Median Failure-free Survival Research Articles

Experience with heat shock protein‐peptide complex 96 vaccine therapy in patients with indolent non‐Hodgkin lymphoma

The objective of this phase II trial was to investigate the safety and efficacy of autologous heat shock protein-peptide complex 96 (HSPPC-96) vaccines prepared from tumor specimens of patients with newly diagnosed or previously treated indolent non-Hodgkin lymphoma (NHL). The study was for patients with indolent B-cell NHL with measurable lesions. HSPPC-96 vaccines were prepared from patients' resected tumor specimens and administered as a 25-microg intradermal injection in the absence of disease progression every week for 4 weeks and then every 2 weeks until the vaccine supply was exhausted. Twenty patients were enrolled in this trial. The median patient age was 59 years. Ten patients had been treated previously (median, 2 regimens; range, 1 to 7). Eighteen (90%) patients had stage III or IV disease. Autologous vaccines were successfully prepared for 17 (85%) patients and all received at least 1 dose. The treatment was very well tolerated. One patient experienced a response with biopsy-proven clearance of the lymphoma cells in 2 of the skin nodules at 3.0 months that lasted for 7.0 months. Eight patients had stable disease for 6.0 to 19.8 months. The median failure-free survival duration in patients who received vaccine therapy was 5.2 months. HSPPC-96 can be prepared from tumor specimens for the majority of lymphoma patients, but it had limited efficacy in inducing responses in patients with active diseases. Further studies of HSPPCs, therefore, should be considered in adjuvant settings or in combination with other immunomodulatory agents to assess survival benefit.

Prolonged follow‐up after initial therapy with 2‐chlorodeoxyadenosine in patients with indolent non‐Hodgkin lymphoma

The objective of this study was to determine the efficacy and toxicity of 2-chlorodeoxyadenosine (2-CdA) in patients with untreated, indolent non-Hodgkin lymphoma (NHL). For this multicenter, single-arm, Phase II study, 44 patients with treatment-naive, stage III or IV, indolent NHL (International Working Formulation subtypes A, B, and C) were enrolled. Patients received 0.14 mg/kg per day of 2-CdA as a 2-hour bolus infusion for 5 consecutive days every 28 days until maximal response or a total of 6 cycles. Thirty-eight patients were eligible for response evaluation. The overall response rate was 100% (95% confidence interval [95% CI], 90.8-100%), and the complete response rate was 31.6% (95% CI, 17.5-48.7%). In the intent-to-treat population, the median failure-free survival was 2.0 years (95% CI, 1.3-3.4 years), and the overall survival rate was 7.0 years (95% CI, 4.3-9.4 years). Six patients had sustained remissions that lasted a median of 8.7 years (range, from 5.9 years to > or =11 years). Although 68% of patients experienced at least 1 grade 3 or 4 event, consisting primarily of myelosuppression, severe infections were rare, with only 8 grade 3 infections. Four late malignancies (prostate adenocarcinoma, ductal carcinoma in situ, and myelodysplasia) and 4 patients with large cell transformation were reported. 2-CdA is an active, well-tolerated therapy for patients with untreated, indolent NHL.

Favorable Outcome of Patients with Relapsed Hodgkin Lymphoma (HL) after Nonmyeloablative Hematopoietic Cell Transplantation (NM-HCT) Using Related Haploidentical Donors.

NM-HCT from related donors who share at least one HLA haplotype with the recipient is a treatment option for patients with hematologic malignancies who do not have suitable HLA-matched related or unrelated donors. We have shown that addition of cyclophosphamide pre-transplant (29 mg/kg) and post-transplant (50 mg/kg on day+3 or days+3 and +4) to a standard nonmyeloablative conditioning regimen of fludarabine and TBI combined with tacrolimus and MMF prophylaxis of GvHD is an effective means of achieving complete engraftment of donor T-cells and granulocytes with low non-relapse mortality and an incidence and severity of acute and chronic GvHD which does not differ from studies of NM-HCT using HLA-matched donors. In a study of 89 patients (FHCRC,N=30; JH,N=59) with advanced myeloid and lymphoid malignancies, patients with relapsed HL had significantly better survival than patients with other diagnoses. Fifteen patients with HL were studied (median follow-up of 17 mo). Patients were heavily pre-treated with a median number of prior cytotoxic therapy regimens of 5 (range: 3–10); 14 patients had failed prior autologous HCT with a median time of 18 mo from auto-HCT to NM-HCT. Donors for 9 patients were HLA-mismatched at ≥4/10 loci. All evaluable patients were complete donor CD3 and CD33 chimeras by day +28 (one patient died on day +28 and was not evaluable). Clinically significant acute GvHD occurred in 9/14 (64%) patients and Grades III/IV GvHD in 3/14 (21%) patients. Extensive chronic GvHD occurred in 5/14 (36%) patients. Two patients (13%) died of non-relapse causes at days +236 and +633 secondary to chronic GvHD. Median failure-free survival (FFS) was 21 mo compared to 6 mo for patients with other lymphoid malignancies (N=23) or myeloid malignancies [(N=51), see Figure]. The hazard of mortality was less among patients with HL compared to those with other lymphoid malignancies [hazard ratio (HR)=0.36 (p=0.05)] yet patients with myeloid malignancies had a similar hazard of mortality compared to those with lymphoid malignancies other than HL [HR=0.88 (p=0.66)]. Difference in FFS between HL and other lymphoid malignancies was not statistically significant [HR=0.54 (p=0.16)], nor was the difference between myeloid and other lymphoid malignancies [HR=1.26 (p=0.44)]. More patients will need to be studied to better demonstrate a graft-versus-lymphoma effect of haploidentical transplantation in relapsed HL. NM-HCT from haploidentical donors may be a good option for such patients who have a limited window of opportunity to proceed to transplant if responsive to salvage chemotherapy. [Display omitted] [Display omitted]

