Partial Clinical Responses Research Articles

Predictors of early response to infliximab in patients with ulcerative colitis

Our objective is to report the outcome of infliximab (IFX) in ulcerative colitis (UC) patients from a single center and to identify predictors of early clinical response. The first 100 UC patients (45 female; median age, 37.9 years) who received IFX at a single center were included. Eighty-four patients received 5 mg/kg IFX, and 37 patients received a 3-dose IFX induction at weeks 0, 2, and 6. The Mayo endoscopic subscore, assessed by sigmoidoscopy before inclusion, was 1, 2, and 3 in 5%, 52%, and 43% of patients, respectively. Sixty percent had pancolitis, 63% were on concomitant immunosuppressive therapy, 9% were active smokers, 64% had C-reactive protein > or =5 mg/dL, and 44% were pANCA+/ASCA-. Five patients received IFX because of severe acute colitis refractory to intravenous corticosteroids. Early complete and partial clinical responses were observed in 41% and 24% of patients. Patients with early clinical response were significantly younger than nonresponders (median age, 35.7 versus 41.6 years, P = 0.041). Patients who were pANCA+/ASCA- had a significantly lower early clinical response (55% versus 76%; odds ratio [OR] = 0.40 (0.16-0.99), P = 0.049). Concomitant immunosuppressive therapy and the use of an IFX induction scheme did not influence early clinical response. Only 1 of 5 patients who received IFX for acute steroid-refractory colitis required colectomy within 2 months. IFX is an efficient therapy in UC, as shown by 65% early clinical response. A pANCA+/ASCA- serotype and an older age at first IFX infusion are associated with a suboptimal early clinical response.

A Phase-II-Study To Evaluate Efficacy and Safety of Imatinib in Eosinophilia-Associated Myeloproliferative Disorders and Idiopathic Hypereosinophilic Syndrome.

Eosinophilia is a common clinical finding which is associated with a large number of highly variable non-clonal and clonal disorders. An idiopathic hypereosinophilic syndrome (HES) is diagnosed when the blood eosinophil count is persistently greater than 1500/μl for at least 6 months (mo), which is neither clonal nor reactive and which causes damage to end organs such as heart, skin or nervous system. Clonal eosinophilia is most frequently found in association with myeloproliferative disorders (EosMPD) where clonality is usually demonstrated by cytogenetic abnormalities and/or the presence of fusion genes with involvement of PDGFRA, PDGFRB, FGFR1 or JAK2. Treatment options for patients (pts) with EosMPD and HES include corticosteroids, chemotherapy, interferon-α and more recently imatinib.We therefore initiated a phase-II-study for the treatment of EosMPD (n=21) with rearrangement of PDGFRA (FIP1L1-PDGFRA fusion gene, n=17) or PDGFRB (variable fusion genes, n=4) and HES (no specific marker, n=14). Median age at diagnosis was 52 years (range, 20–72). The overall male/female ratio was 3.4:1 with a significant male predominance in EosMPD (19/21 pts, 90%). Pts received imatinib at doses ranging between 100 and 400 mg/d according to the type of the underlying fusion gene, tolerability and response to treatment. Median time of treatment has been 7 mo (range, 1–22). In FIP1L1-PDGFRA positive pts, complete hematological remission (CHR) was achieved within 1 or 3 mo in 59% (10/17) and 100% (15/15) of pts, respectively. Complete molecular remission (CMR) defined as a negative nested RT-PCR for FIP1L1-PDGFRA fusion transcripts in peripheral blood, was seen within 3 or 6 mo in 27% (4/15) and 83% (10/12) of pts, respectively. All four pts with PDGFRB fusion genes were treated with 400 mg/d imatinib and achieved a CHR after a median time of 1.4 mo (range 0.5–2), one of them achieved a CMR. No relapses have yet been observed in imatinib-treated EosMPD. All HES pts have been treated with 400 mg/d imatinib. Partial or complete clinical and hematological responses have been observed in 6 of 14 pts (43%) which were transient in 3 pts (median 6 mo, range, 4–6). Three of 14 pts (21%) are in sustained remission in a median period of 21 mo (range, 18–21) after start of imatinib. Overall, imatinib was well tolerated with toxicities only of WHO grade I and II, predominantly oedema (n=6), rash (n=5) and nausea (n=3). We conclude that pts who present with sustained non-reactive eosinophilia should be analysed for the presence of the FIP1L1-PDGFRA fusion gene. Cytogenetic analysis is recommended in FIP1L1-PDGFRA negative cases in order to exclude rearrangements of genes coding for imatinib-sensitive (PDGFRA, PDGFRB) or imatinib-resistant (JAK2, FGFR1) tyrosine kinases. Imatinib seems to be less effective in HES without specific marker. Further studies are warranted to find out optimal dose and duration of treatment with imatinib in responding pts with EosMPD and HES.

