in reflex-blocked anesthetized dogs. Ventricular outflow was directed into either native aorta or the bypass; the latter resulting in an increase in arterial pulse pressure from 37.8 to 107.5 mm Hg (P < .001), with minimal change in mean pressure and flow. Cardiac work load was assessed by pressure-volume area (PVA), which combines external and internal left ventricular work and is linearly related to myocardial oxygen consumption (MVO2), and by MVO2 itself. Regional phasic and mean coronary flow were measured in the left anterior descending coronary artery, and global flow was assessed by radiolabeled microspheres. Myocardial supply-demand balance was assessed by comparing flow at matched PVA or MVO2, flow-PVA relations, and endocardial-to-epicardial flow ratios. When blood flow was directed into the stiff bypass tube, peak systolic pressure, wall stress, and PVA all rose nearly 50%, yet diastolic perfusion pressure fell by 20 mm Hg (all P < .01). Rather than being compromised, however, mean coronary flow rose by 34%, maintaining the same endocardial-to-epicardial flow ratio (approximately 1.1). Flow augmentation persisted when data were compared at matched work load (PVA or MVO2), and mean arterial pressure, as well as over a range of work loads (P < .001 from ANCOVA of flow-PVA relations). The increased flow resulted from enhanced systolic perfusion, which nearly equaled diastolic flow when ejection passed into the stiff bypass. These data counter the notion that cardiac coupling with a stiff arterial system (as with aging) necessarily compromises myocardial flow versus metabolic demand. However, the data highlight a greater role of systolic flow under such conditions and also raise the novel suggestion that enhanced pulsatility of the arterial pressure waveform may itself augment coronary perfusion.