J. D. Hainsworth

Randomized Phase II Comparison of Dose-Intense Gemcitabine: Thirty-Minute Infusion and Fixed Dose Rate Infusion in Patients With Pancreatic Adenocarcinoma

PURPOSE To conduct a randomized phase II trial of dose-intense gemcitabine using a standard 30-minute infusion or the fixed dose rate (FDR) infusion (10 mg/m2/min) in patients with pancreatic adenocarcinoma. PATIENTS AND METHODS In this prospective trial, patients with locally advanced and metastatic pancreatic adenocarcinoma were treated with 2,200 mg/m2 gemcitabine over 30 minutes (standard arm) or 1,500 mg/m2 gemcitabine over 150 minutes (FDR arm) on days 1, 8, and 15 of every 4-week cycle. The primary end point of this trial was time to treatment failure. Secondary end points included time to progression, median survival, safety, and pharmacokinetic studies of gemcitabine. RESULTS Ninety-two patients were enrolled onto this study; 91% of the patients had metastatic disease. Time to treatment failure was comparable in both treatment groups; however, the median survival for all patients was 5.0 months in the standard arm and 8.0 months in the FDR arm (P =.013). For patients with metastases, the median survival was 4.9 months in the standard arm and 7.3 months in FDR arm (P =.094). The 1- and 2-year survival rates for all patients were 9% (standard arm) versus 28.8% (FDR; P =.014) and 2.2% (standard arm) versus 18.3% (FDR; P =.007), respectively. Patients in the FDR infusion arm experienced consistently more hematologic toxicity. Pharmacokinetic analyses demonstrated a two-fold increase in intracellular gemcitabine triphosphate concentration in the FDR arm (P =.046). CONCLUSION Pharmacokinetic and clinical data in this trial supports the continued evaluation of the FDR infusion strategy with gemcitabine.

Molecular Profiling of Carcinoma of Unknown Primary and Correlation With Clinical Evaluation

PURPOSE To evaluate the feasibility of a 10-gene reverse transcriptase polymerase chain reaction assay to identify the tissue of origin in patients with carcinoma of unknown primary (CUP) site. PATIENTS AND METHODS Diagnostic biopsy formalin-fixed, paraffin-embedded (FFPE) specimens from 120 patients with CUP were collected retrospectively from Sarah Cannon Research Institute, Nashville, TN, and prospectively from The University of Texas M. D. Anderson Cancer Center, Houston, TX. Tissue of origin assignments by the assay were correlated with clinical and pathologic features and with response to therapy. RESULTS The assay was successfully performed in 104 patients (87%), and a tissue of origin was assigned in 63 patients (61%). In the remaining 41 patients (39%), the molecular profiles were not specific for the six tumor types detectable by this assay. The tissues of origin most commonly identified were lung, pancreas, and colon; most of these patients had clinical and pathologic features consistent with these diagnoses. Patients with lung and pancreas profiles had poor response to treatment. Patients with colon cancer profiles had better response to colon cancer-specific therapies than they did to empiric CUP therapy with taxane/platinum regimens. Patients with ovarian cancer profiles were atypical, with widespread visceral metastases and a paucity of overt peritoneal involvement. CONCLUSION This gene expression profiling assay was feasible using FFPE biopsy specimens and identified a putative tissue of origin in 61% of patients with CUP. In most patients, the assigned tissue of origin was compatible with clinicopathologic features and response to treatment. Prospective studies in which assay results are used to direct therapy are indicated.

Carcinoma of unknown primary site: treatment with 1-hour paclitaxel, carboplatin, and extended-schedule etoposide.