Immunesurveillance by dendritic cells: potential implication for immunotherapy of endocrine cancers

Dendritic cells (DCs) are highly efficient antigen-presenting cells in the immune system with the potential to regulate the system and induce a cytotoxic T-cell response. As a proof of principle, a multitude of animal and human studies has demonstrated that immunization with antigen-loaded DCs may lead to anti-tumour immune responses with tumour regression and rejection of cancer. The identification of tumour antigens that can be recognized by T lymphocytes has facilitated the development of new protocols and enabled immunologists to monitor immune responses. However, to date, long-term clinical effects on larger numbers of cancer patients are missing, and there is no generally accepted DC generation or activation protocol. This review will focus on the most important findings on the role of DCs within the immune system and how to generate and activate these cells in order to induce cytotoxic immunity in non-endocrine and endocrine malignancies. Recently, we and other researchers reported on DC vaccinations in patients with endocrine malignancies mainly in metastasized medullary thyroid carcinoma resulting in tumour-specific immunity and partial clinical responses in some cases. Based on these and other in vitro data, new DC vaccination protocols for the treatment of patients with endocrine tumours have now been conducted.

Immunological characteristics correlating with clinical response to immunotherapy in patients with advanced metastatic melanoma

Current treatment options for advanced metastatic melanoma are limited to experimental regimen that provide poor survival outcomes. Immunotherapy is a promising alternative and we recently reported a clinical trial in which 6 out of 19 patients enrolled had objective clinical responses to a fully autologous melanoma/dendritic cell vaccine. The mechanism of the vaccine is not well understood, but we hypothesized that general immunocompetence may be a determinant of clinical response. We therefore examined the immune status of an expanded series of 21 patients who displayed varying clinical responses to the melanoma/dendritic cell vaccine. Immunocompetence was assessed using in vitro assays of lymphocyte function: survival, proliferation and cytokine responses to mitogen stimulation as well as T-cell receptor zeta expression and lymphocyte subset analysis. Although lymphocytes from patients mostly performed comparably to age-matched and sex-matched controls, in some assays we identified significant differences between complete clinical responders and other patients, both before and following vaccination. Surprisingly, before vaccination, only lymphocytes from clinical responder patients showed impaired in vitro survival. Following vaccination, T lymphocyte survival improved and cells recovered their ability to produce the Th1-associated cytokines TNF and IFN-gamma in response to anti-CD3 stimulation in vitro. No increase in Th1 cytokine production was observed in lymphocytes from patients who experienced partial clinical responses or progressive disease. We conclude that, before vaccination, patients who go on to have complete responses have immune characteristics suggestive of high cell turnover and low Th1-associated cytokine production, and that these can be reversed with vaccination. These results have potential implications for future immunotherapeutic strategies.

Phase I/II Trial of External Irradiation plus Medium-Dose Brachytherapy Given Concurrently to Liposomal Doxorubicin and Cisplatin for Advanced Uterine Cervix Carcinoma

Although the standard of care for patients with locally advanced uterine cervix carcinoma is cisplatin-(CDDP-)based chemotherapy and irradiation (RT), the optimal regimen remains to be elucidated. A phase I/II study was conducted to evaluate the dose limiting toxicity (DLT) and the maximum tolerated dose (MTD) of liposomal doxorubicin (Caelyx) combined with CDDP and RT for cervical cancer. 24 patients with stage IIB-IVA were enrolled (Table 1). They all received external RT (up to 50.4 Gy) and two medium-dose rate (MDR) brachytherapy implants (20 Gy each at point A). The Caelyx starting dose of 7 mg/m2/week was increased in 5-mg/m2 increments to two levels. The standard dose of CDDP was 20-25 mg/m2/week. Concurrent chemoradiation (CCRT) sequelae and the DLTs (grade 3 myelotoxicity and grade 3 proctitis in five patients treated at the 17 mg/m2/week Caelyx dose level) are shown in Tables 2, 3, 4, and 5. After a median follow-up time of 17.2 months (range 4-36 months), four patients had died, 15 showed no evidence of progressive disease, and five (20.8%, 95% confidence interval [CI]: 12.5-29.1%) were alive with relapse (Figure 1). There were seven complete (29.1%, 95% CI: 19.8-38.4%) and 17 partial clinical responses (95% CI: 61.1-80.1%). The median progression-free survival was 10.4 months. Causes of death were local regional failure with or without paraaortic node relapse combined with distant metastases (Table 6). The MTD of Caelyx given concurrently with CDDP and RT was determined at the 12 mg/m2/week dose level. The above CCRT schema is a well-tolerated regimen, easy to administer in ambulatory patients, and results appear promising.

