Low-dose Combination Chemotherapy Research Articles

Clinical observation of low-dose combination chemotherapy in refractory/recurrent paroxysmal nocturnal hemoglobinuria patients: A single-center retrospective analysis.

BackgroundWe performed a retrospective analysis to investigate the clinical characteristics and therapeutic strategies of 20 refractory/recurrent PNH patients, including the clinical efficacy of chemotherapy treatment, safety, and survival.MethodsThe clinical data of 20 classic PNH patients who were refractory/recurrent or had glucocorticoid dependence in our hospital were analyzed, including clinical manifestations, laboratory examinations, treatment efficacy, and survival.ResultsSeventeen patients had a marked improvement in anemia after chemotherapy, 14 patients acquired blood transfusion independence, and the Hb of 3 patients increased to normal levels. Although 6 patients still needed blood transfusion, the transfusion interval was significantly prolonged. The percentages of LDH, TBIL, and RET, which are indicators of hemolysis, were significantly lower than those before chemotherapy. The dosage of adrenal glucocorticoids was reduced by more than half compared with that before chemotherapy.ConclusionsChemotherapy can reduce PNH clones, promote normal hematopoiesis, and control hemolytic attack. It is a promising and widely used therapeutic method.

A novel chemotherapeutic protocol for peritoneal metastasis and inhibition of relapse in drug resistant ovarian cancer.

The majority of ovarian cancer patients are diagnosed in late stages of the disease, in which the tumor cells have leaked into the peritoneum and are present as tumorspheres. These tumorspheres are rich in cancer stem‐like cells (CSCs), which are resistant to therapy and are a major source of relapse. The purpose of this research was to identify a safe therapeutic approach that could eradicate the peritoneal CSC‐rich tumorspheres and inhibit relapse. Highly metastatic ascitic cells (OVASC‐1) that are resistant to standard‐of‐care chemotherapy due to upregulation of MDR1 gene were obtained from a patient with ovarian carcinoma and recurrent disease. CSC‐rich tumorspheres were generated, characterized, and treated with different chemotherapeutics. The most effective drug combination that could eradicate tumorspheres at nanomolar levels despite upregulation of MDR1 gene was identified. Luciferase‐expressing OVASC‐1 cells were implanted in the peritoneum of nude mice and treated with the identified drug combination. The progression of disease, response to therapy and recurrence were studied by quantitative imaging. Toxicity to abdominal tissues was studied by histopathology. Mice implanted with intraperitoneal (IP) OVASC‐1 xenografts showed limited response to combination therapy with cisplatin/paclitaxel at the maximum tolerated dose. Despite overexpression of MDR1 on OVASC‐1 cells, mice treated with our combination IP low‐dose MMAE and SN‐38 chemotherapy showed complete response without relapse. No signs of toxicity to abdominal tissues were observed. While MMAE and SN‐38 are not administered as free drugs due to their high potency and potential for systemic toxicity, our low‐dose localized therapy approach effectively restricted the cytotoxic effects to the tumor cells in the peritoneum. Consequently, maximum efficacy with minimal adverse effects was achieved. These remarkable results with IP low‐dose combination chemotherapy encourage investigation into its potential clinical application as either first‐line therapy or in cases of acquired resistance to cisplatin and paclitaxel.

Abstract CT061: Novel safety of high dose ascorbic acid and induction chemotherapy for high risk pancreatic cancer

Abstract Background: High dose ascorbic acid has been reported to have in vitro anticancer activity. Low dose combination chemotherapy with GFLIP (gemcitabine, 5fu, leucovorin, irinotecan, oxaliplatin) is an effective regimen for patients with pancreatic cancer. Combining high dose ascorbic acid with GFLIP may be a synergistic and well tolerated treatment regimen. Methods: High dose ascorbic acid with a range of 75-100 grams IV given on an average 1-2 times per week was combined with GFLIP given on a 2 week schedule for patients with pancreatic cancer. Eligibility criteria include locally advanced, unresectable, recurrent and metastatic disease. Patients who progressed on prior treatment, ECOG 0-2, were also included. There was no age cut off. Results: 26 patients were treated, 9 patients were ≥ 70 years of age (35%). 25 out of 26 patients had stage IV disease (96%). Nine out of 26 patients had received at least one prior chemotherapy regimen (35%). Five out of 26 patients had a grade 3 neutropenia (19%) there was no grade 4 neutropenia. One out of 26 patients (4%) had a grade 3 anemia and thrombocytopenia. There was no neutropenic fever and no limiting gastrointestinal (diarrhea, stomatitis) toxicity. This study included patients with a performance status of 2, patients who had progressed on prior chemotherapy and older patients. Conclusion: High dose ascorbic acid combined with GFLIP chemotherapy is a safe and well tolerated treatment regimen for high risk patients with pancreatic cancer. This level of safety justifies the further study of this treatment regimen especially for high risk patients who would not be eligible for standard high dose combination chemotherapy in pancreatic cancer. Citation Format: Howard W. Bruckner, Azriel Hirschfeld, Daniel Gurell, King Lee. Novel safety of high dose ascorbic acid and induction chemotherapy for high risk pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr CT061. doi:10.1158/1538-7445.AM2017-CT061

Anti-Gastrins Antiserum Combined with Lowered Dosage Cytotoxic Drugs to Inhibit the Growth of Human Gastric Cancer SGC7901 Cells in Nude Mice.