PURPOSE To evaluate the efficacy and toxicity of a novel chemotherapy combination that includes paclitaxel, carboplatin, and extended-schedule etoposide in the treatment of patients with carcinoma of unknown primary tumor site. PATIENTS AND METHODS Fifty-five patients with carcinoma of unknown primary tumor site were treated with the following regimen, administered every 21 days: paclitaxel 200 mg/m2 by 1-hour intravenous (I.V.) infusion on day 1, carboplatin at an estimated area under the concentration-time curve (AUC) of 6.0 on day 1, and etoposide 50 mg alternated with 100 mg orally on days 1 through 10. Responding patients received a total of four courses of treatment. The following histologies were included: adenocarcinoma, 30 patients; poorly differentiated carcinoma (PDC) or poorly differentiated adenocarcinoma (PDA), 21; poorly differentiated neuroendocrine carcinoma, three; and squamous carcinoma, one. RESULTS Twenty-five of 53 assessable patients (47%; 95% confidence interval [CI], 33% to 61%) had major objective responses to treatment (seven complete responses). Response rates were similar in patients with adenocarcinoma versus PDC (45% and 48%, respectively). The actuarial median survival time for the entire group was 13.4 months. The regimen was well tolerated, with only seven hospitalizations for treatment of neutropenia and fever (4% of courses) and no treatment-related deaths. CONCLUSION The combination of paclitaxel, carboplatin, and extended-schedule etoposide is highly active and well tolerated in patients with carcinoma of unknown primary tumor site. Response rates and survival in this multicenter community-based trial compare favorably with all previously studied empiric regimens. In addition, this regimen is substantially less toxic and easier to administer than the cisplatin-based regimens previously used in this setting. If this level of efficacy is confirmed, this treatment should be considered standard first-line therapy in patients with carcinoma of unknown primary tumor site.

Phase II pilot trial of imatinib mesylate with weekly docetaxel in metastatic breast cancer

10716 Background: Overexpression of platelet derived growth factor receptor (PDGFR) has been associated with breast cancer tumor progression and may serve as a potential target for therapy. Inhibition of PDGFR signaling in tumor stroma represents a novel strategy that has demonstrated enhanced chemotherapy antitumor effects, decreased tumor interstitial fluid pressure as well as increased tumor transcapillary transport. Imatinib mesylate (G) is a potent PDGFR tyrosine kinase antagonist. This phase II pilot study evaluates the feasibility, toxicity, and efficacy of imatinib administered with docetaxel as a strategy to enhance docetaxels chemotherapeutic effects in metastatic breast cancer (MBC). METHODS Eligibility requirements: 0-1 prior regimens for MBC, > 6 months from prior adjuvant taxanes, RECIST measurable disease, ECOG PS 0-2, adequate organ function, < G2 neuropathy. TREATMENT docetaxel 30 mg/m2 IV weekly 3 of 4 weeks. Imatinib mesylate 600 mg po QD. Pts were evaluated for response every 8 weeks; treatment continued until progression or toxicity. RESULTS 7 pts have been enrolled to date. Median age is 61, all with ECOG PS 0. 5 pts received prior adjuvant therapy; 2 pts received prior taxanes. 43% received prior hormonal therapy. Only 1 pt was ER+/PR+. Hematologic toxicity was mild, consisting only of G3/4 anemia in 2 pts and G3 thrombocytopenia in 1. No febrile neutropenia was noted. Nonhematologic toxicity was characterized primarily by G3 GI toxicity: 4 pts diarrhea, 3 N, V, 1 anorexia, 1 abdominal pain. This was attributed to imatinib in all but 1 pt, in whom both drugs were implicated. 2 pts were removed from treatment and 3 pts required dose reductions, all due to GI toxicity consisting of N, V, and diarrhea. 3 pts experienced dose interruptions and 2 pts exhibited disease progression. CONCLUSION These early preliminary results demonstrate imatinib mesylate, in combination with weekly docetaxel as a strategy to inhibit breast cancer PDGFR signaling, is feasible. GI toxicity with this combination was prominent and warrants dose modifications. Updated toxicity and efficacy data will be presented. [Table: see text].

Carcinoma of unknown primary site with unfavorable characteristics: Survival of 396 patients after treatment with five consecutive phase II trials by the Minnie Pearl Cancer Research Network