Combination of Oxaliplatin, Fludarabine, Cytarabine, and Rituximab in Richter's Syndrome and Fludarabine-Refractory Chronic Lymphocytic Leukemia.

Background: Richter's syndrome (RS) and fludarabine-refractory chronic lymphocytic leukemia (CLL) are associated with poor prognosis. Oxaliplatin is a platinum compound that covalently binds DNA, inducing DNA intra- and inter-strand cross-links. Fludarabine and cytarabine act synergistically to inhibit excision repair of DNA cross-links. We conducted a phase 1–2 trial of oxaliplatin, fludarabine, cytarabine, and rituximab (OFAR) in patients with RS or fludarabine-refractory CLL. The objectives of this trial were to identify a safe, tolerated dose and any dose-limiting toxicities (DLT) of oxaliplatin, to assess pharmacodynamic endpoints (phase 1); and to assess the complete (CR) and partial remission (PR) rates for the OFAR regimen (phase 2).Methods: The OFAR regimen consisted of increasing doses of oxaliplatin (17.5, 20, or 25 mg/m2/d), D1–4 (phase 1); fludarabine 30 mg/m2, D2–3; cytarabine 1 g/m2, D2–3; rituximab 375 mg/m2, D3; and pegfilgrastim 6 mg, D6, every 4 weeks for a maximum of 6 courses. Prophylaxis for PCP pneumonia and DNA virus were given. DLT was defined as any non-hematologic, treatment-related toxicity > grade (G) 3.Results: From November 2004 to August 2006, 46 patients were enrolled, including 19 patients in phase 1. The tolerated oxaliplatin dose identified was 25 mg/m2. No DLT was observed. Pharmacodynamic analyses demonstrated enhanced leukemia cell killing by oxaliplatin in the presence of fludarabine and cytarabine. Thirty-seven patients are currently evaluable (14 RS, 23 fludarabine-refractory CLL). The median age of patients with RS was 69 yrs (range, 41–78) and of fludarabine-refractory CLL was 57 yrs (range, 34–77); the median number of prior therapies was 3 (range, 0–10), and 4 (range, 1–11), respectively. Among patients with fludarabine-refractory CLL, 16 (70%) had Rai stage 3–4. G3–4 septic episodes occurred in 2, pneumonia in 4, and CMV infection occurred in 2 patients. The median number of OFAR cycles was 2 (range, 1–6). RBC and platelet transfusions were required in 56% and 61% of cycles, respectively. Responses are shown in Table [insert].Nine patients (1 RS) received allogeneic stem cell transplantation. Responses included 6 of 16 patients with 17p deletion, 1 of 5 evaluable patients with 11q deletion, 3 of 3 patients with trisomy 12, 1 of 4 patients with 13q deletion, and 2 of 7 others. With a median follow-up of 7 months, 6 of 14 with RS and 11 of 23 patients with fludarabine-refractory CLL have failed. The median failure-free survival has not been reached for RS and is 4 months for fludarabine-refractory CLL.Conclusions: The OFAR regimen is highly active in RS and has activity in fludarabine-refractory patients with CLL. No DLT for oxaliplatin at 25 mg/m2 was noted. Hematologic toxicities did occur, but no prolonged myelosuppression was observed. The trial continues to accrue patients, with a target accrual of 40 patients on phase 2.Oxaliplatin dose (mg/m2/d)17.52025All dosesRSEvaluable25512CR0213PR0224Overall (%)04 (80)3 (60)7 (58)Fludarabine-refractory CLLEvaluable131923CR, nodular0011PR0055Overall (%)006 (32)6 (26)Total (%)04 (50)9 (38)13 (37)

Rituximab combined with cladribine or with cladribine and cyclophosphamide in heavily pretreated patients with indolent lymphoproliferative disorders and mantle cell lymphoma

