Oral melphalan pharmacokinetics--relation to dose in patients with multiple myeloma

The pharmacokinetics of melphalan have been studied after oral doses of 5, 10 and 20 mg, and 10 mg i.v. Seven patients with multiple myeloma received the drug on 4 consecutive days and the concentration of melphalan was determined by liquid chromatography. Melphalan was rapidly absorbed after p.o. administration. Absorption lag-time was less than 1 h. The median time for attaining the peak concentration was 1.12 h (97% confidence interval: 0.68-1.55), 1.21 h (0.85-1.43) and 1.08 h (0.84-1.29) after doses of 5, 10 and 20 mg. The bioavailability showed large interindividual variations, and was not significantly affected by the dose given. There was a significant decrease in bioavailability during the treatment course (P less than 0.05). Absorption of melphalan obeys first-order kinetics in the dose interval studied. The results indicate that it might be of benefit to administrate oral melphalan for fewer days than the usually used 4 day regimen, in an attempt to achieve a higher bioavailability.     

Radiation therapy is well tolerated and produces excellent control rates in elderly patients with locally advanced head and neck cancers

PurposeManagement of locally advanced head and neck cancer (LAHNC) in the elderly is challenging due to multiple co-morbidities, poor organ function and performance status. The aim of this study was to evaluate efficacy of radiation therapy (RT) in elderly patients, defined as 65 years and older, with high-risk LAHNC.Materials and methodsAn IRB approved retrospective chart review of elderly patients was performed, of whom 73 patients were selected for analysis. The stages included were II–IV. Sites included were oropharynx, oral cavity, larynx, salivary gland, nasopharynx, nasal cavity, paranasal sinus, hypopharynx and unknown primary.ResultsMedian age was 74 years. Thirty-nine (53%) patients received concurrent chemotherapy. Median time to completion of RT was 53 days. Median external beam radiotherapy (EBRT) dose was 66 Gy. With a median follow-up of 24 months, overall local control (LC) was 80% and distant metastasis (DM) was 12%. Sixty patients (82%) were alive at the time of study. Two-year overall survival (OS) was 96% (95% CI = 87%, 99%). Chemotherapy did not improve LC [80% (chemo) vs. 79% (no chemo), p = 0.88] or DM [11% (chemo) vs. 14% (no chemo), p = 0.73]. Interestingly, patients receiving RT using intensity-modulated radiation therapy (IMRT) had a significantly higher rate of LC vs. three-dimensional conformal radiotherapy (3DCRT) (94% vs. 68%, respectively, p = 0.008). Grade 2/3 toxicity was seen in 70/73 (96%) patients while grade 4 toxicity was seen in three patients (4%).ConclusionElderly patients with LAHNC have high rates of LC and OS. Prospective studies can reveal more insight into this increasingly important clinical problem in elderly patients.     

Postremission therapy with low-dose interleukin 2 with or without intermediate pulse dose interleukin 2 therapy is well tolerated in elderly patients with acute myeloid leukemia: Cancer and Leukemia Group B study 9420.

PURPOSE: The purpose of the study is to investigate the tolerability of interleukin 2 (IL-2) after intensive chemotherapy in elderly acute myeloid leukemia (AML) patients in first complete remission (CR). EXPERIMENTAL DESIGN: AML patients > or =60 years in CR after induction and consolidation chemotherapy on Cancer and Leukemia Group B study 9420 were eligible if they had neutrophils > or =1 x 10(9)/liters and platelets > or =75 x 10(9)/liters. Patients received low-dose IL-2 (1 x 10(6) IU/m(2)/day s.c. for 90 days) or low-dose IL-2 with intermediate pulse doses (6-12 x 10(6) IU/m(2)/day s.c. for 3 days) every 14 days (maximum five pulses). In a subset of patients, we investigated the expression of NKG2D ligands by leukemic cells because they are likely important mediators of natural killer cytotoxicity. RESULTS: Of 35 CR patients receiving IL-2, 34 were evaluable for toxicity. Median age was 67 (range, 60-76) years. Thirteen of 16 patients receiving low-dose IL-2 completed the planned therapy, and 11 of 18 who also received intermediate pulse dose IL-2 therapy completed all five pulses. The spectrum of toxicity in both groups was similar, with predominantly grade 1-2 fatigue, fever, injection site reactions, nausea, anemia, and thrombocytopenia. Grade 3-4 hematological and nonhematological toxicity were more frequent in patients also receiving intermediate pulse dose IL-2 therapy. Grade 3-4 fatigue and hematological toxicity, although uncommon, were the major causes for discontinuing or attenuating therapy. In 8 cases, mRNA for one or more NKG2D ligands was detected in leukemic cells obtained at diagnosis before treatment. CONCLUSIONS: Low-dose IL-2, with or without intermediate pulse dose therapy, given immediately after chemotherapy in first CR to elderly AML patients is well tolerated. Expression of NKG2D ligands by leukemic cells was detected in the majority of cases tested and should be assessed for correlation with response to IL-2 in future studies.     