4186 Background: Most patients with carcinoma of unknown primary site cannot be assigned to a favorable prognostic subgroup associated with an improved survival. In the past 8 years, several new cytotoxic agents with a broad spectrum of activity have been introduced including the taxanes, gemcitabine (G), and irinotecan (I). METHODS The Minnie Pearl Cancer Research Network has performed 5 consecutive phase II trials in a total of 396 patients from 1995 through 2002. Favorable subsets of patients were excluded. Study 1 included paclitaxel, carboplatin, and oral etoposide (PCE) (N=71), study 2 docetaxel and cisplatin (N=26), study 3 docetaxel and carboplatin (N=47), study 4 gemcitabine, carboplatin, and paclitaxel (N=120), and study 5 sequential PCE with GI (N=132). RESULTS The response rate in all 5 studies was 30% (107 of 353 evaluable patients), with 85 (24%) partial responders and 22 (6%) complete responders. With a minimum follow-up of 1 year, the median survival (MS) is 9.1 months and the 1-, 2-, 3-, 5-, and 8-year survivals are 38%, 19%, 12%, 8%, and 6%, respectively. The median progression-free survival (PFS) is 5 months and the 1-, 2-, 3-, 5-, and 8-year PFS are 17%, 7%, 5%, 4%, and 3%, respectively. The first 144 patients on the first 3 trials have a minimum follow-up of 4.8 years (range 4.8-8 years) and the MS is 10 months with a 1-, 2-, 3-, 5-, and 8-year survival of 42%, 22%, 18%, 12%, and 10%, respectively. The toxicity of these 5 regimens was moderate and primarily myelosuppression. There were 8 (2%) treatment-related deaths. When comparing these results to historical data from 45 prospective trials (since 1964) including 1,515 patients, and in retrospective reviews including 31,419 patients, the 1- and 2-year survival is significantly prolonged (40% versus 20% at 1 year and 22% versus 5% at 2 years). CONCLUSIONS The newer chemotherapy regimens as reported here produce a prolongation of survival for these patients. [Table: see text].

Novel Diagnostic and Therapeutic Strategies in the Management of Patients with Cancers of Unknown Primary Site

The tissue of origin or definitive cancer type can now be determined in most CUP patients by the appropriate use of selected IHC stains and/or a molecular cancer classifier assay. In those patients with a very small biopsy or when standard pathology, including IHC staining, does not make a single tissue of origin diagnosis, a molecular cancer classifier assay frequently will diagnose a single cancer type critical for the selection of appropriate therapy. Many CUP patients have tumor types which are sensitive/responsive to site-directed therapies for their cancer type; they have a better outcome if treated with site-specific therapy based on a tissue of origin diagnosis rather than with empiric chemotherapy. Several retrospective studies and one large prospective study support this assertion. Once the tissue of origin is identified, the diagnosis is established, and treatment should proceed directed at that cancer type. This approach represents a new paradigm for the management of CUP. Empiric chemotherapy should no longer be routinely administered to all CUP patients but may be reserved for the few without a single tissue of origin diagnosis.

Amrubicin as second- or third-line treatment for patients with HER2-negative metastatic breast cancer (MBC): A Sarah Cannon Research Institute phase I trial.

1116 Background: Anthracyclines demonstrate significant activity in breast cancer; however, cumulative cardiotoxicity limits their use. Amrubicin is a novel anthracycline with broad-spectrum antitumor activity and low potential for cardiotoxicity. We initiated a phase I/II trial of amrubicin in patients with MBC. Results from the phase I portion are presented. METHODS Women with HER2-negative MBC, ≤2 prior chemotherapy regimens for metastatic disease, normal LVEF, and measurable disease were eligible. Amrubicin was administered IV every 3 weeks; doses were escalated in sequential cohorts of patients, using standard phase I methodology. Four amrubicin dose levels were evaluated: 90 mg/m2, 100 mg/m2, 110 mg/m2, and 120 mg/m2. The MTD was defined as the highest dose producing ≤2 DLTs in a patient cohort. Prophylactic GCSF support was strongly encouraged due to previous reports of complicated neutropenic events. Cardiac monitoring with serial ECHOs or MUGAs was performed every 4 cycles. Response assessments were performed every 2 cycles. RESULTS Fifteen patients were treated at 4 amrubicin dose levels; data is available for 12 patients. Grade 3/4 toxicity is summarized in the table. No cardiotoxicity was evident. At the 120 mg/m2 dose level, 2 patients had grade 4 neutropenia in spite of GCSF support; 1 pt had neutropenia > 7 days and one pt had her dose delayed by one week due to neutropenia. Due to these events, the MTD of amrubicin in this pt population (and recommended phase II dose) was 110 mg/m2 with GCSF support. CONCLUSIONS Amrubicin 110 mg/m2 was tolerable as 2nd/3rd-line treatment in women with MBC. Myelosuppression was the most common grade 3/4 toxicity and the DLT, despite the use of prophylactic GCSF support. The phase II portion of this trial is proceeding. [Table: see text].

Clinical relevance of HER2 expression/activation, as measured in circulating tumor cells by a multiplexed immunoassay, in women with HER2-negative (by FISH) metastatic breast cancer (MBC).