In vitro studies have shown synergistic or additive interactions between rituximab and purine nucleoside analogues. The results of recent clinical trials seem to confirm these preclinical observations. For the current study, the authors evaluated the feasibility, efficacy, and toxicity of combined regimens that consisted of either rituximab plus cladribine (2-CdA) (the RC regimen) or RC plus cyclophosphamide (the RCC regimen) in the treatment of patients with heavily pretreated, indolent lymphoid malignancies. Fifty-four adult patients with recurrent or refractory, low-grade non-Hodgkin lymphoma (LG-NHL) and B-cell chronic lymphocytic leukemia (B-CLL) were treated according to the RC/RCC regimens. The RC protocol consisted of intravenous rituximab at a dose of 375 mg/m(2) on Day 1 and 2-CdA at a dose of .12 mg/kg per day on Days 2 through 6. The RCC protocol consisted of rituximab at a dose of 375 mg/m(2) on Day 1, 2-CdA at a dose of 0.12 mg/m(2) on Days 2 through 4, and intravenous cyclophosphamide at a dose of 250 mg/m(2) per day on Days 2 to 4. The RC/RCC courses were repeated at 4-week intervals. Thirty-three patients with B-CLL, 12 patients with LG-NHL and 9 patients with mantle cell lymphoma (MCL) entered the study. Thirty-three patients (61%) had recurrent disease after prior therapy, and 21 patients (39%) had refractory disease. Thirty-one patients were treated on the RC regimen, and 23 patients were treated on the RCC regimen. Six patients (11%) achieved a complete response, and 33 patients (60%) achieved a partial response. The median failure-free survival of responders was 10.5 months. The treatment revealed tolerability, with episodes of severe neutropenia (Grade 3 and 4 [according to World Health Organization criteria]) observed in 6 patients (11%), episodes of Grade 3 and 4 infections observed in 11 patients (20%), and episodes of Grade 3-4 thrombocytopenia observed in 4 patients (7%). The RC and RCC regimens were highly effective and well tolerated modalities of treatment in heavily pretreated patients with indolent lymphoproliferative disorders.

Hodgkin transformation of chronic lymphocytic leukemia

Hodgkin transformation is a rare complication of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). In this study, the authors assessed the incidence, presenting characteristics, and outcomes of patients with CLL/SLL who developed Hodgkin lymphoma (HL). An electronic database search of patients with CLL/SLL who presented at The University of Texas M. D. Anderson Cancer Center Department of Leukemia between 1975 and 2005 was performed. Among 4121 patients with CLL/SLL, 18 patients (0.4%) developed HL. Presenting features included B-symptoms (67%), lymph node enlargement (79%), splenomegaly (43%), hepatomegaly (29%), hypercalcemia (6%), infection (6%), and mental status changes (6%). The median age was 72 years (range, 49-81 years), and there was a male preponderance (78%). The median time from CLL to HL diagnosis was 4.6 years (range, 0-12.9 years). Fourteen patients (78%) had been previously treated for CLL/SLL. Ten patients (56%) had received >1 prior therapy. The median beta2-microglobulin level was 4.5 mg/L, and the median lactate dehydrogenase level was 610 IU/L. Epstein-Barr virus (EBV) was positive by in situ hybridization for EBV-encoded RNA in 3 of 4 tested patients. Fourteen patients (78%) received chemotherapy. The overall response rate was 44% (complete response rate, 19%). The median overall survival duration was 0.8 years (range, 0.03 years-6.7+ years). The median failure-free survival (FFS) duration was 0.4 years. The rates of response, survival, and FFS in patients with Hodgkin transformation of CLL/SLL were inferior to those reported in patients with de novo HL and were similar to those in patients with Richter syndrome.

Chemoradiotherapy (CRT) and gefitinib (G) in stage III non-small cell lung cancer (NSCLC): A CALGB stratified phase II trial

7046 Background: G is a small molecule inhibitor of EGFR with activity in advanced NSCLC and preclinical evidence of being a radiosenitizer. Methods: Patients with stage III NSCLC were assigned to stratum 1 (PS 0–1>5% weight loss and/or PS 2) or stratum 2 (PS 0–1weight loss < 5%). Both strata received induction paclitaxel (P) 200 mg/m2 and carboplatin (C) AUC of 6 IV every three weeks for 2 cycles plus G 250 mg PO/day. G was removed 4/05 from induction therapy as stage IV studies showed no benefit from adding G to P and C. Stratum 1 then received RT 200 cGy for 33 fractions (total dose 6,600 cGy) and G 250 mg PO /day. Stratum 2 received the same RT with concurrent G 250 mg/day, and P 50 mg/m2 plus C AUC of 2 weekly for 7 doses. Maintenance G was started after all toxicities were grade ≤2. Results: Activation was 5/02 and administrative closure 5/04 due to results from SWOG S0023. 64 patients were accrued and 59 (20 stratum 1, 39 stratum 2) were eligible and analyzed: median age 67, male 74%, adeno 30%, squamous 45%, other 25%, IIIA 51%, IIIB 49%. There was no clear increase for acute high-grade infield toxicities compared to CRT alone (reported PASCO 2004). Best response for stratum 1 was PR 29% for induction (RR 29%, 95% CI 10%-56%) and CR 5%, PR 45% full treatment (RR 50%, 95% CI 27%-73%); for stratum 2 PR 13% for induction (RR 13%, 95% CI 3%-34%) and CR 5%, PR 76% full treatment (RR 81%, 95% CI 65%-92%). Stratum 1 “poor risk” median failure free survival (FFS) was 11.5 months (95% CI 5.6–21.2), one year survival 60% (95% CI 33%-79%) and median overall survival (OS) 19.0 months (95% CI 7.2–21.2). Stratum 2 “good risk” median FFS was 9.2 months (95% CI 6.7–12.0), one year survival 47% (95% CI 30%–63%) and median OS was 12.0 months (95% CI 8.5–18.6). EGFR and Ras mutation analysis on tumor biopsies (n = 50) will be presented. Conclusions: Small sample size prevented planned data analysis. Survival of “good risk” patients on stratum 2 (CRT + G) was disappointing. The promising survival of the small number of “poor risk” patients on stratum 1 (RT + G) justifies a follow-up phase II trial of induction chemotherapy followed by RT with a concurrent small molecule EGFR inhibitor. [Table: see text]

