Adjuvant Chemotherapy and Tumor Sidedness in Stage II Colon Cancer: Analysis of the National Cancer Data Base.

Background: Current guidelines recommend discussion of adjuvant chemotherapy (AC) for stage II colon cancer (CC) with high-risk features despite lacking conclusive randomized trial data. We examined AC administration in this population and its effect on overall survival (OS) for available patient, tumor, and treatment characteristics Methods: Using National Cancer Data Base, a cohort of 42,971 stage II CC patients diagnosed from 2004 to 2009, who underwent surgery with curative intent, was identified. Chi-square test and multivariate logistic regression were used to analyze baseline characteristics and to calculate odds of chemotherapy administration, respectively. Survival analysis was conducted using Kaplan Meier survival analysis with log-rank test and Cox proportional hazards regression modeling. Results: AC was administered to 26% patients. The use decreased with advancing age and elderly patients received more single-agent than multi-agent chemotherapy (3 vs. 2.4%, p < 0.0001). Major predictors of AC use included pT4 status, evaluation of <12 lymph nodes, high grade tumors, positive resection margins, age <65 years, left sided tumors, and low comorbidity score. AC was associated with improved OS regardless of high-risk features (pT4, undifferentiated histology, <12 lymph node evaluation, or positive resection margins), tumor location, age, gender, comorbidity index, chemotherapy regimen or type of colectomy (adjusted HR: single-agent 0.55, multi-agent 0.6; p < 0.0001). In subgroup analysis, AC use compensated for the survival differences otherwise seen between left and right sided tumors in the non-chemotherapy population. Conclusion: AC in stage II CC was associated with improved OS regardless of age, chemotherapy type or high-risk features. It improved 5-years OS irrespective of tumor location and seemed to compensate for the survival difference seen between right and left sided tumors noted in the non-chemotherapy group.

Age-dependent overall survival benefit of androgen deprivation therapy for metastatic prostate cancer.

BACKGROUND: Androgen deprivation therapy (ADT) remains a standard of care in metastatic prostate cancer. Recent prospective trials have explored addition of chemotherapy to ADT. We retrospectively examined overall survival in metastatic prostate cancer patients treated with ADT, chemotherapy plus ADT (C + ADT), or observation from 2004 to 2010 using National Cancer Database data. METHODS: Using the National Cancer Database, 21,977 patients with metastatic prostate cancer diagnosed from 2004 to 2010 were identified. Multivariate logistic regression, Kaplan-Meier survival analysis and Cox proportional hazards regression modeling were implemented, with overall survival as the primary endpoint. RESULTS: Five-year overall survival was 13.6% in patients aged ≥ 75 years vs. 30.1% (age 65-74) and 34.5% (age 18-64). Subgroup analysis of age-based cohorts (<65 and ≥65 years) showed poor overall survival for C + ADT vs. ADT alone, both in younger (HR 1.35, 95% CI 1.21-1.50; p < 0.0001) as well as older (HR 1.21, 95% CI 1.08-1.34; p = 0.0006) populations. Younger patients had no significant difference in overall survival for observation vs. ADT (HR 0.99, 95% CI 0.92-1.08; p = 0.9121). Besides age, other factors impacting overall survival included race, rural/urban settings, comorbidity score, income, PSA and radiation. DISCUSSION: Younger patients had no significant difference in overall survival between observation or ADT. This implies a group of younger patients in whom ADT does not confer any overall survival benefit. Future clinical trials with genetic and biologic markers are needed to delineate which subgroups would not benefit from C + ADT or ADT alone. This is of utmost clinical importance given the negative impact of ADT on quality of life and comorbidities.

Immune T cells can transfer and boost anti-breast cancer immunity.