The Predictive Value of Clinical Evaluation of Response to Neoadjuvant Chemoradiation Therapy for Rectal Cancer

Multimodality therapy has become the standard treatment for patients with locally advanced (T3 and T4) rectal carcinoma. Accurate preoperative staging of the patients with rectal cancer has increased in importance because the selection of patients with transmural rectal cancer (T3 or T4) or node-positive disease leads to a previous nonsurgical neoadjuvant treatment. The purpose of this study was to evaluate the predictive value of the clinical response to neoadjuvant therapy on the basis of pathological results obtained on rectal cancer patients treated by chemoradiotherapy and surgery. From 1994 to 2003, 58 patients with a primary diagnosis of rectal cancer were studied at our department and enrolled in a neoadjuvant protocol of chemoradiotherapy followed by surgery. All patients were treated by 30 days of chemoradiotherapy. At the end of the chemoradiotherapy, each patient underwent clinical examination, including digital rectal examination, proctoscopy and abdominal-pelvic computerized tomography to define the clinical response to the chemoradiotherapy. Surgical resection was performed in all patients three weeks after the end of chemoradiotherapy, and histological analysis was performed on all resected specimens. The clinical complete response rate corresponded to the pathological complete response rate, whereas the clinical evaluation overestimated partial response and stable disease. The pathologic examination revealed that 3.5% of clinical partial responses and 3.4% of clinical stable disease were really pathological progressive disease. Clinical partial response and clinical stable disease positive predictive values were 92.8% and 90.9%, respectively, whereas the clinical progressive disease negative predictive value was 20%. Then, 6.9% of patients believed to have responded to the therapy, or not to have responded or worsened, actually had worsened by the end of the chemoradiotherapy. Positive and negative predictive values, in particular for partial response and stable disease, of clinical evaluation of the response to chemoradiotherapy were not high enough to consider clinical evaluation accurate enough to make treatment decisions.

Extended-Interval Gentamicin Administration in Malnourished Children

Malnourished children have several physiologic abnormalities that can affect drug distribution and elimination. The aim of this study was to determine the efficacy, safety and pharmacokinetics of a once-daily dose of gentamicin compared with conventional thrice-daily dosing in malnourished children. To our knowledge, it has not been investigated in this population so far. A total of 310 malnourished children of either gender aged 6 months to 5 years with diarrhea and pneumonia were randomized to receive intramuscular gentamicin 5 mg/kg/day once-daily (OD) (n=148) or the same total daily amount given in three divided doses (TD) (n=162) in addition to ceftriaxone 75 mg/kg/day. After 48 h at steady state, gentamicin pharmacokinetics was assessed by fluorescence polarization immunoassay in a subgroup of 59 children and 43 children in the OD and TD groups, respectively. The groups were equivalent in baseline demographic, clinical and laboratory characteristics. Good and partial clinical responses occurred in 64 per cent vs. 54 per cent and 25 per cent vs. 27 per cent in the OD and the TD children, respectively (p=NS for both comparisons). Five patients in each treatment group died. Renal toxicity defined by change in serum creatinine was not observed in any patient from either group. In the OD group, mean+/-SD serum gentamicin concentrations at 1 (peak), 3, 5, 8, 23, and 24 (trough value) hours after the dose were 11.7+/-4.1, 4.4+/-1.2, 2.08+/-0.9, 1.01+/-0.6, 0.31+/-0.09 and 0.29+/-0.07 mg/l respectively. In the TD group, mean +/-SD serum gentamicin concentration at 1 hour (peak) was 4.7+/-1.8 mg/l and the trough concentration was 0.48+/-0.21 mg/l. In OD group, the gentamicin trough concentration was significantly lower (p<0.001) and the peak concentration was significantly higher (p<0.001) compared to TD group. The results of this study indicate that once-daily gentamicin is effective and safe in malnourished children. Widespread implementation of once-daily dosing in malnourished children is appropriate and will reduce number of intramuscular injections and hospital costs.

