Howard W. Bruckner

The modulation of fluorouracil with leucovorin in metastatic colorectal carcinoma: a prospective randomized phase III trial. Gastrointestinal Tumor Study Group.

A total of 343 patients with previously untreated metastatic measurable colorectal carcinoma were studied to evaluate the impact on toxicity, response, and survival of leucovorin-modulated fluorouracil (5-FU). A maximally tolerated intravenous bolus loading course regimen of 5-FU alone (500 mg/m2 x 5 days every 4 weeks with 25 mg/m2 escalation) was compared with a high-dose leucovorin regimen (600 mg/m2 of 5-FU with 500 mg/m2 of leucovorin weekly for 6 weeks with a 2-week rest) and with a similar low-dose leucovorin regimen (600 mg/m2 of 5-FU with 25 mg/m2 of leucovorin weekly for 6 weeks with a 2-week rest). The dose-limiting toxicity for the two 5-FU and leucovorin regimens was gastrointestinal, specifically diarrhea; severe diarrhea was seen frequently, and treatment-related toxicity was implicated in the demise of 11 of the patients (5%). Significant improvements in response rates were observed with a response rate of 33 of 109 (30.3%) on the high-dose leucovorin regimen (P less than .01 v control); 13 of 107 (12.1%) on the 5-FU control; and 21 of 112 (18.8%) on the low-dose leucovorin regimen. A trend toward longer survival in the 5-FU plus high-dose leucovorin regimen was observed. In this study, leucovorin was shown to significantly enhance the therapeutic effect of 5-FU in metastatic colorectal carcinoma.

Ascorbic acid (vitamin C) improves the antineoplastic activity of doxorubicin, cisplatin, and paclitaxel in human breast carcinoma cells in vitro

Utilizing a microplate ATP bioluminescence assay, two human breast carcinoma cell lines, MCF-7 and MDA-MB-231, were tested against doxorubicin (DOX), cisplatin (DDP), and paclitaxel (Tx) alone and in combination with ascorbic acid (Vit C). In both cell lines, Vit C exhibited cytotoxic activity at high concentrations (i.e. 10(2)-10(3) microM). Both cell lines also were resistant to DOX. MCF-7 was found to be DDP-resistant, MDA-MB-231 was moderately sensitive to DDP. Both cell lines were strongly sensitive to Tx. Vit C both at non-cytotoxic (1 microM) and moderately cytotoxic concentrations (10(2) microM) improved the cytotoxicity of DOX, DDP, and Tx significantly. Combination effects between Vit C and DDP or Tx were partly synergistic and partly additive or subadditive whereas a consistent synergism was found between Vit C and DOX. The mechanisms by which Vit C potentiates the cytostatics studied are yet unclear and should be evaluated further.

Irinotecan Plus Gemcitabine Induces Both Radiographic and CA 19-9 Tumor Marker Responses in Patients With Previously Untreated Advanced Pancreatic Cancer

PURPOSE This phase II, multicenter, open-label, single-arm study evaluated the efficacy and safety of irinotecan and gemcitabine as combination chemotherapy for previously untreated patients with unresectable or metastatic pancreatic cancer. PATIENTS AND METHODS Patients received repeated 21-day cycles at starting doses of gemcitabine 1,000 mg/m(2) over 30 minutes followed immediately by irinotecan 100 mg/m(2) over 90 minutes, both given intravenously on days 1 and 8. Patients were evaluated for objective tumor response, changes in the serum tumor marker CA 19-9, time to tumor progression (TTP), survival, and safety. RESULTS Forty-five patients were treated. Eleven patients (24%) had 50% or greater reductions in tumor area. These were confirmed one cycle later in nine patients (response rate, 20%; 95% confidence interval, 8% to 32%). Among 44 patients with baseline CA 19-9 determinations, CA 19-9 decreased during therapy in 22 patients (50%) and was reduced by 50% or more in 13 patients (30%). Median TTP was 2.8 months (range, 0.3 to 10.8 months). There were significant (P <.001) correlations between proportional changes in CA 19-9 and radiographic changes in tumor area with regard to extent of change (r =.67), timing of minimum on-study values (r =.85), and tumor progression (r =.89). Median survival was 5.7 months (range, 0.4 to 19.4+ months), and the 1-year survival rate was 27%. Severe toxicities were uncommon and primarily limited to grade 4 neutropenia (2%), grade 4 vomiting (2%), and grade 3 diarrhea (7%). CONCLUSION Irinotecan/gemcitabine is a new combination that offers encouraging activity in terms of radiographic and CA 19-9 response and notable 1-year survival in pancreatic cancer. The regimen was well tolerated, with minimal grade 3 and 4 toxicities and excellent maintenance of planned dose-intensity.

Use of an ex vivo ATP luminescence assay to direct chemotherapy for recurrent ovarian cancer.

