Duration Of Response In Patients Research Articles

Therapy of chronic lymphocytic leukemia with purine analogs and monoclonal antibodies

B-cell chronic lymphocytic leukemia (CLL) is a clonal hematopoietic disorder characterized by proliferation and accumulation of small lymphocytes. It is the most common form of leukemia in North America and Europe. The management of CLL is determined by the stage and activity of the disease. Several randomized studies indicate that cytotoxic therapy based on alkylating agents in the indolent phase of disease, does not prolong the survival time of CLL patients. Chlorambucil, with or without steroids, has been for many years the drug of choice in previously untreated patients with this leukemia. Alternative treatment approaches, including new purine nucleoside analogs (PNA), such as fludarabine and 2-chlorodeoxyadenosine (cladribine) have also shown activity in CLL. The randomized studies have indicated a higher overall response, complete remission rates and longer response duration in patients treated initially with PNA than with chlorambucil or cyclophosphamide based combination regimens. These agents alone or in combinations, seem to be the treatment of choice for patients failing standard therapies. The monoclonal antibodies directed against CD52 antigen (alemtuzumab, Campath-1H) and CD20 antigen (rituximab) demonstrate also significant activity in CLL patients. These agents have significant single-agent activity, distinct mechanism of action and generally, favorable toxicity profiles. Both antibodies achieved the most promising results in the treatment of patients with relapsed or refractory CLL. More recently the effect of alemtuzumab in previously untreated patients has been also investigated and results are very encouraging. A multicenter prospective randomized study comparing alemtuzumab and chlorambucil as first line therapies are ongoing and preliminary results show acceptable toxicity profile of monoclonal antibody.

Outpatient treatment with subcutaneous interleukin‐2, interferon alpha and fluorouracil in patients with metastatic renal cancer: an Australian experience

Metastatic renal cell cancer has a poor prognosis and survival. Conventional cytotoxic chemotherapy has no impact on survival and response rates are low. Biologic agents are the most active in treating this disease. We report the feasibility of administering a combination of interferon alpha, subcutaneous interleukin-2 and 5Fluorouracil in the outpatient setting to patients with metastatic renal cell cancer. Between September 1996 and August 2003, fourteen patients were treated with this combination: ten males and four females with a median age of 50 (42-66). Thirteen patients had Eastern Cooperative Oncology Group performance scores of 0 or 1. Ten patients had had nephrectomies. Six patients had undergone prior treatments with chemotherapy or hormonal therapy. Twenty-two cycles were administered (median 1, range of 1-4). Three patients achieved partial response, eight patients had stable disease, and three had progressive disease. The duration of response in patients with stable disease was (3, 3+, 4, 4+, 5+, 6, 10, 11 months) and for the patients with a partial response was 2+, 11 and 12 months. Toxicities with this combination were predictable. There were no treatment-related deaths and no episodes of febrile neutropenia. One patient ceased treatment as a result of toxicity. Fatigue was the most common side-effect. Myalgias, fever and rigors occurred within 6-12 h of administration of interleukin-2, and resolved within 12 h. Grade 1-2 nausea and vomiting occurred in most patients. Four patients had transient asymptomatic transaminitis, which resolved spontaneously. As a result of toxicity, one patient had treatment ceased in his 6th week. This combination was feasible, well tolerated and manageable in an outpatient setting.

Rituximab (Rituxan) Combined with ESHAP Chemotherapy Is Highly Active in Relapsed/ Refractory Aggressive Non-Hodgkin's Lymphoma.