Mistletoe extract/gemcitabine combination treatment: An interim report from the NCCAM/NCI phase I study in patients with advanced solid tumors

3098 Background: European Mistletoe (viscum album L.) extracts (ME) are used in varying doses and schedules as herbal adjunct treatment for solid tumors in Europe. Clinical efficacy remains controversial. Controlled data on safety, toxicity and drug interactions are lacking. Methods: Subjects with stage IV cancer (average age 51 years; breast 5, pancreas 4, colorectal 3, NSCLC 4) enrolled on a 2 stage dose escalation phase I trial of toxicity profile, dose limiting toxicity (DLT), MTD, and gemcitabine (GEM) pharmacokinetics (with and without ME) on s.c.qd ME (HELIXOR A, Helixor GmbH, KG, Rosenfeld, Germany) combined with GEM 750mg/m2i.v. on a weekly x 2 q 21d schedule for 3 cycles. We report on stage I (fixed dose GEM). Starting target ME dose level was 20mg (n=3), with escalations to 50 (n=3), 100 (n=3), 200 (n=5), and 250 mg (n=2). DLT for GEM is neutropenia. GEM and 2’,2’-difluorodeoxyuridine (dFdU) plasma concentrations (Cp) at baseline and week 8 (stable ME dose for 7 days) were determined by HPLC with UV detection o 12 subjects who completed 3 cycles (ME dose 20–200mg). The area under the curve (AUC) was determined using WinNonLin version 4.0. This project was approved by the Navy Clinical Investigation Program Project Number: 02–074 Results: No ME DLT was observed. Ten ME related grade 2 adverse events (AE, injection site reaction 4, flu-like syndrome 4, other local reaction 2), 30 grade 3 GEM-related AE (lymphopenia 12, neutropenia/low WBC 10, thrombocytopenia 2, nausea/vomiting 2, other 4) and 1 GEM related grade 4 lymphopenia were observed. Median baseline and week 8 AUC (664/670 min*nmol/ml, p=0.97) and Cp (47.7/49.7 nmol/ml, p=0.85) of GEM and dFdU (AUC 1038/1099 min*nmol/ml, p= 0.46, Cp 75.7/84 nmol/ml, p=0.67) were equivalent (signed rank test). 1038 of 1059 scheduled ME doses were given (compliance 98.2%). Tow subjects had partial clinical responses (PR) by RECIST (pancreas 1, NSCLC 1) and four subjects had stable disease > 18 wks (pancreas 1, NSCLC 2, rectal 1). Conclusions: The ME/GEM combination has been well tolerated. GEM Cp during infusion was unaffected by ME. Two subjects had a PR. Stage II (GEM dose escalation) will determine if addition of ME alters GEM toxicities and MTD. No significant financial relationships to disclose.

A phase II study of docetaxel and gemcitibine as neoadjuvant chemotherapy in stages IIIA &amp; B breast cancer

879 Background: Phase II studies have demonstrated activity for the combination of docetaxel (D) and gemcitabine (G) in women with anthracycline resistant stage IV breast cancer. The Greek Breast Cancer Cooperative Group reported a 50% response rate to D&G in aforementioned patient population. Our objective was to determine the clinical and pathologic response rates, time to treatment failure (TTF) and survival of women with stages IIIA&B breast cancer who received D&G as neoajuvant chemotherapy. Methods: From 11/1/98 to 9/30/03 we enrolled 15 women with stage III breast cancer(12 with IIIA, 3 with IIIB, 5 ER/PR+, 10 ER/PR-, 10 Her2/neu overexpressive) in this phase II study. The median age was 48 yrs (range 37–75); the median PS was ECOG 0 (range 0–1). All patients received neoadjuvant G 725 mg/m.sq IVPB days 1 and 8 and D 75mg/m.sq IVPB day 8. Filigramstim 5 micrograms/kg/d was given sc on days 9–16. D&G cycles were repeated every 21 days. Dose modifications for D&G were permitted solely for Grade 3 or 4 neutropenia or thrombocytopenia.Four cycles of D&G were given prior to loco-regional therapy. Clinical responses were determined by the usual criteria. Pathologic responses were determined by the absence of microscopic breast cancer (pCR) or its presence (pPR). Results: The clinical response rate was 13/15 (87%[95% confidence limits59–98%]) with 6 clinical complete (cCR) and 7 clinical partial responses (cPR). Two patients failed to respond. Of the 13 patients who had cCR or cPR, there were 3pCR’s (23% [95% confidence limits 6–53%]) and 10pPR’s (77%). Toxicities were generally mild (alopecia, fatigue, arthalgias, diarrhea); there were no Grade 3 or 4 toxicities. 12 patients underwent modified radical mastectomy (9 stageIIIA and 3 IIIB) and 3 patients underwent lumpectomy, axillary sampling and breast irradiation. At a median followup of 48 months, the median TTF has not yet been reached. Conclusions: D&G is an active combination when used as neoadjuvant chometherapy in stage III breast cancer; comparative trials are warranted. Supported in part by Aventis. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Aventis