Chemotherapy for recurrent ovarian carcinoma (ROC) produces response rates of 10-80% depending on the prevalence of platinum resistance. Most patients relapse within 1 year and median progression-free survival (PFS) is generally no more than 6 months. Previous pretherapeutic chemosensitlvity assays mostly failed to improve the outcome of patients with ROC. Newly developed ATP assays show promising retrospective correlation with clinical outcome. We report here the first results of ATP assay-directed chemotherapy in patients with ROC. Therapy was selected by the ATP tumor chemosensitivity assay (ATP-TCA) in a prospective open-label pilot trial for ROC. Objective response rate (ORR), PFS and overall survival (OAS) of the first 25 evaluable patients were retrospectively compared with those of 30 others having similar characteristics who were treated empirically within the same period. The actuarial median observation times were 80 weeks for the ATP-TCA group and 83.5 weeks for the control group, respectively. In the control group, a 37% ORR [two complete responses (CR) and nine partial responses (PR)] was followed by a median PFS of 20 weeks and a median OAS of 69 weeks, mainly related to the use of single-agent chemotherapy. The ORR in the ATP-TCA group was 64% (eight CR and eight PR) (p=0.04) with the majority of responses (11 of 16) achieved with novel combinations. The median PFS in this group was 50 weeks (p=0.003) and the median OAS was 97 weeks (p=0.145). Survival of responding patients was similar in both groups. Chemotherapy guided by the ATP-TCA produced a greater benefit with regard to both ORR and PFS in platinum-refractory patients. ATP-TCA-directed chemotherapy for ROC compares favorably with chemotherapy chosen by a clinician and often leads to the choice of novel drug combinations. These promising results now warrant confirmation by prospective randomized trials.

Endoscopic ultrasonographic criteria of vascular invasion by potentially resectable pancreatic tumors

Endoscopic ultrasonography was used to examine 38 patients with a pancreatic neoplasm (mean size, 2.8 cm; range, 1 to 5 cm). Three EUS signs appear to be reliable criteria for the identification of tumor invasion of major veins forming the portal confluence: (1) peri-pancreatic venous collaterals in the area of a mass that obliterates the normal anatomic location of a major portal confluence vessel; (2) tumor within the vessel lumen; and (3) abnormal vessel contour with loss of the vessel-parenchymal sonographic interface. At least one of these signs was present in each of the 21 patients with vascular invasion; none of them was present in the 17 patients without vascular invasion. Findings were confirmed by laparotomy plus biopsy (33 patients), autopsy (1 patient), or angiography plus biopsy (4 patients). Arterial involvement was identified by alteration of vessel course and caliber. All 7 patients with arterial involvement also had venous involvement. These signs provide reliable criteria for endoscopic ultrasonographic definition of unresectable tumors in patients with a pancreatic neoplasm that appears to be resectable on standard radiologic tests.

Combined modality therapy for stage II and stage III pancreatic carcinoma.

PURPOSE To study the outcome achieved with three-drug chemotherapy and split-course external-beam radiotherapy as a treatment for unresectable stage II and III pancreatic carcinoma. PATIENTS AND METHODS Radiotherapy was given in three cycles of 2 Gy/d on days 1 to 5 and 8 to 12 (total dose, 54 Gy) concurrently with fluorouracil (FU) 1,000 mg/m2/d by continuous infusion for 4.5 days, streptozocin (STZ) 300 mg/m2 on days 1, 2, and 3 and cisplatin (P) 100 mg/m2 on day 3 of each every-28-day cycle. Subsequent treatment consisted of leucovorin (LV) 200 mg/m2 and FU 600 to 1,000 mg/m2 every 14 days. RESULTS The median survival time for the 35 patients was 15 months and 26% of patients were alive at 24 months. Fifteen patients (42.8%) had objective responses to therapy. Six (17%) had a complete response (CR). Three of nine patients with partial responses (PRs) achieved a radiographic CR within the next 3 months. Nine patients underwent attempts at surgical resection: five were resected (median survival time, 31 months; range, 12.8 to 44.7+), two had no residual disease found at complete resection, and three others also had a complete resection. Of four others who could not be resected, three underwent intraoperative radiotherapy and one had occult metastatic disease. Of primary tumors, 91% did not produce either back pain or local gastrointestinal complications for 2 years. The rates of severe side effects were stomatitis 15%, anemia 14%, granulocytopenia 6%, and thrombocytopenia 6%. CONCLUSION Palliation and survival compare favorably with other series, including many surgical series. The response findings encourage studies of both unresectable and (as neoadjuvant therapy) resectable tumors.

Improved therapy with cisplatin regimens for patients with ovarian carcinoma (FIGO Stages III and IV) as measured by surgical end-staging (second-look operation)

Between 1974 and 1982, 273 patients with epithelial cancer of the ovary (International Federation of Gynaecology and Obstetrics Stages III and IV) were randomized in four therapeutic trials. In Trial I Adriamycin plus cisplatin versus cisplatin alone versus thiotepa plus methotrexate was tested. The superiority of Adriamycin plus cisplatin in producing the best response rate led to its use as the reference arm in subsequent trials. All investigational arms included cisplatin plus other drugs (cyclophosphamide, Adriamycin, hexamethylmelamine, and thiotepa) in various combinations. Eligibility for second look required complete clinical remission and completion of at least 10 cycles of chemotherapy. To date, 73 second-look operations have been performed on randomized patients. An additional 43 nonrandomized patients underwent second-look procedures and are analyzed separately. Between 40% and 46% of patients treated with cisplatin regimens had no disease at second look. Cell differentiation and volume of postoperative disease did not influence response.