Patients with relapsed/refractory aggressive lymphoma have limited options for achieving long-term remission other than stem cell transplantation. ESHAP is active in aggressive NHL and has the added advantage of being a non-anthracycline regimen. However, the response rate and remission duration with ESHAP chemotherapy alone are low in this group of patients. Encouraged by the increased efficacy of chemo-immunotherapy combinations like CHOP + Rituximab (Rituxan) in untreated aggressive lymphoma, and the in vitro synergy of Rituximab with cisplatin, cyclophosphamide and steroids, we studied the safety and efficacy of ESHAP + Rituximab combination in this group of patients. Standard ESHAP regimen (Etoposide 40 mg/m2/d IV/2h day1–4; Methylprednisolone 500 mg/m2 IV days 1–4; Cytarabine 2 g/m2 IV/3h day 5 and Cisplatin 25 mg/m2/d CIV days 1–4) was administered. Rituximab 375 mg/m2 IV was administered in the following manner: 2 doses separated by one week prior to the first cycle of ESHAP and 2 doses administered similarly after completion of the sixth cycle of ESHAP; one dose of Rituximab each was also given 48 hours prior to the third and fifth cycle of ESHAP. Treatment cycles were repeated every 28 days x 6. GMCSF (Leukine) and Erythropoietin (Procrit) were used at the discretion of the investigator. 14 patients were enrolled in the study. Median age was 55.5 years (range 37–70); there were 12 males and 2 females. 11/14 (71%) of patients had advanced disease (stage III/IV). Extranodal disease sites included kidney, lungs and adrenals. Histology was Diffuse Large Cell: 13 (93%) and Mantle Cell Lymphoma: 1 (7%). All patients had prior therapy: 1st relapse 11, 2nd relapse 1 and 3rd relapse 2. Prior therapies included CHOP, modified CHOP, Fludarabine-based regimen, Rituxan and Bexxar. 7 patients (50%) achieved CR, 2 PR, 1 stable disease and 4 PD. Among the 6 patients who received all 6 cycles of therapy, 4/6 (67%) achieved CR and 2/6 (33%) PR, (ORR 100%). Duration of response in patients who received all 6 cycles: All Responders: 26.3 months (1–53.3) and Patients who achieved CR: 35 months (24.1–53.3). Significant toxicity included grade III/IV hematologic in 43% and grade III/IV infection/febrile neutropenia in 21%.Conclusion: ESHAP combined with Rituximab appears to be more active than ESHAP alone with no additional toxicity other than infusion-related adverse events in patients with relapsed/refractory aggressive lymphoma. Patients who achieved CR with this regimen appear to have longer remissions. Prospective, controlled trials are warranted.

Phase II Trial of erlotinib (OSI-774) in patients with hepatocellular or biliary cancer

4025 Background: The overexperession of the epidermal growth factor receptor (EGFR) and its ligand is frequently seen in hepatobiliary tumors and may be associated with worse prognosis. Erlotinib (Tarceva) is a receptor tyrosine kinase inhibitor with specificity to the EGFR. Methods: The primary objective of this study was to determine the proportion of patients with either biliary cancer (BILI) or hepatocellular cancer (HCC) who were progression-free at 6 months. A potential benefit was assumed if the proportion of patients who are progression-free at 24 weeks was at least 20%. Thirty-five evaluable patients were targated for each diagnostic category. Patients were not selected on the basis of EGFR expression but tumor samples were submitted for EGFR analysis from all patients. Tarceva was given continuously at a dose of 150 mg per day orally. Dose adjustments were performed for toxicity. Objective response assessment was undertaken every 8 weeks and treatment continued until disease progression and/or undue toxicity. Results: Thirty-nine and 35 patients with BILI and HCC were enrolled, respectively. Median age of patients was 67 and 70 for the BILI and HCC groups, respectively. Median number of cycles (=4 weeks of treatment) was two in both groups. Fewer patients had toxicity-related dose reductions in the BILI group. Greater grade 3/4 skin toxicity and diarrhea was encountered in the HCC group. Of the 36 evaluable patients with BILI, 7 (25%, 95% CI, 10, 38%), were progression-free at 6 months. Seven (35%, 95% CI 18, 52%) of the 20 evaluable patients with HCC were progression free at 6 months. Two and three patients had partial radiological response in the BILI and HCC groups, respectively. Median time to response was 58 days and 214 days for BILI and HCC groups, respectively. Duration of response for the BILI group was 3 and 12+ months. Response duration for patients with HCC was 3, 4+, 7+ months. All responding patients had skin rash. Conclusions: Preliminary results suggest a benefit for EGFR blockade with tarceva in patients with hepatobiliary cancers with acceptable toxicity. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Roche Pharmaceuticals Roche Phamaceuticals