Pegylated liposomal doxorubicin, melphalan and prednisone therapy for elderly patients with multiple myeloma

Melphalan & Prednisone (MP) is considered as the standard therapy for Multiple Myeloma (MM) patients not eligible for high-dose therapy. Here, we report the results of a phase I-II study to evaluate the feasibility and efficacy of the association of PLD to the conventional MP regimen during the first six cycles of the front-line therapy for untreated MM patients older than 70. Thirty patients were included in the study with a median age of 77 years (71-84) and a M/F ratio of 17/13. The phase I of the study demonstrated that the maximum tolerable dose of PLD in this setting was 30 mg/m(2), so it was the final dose evaluated in the study. Twenty-nine patients were valuable for response, which was: complete in 4 (14%) partial in 15 (52%) minor/no changes in 7 (24%) and progressive in 3 (10%). The median progression free survival (PFS) was 24 months. The median overall survival (OS) has not been reached yet, with a 3-year probability for OS and PFS of 52 and 37%, respectively. Haematological toxicity was frequent but usually weak/moderate (grades 1 & 2 of the WHO scale) and it was resolved only with dose delays. Infection was a relatively frequent event (30% of patients), but only in 4 cases it was of grade 3. No cases of palmar-plantar erythrodysesthesia were observed. In conclusion, pegylated liposomal doxorubicin can be safely added to the other chemotherapeutic drugs in the treatment of elderly MM patients, which can be very useful for patients in whom novel agents are not tolerated or inefficient.     

Bortezomib,melphalan, and prednisone in elderly patients with relapsed/refractory multiple myeloma

BACKGROUND:

In elderly patients with newly diagnosed multiple myeloma (MM), the addition of bortezomib to standard, combined oral melphalan and prednisone (MP) significantly increases the response rate and event‐free survival compared with MP alone.

METHODS:

In this phase 1/2 trial, the authors assessed the dosing, efficacy, and safety of a lower dose‐intensity MP schedule plus weekly bortezomib as salvage treatment for elderly patients with MM. To assess the maximum tolerated dose, 19 patients who had relapsed/refractory MM after 1 or 2 lines of treatment entered the first phase of the study. They received melphalan at a dose of 24 mg for 28 days; bortezomib 1.3 mg/m² on days 1, 8, 15, and 22; and prednisone at a dose of 50 mg every other day of a 28‐day cycle for a total of 9 cycles. At the end of the first phase, based on the good efficacy and acceptable toxicity of this combination, an additional 23 patients were enrolled.

RESULTS:

After a median follow‐up of 21 months, of 42 patients who relapsed, 24 (57%) obtained at least a partial response, 4 had stable disease, and 11 had progressive disease. The median time to progression was 18 months, and the median overall survival was 30 months. Grade 3 and 4 toxicity was observed in 16 of 42 patients (38%) and was more frequent during the early cycles.

CONCLUSIONS:

A weekly infusion of bortezomib associated with lower dose‐intensity MP induced a high proportion of responses and was well tolerated in elderly patients with relapsed/refractory MM. Cancer 2013. © 2012 American Cancer Society.     