This proof-of-concept study investigates the immune effects in metastatic breast cancer (MBC) patients after "vaccination" with activated T cells (ATC) armed with anti-CD3 x anti-HER2 bispecific antibody (HER2 BATs) followed by immune consolidation with immune ATC "boost" after high dose chemotherapy (HDC) and autologous stem cell transplant (SCT). Approximately 2 weeks after completion of vaccination portion of the study, immune T cells were obtained by leukopheresis, activated and expanded ex vivo and re-infused after HDC and SCT to test the hypothesis that transfer of immune unarmed ATC would accelerate reconstitution of anti-tumor activity after SCT. Eight metastatic breast cancer (MBC) patients received 8 infusions of HER2 BATs, low dose IL-2, and GM-CSF in the first part of the protocol to induce adaptive cellular and humoral responses. In the "boost" portion of the protocol, 6 of 8 patients received multiple infusions of unarmed ATC post SCT. There were no dose-limiting toxicities or delays in engraftment. Four of 6 patients tested for the immune correlative studies exhibited increases in anti-breast cancer (BrCa) cytotoxicity, antigen specific IFN-γ Elispots, anti-BrCa antibodies and increased IL-12 and Th1 serum cytokine levels after HER2 BATs infusions. Anti-BrCa tumor responses were seen as early as 2 weeks after SCT and persisted up to 2 years post-SCT. One out of 6 patients' rapidly progressed and showed poor immune responses and high Th2 cytokine levels. There was a significant correlation (p < 0.002) between time to progression (TTP) and anti-BrCa cytotoxicity by immune T cells. This is the first study to show that adoptive transfer of immune T cells after SCT accelerates reconstitution of anti-BrCa specific immunity and correlates with delay TTP.

Adequate lymph node evaluation in the elderly is associated with improved survival in patients with stage I-III colon cancer: A validation study using the National Cancer Data Base.

BACKGROUND: Lymph node involvement (LNI) is an important prognostic factor in colon cancer. But, variations in LNI among different age groups are less known. Adequate lymph node evaluation (LNE) requires assessment of ≥12 nodes. In our previous study, using Surveillance, Epidemiology and End Results (SEER) data, we demonstrated that older patients are less likely to have LNI (Khan et al. 2014). Our current study validates those findings using National Cancer Data Base (NCDB). METHODS: NCDB was queried for patients diagnosed with stages I-III colon adenocarcinoma from 2004 to 2008 who underwent surgical resections. Pearson Chi-square test and Cox proportional hazards regression model were utilized for statistical analysis. RESULTS: A cohort of 97,831 patients was identified for analysis. Among patients belonging to 18-64, 65-74 and >75 years age groups, frequency of adequate LNE was 73.6%, 69% and 67.4% respectively, with pathologically confirmed LNI rates being 44.7%, 37.8% and 29.3% respectively (p < 0.0001). Adequate LNE was associated with improved 5-year overall survival (OS) regardless of age, gender, race, comorbidity index, insurance, income, year of diagnosis, pathologic tumor status, stage, grade, type of colectomy, adjuvant chemotherapy or academic level of facility. Rates of adequate LNE increased from 2004 to 2008, with a corresponding increase in survival outcomes (p < 0.0001). CONCLUSION: Adequate LNE is very crucial for appropriate staging of colon cancer, and carries a high prognostic value. This study validates our previous findings of lower rates of LNI in elderly and reiterates the importance of adequate LNE, which is associated with improved survival. Also identified were increasing rates of adequate LNE over the years, with corresponding improvement in OS.

Phase I Trial of Anti-PSMA Designer CAR-T Cells in Prostate Cancer: Possible Role for Interacting Interleukin 2-T Cell Pharmacodynamics as a Determinant of Clinical Response.