Maintenance Therapy with a Monthly Injection of Alemtuzumab Prolongs Response Duration in Patients with Refractory B-cell Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (B-CLL/SLL)

Alemtuzumab, the monoclonal anti-CD52 antibody, has clinical activity in B-cell and T-cell malignancies at the dose of 30 mg three times weekly for 9 – 12 weeks. This standard regimen induced responses usually shorter than 6 months. To prolong time to progression, we initialized a phase II study with an identical initial scheme until partial response, followed by a maintenance therapy lasting at least 4 months. Eleven heavily pretreated patients (8 with B-chronic lymhocytic leukemia (B-CLL) and 3 with small lymphoctyic lymphoma (SLL)) have been treated with this maintenance regimen (MR patients) and were retrospectively compared to 5 patients (3 B-CLL and 2 SLL) treated with the standard regimen (SR patients). Patients characteristics before treatment were identical in both groups. Objective response was reached by 9 (82%) MR patients and 3 (60%) SR patients (p NS). After the treatment, 8 (73%) MR patients and all SR patients progressed with a median time at 12.2 months and 3 months respectively. Survival time from alemtuzumab was significatively different (P < 0.005). None of the patients died in the MR group with a median follow-up at 16 months. In the SR group, the median survival from alemtuzumab was 5.9 months. We did not observe any differences in terms of hematological toxicites and infections between the two groups. In conclusion, maintenance alemtuzumab therapy seems to increase the time to progression and the survival, without adding hematological toxicities and infectious complications. More patients are needed to confirm this observation.

Alkylating agents and nucleoside analogues in the treatment of B cell chronic lymphocytic leukemia.

Chronic lymphocytic leukemia (CLL) is the most common form of leukemia in the Western world. The natural clinical course is highly variable and chemotherapy is usually not indicated in early and stable disease. Treatment is needed in the progressive form of this leukemia. Chlorambucil, with or without steroids, has been for many years the drug of choice in the treatment of CLL. More recently, treatment approaches have included nucleoside analogues, (NA) fludarabine (FAMP) and cladribine (2-CdA, 2-chlorodeoxyadenosine), which seem to be the treatment of choice for patients failing standard therapies. Their role as first line therapy is being investigated in randomized trials and the results have recently been published. These studies have shown a higher overall response and complete remission (CR) rate and longer response duration in patients treated initially with NA than with chlorambucil or cyclophosphamide-based combination regimens. In contrast, overall survival is similar in patients treated with NA and alkylating agents. However, the randomized trials were designed as crossover studies which may influence survival. Combined use of NA with other cytotoxic drugs, cytokines, monoclonal antibodies and other agents may increase the CR and prolong survival time. However, the results of randomized trials comparing combination treatment with NA alone are not yet available. In conclusion, alkylating agents still have an important place in the routine management of the majority of CLL patients. NA should be routinely used as second line treatment and possibly as first line therapy in younger patients, who are candidates for potentially curative treatment such as stem cell transplantation and/or monoclonal antibodies.

The Role of Nucleoside Analogues in the Treatment of Chronic Lymphocytic Leukemia-Lessons Learned from Prospective Randomized Trials