Weekly Docetaxel/Carboplatin as Primary Systemic Therapy for HER2-Negative Locally Advanced Breast Cancer

To evaluate the effectiveness and safety of weekly docetaxel/carboplatin as primary systemic therapy (PST) for locally advanced breast cancer, we conducted a phase II study. Forty-four patients with HER2-negative locally advanced or inflammatory breast cancer (IBC) received docetaxel 35 mg/m 2 and carboplatin to an area under the curve of 2 mg/mL/min for 3 of 4 weeks over 16 weeks. After completion of PST, patients had breast surgery and then received 4 cycles of adjuvant cyclophosphamide/doxorubicin, standard radiation therapy, and, for hormone receptor—positive tumors, tamoxifen. The mean tumor size was 9.3 cm (range, 5-24 cm). Thirty-seven patients (85%) had palpable lymph nodes; 13 patients (30%) had matted or fixed nodes (N2). Eight patients had IBC. There were 11 clinical complete responses (25%) and 29 clinical partial responses (66%), resulting in 40 objective responses (91% [95% CI, 78%–96%]). Invasive disease disappeared (pathologic complete response) from the breast and axilla in 6 patients (14% [95% CI, 5%–27%]) and from the axilla in 17 patients (39% [95% CI, 24%–55%]). The only significant adverse hematologic event was grade 3 neutropenia in 4 patients (9%). The most common adverse nonhematologic events were fatigue (84% of patients) and alopecia (84%), which were usually grade 1/2. Weekly docetaxel/carboplatin appears to be active and feasible as PST in patients with large breast tumors.

Intraperitoneal cisplatin and whole abdomen hyperthermia for relapsed ovarian carcinoma

5038 Background:The study was designed to determine the maximum tolerated dose (MTD) of intraperitoneal cisplatin [CDDP] combined with intravenous thiosulfate and concurrent whole abdomen hyperthermia for advanced, recurrent or progressive ovarian carcinoma. Furthermore, clinical activity, toxicity and feasibility of the treatment regimen were assessed. Methods:Between September 1991 and November of 1998 forty one patients with advanced epithelial ovarian cancer received escalating doses of intraperitoneal cisplatin (6 cycles given every 3–4 weeks) and whole abdomen hyperthermia with intravenous thiosulfate as second line treatment. Thermometry was obtained both intraperitoneally as well as intravaginally and intrarectally. Results:The first three patients started at a dose of 60 mg/m2 of intraperitoneal cisplatin. All patients completed this dose without complication. Nine patients were entered at the 100 mg/m2 dose, nine patients at 140 mg/m2 and twenty patients at 180 mg/m2. Seven patients completed the full six cycles at 180 mg/m2 dose level and this was deemed to be the maximally tolerated dose (MTD). There were two clinical partial responses (PR) at 60 mg/m2, and one pathologic complete response (CR) and two clinical PR at 100 mg/m2. At 140 mg/m2 there was one pathologic CR, one clinical CR, and two clinical PR. At 180 mg/m2 there were three pathologic CR, four clinical CR, and two clinical PR. This was determined both by CA 125 measurements as well as third look laproscopic evaluation. Median survival for all patients from protocol entry was 30 months (range 2 to 107 months). Median duration of complete response for those achieving a pathologic CR was 14 months (range 2 – 27 months), and median survival for those achieving a CR to this regimen was 35 months (range 14 – 71 months, 95% CI 16 – 54 months). Conclusions:Salvage platinum based intraperitoneal cisplatin with hyperthermia did achieve pathologic complete response in selected patients, and the proportion of responders increased with greater cisplatin doses. These promising results suggest a role for the use of adjuvant whole abdomen hyperthermia as a means of augmenting chemosensitization. No significant financial relationships to disclose.