Axillary dissection can be avoided in selected patients with breast cancer

Acknowledgment  This study was supported by the Grant for Scientific Research Expenses for Health and Welfare Programs (Second Term Comphrehensive 10-Year Strategy for Cancer Control).     

Low dose thalidomide in patients with relapsed or refractory multiple myeloma

Remarkable results of the treatment of refractory multiple myeloma with thalidomide have been reported. In most preceding studies, the given thalidomide dose was escalated to a maximum tolerated dose of up to 800 mg/d. The frequency of adverse effects correlates with dose intensity. Since a significant gain of therapeutic effects could not be observed as thalidomide dosage was escalated, the optimal dose of thalidomide remains to be determined. We report the results of a study with low dose thalidomide (median administered dose 100 mg/d, range 50-400 mg/d). Twenty-four relapsed (n=19) or resistant (n=5) multiple myeloma patients were included in the study. Twelve patients (50%) received thalidomide as monotherapy, 8 patients (33%) received a combination of thalidomide and dexamethasone (every 4 weeks 40 mg/day for 4 days) and 4 patients (17%) who were resistant to vincristine, doxorubicin, dexamethasone (VAD) received VAD combined with thalidomide. Overall, a response was observed in 12 patients (50%). Of the 12 patients treated with low dose thalidomide alone 5 (42%) responded, of the 8 patients who received a combination of thalidomide and dexamethasone 5 (63%) responded and of the 4 patients who had thalidomide in addition to VAD 2 patients (50%) responded. In 3 patients, thalidomide treatment had to be discontinued because of side effects and 1 patient died before response could be assessed. We conclude that low dose thalidomide is an effective and safe rescue therapy in relapsing or refractory multiple myeloma. Response to thalidomide might be dependent on prognostic parameters and tumor burden. To answer these questions larger prospective studies are necessary.     

Prognostic features for response and survival in elderly patients with de novo acute myeloid leukemia treated with mitoxantrone and intermediate dose cytarabine

Forty-three fit elderly patients with de novo acute myeloid leukemia (AML) received chemotherapy with mitoxantrone and intermediate dose cytarabine (MIDAC) in a phase II clinical trial conducted by the Australasian Leukaemia and Lymphoma Group. The main aim of the study was to evaluate the tolerability and efficacy of MIDAC in inducing durable remissions. While the chemotherapy was generally well tolerated, less than half the patients achieved complete remission (CR) after induction and many of those in CR could not receive planned consolidation cycles. The median overall survival for all patients was 6.5 months and the median disease-free survival for those achieving CR was 8.3 months. Only 2 patients survived beyond 4 years. Factors significantly associated with shorter survival were adverse cytogenetics, marrow dysplasia and increasing age. These results suggest that only selected elderly patients with AML are likely to benefit from aggressive chemotherapy and that novel therapies are required to improve the poor prognosis of this group.     

Discordant response or progression in patients with myeloma treated with thalidomide-based regimens

Thalidomide-based regimens (TBR) are now widely used for the treatment of refractory multiple myeloma and have shown significant activity in newly diagnosed patients. In some patients with secretory disease, we observed discrepancies between the reduction of the monoclonal protein levels and the plasma cell infiltration in the bone marrow and/or extramedullary sites of relapse after treatment with TBR. The purpose of this study was to assess the incidence and analysis of this phenomenon in all myeloma patients treated with TBR in our Institution. PATIENTS AND METHODS: We studied all patients who received TBRs and had a follow up time of at least 6 months. Partial response (PR) was defined as at least 50% reduction of serum myeloma protein and soft tissue plasmacytomas and/or > 90% reduction of Bence Jones protein excretion and minor response as a > 25% reduction of the serum myeloma protein or > 50% reduction of the Bence Jones myeloma protein. RESULTS: Between July 1999 and July 2002 we treated 94 patients with advanced myeloma and 9 patients with newly diagnosed disease with TBR. Sixty-seven patients (66%) achieved either partial or minor response. In 4 patients (3 with advanced and 1 with newly diagnosed myeloma) the bone marrow was heavily infiltrated by plasma cells, despite a decrease of the paraprotein levels ranging from 38% to 68%. This discordance between monoclonal protein levels and bone marrow plasmacytosis was noted in 6% of patients rated as responders and in 11% of responding patients who actually had a repeat bone marrow assessment. Furthermore 6 responding patients, after achieving a PR which lasted between 5 and 9 months, relapsed with bone marrow (all cases), and extramedullary (2 cases) plasmacytosis, without increase of serum and/or urine monoclonal protein. This hyposecretory conversion was noted in 12.5% of relapsing patients. CONCLUSION: Our data indicate that after treatment with TBR some patients with myeloma show discordant responses of the monoclonal protein levels and the bone marrow or extramedullary plasmacytosis. If our data are confirmed, they may have practical implications for assessment of response and follow up of patients treated with TBR.     