The enhancement of 5-fluorouracil antimetabolic activity by leucovorin, menadione and α-tocopherol

Abstract Studies were designed to develop approaches for increasing the intracellular levels of 5–10 methylene tetrahydrofolate and to see if this would augment the antimetabolic effect of 5 -fluorouracil ( 5 -FU). This was studied in the Friend murine erythroleukemia cell line (FLC). The ability to inhibit tritiated deoxyuridine ([ 3 H ] UdR) incorporation into DNA and a 72-hr cell growth curve determination were used as indicators of the 5 -FU anti-metabolic effect. The cell growth inhibition by continuous 5 -FU exposure (3 × 10 −7 to 2 × 10 −6 M) at 48 and 72 hr was time and dose-related, and was less in cells depleted of folate. The simultaneous addition of dl - 5 -formyltetrahydrofolate in the form of Leucovorin (LV) (1 × 10 −5 M) enhanced 5 -FU cell growth inhibition at all times recorded and was greater than 3 -fold at the highest 5 -FU concentration. Similarly, a 1 to 6-hr exposure to this combination, followed by washing, was 3 -fold greater than that of 5 -FU cell growth inhibition. The potentiation of 5 -FU anti-metabolic effect by LV was also demonstrated by further inhibition of [ 3 H ] UdR incorporation into DNA after 72 hr of varying concentrations of drug exposure. The 5 -FU inhibition of [ 3 H ]UdR incorporation into DNA was significantly increased and prolonged in the presence of LV after brief exposures of 1–6 hr . Under similar conditions, LV did not potentiate the 5 -FU effect in an LV transport-defective FLC line, demonstrating that LV enhances 5 -FU by an intracellular mechanism. The addition of menadione (5 × 10 −7 to 1 × 10 −6 M) significantly enhanced the anti-metabolic effect of 5 -FU as measured by [ 3 H ]UdR incorporation into DNA or by cell growth inhibition curves, but for only the initial 24 hr . Levels of menadione greater than 1 × 10 −6 M were toxic in the FLC system. In contrast, α-tocopherol (1 × 10 −5 M), itself non-toxic, potentiated the anti-metabolic effect of 5 -FU over a continuous exposure for 72 hr , as measured by both inhibition of [ 3 H ]UdR into DNA and cell growth curves. The α-tocopherol potentiation of 5 -FU was not as great as that of LV, but when added in combination with LV was more effective than 5 -FU and LV. These data suggest that the intracellular levels of 5–10 methylene tetrahydrofolate necessary for the pharmacologic interaction of FdUMP with thymidylate synthetase may be a limiting factor under certain conditions and that it is possible to overcome this metabolic limitation with exogenous reduced folate or by the addition of oxidizing agents which may increase intracellular levels of 5–10 methylene tetrahydrofolate.

High-dose platinum for the treatment of refractory ovarian cancer.

Abstract High-dose cis -diamminedichloroplatinum, 120 mg/m 2 , produced six clinical responses (three complete) for 12 patients with advanced ovarian adenocarcinoma failing initial therapy with an alkylating agent. Responders survived 8+ to 20+ months. The same dosage produced four (zero complete, one short) responses for 20 patients refractory to a 50 mg/ m 2 dosage. Ten instances of nephrotoxicity and five of neurotoxicity were apparently related to a total cumulative dose of DDP and were predominantly seen in patients with prior DDP therapy and in patients with maintained responses to high-dose DDP.

Correlation of the clinical response to chemotherapy in breast cancer with ex vivo chemosensitivity.

Chemotherapy for breast cancer is given on the basis of empirical information from clinical trials, an approach which fails to take into account the known heterogeneity of chemosensitivity between patients. Previous attempts to determine chemosensitivity ex vivo have been disappointing, but in this study results from a newly developed tumor chemosensitivity assay (TCA) have been correlated prospectively with patient response. In this study, we have used heterogeneity data for standard regimens obtained from 116 breast TCAs to set sensitivity/resistance thresholds which were then used to interpret the results from those with known clinical responses. Assay evaluability was 97% in surgical biopsies. Clinical follow-up of stage III/ IV assessable disease was obtained from 27 breast tumors which were successfully tested for chemosensitivity, including 13 needle biopsies. The ATP-TCA assay predicted response correctly in 22 out of 29 (76%) tumors with clinically evaluable disease, suggesting that it is capable of predicting outcome in individual patients. Assays were performed in seven patients before and after chemotherapy using residual or recurrent tumor tissue. Four cases with initial sensitivity showed a decrease in sensitivity within 6 months of starting chemotherapy, while two others without clinical resistance were still sensitive by TCA. All nine courses of therapy given on the basis of TCA sensitivity resulted in partial or complete responses. Controlled trials of TCA-directed treatment against standardized empirical therapy should be conducted before this technology is widely adopted to assess its impact on rates of response, survival and the cost of treatment.