An open label, randomized phase II trial of primary systemic therapy with exemestane (EXE 25 mg/d) plus epirubicin (EPI, 20 vs 30 mg/m2 q1w × 8–12) in breast cancer: An interim analysis of the German Neoadjuvant Aromasin Initiative (GENARI-3)

826 Background: This randomized phase II trial explores the efficacy of EXE, a steroidal aromatase inactivator, in combination with lower doses of EPI, a topoisomerase-II targeted anthracycline, as an alternative presurgical therapy (PST) option for women who may not be eligible for more toxic primary chemotherapy regimens. Methods: Age: ≥ 50 years, postmenopausal hormone receptor (HR) + /−, primary tumors T2, 3, 4a-c, Nx, M0, ECOG PS 0–2. All patients (pts) obtained continuous EXE and were randomized to either 20 mg/m2 (A) or 30 mg/m2 (B) EPI q1w × 8–12. Endpoints (1st/2nd): pathological complete remissions (pCR), rate of breast conserving surgery (BCS), and grade/frequency of toxicity. Results: A total of 23 pts (12 in arm A, 11 in B) with median age of 68 (53–77) and tumor status T2 were enrolled. 28 patients are still under therapy and will be applicable for final analysis at the time of this presentation. All pts were HR+ and were evaluable for toxicity. Four patients (n=3: 20 mg/m2; n=1: 30 mg/m2) had reduced numbers of cycles [5(n=2), 6(n=1), 11(n=1)] after dose delay due to grade (G) 2 toxicity (NCI-CTC): leukopenia (n=2), infection (n=2) or G 3 toxicity: infection (n=1). One patient withdrew consent for pre-operative staging and surgery (arm B, no DLT). Efficacy (22 pts): Clinical responses were as follows: (A/B): clinical partial responses, n= 9/7; clinical stable disease, n= 3/3. Pathological tumor response (A/B): ypT0 (pCR), n=0/1, ypT1a, n=1/0; ypT1c, n=6/2; ypT2, n=4/5; ypT3, n=1/2. BCS: n=19/3. Conclusions: The interim results for 23 of 60 patients suggest good therapeutic efficacy and excellent tolerability of combined EXE and EPI . It has to be shown wether this treatment offers additional benefit for women with hormone- receptor positive breast cancer, who showed lower response to primary chemotherapy when compared to receptor- negative patients. In addition this supports the concept of combination PST as an alternative to hormonal PST in postmenopausal patients. No significant financial relationships to disclose.

Phase II trial combining docetaxel and doxorubicin as neoadjuvant chemotherapy in patients with operable breast cancer

BackgroundThis study was conducted to assess the antitumour activity of docetaxel in combination with doxorubicin for neoadjuvant therapy of patients with breast cancer. Patients and methodsForty-eight women were treated with intravenous doxorubicin 50 mg/m2 over 15 min followed by a 1-h infusion of docetaxel 75 mg/m2 every 3 weeks for six cycles. Dexamethasone or prednisolone premedication was allowed. Granulocyte colony-stimulating factor was not allowed as primary prophylaxis. The primary end point was the pathologically documented complete response rate (pathological response). ResultsThe mean relative dose intensity calculated for four or more cycles was 0.99 for doxorubicin and 0.99 for docetaxel. Overall, the pathological response rate was 13%. There were 11 complete and 29 partial clinical responses for an overall response rate of 85% [95% confidence interval (CI) 75% to 95%] in the evaluable population (n = 47). Disease-free and overall survival rates were 85% (95% CI 71% to 94%) and 96% (95% CI 85% to 99%), respectively, after a median follow-up of 36.6 months. Grade 3/4 neutropenia was observed in 65% of patients and 17% reported grade 4 febrile neutropenia. ConclusionsDocetaxel and doxorubicin is an effective and well-tolerated combination in the neoadjuvant therapy of breast cancer. Future controlled trials are warranted to investigate the best schedules and to correlate response with biological factors.