A Phase II Trial of Intraperitoneal Photodynamic Therapy for Patients with Peritoneal Carcinomatosis and Sarcomatosis

A previous phase I trial of i.p. photodynamic therapy established the maximally tolerated dose of Photofrin (Axcan Pharma, Birmingham, AL)-mediated photodynamic therapy and showed encouraging efficacy. The primary objectives of this phase II study were to determine the efficacy and toxicities of i.p. photodynamic therapy in patients with peritoneal carcinomatosis and sarcomatosis. Patients received Photofrin 2.5 mg/kg i.v. 48 hours before debulking surgery. Intraoperative laser light was delivered to the peritoneal surfaces of the abdomen and pelvis. The outcomes of interest were (a) complete response, (b) failure-free survival time, and (c) overall survival time. Photosensitizer levels in tumor and normal tissues were measured. One hundred patients were enrolled into one of three strata (33 ovarian, 37 gastrointestinal, and 30 sarcoma). Twenty-nine patients did not receive light treatment. All 100 patients had progressed by the time of statistical analysis. The median failure-free survival and overall survival by strata were ovarian, 2.1 and 20.1 months; gastrointestinal cancers, 1.8 and 11.1 months; sarcoma, 3.7 and 21.9 months. Substantial fluid shifts were observed postoperatively, and the major toxicities were related to volume overload. Two patients died in the immediate postoperative period from bleeding, sepsis, adult respiratory distress syndrome, and cardiac ischemia. Intraperitoneal Photofrin-mediated photodynamic therapy is feasible but does not lead to significant objective complete responses or long-term tumor control. Heterogeneity in photosensitizer uptake and tumor oxygenation, lack of tumor specificity for photosensitizer uptake, and the heterogeneity in tissue optical properties may account for the lack of efficacy observed.

Phase II Trial of Subcutaneous Interferon Followed by Intravenous Hybrid Bolus/Continuous Infusion Interleukin-2 in the Treatment of Renal Cell Carcinoma: Final Results of Cancer Biotherapy Research Group 95-09

We conducted a phase II trial in metastatic renal cell cancer of outpatient subcutaneous (s.c.) interferon-alpha2b (IFN), followed by an inpatient hybrid schedule of bolus and continuous interleukin-2 (IL- 2). Treatment consisted of monthly IFN 10 MU/m(2) s.c. for 4 consecutive days, followed by 36 MIU/m(2) bolus IL-2, then 72-hour continuous intravenous (i.v.) infusion of 18 MIU/m(2) IL-2 per day. Between May 1997 and June 2000, 25 men and 11 women enrolled, with a median age of 57 years (range, 42-77), including 9 patients over 65. Prior treatment included nephrectomy (31), radiation (8), biotherapy (7), and chemotherapy (4). Sites of disease included 26 lung, 13 lymph node, 9 bone, 8 liver, 4 kidney, and 4 adrenal locations. Patients received an average of 3.1 treatment cycles (range, 1-6). There was 1 complete and 3 partial responses, for a response rate of 11% (3% to 27%; 95% confidence interval [CI]); 40% had stable disease. Median failure-free survival was 2.5 months; median overall survival was 15.0 months. The 1-, 2-, and 5-year survival rates were 53%, 30%, and 12%, respectively. Only 8 patients required a reduction in IL-2 dose. The most frequent grade 3 or 4 toxicities were 11% fatigue, 9% renal insufficiency, and 7% hypotension. Response and survival rates were similar to those seen in other multicenter trials using inpatient high-dose IL-2.

