Vivien Bramwell

Phase III Randomized, Intergroup Trial Assessing Imatinib Mesylate At Two Dose Levels in Patients With Unresectable or Metastatic Gastrointestinal Stromal Tumors Expressing the Kit Receptor Tyrosine Kinase : S0033

PURPOSE To assess potential differences in progression-free or overall survival when imatinib mesylate is administered to patients with incurable gastrointestinal stromal tumors (GIST) at a standard dose (400 mg daily) versus a high dose (400 mg twice daily). PATIENTS AND METHODS Patients with metastatic or surgically unresectable GIST were eligible for this phase III open-label clinical trial. At registration, patients were randomly assigned to either standard or high-dose imatinib, with close interval follow-up. If objective progression occurred by Response Evaluation Criteria in Solid Tumors, patients on the standard-dose arm could reregister to the trial and receive the high-dose imatinib regimen. RESULTS Seven hundred forty-six patients with advanced GIST from 148 centers across the United States and Canada were enrolled onto this trial in 9 months. With a median follow-up of 4.5 years, median progression-free survival was 18 months for patients on the standard-dose arm, and 20 months for those receiving high-dose imatinib. Median overall survival was 55 and 51 months, respectively. There were no statistically significant differences in objective response rates, progression-free survival, or overall survival. After progression on standard-dose imatinib, 33% of patients who crossed over to the high-dose imatinib regimen achieved either an objective response or stable disease. There were more grade 3, 4, and 5 toxicities noted on the high-dose imatinib arm. CONCLUSION This trial confirms the effectiveness of imatinib as primary systemic therapy for patients with incurable GIST but did not show any advantage to higher dose treatment. It appears reasonable to initiate therapy with 400 mg daily and to consider dose escalation on progression of disease.

Ineffectiveness of Doxorubicin Treatment on Solitary Dormant Mammary Carcinoma Cells or Late-developing Metastases

Breast cancer is noted for long periods of tumor dormancy and metastases can occur many years after treatment. Adjuvant chemotherapy is used to prevent metastatic recurrence but is not always successful. As a model for studying mechanisms of dormancy, we have used two murine mammary carcinoma cell lines: D2.0R/R cells, which are poorly metastatic but form metastases in some mice after long latency times, and D2A1/R cells, which form more numerous metastases much earlier. Previously we identified a surprisingly large population of dormant but viable solitary cells, which persisted in an undivided state for up to 11 weeks after injection of D2.0R/R cells. Dormant cells were also detected for D2A1/R cells, in a background of growing metastases. Here we used this model to test the hypothesis that dormant tumor cells would not be killed by cytotoxic chemotherapy that targets actively dividing cells, and that the late development of metastases from D2.0R/R cells would not be inhibited by chemotherapy that effectively inhibited D2A1/R metastases. We injected mice with D2A1/R or D2.0R/R cells via a mesenteric vein to target liver. We developed a doxorubicin (DXR) treatment protocol that effectively reduced the metastatic tumor burden from D2A1/R cells at 3 weeks. However, this treatment did not reduce the numbers of solitary dormant cells in mice injected with either D2A1/R or D2.0R/R cells. Furthermore, DXR did not reduce the metastatic tumor burden after an 11-week latency period in mice injected with D2.0R/R cells. Thus, apparently effective chemotherapy may spare non-dividing cancer cells, and these cells may give rise to metastases at a later date. This study has important clinical implications for patients being treated with cytotoxic chemotherapy.

Phase 2 Southwest Oncology Group‐directed intergroup trial (S0505) of sorafenib in advanced soft tissue sarcomas

Patients with advanced soft tissue sarcomas (STS) have limited therapeutic options. Sorafenib (BAY 43‐9006) is a multitargeted tyrosine kinase inhibitor of raf, vascular endothelial growth factor receptors 1 (VEGFR1) through 3, platelet‐derived growth factor B, fms‐like tyrosine kinase 3, and c‐kit, and some of these may be relevant in STS.