The newer purine nucleoside analogues (PNA), fludarabine (FAMP) and cladribine (2-chlorodeoxyadenosine, 2-CdA) have been synthesized recently and introduced into the treatment of chronic lymphocytic leukemia (CLL). The results of large phase II studies indicate that FAMP and 2-CdA are similarly active in CLL. Unfortunately, no prospective randomized study comparing the results of the treatment of CLL patients with FAMP and 2-CdA has been published so far. Significantly higher overall response (OR) and complete remission (CR) in patients treated initially with PNA than with chlorambucil or cyclophosphamide based combination regimens has been recently confirmed in five prospective multicentre randomized trials. These studies have also shown longer response duration in patients treated with PNA than with conventional chemotherapy. Overall survival progression free and events free survival were similar in patients treated with PNA and with chlorambucil or other alkylating agent based regimens. However, the majority of randomized trials were designed as cross over studies and most patients, treated with conventional chemotherapy were given PNA when refractory or in early relapse, which may influence the survival time. The results of a randomized study have shown a higher incidence of neutropenia and infections in patients treated with PNA than with chlorambucil. However, the frequency of autoimmune hemolytic anemia, pure red cell aplasia, secondary neoplasms and Richter's syndrome seems to be similar in patients treated with PNA and standard alkylating agents based chemotherapy. In conclusion, alkylating agents still have an important place in the routine management of the majority of CLL patients. They are in general safe, given on an out patients basis and significantly cheaper than PNA. PNA should be routinely used as second line treatment, and possibly as first line therapy in younger patients, who are candidates for potentially curative treatment such as stem cell transplantation and/or monoclonal antibodies.

Liposomal Daunorubicin (Daunoxome) in Combination with Cyclophosphamide, Vincristine and Prednisolone (COP-X) as Salvage Therapy in Poor-Prognosis Non-Hodgkins Lymphoma

We treated 33 patients with a variant of the standard 3 weekly CHOP regime, replacing doxorubicin with liposomal daunorubicin (DaunoXome, NeXstar Pharmaceuticals) 120 mg/m2 (COP-X). Eighteen subjects had relapsed / refractory aggressive NHL and 15 had indolent NHL/CLL. Median number of courses received was 4 (1–8). Thirty-two patients were evaluable for efficacy and 26 (81%) responded. 88% of patients with aggressive NHL responded; three (18%) patients achieved complete remission (CR), 12 (70%) achieved partial remission (PR), 1 (6%) patient had stable disease (SD) and 1 (6%) patient progressed through treatment. Median duration of response for patients with aggressive NHL was 3 months. The response rate in indolent NHL/CLL was 73%. Four (27%) patients achieved CR, 7 (46%) PR and 4 (27%) SD. At two years post treatment, 55% of the patients with indolent NHL/CLL remain progression-free, although 4 patients have proceeded to consolidation therapy. Twenty-seven out of 28 (96%) patients developed neutropenia of short duration following one or more of their treatments. Twenty-three patients developed an infection at some stage during therapy (all associated with neutropenia) and required hospitalisation. There were two toxic deaths (infection) both of which occurred in patients who were neutropenic before starting COP-X. Platelet toxicity was mild in patients with normal platelet counts at the commencement of therapy. Alopecia and mucositis were mild. No clinical evidence of myocardial failure was observed. We conclude that the substitution of DaunoXome for doxorubicin in the CHOP regimen to form COP-X provides excellent efficacy against non-Hodgkin's lymphoma. Response durations were short but comparable to those reported with other regimes. COP-X was well tolerated with some suggestion of reduced non-haematological toxicity. The regimen should be considered as an alternative to CHOP with potentially less non-haematological toxicity, particularly cardiac; further studies are required to evaluate the regimen in this context.

Chemotherapy with cisplatin, epirubicin and docetaxel in transitional cell urothelial cancer. Phase II trial