TPS125 Background: HER2-targeted agents markedly improve survival in women with HER2-positive breast cancer. HER2 expression is currently assessed using immunohistochemistry or FISH techniques, usually at the time of diagnosis. The ProONC assay (Prometheus, Inc.) is a multiplexed immunoassay that allows assessment of HER2 expression/activation in circulating tumor cells (CTCs) or FNA specimens, thereby enabling reassessment at multiple timepoints during the disease course. For patients with MBC, the ProONC assay correlated strongly with FISH in tumors previously identified as HER2-positive, but identified HER2 expression/activation in 29% of patients who had previously tested HER2-negative by FISH. The clinical relevance of this finding is currently unknown. The study objectives were to: 1) determine the frequency of HER2 expression/activation, as measured in CTCs by the ProONC assay, in women with HER2-negative MBC by FISH testing; 2) evaluate the efficacy of HER2-targeted treatment in this group of wome...

Weekly bolus topotecan as first-line therapy for extensive stage small cell lung cancer in patients who are elderly, poor performance status, or have severe coexistent illness: A Minnie Pearl Cancer Research Network phase II trial

7275 Background: Topotecan given intravenously for 5 consecutive days every 3 weeks is standard second-line therapy for patients (pts) with relapsed small cell lung cancer (SCLC) and ovarian cancer. Weekly bolus topotecan produces significantly less toxicity than the 5 day schedule, and appears as active as the standard schedule in pts with relapsed ovarian cancer. METHODS This ongoing phase II study was designed to evaluate the toxicity and response rate of weekly bolus topotecan in pts with previously untreated extensive stage SCLC who were elderly (> 65 years), poor performance status (PS), or had severe coexistent medical illness. Topotecan 4mg/m2 IV over 30 minutes for 12 consecutive weeks was planned. Dose modifications were made based on toxicity. Pts were evaluated for response after 4 weeks; at least 3 weekly treatments were required to be evaluable. RESULTS Seventeen pts of the required 40 pts have thus far been enrolled; 12 men, 5 women, ages 64-81 (median 71); PS 0=1, 1=4, 2=12). Thirteen pts are evaluable for response. Two pts have had partial responses (15%); 6 pts stable tumor (45%). Grade 3/4 neutropenia has been seen in 4 of 17 pts (24%), but no grade 3/4 thrombocytopenia was observed. Grade 2 fatigue was observed in 10 pts (56%) and grade 3 fatigue in 6 pts (35%). A total of 107 weeks of therapy have been administered. There were 15 weeks of treatment delay and 8% required dose reductions. CONCLUSIONS Weekly bolus topotecan appears to have modest activity and is well tolerated in this poor prognostic group of pts with previously untreated extensive stage SCLC. We expect to evaluate 15 additional pts soon. Severe myelosuppression is seen less often than expected compared to the standard 5 day schedule of topotecan. Fatigue is an important toxicity and may be reduced by planned rest weeks. Studies of weekly topotecan in combination with other active cytotoxic agents should be considered in pts with extensive stage SCLC. [Table: see text].

Non-Curative Chemotherapy for Patients with Unknown Primary Cancers

Cancer of unknown primary site is common, accounting for about 5% of cancer patients. Relatively little attention has been given to this group of patients, and treatment directed against these tumours has been slow to develop. Pessimism concerning the therapy and prognosis of these patients has been one major reason for the lack of effort. The patient with carcinoma of unknown primary is commonly visualized as elderly and debilitated with metastases at multiple sites. Early chemotherapy trials did not seem to provide much palliation and had negligible effect on survival. The heterogeneity of tumours represented in these patients has also made the design of therapeutic studies difficult. Many cancers with different biologies are represented. Effective palliative chemotherapy is now available for many types of advanced cancers, often providing substantial relief of symptoms and extending the length and quality of life. It follows that some patients with carcinoma of unknown primary site have sensitive or treatable tumours. A small minority of these patients have curable metastatic carcinoma (i.e. germ-cell tumours), and these relatively rare examples will not be discussed in detail. However, it must be stressed that precise identification of the lineage and biology of these tumours is often not possible, and a therapeutic plan is desired in an attempt to provide broad coverage for patients with “treatable” cancers. When one reviews the outcome of chemotherapy it is obvious that the major benefit for the majority of the “treatable” patients is palliative in nature (i.e. improvement of qualitv of life and/or duration of survival).