BACKGROUND: Chimeric antigen receptor (CAR)-modified "designer" T cells (dTc, CAR-T) against PSMA selectively target antigen-expressing cells in vitro and eliminate tumors in vivo. Interleukin 2 (IL2), widely used in adoptive therapies, was proven essential in animal models for dTc to eradicate established solid tumors. METHODS: Patients under-went chemotherapy condi-tion-ing, followed by dTc dosing under a Phase I escalation with continuous infusion low dose IL2 (LDI). A target of dTc escalation was to achieve ≥20% engraftment of infused activated T cells. RESULTS: Six patients enrolled with doses prepared of whom five were treated. Patients received 10(9) or 10(10) autologous T cells, achieving expansions of 20-560-fold over 2 weeks and engraftments of 5-56%. Pharmacokinetic and pharmacodynamic analyses established the impact of conditioning to promote expansion and engraftment of the infused T cells. Unexpectedly, administered IL2 was depleted up to 20-fold with high engraftments of activated T cells (aTc) in an inverse correlation (P < 0.01). Clinically, no anti-PSMA toxicities were noted, and no anti-CAR reactivities were detected post-treatment. Two-of-five patients achieved clinical partial responses (PR), with PSA declines of 50% and 70% and PSA delays of 78 and 150 days, plus a minor response in a third patient. Responses were unrelated to dose size (P = 0.6), instead correlating inversely with engraftment (P = 0.06) and directly with plasma IL2 (P = 0.03), suggesting insufficient IL2 with our LDI protocol to support dTc anti-tumor activity under optimal (high) dTc engraftments. CONCLUSIONS: Under a Phase I dose escalation in prostate cancer, a 20% engraftment target was met or exceeded in three subjects with adequate safety, leading to study conclusion. Clinical responses were obtained but were suggested to be restrained by low plasma IL2 when depleted by high levels of engrafted activated T cells. This report presents a unique example of how the pharmaco-dynamics of "drug-drug" interactions may have a critical impact on the efficacy of their co-application. A new Pilot/Phase II trial is planned to test moderate dose IL2 (MDI) together with high dTc engraftments for anticipated improved therapeutic efficacy. Prostate 76:1257-1270, 2016. © 2016 Wiley Periodicals, Inc.

Phase I Study of Anti-CD3 x Anti-Her2 Bispecific Antibody in Metastatic Castrate Resistant Prostate Cancer Patients.

Background. New nontoxic targeted approaches are needed for patients with castrate resistant prostate cancer (CRPC). Our preclinical studies show that activated T cells (ATC) armed with anti-CD3 x anti-Her2 bispecific antibody (Her2Bi) kill prostate cancer cells lines, induce a Th1 cytokine pattern upon engagement of tumor cells, prevent the development of prostate tumors, and retard tumor growth in immunodeficient mice. These studies provided strong rationale for our phase I dose-escalation pilot study to test ATC armed with Her2Bi (aATC) for safety in men with CRPC. Methods. Seven of 8 men with CRPC were evaluable after receiving two infusions per week for 4 weeks. The men received 2.5, 5 or 10 × 10(9) aATC per infusion with low dose interleukin-2 and granulocyte-macrophage colony stimulating factor. Results. There were no dose limiting toxicities, and there was 1 partial responder and 3 of 7 patients had significant decreases in their PSA levels and pain scores. Immune evaluations of peripheral blood mononuclear cells in 2 patients before and after immunotherapy showed increases in IFN-γ EliSpot responses and Th1 serum cytokines. Conclusions. These results provide a strong rationale for developing phase II trials to determine whether aATC are effective for treating CRPC.

Targeted T-cell Therapy in Stage IV Breast Cancer: A Phase I Clinical Trial.

PURPOSE: This study reports a phase I immunotherapy trial in 23 women with metastatic breast cancer consisting of eight infusions of anti-CD3 × anti-HER2 bispecific antibody (HER2Bi) armed anti-CD3-activated T cells (ATC) in combination with low-dose IL-2 and granulocyte-macrophage colony-stimulating factor to determine safety, maximum tolerated dose (MTD), technical feasibility, T-cell trafficking, immune responses, time to progression, and overall survival (OS). EXPERIMENTAL DESIGN: ATC were expanded from leukapheresis product using IL2 and anti-CD3 monoclonal antibody and armed with HER2Bi. In 3+3 dose escalation design, groups of 3 patients received 5, 10, 20, or 40 × 10(9) armed ATC (aATC) per infusion. RESULTS: There were no dose-limiting toxicities and the MTD was not defined. It was technically feasible to grow 160 × 10(9) ATC from a single leukapheresis. aATC persisted in the blood for weeks and trafficked to tumors. Infusions of aATC induced anti-breast cancer responses and increases in immunokines. At 14.5 weeks after enrollment, 13 of 22 (59.1%) evaluable patients had stable disease and 9 of 22 (40.9%) had progressive disease. The median OS was 36.2 months for all patients, 57.4 months for HER2 3+ patients, and 27.4 months for HER2 0-2+ patients. CONCLUSIONS: Targeting HER2(+) and HER2(-) tumors with aATC infusions induced antitumor responses, increases in Th1 cytokines, and IL12 serum levels that suggest that aATC infusions vaccinated patients against their own tumors. These results provide a strong rationale for conducting phase II trials.