Cisplatin (CDDP), epirubicin (EPI) and docetaxel have single agent activity against urothelial transitional cell carcinoma (TCC). We evaluated the efficacy and toxicity of this combination in locally advanced or metastatic urothelial TCC. Patients with urothelial TCC who had no prior chemotherapy (prior adjuvant chemotherapy >6 months allowed) were eligible for entry the study. Eligibility criteria were performance status 0–3, granulocyte count (AGC) ⩾1.5 (10 9/l), platelet count ⩾100 (10 9/l), clearance creatine ⩾60 ml/min and total bilirubin level ⩽1.5 mg/dl. Treatment consisted of EPI 40 mg/m 2 intravenous push, docetaxel 75 mg/m 2 in 1 h infusion with premedication and CDDP 75 mg/m 2 with pre- and posthydration. Treatment was repeated every 21 days. Anti-emetics with dexamethasone and 5-HT 3 antagonists were used routinely. Prophylactic haematopoietic growth factors were not used. Patients were evaluated for toxicity weekly and assessed for response every two cycles of treatment. 32 patients were entered into the study and 30 patients (7 with locally advanced and 23 with metastatic disease) were assessable for response. There were 9 (30.0%) complete responses (2, 28.6% in locally advanced and 7, 30.4% in metastatic disease) and 11 (36.7%) partial responses (3, 42.9% in locally advanced and 8, 34.8% in metastatic disease) with an overall response rate (RR) of 66.7% (71.5% in locally advanced, 65.2% in metastatic disease). Overall median survival was 14.5 months (15 months for locally advanced, 12.5 months for metastatic disease). The median duration of response in patients with metastatic disease was 8.5 months. 16 (53.3%) patients required one dose reduction and 5 (16.7%) patients required two dose reductions for a nadir AGC ⩽500/mm 3. Four episodes of febrile neutropenia and sepsis occurred. No patient had a dose reduction or treatment delay for any other grade 3/4 toxicity. There were no treatment delays due to myelotoxicity. Alopecia was universal. Non-haematological toxicity including mucositis, fluid retention, allergy, cutaneous toxicity, diarrhoea and neurotoxicity were mild and infrequent. The combination of EPI, docetaxel and CDDP is an active regimen for urothelial TCC. The response rate and toxicity were comparable with the M-VAC (methotrexate, vinblastine, doxorubicin, cisplastin) regimen. Phase III trials comparing this regimen with M-VAC are warranted.

Effectiveness of hypofractionated radiotherapy in painful bone metastases. Two prospective studies with 1 x 4 Gy and 4 x 4 Gy.

Although effectiveness of fractionated radiotherapy for painful bone metastases is well documented, there are unanswered questions regarding the adequacy of low-dose short radiation schedules for long-term pain control which give maximum benefit in patients with a short life expectancy. Two consecutive non-randomized prospective follow-up studies were performed at a single institution to analyze pain response and duration of response in patients with a variety of primary tumors. Included were only patients with symptomatic nonvertebral bone metastases and without impending pathologic fracture. Forty-five patients received 1 x 4 Gy to 50 different sites (group I) while 86 patients received 4 x 4 Gy to 96 sites (group II). Pain relief to irradiation was evaluated according to patient interviews using a 4-point categorical scale. Follow-up was performed 7 and 90 days after radiotherapy. Pain relief after 4 x 4 Gy was significantly superior to 1 x 4 Gy with pain control rates being 86.5% vs 48% at day 7 (after end of treatment) and 80% vs 55% at day 90, respectively. A subgroup analysis of patients treated with 4 x 4 Gy demonstrated a more favorable outcome for breast cancer patients in comparison to patients with other primaries concerning pain relief (96% vs 81%), pain control after 90 days (93% vs 72%), median time to pain progression (9 vs 3 months), and median overall survival (14 vs 5.5 months). In this study 4 x 4 Gy proved to be clearly superior to 1 x 4 Gy in relieving pain from symptomatic nonvertebral bone metastases without impending pathologic fracture. Even if radiotherapy with 1 single fraction seems to be applicable in specific cases doses higher than 4 Gy should be chosen. In breast cancer patients pain control seems to be better compared to other primaries.

Randomized trial of interferon maintenance in multiple myeloma: a study of the National Cancer Institute of Canada Clinical Trials Group.