Richter’s Transformation in Chronic Lymphocytic Leukemia

Richter's syndrome (RS) is characterized by the development of high-grade non-Hodgkin's lymphoma (NHL) in a patient with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma. At The University of Texas M.D. Anderson Cancer Center the incidence of RS is 3.9%. The large cells of RS may arise through transformation of the original CLL clone or represent a new neoplasm. RS may be triggered by viral infections, such as Epstein-Barr virus (EBV). Trisomy 12 and chromosome 11 abnormalities, as well as multiple genetic defects, have been described in patients with RS. These abnormalities may cause CLL cells to proliferate and, by facilitating the acquisition of new genetic abnormalities, to transform into RS cells. The therapeutic strategies for RS typically include therapies developed for NHL or acute lymphoblastic leukemia. The reported response rates with these therapies are 5% to 43%, and the median survival duration ranges from 5 to 8 months. The median overall survival duration at our institution of patients with RS is 9.1 months (95% confidence interval, 7.8 to 11 months), and the median failure-free survival duration is 7.1 months (95% confidence interval, 5.1 to 10.4 months). Patients appear to benefit from cytoreductive therapy consisting of chemotherapy and immunotherapy, followed by allogeneic stem cell transplantation, as postremission therapy. As part of a program aiming to cure RS, we are currently conducting a clinical trial of oxaliplatin, fludarabine, and cytarabine in combination with rituximab and recommend postremission therapy, including allogeneic stem cell transplantation in patients with available donors.

Nodal downstaging predicts survival following induction chemotherapy for stage IIIA (N2) non-small cell lung cancer in CALGB protocol #8935

CALGB 8935 was a phase II protocol for mediastinoscopically staged IIIA (N2) non-small cell lung cancer. Induction cisplatin/vinblastine chemotherapy was followed by surgical resection, adjuvant cisplatin/vinblastine, and radiotherapy. We now evaluate the prognosis of pathologic nodes. Failure-free survival was calculated from a landmark 3 months after resection to account for heterogeneity in adjuvant therapy. Nine of 42 (21%) resected patients had no residual N2 disease. This subset of 9 had a median failure-free interval of 47.8 months from landmark, whereas the 33 patients (79%) with persistent N2 disease had a median failure-free survival of 8.2 months from landmark (P=0.01). Although 21/42 (50%) had an incomplete resection (positive highest resected node and/or margin), completeness of resection did not influence failure-free survival. There were 3 distant and no local recurrences among the N2 negative group, and 12 local recurrences among patients with residual N2 disease (P=0.041). These data suggest: (1) persistent N2 disease following induction chemotherapy is unfavorable; (2) patients downstaged to N2 negative may benefit from surgical resection; however, (3) 33% of N2 negative patients suffered disease relapse.

Transformation of Chronic Lymphocytic Leukemia into Hodgkin's Disease The M D Anderson Cancer Center Experience.

Introduction: Hodgkin's disease (HD) is a rare complication of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). Outcome in patients with HD following CLL/SLL is thought to be inferior to that of patients with de novo HD and superior to that of patients with Richter's syndrome (RS), but data are lacking. The purpose of this study was to assess the incidence, presenting characteristics, and clinical outcomes of HD.Methods: An electronic database search of patients with CLL/SLL who presented at U.T. M. D. Anderson Cancer Center Department of Leukemia between 1975 and 2005 was performed, and patients who developed HD were identified.Results: Among 3986 patients with CLL/SLL, 13 patients (0.3%) developed HD. Patients with HD presented with B symptoms (62%), lymph node enlargement (46%), splenomegaly (15%), hepatomegaly (8%), hypercalcemia (8%), thrombocytopenia (8%), and infection (8%). The median age was 72 years (range, 49–81 years). There were 11 men (85%). The median time from CLL/SLL to HD was 5.0 years (range, 1.8–12.9 years). HD was confirmed by biopsy of involved lymph nodes (46%), bone marrow (38%), spleen (8%), or buccal mucosa (8%). All patients were previously treated for CLL/SLL. Nine patients had received >1 prior therapies. Prior therapies included fludarabine +/− cyclophosphamide +/− rituximab (85%), chlorambucil (31%), rituximab (23%), alemtuzumab (15%), platinum-based combination regimens (15%), or other therapies (38%). At presentation of HD, the median β2-microglobulin levels were 4 mg/dL (range, 2.2–11.5 mg/dL) and the median lactate dehydrogenase levels were 717 IU/L (range, 336–1883 IU/L). Cytogenetics were as follows: normal, 4 (44%) of 9 patients; -Y, 3 patients; 11q-, 1 patient; and complex including del(13)(q14q22) and trisomy 12, 1 patient. Epstein-Barr virus (EBV) was positive by in situ hybridization in 3 (75%) of 4 tested patients. Ten (77%) of 13 patients were treated with chemotherapy for HD. Five patients were treated with doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD), 2 patients were treated with cyclophosphamide, vinblastine, procarbazine, and prednisone (CVPP), 1 patient with CVPP/ABVD, 1 patient with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP), and 1 patient with fludarabine, cytarabine, cyclophosphamide, and cisplatin (FACP). One patient was treated with cidofovir, and the other 2 patients received no therapy. The overall response rate was 60%. Responses were noted in patients treated with ABVD (complete remission [CR], 1; partial remission [PR], 2), CVPP (CR, 1), CVPP/ABVD (PR, 1), and CHOP (PR, 1). The median overall survival duration was 0.8 years (95% C.I., 0.4 – 6.7+ years). The median failure-free survival (FFS) duration was 0.4 years (95% C.I., 0.2 – 6.7+ years).Conclusions: These data suggest that the response to treatment, survival, and FFS of patients with HD following CLL are inferior to that reported in patients with de novo HD. These outcomes, as well as the presenting characteristics of HD following CLL/SLL, are similar to those reported for patients with RS.