Cetuximab, paclitaxel, carboplatin, and radiation for head and neck cancer: a survival analysis of a Brown University Oncology Group phase II study.

OBJECTIVES: To assess the effect on progression-free and overall survival from the addition of cetuximab to paclitaxel-based chemoradiation for patients with squamous cell head and neck cancer from Brown University Oncology Group studies. METHODS: BrUOG HN-204 patients with stage III or IV locally advanced squamous cell cancer of the head and neck without distant organ metastases received 4 weeks of induction cetuximab followed by weekly cetuximab, paclitaxel, carboplatin, and concurrent radiation. Recurrence and survival data were compared with previous Brown University studies utilizing the same paclitaxel-based chemoradiation with and without induction chemotherapy. RESULTS: The progression-free survival and overall survival at 3 years for all 37 patients initiating chemoradiation was 54% and 57%, respectively. All surviving patients were followed for at least 3 years and the median follow-up is 4.4 years. Of 14 patients who recurred within 3 years, 7 patients recurred locally only, 5 had a systemic recurrence, and 2 recurred both locally and systemically. CONCLUSIONS: The addition of cetuximab to paclitaxel, carboplatin, and radiation achieves overall survival that is virtually identical to prior Brown University Oncology Group studies of paclitaxel-based chemoradiation without cetuximab. Improvements in locoregional control are needed despite the use of 3 agents to enhance the effects of radiation.

Weekly paclitaxel and carboplatin induction chemotherapy followed by concurrent chemoradiotherapy in locally advanced squamous cell carcinoma of the head and neck.

OBJECTIVE: To perform a phase II trial evaluating dose dense induction chemotherapy for locally advanced head and neck cancer. PATIENTS AND METHODS: Thirty-five patients received 6 weekly doses of carboplatin (area under the curve=2) and paclitaxel (135 mg/m) followed by concurrent weekly paclitaxel (40 mg/m) and carboplatin (area under the curve=1) and daily radiation (66-72 Gy). RESULTS: There was 1 induction death from neutropenic sepsis and 1 sudden death during chemoradiotherapy. The overall response rate with induction was 79%. With >40 months of follow-up, the 36-month overall survival was 67% and squamous cell carcinoma of the head and neck survival 84%. Patients undergoing biopsy of the primary tumor site after the therapies had 17/18 (94%) pathologic complete response rate. The locoregional relapse rate was 40% (24 mo 28%) and distant relapse rate was 8% with only 1 distant site. CONCLUSIONS: Therapy was active but patients must be carefully selected and monitored. Compared with the historical controls, dose dense and intense induction chemotherapy decreased distant failure rate without compromising the locoregional control.

Selective organ preservation in operable locally advanced head and neck squamous cell carcinomas guided by primary site restaging biopsy: long-term results of two sequential brown university oncology group chemoradiotherapy studies.

OBJECTIVES: The long-term outcomes of selective organ preservation in operable, locally advanced head and neck cancers in two sequential chemoradiotherapy (CRT) protocols (HN-53, HN-67) are reported. METHODS: A total of 65 patients were treated with CRT consisting of carboplatin (AUC=1/week) and paclitaxel (60 or 40 mg/m2/week) with radiation (1.8 Gy/day). After 5 weeks of CRT, if primary site biopsies were pathologically negative, then completion CRT to 67-72 Gy was done with neck dissection in node-positive cases. Alternatively, a positive rebiopsy required primary site resection and neck dissection followed by radiotherapy boost as deemed necessary. RESULTS: Pathologic complete responses occurred in 71% patients who then completed CRT; the remaining 29% patients underwent primary site surgery. The 5-year and median overall survival were 47% and 57 months with no statistically significant differences between the two groups. Overall long-term failure rates were: 6% local, 6% regional, and 32% distant. CONCLUSIONS: This strategy of selective organ preservation was effective in 71% patients with CRT, whereas salvage surgery was required in the remainder. Long-term survival was equivalent in both treatment groups.

Carboplatin with weekly docetaxel and ifosfamide in advanced head and neck cancers: a phase I Brown University Oncology Group dose escalation study (HN-93).