To determine whether interferon maintenance therapy improves overall survival and response duration in patients with multiple myeloma who have responded to induction therapy with melphalan and prednisone. In a multicenter trial, patients with symptomatic clinical stage I and stage II and III multiple myeloma were registered at diagnosis and those who responded to melphalan-prednisone (MP) were randomized either to receive interferon (2 mU/m2) subcutaneously three times per week or no maintenance. MP was discontinued in both groups once a stable response plateau of the monoclonal protein was reached. Interferon was continued until relapse, and then was restarted on subsequent response to MP. Interferon toxicity was recorded using a self-report diary. Survival and response duration were calculated using life-table methods, and were adjusted in the analysis for imbalances in baseline prognostic factors. Four hundred two patients were registered and 176 responders were randomized (85 to interferon and 91 to control). At a median follow-up time of 43 months, the median survival duration was 43 months for interferon and 35 months for control (P = .16), but when adjusted for chance imbalances in baseline prognostic factors (mainly performance status), the median survival duration was 44 months and 33 months for interferon and control, respectively (P = .049). Progression-free survival from randomization to first relapse also favored interferon (unadjusted P < .002; adjusted P < .003). Interferon toxicity caused 58% of patients to reduce their dose, of which 84% were able to return to the initial dose; 14% had to discontinue interferon treatment. Interferon maintenance therapy improves progression-free and overall survival of patients with multiple myeloma who respond to melphalan and prednisone. Toxicity is substantial and must be weighed by patients against the potential benefits in response duration and survival.

FEC (FLUOROURACIL, EPIRUBICIN, CYCLOPHOSPHAMIDE) PLUS GRANULOCYTE MACROPHAGE-COLONY-STIMULATING FACTOR (GM-CSF) IN ADVANCED OR INFLAMMATORY BREAST-CANCER - A DOSE-FINDING STUDY

Seven patients with inflammatory and 11 with metastatic breast cancer were treated with high dose FEC chemotherapy plus GM-CSF; 5-fluorouracil and cyclophosphamide were administered at 500 mg/m2/iv/day 1, epirubicin at three dose levels: 100 mg, 120 mg and 140 mg/m2/iv/day 1 every three weeks (six patients per level). GM-CSF was administered at a dosage of 5 mg/kg/sc from day 5 to 12 of each cycle. The overall response rate was 83% (95% CI: 66%-100%) with 22% complete response. The median response duration for patients with metastatic disease was 7 months (range: 4-10). The hematological toxicity was moderate but reversible due to GM-CSF rescue; mucositis represented the dose limiting toxicity. In conclusion, the increase of dose intensity resulted in a higher response rate but not longer response duration, which must be taken into account when administering high-dose chemotherapy with growth factor rescue.

Response after withdrawal of tamoxifen and progestogens in advanced breast cancer.

Tumor response after withdrawal of endocrine therapy for advanced breast cancer with estrogens and androgens is well described. There have been few reports of withdrawal responses (WRs) after cessation of treatment with the newer antiestrogens and progestogens. We assessed WR in women after cessation of adjuvant therapy at first relapse, and after progression on first, second or third line endocrine therapy for advanced disease. One of seven patients (14%) responded after cessation of tamoxifen adjuvant therapy at relapse. Sixty-five of 72 patients were evaluable for WR after cessation of tamoxifen as first line therapy for advanced disease. There were five partial responses (8%) and 14 (22%) 'no change' with a median duration of WR of 10 months (range 3-40 months). WR were seen mainly in soft tissue disease but there were two responses in lung and two in bone. Four of 21 (19%) patients had a WR after cessation of norethisterone acetate (3) and tamoxifen (1), all used as second line therapy. WR are therefore demonstrable after cessation of tamoxifen and norethisterone acetate with durations of response similar to those found with additive therapy. Assessment of WR may represent a way of prolonging the overall response duration in patients with relatively indolent metastatic breast cancer, particularly in soft tissues.

Predictive value of tumor estrogen and progesterone receptor levels in postmenopausal women with advanced breast cancer treated with toremifene

The predictive value of estrogen receptor (ER) concentrations was evaluated in a group of 113 postmenopausal patients with estrogen-receptor-positive (ER greater than 7 fmol/mg protein) advanced breast cancer. In 103 patients, tumors were also sampled for progesterone receptor (PgR) determination. All patients were treated with toremifene, a novel antiestrogen, 60 mg daily. The median ER in 51 responders was 78 fmol/mg protein, and in 62 nonresponders, 51 fmol/mg protein; the median PgR levels were 40 and 37 fmol/mg protein, respectively. The response rate in patients with ER less than 50 fmol/mg protein was 38%, and 51% in the group with ER greater than 50 fmol/mg protein (not significant [NS]). The response rate in patients with PgR less than 10 fmol/mg protein was 42%, and in patients with greater than 10 fmol/mg protein, 44%. The duration of response in patients with ER greater than 50 fmol/mg protein was significantly longer than with lower ER levels (P = 0.002). PgR was not associated with the duration of response. In Cox's multiple regression analysis, ER was an independent prognostic factor (P = 0.005) for response duration. Thus, the ER concentration of tumor tissue predicts the duration of response but not the response rate to toremifene in patients with advanced breast cancer. The PgR status does not predict the response rate or the duration of response.