High (95%) Response Rates in Relapsed/Refractory Mantle Cell Lymphoma after R-HCVAD Alternating with R-Methotrexate/Cytarabine (R-M-A).

Mantle cell lymphoma (MCL) has a poor prognosis. Relapsed/refractory patients must respond to salvage chemotherapy in order to receive potentially curative stem cell transplantation (SCT). A salvage regimen with higher rate of response will offer the patient a better chance of survival. We have previously reported the results of R-HCVAD alternating with R-M-A in frontline therapy of MCL (Blood , 104:40a, 2004, (Abstract #128).The current trial looked at relapsed/refractory MCL patients treated also with R-HCVAD alternating with R-M-A. Since August 2001, the trial has accrued 24 out of a planned number of 41 patients of whom 21 are evaluable for response and survival. Median age was 63 years (range 45–78) and male:female ratio was 5:1. Three patients had received previous R-HCVAD alternating with R-M-A and three patients had failed an autologous stem cell transplant. Immediate therapy prior to the study for the 21 patients included R-HCVAD/SCT (1), CHOPw/wo rituximab (8 patients), cyclophosphamide, vincristine and rituximab (1), fludarabine (1), fludarabine, mitoxantrone, dexamethasone and rituximab (2), fludarabine and cyclophosphamide (1), radiotherapy (2), gemcitabine, mitoxantrone and dexamathasone (1) ifosfamide, carboplatin, etoposide and rituximab (1), Velcade (1), gemcitabine (1), and rituximab (1). The median number of prior regimens was one (range 1–6). Responses to the previous treatment included complete response (CR; 8 patients, 38%), partial response (PR; 6 patients, 29%), and no response or progression (7 patients, 33%). Results of the trial are as follows: Median number of cycles received = 4 (range 1–7), with an overall response rate (ORR) of 95% (43% CR/Cru; 52% PR). 5/5 patients who had progressed through the previous treatment responded (1CR, 4 PR), and 2/2 patients who had no change to the prior therapy responded (2 PR's). We evaluated 12 cases whose response in our trial was classified as PR and found that in 4 of them it was the best response achieved but another 4 were referred to transplant while the tumor was still responding and in another case treatment was still ongoing. In 3 cases toxicity precluded continuation of therapy. Five (24%) of the patients were consolidated with non-myeloablative allogeneic stem cell transplantation. Sixteen were not transplanted for the following reasons: age (2 patients), lack of donor (5), Progressive disease (2), patient refusal (4), physician's choice (1), waiting for match (1), and lost to follow up (1). Toxicity after 81 cycles included neutropenic fever (14%), grade 4 neutropenia (58%) and grade 4 thrombocytopenia (53%). The were no deaths due to toxicity. With a median follow-up of 21 months range 5–45 months), the median failure-free survival is 18 months as compared to a median FFS of 9 months response duration with the previous therapy, with no plateau in the curve. Patients who underwent stem cell transplant were censored at the time of transplant.The high response rates achieved R-HCVAD alternating with R-M-A makes this regimen an excellent choice for induction therapy prior to stem cell transplantation.

Capecitabine and mitomycin C as third-line therapy for patients with metastatic colorectal cancer resistant to fluorouracil and irinotecan

Protracted venous infusion 5-fluorouracil (5FU) combined with mitomycin C (MMC) has demonstrated significant activity against metastatic colorectal cancer. Owing to potential synergy based upon upregulation of thymidine phosphorylase by MMC, the combination of capecitabine and MMC may improve outcomes in irinotecan-refractory disease. Eligible patients with progressive disease during or within 6 months of second-line chemotherapy were treated with capecitabine (1250 mg m−2 twice daily) days 1–14 every 3 weeks and MMC (7 mg m−2 IV bolus) once every 6 weeks. A total of 36 patients were recruited, with a median age of 64 years (range 40–77), and 23 patients (78%) were performance status 0–1. The objective response rate was 15.2%. In all, 48.5% of patients had stable disease. Median failure-free survival was 5.4 months (95% CI 4.6–6.2). Median overall survival was 9.3 months (95% CI: 6.9–11.7). Grade 3 toxicities were palmar-plantar erythema 16.7%, vomiting 8.3%, diarrhoea 2.8%, anaemia 8.3%, and neutropenia 2.8%. No patients developed haemolytic uraemic syndrome. Symptomatic improvement occurred for pain, bowel symptoms, and dyspnoea. Capecitabine in combination with MMC is an effective regimen for metastatic colorectal cancer resistant to 5FU and irinotecan with an acceptable toxicity profile and a convenient administration schedule.