Lack of correlation between objective response and death rate in multiple myeloma patients treated with oral melphalan and prednisone

An analysis of survival by response category was performed on 76 patients with stage II and III multiple myeloma, who were treated with oral melphalan and prednisone. The analysis demonstrated a survival advantage for responders over non-responders only in stage III patients (32.3 months for responders vs. 15.6 months for non-responders, p = 0.03). However, two possible sources of error must be considered: a) the poor prognosis of early responders that may adversely affect the survival of all responders, and b) the bias introduced by the 'guarantee time' of responders (i.e., the time on-study required to detect the response). Exclusion from the analysis of the unfavourable subgroup of 'early' responders (median survival 14.7 mos.) provided an improvement of the difference in survival between the remaining 'slow' responders and non-responders in stage III (p = 0.005) as well as in the series as a whole (p = 0.025). Because of the consistent 'guarantee time' of slow responders, the Mantel-Byar test (which credits survival to responders only after the response has been obtained) was then applied. The survival advantage of slow responders over non-responders, previously observed in all patients, particularly those with stage III, was not confirmed by the Mantel-Byar test (chi-square 0.831 and 1.457, respectively), thus supporting the hypothesis of an equal death rate over time in each response category. It therefore appears that the usual response criteria (which require at least a 50% reduction of the myeloma protein) should perhaps be reassessed, as they seem to be an inadequate parameter for evaluation of treatment effectiveness in multiple myeloma.     

No correlation between response and survival in patients with multiple myeloma treated with vincristine, melphalan, cyclophosphamide, and prednisone

A vincristine, melphalan, cyclophosphamide, and prednisone (VMCP) multi-drug regimen was used in 85 previously untreated patients with multiple myeloma (MM) (symptomatic Durie Stages II and III) until they became refractory. The prognostic significance of various pretreatment characteristics was evaluated in terms of therapeutic response (according to Southwest Oncology Group [SWOG] and Chronic Leukemia-Myeloma Task Force [TF] criteria) and survival. Therapeutic responses, obtained in 31.2% (SWOG) and 68.7% (TF) of patients, had a significant inverse correlation with myeloma cell mass, serum calcium, and bone status. Median survival time of Stage II and Stage III patients was 39 and 34 months, respectively. Serum B2 microglobulin greater than or equal to 6 micrograms/ml was the only variable correlating unfavorably with survival duration after multi-variate analysis (increased risk = 2.79), although therapeutic response as a time-dependent variable had no effect on survival. These data suggest no correlation between response and survival, partially because of inadequate response assessment criteria and partially because no existing treatment is curative (although current therapeutic approaches may prevent death from complications).     

Cost-effectiveness of a transplantation strategy compared to melphalan and prednisone in younger patients with multiple myeloma

High dose chemotherapy with autologous stem cell transplantation (ASCT) improves outcomes in patients 65 years of age or less with multiple myeloma. Survival and costs in a cohort of 16 patients who received melphalan and prednisone as part of a clinical trial were compared with those of 36 patients referred to our centre for consideration of ASCT. In the transplant group, survival and costs were extrapolated to match the period of observation in the melphalan and prednisone group. Patient-specific and average costs were calculated from the perspective of the Ontario Ministry of Health. Costs and survival were varied by 50% in the sensitivity analysis. Transplantation improved life expectancy by 19.3 months with a cost difference of $30,517 Canadian. The incremental cost-effectiveness of transplantation compared with melphalan and prednisone was $25,710 Canadian per life-year gained when additional pamidronate and follow-up costs were considered. Discounting costs and survival at 3 and 5% did not result in important differences. The sensitivity analysis resulted in best and worse case scenarios for transplantation compared with melphalan and prednisone of $13,049 and $63,954 per life-year gained respectively. In comparison with melphalan and prednisone, ASCT appears to be cost-effective in patients 65 years old or younger with myeloma.     