PURPOSE: A phase I study was performed to determine the maximally tolerated dose of carboplatin, ifosfamide, and docetaxel in advanced head and neck cancers. METHODS: Carboplatin (week 1) was administered with weekly docetaxel and ifosfamide for 3 weeks in an every 4-week cycle. Restaging was done after two cycles, while dose level escalation was done in cohorts of three patients. RESULTS: Fifteen patients (recurrent/metastatic disease, n = 8; bulky locally advanced disease, n = 7) were enrolled. No dose-limiting toxicities were observed. Toxicities included grade 3 neutropenia and anemia (n = 2, each), and grade 2 thrombocytopenia (n = 3). The final level of carboplatin AUC = 6 (week 1) with docetaxel 30 mg/m(2) per week and ifosfamide 1,000 mg/m(2) per week was chosen for further evaluation. CONCLUSIONS: This novel regimen of carboplatin with weekly docetaxel and ifosfamide has a favorable toxicity profile and is active in this setting. Phase II study results are awaited.

Phase I study of hepatic arterial infusion of oxaliplatin in advanced hepatocellular cancer: a brown university oncology group study.

PURPOSE: We performed a phase I study to evaluate the feasibility and determine the maximally tolerated dose of hepatic arterial infusion (HAI) of oxaliplatin in advanced hepatocellular carcinoma (HCC). PATIENTS AND METHODS: Patients with unresectable or recurrent HCC received HAI-oxaliplatin over 2 hours at dose escalation levels of 90, 110, 130, and 150 mg/m given every 3 weeks. The therapy was continued until disease progression or excessive toxicity not amenable to appropriate modifications. Restaging was performed after every 2 cycles. RESULTS: A total of 23 patients were enrolled, with 17 patients evaluable for toxicity assessment. The median age was 63 years (range: 47-84 years), with 22 men and 1 woman. Stage distribution was as follows: stage II, 3 patients; stage III, 12 patients; and stage IV, 8 patients. A total of 53 cycles (range: 1-3) of HAI-oxaliplatin were delivered. The conventional grade 3/4 hematologic and gastrointestinal toxicities were infrequent. Among 17 evaluable patients receiving >2 cycles, 3 patients had partial responses and 8 had stable disease. A greater than 50% reduction in alphafetoprotein was seen in the 3 patients with partial responses and 3 patients with stable disease. CONCLUSIONS: HAI-oxaliplatin is a feasible, well tolerated, and demonstrated activity in this advanced HCC cohort. HAI-oxaliplatin 150 mg/m every 3 weeks was determined as the dose for further evaluation in phase II trials.

Cetuximab, paclitaxel, carboplatin, and radiation for head and neck cancer: a toxicity analysis.

OBJECTIVE: To determine the feasibility and toxicity of the addition of cetuximab to paclitaxel, carboplatin, and concurrent radiation for patients with head and neck cancer. MATERIALS AND METHODS: Patients with stage III or IV locally advanced squamous cell cancer of the head and neck, without distant organ metastases, were eligible. Patients received 4 weeks of induction cetuximab followed by weekly cetuximab, paclitaxel, carboplatin, and concurrent radiation. RESULTS: Thirty-two patients were assessable for chemoradiation toxicities. Grade 3 and grade 4 mucositis occurred in 53% and 16% of patients, respectively. Grade 3 and grade 4 radiation dermatitis occurred in 44% and 9% of patients, respectively. Grade 3/4 radiation dermatitis was associated with the use of intensity modulated radiation therapy (64% vs.14%, respectively, P < 0.0001). Grade 3 and grade 4 cetuximab associated acneiform rash developed in 6% and 3% of patients. Overall 21 patients (66%) had any grade 3 toxicity and 10 patients (31%) had any grade 4 toxicity. The percentages of the intended total dose delivered of carboplatin, cetuximab, paclitaxel, and radiation were 86%, 89%, 89%, and 96%, respectively. CONCLUSION: Cetuximab, when combined with paclitaxel, carboplatin and intensity modulated radiation therapy, increases dermatologic toxicity but does not increase mucosal toxicity as compared with previous Brown University Oncology Group studies of paclitaxel, carboplatin, and conventional radiation for patients with head and neck cancer.

Concurrent chemoradiotherapy with weekly paclitaxel and carboplatin for locally advanced head and neck cancer: Long-term follow-up of a Brown University Oncology Group Phase II Study (HN-53).