A phase II trial of iproplatin (CHIP) in previously treated advanced breast cancer.

Iproplatin (CHIP) was administered to 35 previously treated women with metastatic adenocarcinoma of the breast. The drug was given at a dose of 45 mg/m2 intravenously for 5 consecutive days and was repeated every 28 days. In this trial, there was one partial response and two patients with stable disease out of 29 evaluable patients. The median duration of response in patients with either a partial response or stable disease was 4.8 months. Myelosuppression was the major toxicity, 11 patients had severe thrombocytopenia and 3 severe neutropenia. Mild renal insufficiency, anemia, and nausea and vomiting were also noted. Iproplatin has limited activity in heavily pretreated women with advanced breast carcinoma; further studies in patients less heavily treated may show an improved response rate.

High-dose cyclophosphamide in the treatment of refractory lymphomas and solid tumor malignancies.

Twenty-two patients with refractory solid tumors or lymphoma were treated with a single course of high-dose cyclophosphamide (120 mg/kg intravenously [IV] over 2 days) whereas three patients received two courses each. Marrow infusion was not used. In the 22 courses evaluable for tumor response there were 14 responses (64%) of which 11 were partial responses (PR) (50%) and three complete responses (CR) (14%). In the 12 evaluable courses given in patients with lymphoid malignancies a partial response was obtained in seven (58%) and complete response in two (17%) for an overall response rate of 75%. The median duration of response was short: 2 months (range, 1-12 months). Twenty-seven courses were evaluable for toxicity. All patients had nadir polymorphonuclear leukocytes counts less than 500/mm3 with median time to recovery to a level greater than 500/mm3 of 9 days (range, 6-21 days). The median nadir platelet count was 30,000/mm3. One patient had prolonged thrombocytopenia of 225 days. There were two toxic deaths related to leukopenia, one secondary to Pneumocystis carinii pneumonia, and the second from probable sepsis and cholecystitis. Nineteen patients had previously received cyclophosphamide in standard doses. In the patients with lymphoid malignancies who had previously received cyclophosphamide, 22% achieved a CR with an overall response rate of 78%. High-dose cyclophosphamide may be given with acceptable toxicity in heavily pretreated patients. Given the short response duration in patients with progressive disease, the optimal results of such high-dose cyclophosphamide may be achieved when it is employed earlier in the natural history of the disease in conjunction with other alkylators, or as consolidation therapy.

Cisplatin, doxorubicin, and 5-fluorouracil chemotherapy for salivary gland malignancies: a pilot study of the Northern California Oncology Group.

Seventeen patients with advanced or recurrent salivary gland cancer were treated with cisplatin, doxorubicin, and 5-fluorouracil combination chemotherapy (PAF). Two patients achieved a complete response and four patients achieved a partial response, for an overall response rate of 35%. Six of the nine patients who received PAF in the neoadjuvant setting did not respond and proceeded to surgery and/or radiation therapy. No difference in response rate was found between those patients treated for recurrent disease v those treated with neoadjuvant chemotherapy. All three patients with adenocarcinoma responded. The response duration in patients with metastatic or recurrent disease ranged from 6 to 15 months. The PAF regimen was delivered primarily in the outpatient setting and was associated with acceptable toxicity. PAF demonstrates activity in salivary gland malignancies, and further evaluation of this combination seems warranted.

VP-16 and cisplatin as first-line therapy for small-cell lung cancer.