A combination of thalidomide and arsenic trioxide is effective and well tolerated in patients with myelodysplastic syndromes

Twenty-two patients with myelodysplastic syndromes (MDS) were treated with thalidomide plus arsenic trioxide (ATO). Twenty-two MDS patients receiving supportive care were used as controls. The remission was achieved in 4 patients (18.2%) receiving thalidomide/ATO, and none in the control group (p<0.05). Fifteen of 22 patients in the treatment group achieved hematologic improvement (68.2% vs. 27.3% in the control, p<0.05). The progression-free survival was longer in the treatment group than that in the control (26 vs. 10 months, p<0.05). The overall survival was also longer in the treatment group than that in the control (36 vs. 16 months, p<0.05). No severe adverse reactions were observed. These preliminary findings suggest that thalidomide/ATO combination treatment is effective and safe for MDS.     

High response rates in patients with pancreatic cancer using the novel oral fluoropyrimidine S-1

S-1 is a newly developed oral fluoropyrimidine derivative with demonstrated activity against several tumor types. The aim of this study was to evaluate the feasibility and efficacy of S-1 administered as a single-agent and in combination with cisplatin, for the treatment of patients with pancreatic cancer. A total of 33 patients with locally advanced or recurrent pancreatic cancer were entered into this study. Seventeen patients were treated with S-1 alone (group A), and 16 patients were treated with S-1 plus weekly cisplatin (group B). Objective tumor responses among the 15 evaluable patients in group A were 1 CR, 2 PR, 9 SD and 3 PD, and among the 14 evaluable patients in group B were 8 PR, 5 SD, and 1 PD. The overall response rates were 20.0% and 57.1% in groups A and B respectively. Seven of the 17 patients in group A with elevated CA19-9 serum concentration and 12 of the 13 patients in group B with elevated CA19-9 level, reduced their CA19-9 by more than 50%. The median follow-up periods/median durations of response were 152/102 days in group A and 105/66 days in group B. Median survivals have not been reached in either group. In group A, no patient developed severe toxicities over grade 3, but in group B, 3 patients developed hematotoxicity over grade 3, and 2 patients experienced grade 3 anorexia. S-1, especially in combination with CDDP, shows promising activity with acceptable toxicities against pancreatic cancer. Further evaluation of this combination in patients with this disease is warranted.     

High mobility group box 1 can be used to monitor perioperative course in patients with liver cancer

ObjectiveHigh mobility group box 1 (HMGB1) is produced by inflammation. Regarding liver injuries, HMGB1 is reportedly involved in liver regeneration. The present study investigated the use of HMGB1 as a postoperative marker of surgical course in patients with liver cancer.MethodsPatients were enrolled if they had liver cancer, had undergone liver surgery, and did not develop postsurgical complications. Patients who received emergency surgery or patients with unresectable cancerous lesions were excluded. Blood samples were preoperatively obtained as well as at 1 day, 1 week, and 4 weeks following surgery; white blood cell count, serum C-reactive protein, serum albumin, and serum HMGB1 levels were measured.ResultsA total of 36 patients were included in this study. HMGB1 levels significantly changed over time, increasing from a median of 7.1 ng/ml (preoperatively) to 13.9 ng/ml at 1 week postoperatively, and then decreased to 6.3 ng/ml at 4 weeks postoperatively. Peak HMGB1 levels were delayed, and elevated HMGB1 levels persisted as compared with the changes in conventional markers.ConclusionsHMGB1 indicates a unique perioperative inflammatory state in patients with liver cancer. Serum HMGB1 may serve as a marker for monitoring surgical course in patients undergoing surgery for liver cancer.