Escalated as Compared with Standard Doses of Doxorubicin in BACOP Therapy for Patients with Non-Hodgkin's Lymphoma

BACKGROUND AND METHODS In 1981 the Clinical Trials Group of the National Cancer Institute of Canada completed a pilot study in patients with advanced-stage non-Hodgkins lymphoma with aggressive tumor histology. That study demonstrated the potential efficacy of escalating the dose of doxorubicin used in a regimen of bleomycin, doxorubicin, cyclophosphamide, vincristine, and prednisone (BACOP). In the present study, we compared standard BACOP (s-BACOP) with BACOP that included escalated doses of doxorubicin (esc-BACOP) in 238 patients 16 to 70 years old with previously untreated, advanced-stage intermediate- or high-grade non-Hodgkins lymphoma. During the first 28-day cycle all patients received doxorubicin in a dose of 25 mg per square meter of body-surface area on days 1 and 8. Patients randomly assigned to receive s-BACOP subsequently received five identical cycles, whereas those assigned to receive esc-BACOP received 40 mg of doxorubicin per square meter on days 1 and 8 of five subsequent cycles if granulocytopenia (< 1000 cells per cubic millimeter) had not developed during the first cycle. RESULTS The 119 patients assigned to the esc-BACOP regimen received doxorubicin at a significantly higher mean weekly dose intensity (13.5 vs. 10.4 mg per square meter per week, P < 0.001) and mean total dose (296 vs. 231 mg per square meter, P < 0.001). Because of granulocytopenia during the first cycle of therapy, only 56 of these patients (47 percent) received the escalated doses of doxorubicin. During a median follow-up of 65 months, there were no differences between the s-BACOP and esc-BACOP groups in response rate, overall survival, or survival without disease progression. When the patients who actually received the escalated doses of doxorubicin were compared with the patients in the s-BACOP group in whom neutropenia did not develop during the first treatment cycle, no difference between their outcomes was observed. Toxicity was greater in the esc-BACOP group. CONCLUSIONS In patients with advanced-stage intermediate- or high-grade non-Hodgkins lymphoma, escalating the dose of doxorubicin in the BACOP regimen increases toxicity but does not improve the rate of response or survival.

The predictive power of semiquantitative immunohistochemical assessment of p53 and c-erb B-2 in lymph node-negative breast cancer

A series of 107 lymph node-negative (LNN) breast cancers was stained immunohistochemically with a combination of p53 and c-erb B-2. The immunohistochemical results were semiquantitated using a previously described system by Allred et al. p53 immunopositive cases were further screened for DNA mutations by the polymerase chain reaction-single-strand conformation polymorphism method (PCR-SSCP). Three representative cases showing mobility shifts were directly sequenced. One hundred of 103 invasive carcinomas were of no special type (infiltrating ductal carcinomas not otherwise specified). The three special type carcinomas included a tubular carcinoma, a classic infiltrating lobular carcinoma, and a mucinous carcinoma. Twenty-six patients (25.2%) had grade I carcinomas, and 77 patients (75%) had grade 2 or 3 carcinomas. There were four cases composed predominantly of ductal carcinoma in situ (DCIS) with foci of microinvasion. Twenty-seven of 107 patients (25%) died of disease. All those who died had grade 2 or 3 tumors. Univariate analysis showed that p53 and c-erb B-2 positivity (score > 6) were associated with a decreased overall survival (OS) (P = .0012 and P = .010, respectively), and a decreased disease-free survival (DFS) (P = .0009 and P = .027, respectively). The multivariate model selected these two variables as the best predictors of both OS and DFS (all P = or < .01). These results suggest that semiquantitative immunohistochemical analysis of p53 and c-erb B-2 provides prognostic information in LNN disease.

A prospective study of magnetic resonance imaging in lymphoma staging

In this prospective study, magnetic resonance imaging (MRI) was compared with computed tomography (CT) in patients with non‐Hodgkins lymphoma (NHDL), and with CT and laparotomy in patients with Hodgkins disease (HD). Among 31 patients with NHDL, there was agreement between MRI and CT findings in 21 patients; MRI findings were positive and CT findings were negative in 8 patients; and MRI findings were negative and CT findings were positive in 2 patients. The false‐negative findings of MRI included a laparotomy‐proven mesenteric mass and a 6.6‐cm lesion in the spleen, both shown by CT. In 13 evaluable patients with HD, there was agreement between MRI and laparotomy findings in 8 patients; MRI findings were positive and laparotomy findings were negative in 4 patients; and MRI findings were negative and laparotomy findings were positive in 1 patient. CT findings agreed with laparotomy findings in nine patients; CT findings were positive and laparotomy findings were negative in one patient; and CT findings were negative and laparotomy findings were positive in three patients. This suggested that MRI, although more sensitive than CT, was less specific with more falsepositive findings. The spin‐lattice relaxation time (T1) for the spleen was generally higher in patients with HD who had pathologically confirmed splenic involvement, and tended to increase with increasing spleen weight. This study was performed on a prototype 0.15 Tesla (Technicare Inc., Solon, OH) resistive unit at a time when methods and reporting for MRI were still being developed. Although MRI appears to have fewer false‐negative findings than CT in evaluating the abdomen of lymphoma patients, the lack of a gastrointestinal contrast agent and specificity of T1 elevations in the spleen would not suggest that MRI could replace CT or laparotomy as a staging technique.