A trial of IRX-2 in patients with squamous cell carcinomas of the head and neck

A Phase II trial in 42 patients with squamous cell cancer of the head and neck (H&NSCC) was performed using a combination immunotherapy with 10–20 days of perilymphatic injections of a natural cytokine mixture (NCM: IRX-2; 200 units IL-2 equivalence) preceded by low dose cyclophosphamide (CY; 300 mg/m 2) and followed by daily oral indomethacin (25 mg t.i.d.) and zinc (65 mg in a multivitamin preparation). Thirty-nine patients underwent subsequent surgical resection and 22 stage IV patients received additional radiotherapy. Forty-two percent were adjudged to have complete and partial clinical responses (>50% tumor reduction); an additional five patients had minor responses for a total of 58%. Comparison of post-treatment biopsies or surgical specimens showed 90% of patients had reduction in tumor area from 79% to 48% (over half of which was fragmented) and increased area of leukocyte infiltration from 9% to 32% (79% of which was lymphoid). The treatment with IRX-2 was not associated with significant side effects and 24 of patients showed improvement in eating, breathing or phonation or reduced pain and bleeding. Fifteen patients with lymphocytopenia (lymphocyte counts [LC] less than or equal to 1500 mm 3) showed significant increases in LC, CD3+, CD4+ and CD8+ T lymphocytes of 401, 147, 95 and 100/mm 3, respectively. Analysis of outcome of 32 on protocol patients after 36 months versus 32 concurrent institutional H&NSCC controls showed delayed recurrences and significant increases in mean survival time (MST) and survival ( p's<0.02). The data document immunotherapy induced regression of H&NSCC with delayed recurrence and improved mean survival time.

Gemcitabine combined with cisplatin as first-line treatment in patients 60 years or older with epithelial ovarian cancer: a phase II study

This phase II study evaluated the activity and toxicity of gemcitabine plus cisplatin as first-line treatment of patients with advanced ovarian cancer. Chemonaive patients ≥60-year-old with FIGO stage IIIC or IV epithelial ovarian carcinoma were enrolled. Patients received cisplatin 75 mg/m2 on day 1 and gemcitabine 1250 mg/m2 on day 1 (before cisplatin) and day 8 of a 21-day cycle. Of 44 female patients (median age, 70 years), 72.7% had stage IIIC disease and 67.4% had a Karnofsky performance status ≥80. Of the 37 response-evaluable patients (35 with measurable lesion[s] ≥2 cm), there were seven (18.9%) pathologic complete responses, two (5.4%) pathologic partial responses, two (5.4%) clinical complete responses, and 12 (32.4%) clinical partial responses, for an overall response rate of 62.2% (95% CI, 44.8%–77.5%), and a pathologic response rate of 24.3% (95% CI, 11.8%–41.2%). Median survival was 27.7 months (95% CI, 14.3–40.8 months). Grade 3/4 neutropenia and thrombocytopenia occurred in 59.5% and 30.2% of patients, respectively, with neutropenic fever in one patient. Grade 3 nausea /vomiting and alopecia occurred in 25.6% and 9.5% of patients, respectively. We conclude that gemcitabine plus cisplatin is active and feasible as first-line treatment of advanced epithelial ovarian cancer in patients ≥60 years. Further clinical trials adding gemcitabine to current standard, first-line treatment seem warranted in younger as well as older patients.

Interferon-alpha and ribavirin treatment in patients with hepatitis C virus-related systemic vasculitis.

Hepatitis C virus (HCV)-related vasculitis may involve multiple organs, including the skin, kidneys, and nervous system, and may be life-threatening. Although HCV is increasingly recognized as a cause of systemic vasculitis, limited data are available regarding the optimal treatment of this potentially serious condition. Therefore, we retrospectively analyzed the response to treatment in patients with chronic hepatitis C complicated by systemic vasculitis who had received antiviral therapy with interferon-alpha (IFNalpha) and ribavirin. This retrospective study included 27 patients with systemic vasculitis and chronic HCV infection. Each patient had received treatment with IFNalpha and ribavirin for at least 6 months. The response to antiviral treatment was analyzed by comparing clinical, immunologic, and virologic data at the time of entry and during followup. Clinical response was defined according to the evolution of weight, arthralgia, nervous system, renal system, and cutaneous involvement. The virologic and immunologic responses were defined by the absence of HCV RNA and the absence of cryoglobulinemia, respectively, both 6 months after stopping antiviral therapy and at the end of followup. Patients received IFNalpha for a mean +/- SD of 20 +/- 14 months and ribavirin (at a mean +/- SD dosage of 895 +/- 250 mg/day) for 14 +/- 12 months. Other treatments included low-dose corticosteroids and plasma exchange. After a mean +/- SD followup of 57 +/- 29 months, 25 of 27 patients are alive and are being followed up as outpatients. Because of the heterogeneity of anti-HCV treatments received, the main results were stratified according to patients with 6 months of followup after stopping antiviral treatment (group 1, n = 14) and those who were still undergoing antiviral therapy at the time of analysis (group 2, n = 13). Nine patients in group 1 had a sustained virologic response and were clinical and immunologic complete responders. Four patients in group 1 were virologic nonresponders, and 3 of these patients had partial clinical and immunologic responses. Overall, 10 patients in group 1 had a complete clinical and immunologic response of their vasculitis (all 9 of the sustained virologic responders and 1 of the 5 patients who remained viremic). At the end of followup, 7 patients in group 2 were negative for HCV RNA; 6 were complete clinical responders. Among the other 6 patients in group 2, who had persistent viremia, 4 had a partial clinical response. Among the patients in group 1, HCV RNA was more often undetectable and genotype 1 was less frequent in complete clinical responders compared with partial/nonresponders. Age, sex, clinical vasculitic involvement, mean duration or total cumulative dose of IFNalpha or ribavirin, and use of steroids or plasmapheresis did not differ significantly according to clinical response. Treatment with IFNalpha and ribavirin can achieve a complete clinical response in most patients with HCV-related systemic vasculitis. Complete clinical response correlates with the eradication of HCV.