BACKGROUND: A phase II study was conducted using concurrent paclitaxel, carboplatin, and external beam radiotherapy (RT) in patients with advanced head and neck cancer. METHODS: Forty-three patients (stage III, n = 12; stage IV, n = 31) were treated with 8 cycles of weekly paclitaxel (60 mg/m(2)), carboplatin (area under the curve [AUC] = 1), and RT (1.8 Gy daily; total dose, 66-72 Gy). Patients with initially palpable lymph nodes underwent neck dissection. RESULTS: The overall clinical response rate was 91% (65% complete, 26% partial). Severe mucositis occurred in 37 (90%) patients, necessitating hospitalization in 13 (31%) patients. With a median follow-up of 49 months, the locoregional and distant failure rates were 26% and 21%, respectively. CONCLUSIONS: Concurrent paclitaxel, carboplatin, and RT for advanced head and neck cancer results in high complete response rates. Long-term follow-up has revealed the curative potential of this regimen, though the doses used resulted in unacceptable toxicity.

Anti-CD3 x anti-epidermal growth factor receptor (EGFR) bispecific antibody redirects T-cell cytolytic activity to EGFR-positive cancers in vitro and in an animal model.

PURPOSE: Targeting epidermal growth factor receptor (EGFR) overexpressed by many epithelial-derived cancer cells with anti-EGFR monoclonal antibodies (mAb) inhibits their growth. A limited number of clinical responses in patients treated with the anti-EGFR mAb, (cetuximab), may reflect variability in EGFR type or signaling in neoplastic cells. This study combines EGFR-targeting with the non-MHC-restricted cytotoxicity of anti-CD3 activated T cells (ATC) to enhance receptor-directed cytotoxicity. EXPERIMENTAL DESIGN: ATC from normal and patient donors were expanded ex vivo. Specific cytolytic activity of ATC armed with anti-CD3 x anti-EGFR (EGFRBi) against EGFR-expressing cancer cells derived from lung, pancreas, colon, prostate, brain, skin, or EGFR-negative breast cancer cells was evaluated in (51)Cr release assays. In vivo studies comparing tumor growth delay induced by EGFRBi-armed ATCs or cetuximab were done in severe combined immunodeficient/Beige mice (SCID-Beige) bearing COLO 356/FG pancreatic and LS174T colorectal tumors. RESULTS: At effector/target ratios from 3.125 to 50, both EGFRBi-armed normal and patient ATC were significantly more cytotoxic, by 23% to 79%, against EGFR-positive cells over ATC, cetuximab, anti-CD3 alone, or ATC armed with irrelevant BiAb directed at CD20. EGFRBi-armed ATC also secreted significantly higher levels of some T(H1)/T(H2) cytokines compared with ATC alone. In mice, i.v. infusions of EGFRBi-armed ATC (0.001 mg equivalent/infusion) were equally effective as cetuximab (1 mg/infusion) alone for significantly delaying growth of established COLO 356/FG but not LS174T tumors compared with mice that received ATC alone or vehicle (P < 0.001). CONCLUSIONS: Combining EGFR antibody targeting with T cell-mediated cytotoxicity may overcome some limitations associated with EGFR-targeting when using cetuximab alone.

Phase I study of docetaxel, capecitabine, and carboplatin in metastatic esophagogastric cancer.

OBJECTIVES: A phase I trial was conducted to determine the maximally tolerated dose (MTD) and dose-limiting toxicities (DLTs) of docetaxel, capecitabine, and carboplatin for first-line treatment of patients with metastatic esophageal and gastric cancers. METHODS: Twenty-eight patients were treated over 5 dose levels in a 21-day cycle. Patients received carboplatin (AUC = 2) on days 1 and 8, docetaxel (35-40 mg/m2) on days 1 and 8, and capecitabine (500-2000 mg/m2) on days 1 to 10. RESULTS: There were no DLTs in the first cycle of treatment. Dose reductions were required in 10 of 15 patients at the final dose level due to neutropenia, nausea, vomiting, diarrhea, dehydration, and hand/foot syndrome following a median of 3 cycles of treatment. Therefore, escalation beyond dose level 5 was not attempted. The MTD was docetaxel, 40 mg/m2 days 1 and 8; carboplatin, AUC = 2 days 1 and 8; and capecitabine, 1500 to 2000 mg/m2 days 1 to 10 in a 21-day cycle. Ten of 25 patients who could be evaluated (40%) responded and 8 of 14 patients treated at the final dose level responded (57%). CONCLUSIONS: Cumulative gastrointestinal toxicities and neutropenia were the DLTs of docetaxel, capecitabine, and carboplatin. This combination represents an easily administered, active regimen for patients with metastatic gastric and esophageal cancers. Further evaluation of this regimen is indicated.