Thirty-one patients with small-cell lung cancer (SCLC) were treated with VP-16 and cisplatin as first-line therapy. In the majority of cases an Adriamycin (Adria Laboratories, Columbus, Ohio) containing regimen was contraindicated because of severe cardiac or hepatic disease. Eight patients who presented with cerebral metastases were also included in the series. Eleven patients had limited disease (LD), and 20 had extensive disease (ED). Of the 28 evaluable patients, 12 (43%) achieved a complete response (CR) and 12 (43%) had a partial response (PR). Four patients (14%) either had no response or progressed on treatment. The median duration of response for patients with LD was 39 weeks and for those with ED, 26 weeks. The median survival time (MST) for the whole group of responding (CR and PR) LD patients was 70 weeks (range, 28 to 181 + weeks), and for responding ED patients, it was 43 weeks (range, 17 to 68 weeks). Gastrointestinal toxicity was mild, but leukopenia and thrombocytopenia were common. There were four febrile episodes during periods of drug-induced neutropenia and this led to one treatment-related death. Nephrotoxicity occurred in 15 patients and required discontinuation of cisplatin in two. These results compare favorably with reports of standard induction chemotherapy regimens and provide further evidence of the activity of the VP-16 and cisplatin regimen in patients with SCLC.

Doxorubicin, mitomycin-C, and 5-fluorouracil (DMF) in the treatment of metastatic hormonal refractory adenocarcinoma of the prostate, with a note on the staging of metastatic prostate cancer.

Sixty-two patients with metastatic hormonal refractory adenocarcinoma of the prostate received a combination of doxorubicin, mitomycin-C, and 5-fluorouracil (DMF). Thirty (48%) of the patients achieved an objective response. Response criteria excluded disease "stabilization" as a manifestation of response. Four clinical prognostic categories were identified: osseous I (OI) had metastatic axial skeletal involvement (23 patients); osseous II (OII) had axial and extremity skeletaL involvement (18 patients); visceral I (VI) had pulmonary metastasis (9 patients); and visceral II (VII) had pulmonary metastasis and involvement of other viscera (12 patients). The 20 responding patients survived a median of 47.5 weeks, whereas the 32 nonresponding patients survived a median of 23.8 weeks (n = 0.002). Response rates were highest among patients with OI (52%) and VI (88%) disease; response rates were lower amont patients with OII (33%) and VII (33%) disease. Responding patients in each clinical category survived longer than nonresponding patients except for those patients with VII disease. The median duration of response for patients with OI disease was 11 months, for OII 9.5 months, for VI patients it was 6.5 months, and VII patients it was 5 months. DMF is an effective treatment of metastatic hormonal refractory prostate cancer, resulting in consistent objective responses. The staging system employed identifies four clinical categories of metastatic prostate cancer and allows for accurate comparison of diet and stratification of study populations.

A pilot study of mitomycin-C and tamoxifen (MT) versus dibromodulcitol, adriamycin, and tamoxifen (DAT)

The aim of this study was to compare the treatment efficacy of mitomycin-C plus tamoxifen (MT) to adriamycin, dibromodulcitol and tamoxifen (DAT) in previously treated patients with metastatic breast cancer. Thirty-two patients with measurable or evaluable disease were entered on the study. Twenty-three were prospectively randomized to receive DAT (Group 1) or MT (Group 2). Nine patients with prior exposure to adriamycin were directly assigned to receive MT (Group 3). Thirty-one patients were evaluable for response and toxicity. The hematological toxicities were comparable among the three treatment groups. DAT gave more nausea and vomiting than MT. One patient developed irreversible fatal congestive heart failure while receiving DAT. The response for Group 1 was 5/11, Group 2, 3/12, and Group 3, 3/8. The duration of response for patients in Group 1 was 455+, 315, 251, 239, 231 days, in Group 2 it was 328+, 144+, 119, and in Group 3 it was 35+, 84, and 112 days. The median time to treatment failure did not differ significantly between Group 1 (114 days), 2 (83 days) and 3 (61 days) (p = 0.24). The median survival time was similar among the three groups (p = 0.41). This pilot study suggests that MT and DAT are both effective treatment programs in patients with metastatic breast cancer who have failed prior chemotherapy regimens.