Effect of indomethacin plus ranitidine in advanced melanoma patients on high-dose interleukin-2

Preclinical models of advanced melanoma have shown that chronic indomethacin therapy combined with interleukin 2 (IL-2) can eradicate experimental metastases. A phase II trial was done in patients with advanced melanoma. Indomethacin and ranitidine were begun at least one week before IL-2. Of the objective responses in 3 patients, 2 were achieved on ranitidine and indomethacin alone, before start of IL-2. Indomethacin and ranitidine may be responsible for some responses in melanoma patients previously attributed to IL-2.

Combination of Chronic Indomethacin and Intermittent IL-2 Therapy in the Treatment of Disseminated Cancer

Numerous effector cells of the immune system are capable of killing tumor cells in vitro as well as in vivo when properly activated. Antigen-specific T lymphocytes when exposed to certain tumor-specific antigens (TSA) in association with self MHC antigen can be triggered to produce tumor-specific cytotoxic cells in the presence of a second signal derived from T helper cells, now recognized as interleukin-2 (IL-2). However, only a small minority of spontaneously-derived tumors express TSA1. Secondly, T lymphocytes infiltrating tumor sites often remain inactive in situ because of host or tumor-related suppressor mechanisms, so that immunotherapy employing IL-2 alone may not be fully effective. However, the findings that tumor-infiltrating lymphocytes (TIL), when adoptively transferred, can selectively migrate to the tumor site, have led to promising therapeutic strategies employing IL-2 therapy in combination with TIL, or therapy with genetically modified TIL designed to deliver tumoricidal molecules at the tumor site2. Other anti-tumor effector cells do not require antigen-specific priming. These are natural killer (NK) lymphocytes and macrophages. When appropriately activated, e.g. with IL-2 or IL-2 in combination with other cytokines, these cells can kill a large spectrum of tumor cells in vitro as well as in vivo, and thus constitute a major effector arm of IL-2 therapy. Both these cell classes, NK cells in particular, represent a major component of the tumor-infiltrating mononuclear cells3,6. However, these cells also remain inactive in situs 5,6 and may resist adequate activation with IL-2 therapy alone. Our aims have been to elucidate the mechanisms underlying this inactivation and exploit this information to achieve maximal in situ activation of all killer cell lineages for eradication of the metastatic disease.

Osteopontin (OPN): A novel tumor marker of potential utility in metastatic breast cancer

575 Background: OPN, a secreted integrin-binding malignancy-associated protein measurable in blood and tumor tissue, has potential clinical utility as a tumor marker in breast cancer. METHODS In metastatic breast cancer, a prospective study to determine if (a) OPN blood levels are prognostic for survival (b) changes in OPN levels beyond baseline provide additional information (c) OPN has advantages over other blood markers (CEA, CA 15.3, secreted HER2 (ECD/HER2)). Blood was collected before treatment, and every 3-12 weeks until death. OPN: measured in plasma, using our validated ELISA assay (Clin. Bioch. 29:231, 1996). Serum markers: measured by standard clinical (CEA, CA 15.3), and ELISA (ECD/HER2) assays. RESULTS Study entry - 158 women within 8 weeks of diagnosis of metastatic breast cancer; median age 61 (20-84) years; postmenopausal (138); time to first metastasis 36 (0-397) months. First systemic treatment: chemotherapy (43), hormone therapy (111), none (4). Analysis July 2003: 132 (84% dead, median follow-up 19 (0.2-62) months. All 4 markers measured in 1378 samples (median 9 (1-26) per patient). OPN levels (median 177, range 1-2648) were elevated relative to previously determined normal levels. We used survival analysis with time-dependent covariates to investigate changes in OPN levels and survival (alive/dead) at 3, 6 and 12 months from final OPN measurement. These analyses show (i) the higher the initial OPN, the lower a patients chance of being alive at 3 months (p=0.0005); 6 months (p=0.0142); 12 months (p=0.02) and (ii) controlling for initial OPN level, any increase in OPN levels between readings confers an increased risk of death at 3 months (RR 1.73, p=0.04); 6 months (RR 1.55, p=0.04); 12 months (RR 1.58, p=0.03). We will present further analyses comparing OPN with the 3 other tumor markers. CONCLUSIONS In metastatic breast cancer, we found that OPN levels, both at baseline and changes over time, are prognostic for outcome. No significant financial relationships to disclose.