Trastuzumab, paclitaxel, cisplatin, and radiation for adenocarcinoma of the esophagus: a phase I study.

PURPOSE: To conduct a phase I study incorporating trastuzumab with paclitaxel, cisplatin, and radiation for adenocarcinoma of the esophagus. METHODS AND MATERIALS: Patients with adenocarcinoma of the esophagus without distant organ metastases were eligible. All patients received cisplatin 25 mg/m2 and paclitaxel 50 mg/m2 weekly for 6 weeks with radiation 50.4 Gy. HER-2/neu-positive patients (2+/3+ by immunohistochemistry) received weekly trastuzumab at dose levels of 1, 1.5, or 2 mg/kg weekly for 5 weeks after an initial bolus of 2, 3, or 4 mg/kg, respectively. HER-2/neu-negative patients received the same chemoradiation without trastuzumab as a control for toxicity. Dose-limiting toxicities were defined as grade 3 esophageal, cardiac, or pulmonary toxicity. RESULTS: Twelve of 36 screened patients (33%) overexpressed HER-2/neu by immunohistochemistry (seven 3+ and five 2+). Eight of 12 patients with HER-2/neu overexpression by IHC had an increase in the number of HER-2/neu genes, six from amplification of the HER-2/ neu gene and two were hypderdiploid for chromosome 17. Thirty patients were enrolled (12 HER-2/neu-positive and 18 HER-2/neu-negative controls). No increase in toxicity was seen with the addition of trastuzumab. One of 12 patients in the trastuzumab arm and 8 of 17 in the control arm had grade 3 esophagitis (p < or = .026). Mean left ventricular ejection fraction for the trastuzumab group was 57% before treatment and 56% after treatment. CONCLUSION: HER-2/neu is overexpressed in approximately one-third of esophageal adenocarcinomas. Trastuzumab can be added at full dose to cisplatin, paclitaxel, and radiation. Future studies of trastuzumab in esophageal adenocarcinoma are indicated.

Herceptin and gemcitabine for metastatic pancreatic cancers that overexpress HER-2/neu.

PURPOSE: To determine the response rate and toxicities of Herceptin and gemcitabine for patients with metastatic pancreatic adenocarcinomas that overexpress HER-2/neu. METHODS AND MATERIALS: Patients with metastatic pancreatic cancer with 2+/3 + HER-2/neu expression by immunohistochemistry were eligible. Patients received gemcitabine, 1 g/m2/week, for 7 of 8 weeks followed by 3 of every 4 weeks, and Herceptin, 4 mg/kg loading dose, followed by 2 mg/kg/week. RESULTS: Screening logs demonstrated the rate of HER-2/neu overexpression was 16%. Thirty-four patients were enrolled. Thirty patients (88%) had pancreatic cancers with 2+ overexpression and 4 patients (12%) had 3+ overexpression. Toxicity was similar to gemcitabine alone. Confirmed partial responses were observed in 2 of 32 patients (6%). Thirteen of 32 patients (41%) had either a partial response or a >50% reduction in CA 19-9. The median survival for all 34 patients was 7 months, and the 1-year survival was 19%. CONCLUSION: The response rate of Herceptin and gemcitabine is similar to gemcitabine alone. The 7-month median survival in patients with metastatic pancreatic cancer suggests there may be a modest benefit for some patients. Infrequent HER-2/neu overexpression limits the role of targeting the HER-2/neu gene and prevents definitive conclusions on the addition of Herceptin to gemcibine for patients with pancreatic cancer.

The chronic leukemias: current and novel therapeutic approaches.

Recent developments with targeted therapies have expanded the therapeutic armamentarium (Table 1) for patients with both CLL and CML. Significant advances in allogeneic and autologous donor transplantation have increased the patient eligibility pool and reduced the toxicities while improving upon long term survival results.