Phase II study of oxaliplatin in patients with recurrent or refractory non‐Hodgkin lymphoma

Oxaliplatin is a platinum derivative with a broad range of anticancer activity. The objective of the current Phase II trial was to investigate the activity of oxaliplatin in patients with recurrent or refractory non-Hodgkin lymphoma (NHL). Patients with recurrent and refractory NHL who received a maximum of 3 previous chemotherapy regimens were considered eligible if they had an Eastern Cooperative Oncology Group performance status of 0-2 and adequate organ function. Oxaliplatin was administered in an outpatient setting at a dose of 130 mg/m(2) by 2-hour intravenous infusion every 21 days for < or = 6 cycles in the absence of disease progression. Thirty-one patients (23 with aggressive NHL and 8 with indolent NHL) were enrolled, of whom 30 were assessable for toxicity, response, and survival. The median patient age was 62 years, and 20% of the patients previously received platinum-containing therapy. Eighty-three percent of the patients were refractory to their last treatment regimens. Grade 3 and 4 toxic effects (according to the National Cancer Institute's Common Toxicity Criteria [version 2.0]) included sensory neuropathy (10%), neutropenia (17%), and thrombocytopenia (20%). Objective responses occurred in 8 (27%; 95% confidence interval, 13-47%) of the patients. Responses were observed in platinum-naive patients as well as in those previously treated with platinum. The overall median failure-free survival duration was 3.0 months (range, 0.1-18.1 months). Oxaliplatin had favorable single-agent activity in previously treated patients with refractory lymphoma. The favorable safety profile and the ease of its administration in outpatient settings warrant investigating it in combination with other active drugs for the treatment of recurrent and refractory NHL.

High-Dose Chemotherapy and Autologous Stem Cell Rescue for Metastatic Breast Cancer

During 1990-1999, we treated 60 patients with breast cancer who had distant metastases with high-dose chemotherapy and autologous stem cell rescue (HDC) after they had responded to induction chemotherapy. HDC regimens were MiTepa (60 mg/m2 mitoxantrone by continuous intravenous infusion over 3 days plus 300 mg/m2 thiotepa intravenously over 2 hours daily x 3 days) and ICE (12 g/m2 ifosfamide, 1800 mg/m2 carboplatin, 2 g/m2 etoposide; all 3 by continuous intravenous over 4 days). At a median follow up >8 years, the median failure-free survival (FFS) was 13.9 months, median overall survival (OS) 29.1 months, 5-year FFS 12%s and 5-year OS 25%. Thirty-three patients underwent tandem (T) transplants; 27 underwent a single (S) HDC. Median ages for these 2 groups were 45 and 48 years; bone and liver metastases were more prevalent in the T cohort, whereas lung metastases were more prevalent in the S cohort. At a median follow up of 6.5 years for the S group and >9 years for the T group, there were 52 deaths. FFS was better for T: median 15.7 versus 7.7 months (p2 = 0.010) as was OS: median 32.7 versus 17.7 months, 2-year survival 68% versus 41%, and 5-year survival 32% versus 15% (p2 = 0.010). As a group, patients with distant metastatic breast cancer who underwent tandem transplants had a better posttransplant survival than patients who underwent a single HDC.

Oxaliplatin plus high-dose folinic acid and 5-fluorouracil i.v. bolus (OXAFAFU) versus irinotecan plus high-dose folinic acid and 5-fluorouracil i.v. bolus (IRIFAFU) in patients with metastatic colorectal carcinoma: a Southern Italy Cooperative Oncology Group phase III trial

Purpose:: The primary end point of this phase III trial was to compare the response rate (RR) of oxaliplatin (OXA) plus levo-folinic acid (l-FA) and 5-fluorouracil (5-FU) bolus with that of irinotecan (IRI) plus l-FA and 5-FU bolus in advanced colorectal carcinoma.Patients and methods:: Patients with measurable metastatic colorectal carcinoma were randomly allocated to receive: IRI 200mg/m2 on day 1, l-FA 250mg/m2 intravenously plus 5-FU 850mg/m2 on day 2 (IRIFAFU); or OXA 100mg/m2 on day 1, l-FA 250mg/m2 plus 5-FU 1050mg/m2 on day 2 [OXAFAFU high dose (hd)]. Cycles were given every 2 weeks. After a planned interim analysis, OXA was reduced to 85mg/m2 and 5-FU to 850mg/m2 [OXAFAFU low dose (ld)].Results:: Two hundred and seventy-four patients (IRIFAFU, 135; OXAFAFUhd, 71; OXAFAFUld, 68) were treated. Forty-two confirmed responses were achieved with IRIFAFU, 29 with OXAFAFUhd and 32 with OXAFAFUld. The response rate with OXAFAFU [44%; 95% confidence interval (CI) 35% to 52%] was significantly higher (P=0.029) than that of IRIFAFU (31%; 95% CI 23% to 40%). Occurrence of grade ≥3 neutropenia with OXAFAFUld was similar to that for IRIFAFU (29% versus 31%), while severe diarrhoea was significantly lower (12% versus 24%). Median failure-free survival (7 versus 5.8 months; P=0.046) and overall survival of patients (18.9 versus 15.6 months; P=0.032) were significantly prolonged with OXAFAFU.Conclusions:: OXAFAFU was more active and less toxic than IRIFAFU, and it should be preferred in the first-line treatment of advanced colorectal cancer patients.