Effect of Treatment on Health-Related Quality of Life in Acquired Immunodeficiency Syndrome (AIDS)-Related Kaposi's Sarcoma: A Randomized Trial of Pegylated-Liposomal Doxorubicin Versus Doxorubicin, Bleomycin, and Vincristine

The purpose of this study was to determine whether health-related quality of life (HRQL) would be improved in patients with acquired immunodeficiency syndrome (AIDS)-related Kaposi's sarcoma treated by pegylated-liposomal doxorubicin (PLD) as compared to those treated by a conventional combination of doxorubicin, bleomycin, and vincristine (ABV). One hundred thirty-three patients received PLD and 125 patients received ABV every 2 weeks with a planned total of 6 cycles. Patients completed a 30-item AIDS-related HRQL questionnaire before beginning treatment (baseline), every 2 weeks while on treatment, and about 21 days after the end of treatment. Twenty-two items, involving nine domains, were analyzable. While on treatment, PLD-treated patients with partial clinical responses achieved statistically significant greater improvement (compared to baseline) in general health than did ABV-treated patients with partial clinical responses (ρ = 0.008). By the end of treatment, the overall group of patients receiving PLD showed statistically significant greater improvement in pain and energy/fatigue than did the group receiving ABV (ρ = 0.01–0.002). In addition, duration of clinically significant improvement in global QL was longer in the PLD arm.

Successful treatment of two patients with recurrent endometrial cancer by weekly paclitaxel

Objective: The aim of this study was to evaluate the toxicity and efficacy of weekly paclitaxel in patients with recurrent endometrial cancer. Methods: Paclitaxel (70 mg/m 2 by 1-h infusion weekly) was administered to two patients with recurrent endometrial cancer of the lung. Results: After 5 cycles, both patients with platinum-resistant disease achieved clinical partial responses confirmed by computed tomography (CT) scan. The serum CA125 levels of case 1 decreased to cut-off level. The response duration of both patients was 4 months. The toxicity was acceptable and probably less pronounced than that characterize of the standard tri-weekly schedules. Conclusion: Although conclusions regarding survival are premature, weekly paclitaxel might offer better quality of life during treatment.

Thymidylate synthase quantitation and in vitro chemosensitivity testing predicts responses and survival of patients with isolated nonresectable liver tumors receiving hepatic arterial infusion chemotherapy

Patients with isolated, nonresectable liver tumors may receive regional hepatic arterial infusion (HAI) chemotherapy with response rates of about 50%. The objective of this study was to investigate the value of thymidylate synthase (TS) determination in combination with in vitro chemosensitivity testing to predict the responses and survival of patients receiving HAI. TS mRNA expression was quantitated using a reverse transcription-polymerase chain reaction technique with beta-actin as the internal standard. In vitro chemosensitivity testing was performed with tumor cell suspensions using the human tumor colony-forming assay (HTCA). An analysis of the test combination in 24 consecutive patients revealed that 77% (10 of 13) of the sensitive and 9% (1 of 11) of the resistant patients had complete or partial clinical responses. Sensitive patients were 8.5-fold more likely to respond (P = 0.0036) and displayed with 32 months (range, 5-75 months) a longer median survival than resistant patients with 17 months (range, 3-28 months, P = 0.003). Analysis of the Kaplan-Meier curves revealed that sensitive patients had a higher overall survival probability, as determined by the log rank test (P = 0.044). These results suggest that the clinical outcomes of patients receiving HAI therapy may be predictable with TS quantitation and HTCA. It is possible, therefore, that this combination may be used in the future to select patients with liver tumors who will benefit from HAI before the start of regional chemotherapy.

Dendritic cells: at the clinical crossroads.

Dendritic cells: at the clinical crossroads.