Randomized Phase III Intergroup Trial of Etoposide and Cisplatin With or Without Paclitaxel and Granulocyte Colony-Stimulating Factor in Patients With Extensive-Stage Small-Cell Lung Cancer: Cancer and Leukemia Group B Trial 9732

To determine, in a randomized comparison, whether the addition of paclitaxel to etoposide and cisplatin improves the time to progression and overall survival in patients with extensive small-cell lung cancer (SCLC) compared with standard etoposide and cisplatin and to compare the regimens' toxicity. Eligible patients (N=587) with untreated extensive SCLC were randomly assigned to receive either cisplatin 80 mg/m2 on day 1 and etoposide 80 mg/m2 on days 1 through 3 administered every 3 weeks for six cycles (EP) or cisplatin 80 mg/m2 on day 1, paclitaxel 175 mg/m2 over 4 hours on day 1, and etoposide 80 mg/m2 on days 1 to 3 followed by recombinant human granulocyte colony-stimulating factor on days 4 to 18 administered every 3 weeks for six cycles (PET). Reporting of demographics, response, and survival included 565 patients, of whom 282 were randomly assigned to receive EP and 283 were assigned to receive PET. Overall response rates were 68% for the EP arm and 75% for the PET arm. Median failure-free survival time was 5.9 months for the EP arm and 6 months for the PET arm (P = .179). Median overall survival time was 9.9 months for patients on EP and 10.6 months for patients on PET (P = .169). Toxic deaths occurred in 2.4% of the patients on EP and 6.5% of patients on PET. PET did not improve the time to progression or survival in patients with extensive SCLC compared with EP alone and was associated with unacceptable toxicity.

Results of treatment intensification for progressive locoregional disease in head-and-neck cancer patients undergoing postoperative radiotherapy

Patients who develop progressive locoregional disease during radical surgery and postoperative radiotherapy for squamous cell carcinoma of the head and neck represent a management dilemma. We present our experience using treatment intensification for such patients. A prospective record of eligible patients was kept between May 1998 and December 2001. The study included 15 patients, 11 men and 4 women (median age, 60 years); 67% had Stage III-IV disease. The sites of progression were primary in 3, nodes/scar in 10, and both primary and nodes in 2. Relative to the initial plan, treatment intensification was achieved by an increased radiation dose in 7 (using accelerated fractionation in 5), an increased radiation dose and the addition of concomitant chemotherapy in 7, and the addition of concomitant chemotherapy alone in 1 patient. The median follow-up was 40 months. Eight patients had a complete response to intensified treatment. At the closeout date, 6 patients were alive with no evidence of disease. Eight patients had died with locoregional disease; two also had distant metastases. One patient was lost to follow-up after achieving a complete response. The median failure-free survival for all patients was 6 months, but for those with a complete response, it was 37 months. The median overall survival time was 28 months. The 2-year and 3-year overall survival rate was 50% and 42%, respectively. Acute mucosal and skin toxicity was increased relative to standard postoperative radiotherapy but was not dissimilar to that expected after radical definitive chemoradiotherapy. Intensification of treatment in patients who develop progressive locoregional disease is warranted, because it can lead to long-term disease control in a subset of patients with significant but acceptable toxicity.

Long-term follow-up of a randomized trial of fludarabine–mitoxantrone, compared with cyclophosphamide, doxorubicin, vindesine, prednisone (CHVP), as first-line treatment of elderly patients with advanced, low-grade non-Hodgkin's lymphoma before the era of monoclonal antibodies

This randomized study compared the efficacy and safety of fludarabine-mitoxantrone (FM) with mini-CHVP (cyclophosphamide, doxorubicin, vindesine, prednisone) in elderly patients with advanced, low-grade non-Hodgkin's lymphoma. End points were remission rates [overall response (OR) and complete response (CR)], failure-free survival (FFS), survival and toxicity. One hundred and fifty-five patients were randomized, 144 were evaluable for safety and 142 for response. Each treatment arm was given as six monthly cycles, followed by three bimonthly cycles. FM comprised fludarabine (20 mg/m(2) i.v.), days 1-5, plus mitoxantrone (10 mg/m(2) i.v.), day 1. CHVP cycles comprised cyclophosphamide (750 mg/m(2) i.v. infusion), doxorubicin (25 mg/m(2) i.v.) and vindesine (3 mg/m(2) i.v.) on day 1, and prednisone (50 mg/m(2)) on days 1-5. FM therapy resulted in superior remission rates (OR 81% versus 64%, CR 49% versus 17%; P = 0.0004). Median FFS for FM patients was 36 months, compared with 19 months for CHVP patients, and has not yet been reached for early CR patients at 53 months. Treatment arm was the major risk factor influencing survival. Both treatments were well tolerated, with only few infectious complications. FM was more effective than CHVP in achieving OR and CR, and favorably affected the outcome.