The objective of this study was to determine the effect of anti-gastrin antiserum in combination with varied dosages of cytotoxic drugs (5-Fluorouracil (5FU) + Cisplatin (CDDP)) in vivo growth of the human gastric cancer cell-line, SGC-7901, which expressed cholecystokininB/gastrin receptors and secreted gastrin. The anti-gastrin antiserum was obtained by immunizing rabbits using a novel immunogen vaccine, which was composed of the common amino-terminal portion of human carboxy-amidated gastrin-17 (G17) and glycine-extended gastrin-17 (gly-G17) and the common carboxy-terminal portion of progastrin (in a 50:50 mixture) all covalently linked to tetanus toxoid (TT) by specific peptide spacers. The antiserum neutralized both G17 and gly-G17 by enzyme-linked immunosorbent assay (ELISA), and a synthetic progastrin peptide, as well, using an E. coli expressed his-tagged progastrin.The tumor was implanted subcutaneously into the backside of BALB/c nude mice, and the combination antibody-drug treatment using low dose combination chemotherapy had significantly reduced median tumor volumes (62% reduction; p =0.0018) and tumor weights (53% reduction; p =0.0062) when compared to the conventional high dose chemotherapy treated control mice that had a corresponding similar reductive effect, using just the two standard cytotoxic drugs alone; namely by reducing the tumor volumes (65%; p =0.0016) and tumor weights (59% reduction; p=0.0033). Importantly, the immunological treatment had little of the toxicities and side-effects of the full chemotherapy doses alone, which was effected by using a significant decrease in the dosage of chemotherapeutic drugs, while maintaining the same level of efficacy at reduction of tumor growth.

Successful treatment of ileal pouch desmoids using multimodal chemotherapy with low-dose vinblastine and methotrexate in a patient with familial adenomatous polyposis.

We describe a case of multiple desmoid tumors (DT) that developed in an ileal J pouch, which were successfully treated by low-dose combination chemotherapy using vinblastine (VBL) and methotrexate (MTX). Serial changes in the serum D-dimer levels reflected the treatment response. DT involving both the abdominal wall and the ileal pouch developed after total proctocolectomy with ileoanal anastomosis for familial adenomatous polyposis in a 26-year-old female who was treated in an outpatient unit with low-dose VBL and MTX biweekly for 12 months. The treatment response was assessed at routine intervals by physical examination and abdominal computer tomography (CT) imaging. We assessed serial changes in plasma D-dimers, a potential marker for angiogenic activity, during the low-dose VBL and MTX treatment. DT were successfully treated with low-dose VBL and MTX chemotherapy without any significant side effects or pouch sacrifice. Abdominal CT imaging revealed a decrease in tumor size, and the plasma D-dimer levels decreased in association with tumor regression. This case report shows the efficacy of a low-dose combination chemotherapeutic regimen of VBL and MTX for the treatment of ileoanal pouch mesenteric DT in an outpatient setting. In addition, plasma D-dimers may be a marker for desmoid tumor treatment efficacy.

Early Chemotherapy Response Evaluation in Tumors by 99mTc-DTPA-DG

The aim of this study was to evaluate the utility of 99mTc-diethylenetriaminepentaacetic acid-deoxyglucose (DTPA-DG) for monitoring the early response of tumors to chemotherapy. To evaluate the role of 99mTc-DTPA-DG in vitro chemotherapy, the uptake ratios assays were conducted using A549 lung cancer and MCF-7 breast cancer cells after the 2 tumor cell types had been treated with cisplatin and paclitaxel chemotherapeutic agents, respectively. Apoptosis in the 2 cell types, an indicator of chemotherapeutic action, was assessed by inverted fluorescence microscope and flow cytometry. The assessment of 99mTc-DTPA-DG in vivo was performed by scintigraphic imaging studies of 99mTc-DTPA-DG in MCF-7 mammary tumor cell xenografts at timed intervals after treatment. The animals were randomly assigned to 5 groups: group A, saline injection; group B, low-dose cisplatin; group C, high-dose cisplatin; group D, low-dose combination chemotherapy; and group E, high-dose combination chemotherapy. Imaging findings were correlated with the effectiveness of chemotherapy. The uptake rates of 99mTc-DTPA-DG by A549 lung cancer cells and MCF-7 breast cancer cells in the chemotherapeutic groups were all significantly lower than those in the controls (p < 0.01). The apoptotic ratios in the control groups were significantly lower than the apoptotic ratios in the chemotherapeutic treatment groups in the 2 tumor cell types. The uptake ratios and the apoptosis ratios are inverse correlation, which suggested that we could evaluate the chemotherapy response by the uptake of 99mTc-DTPA-DG in vitro. Scintigraphy in MCF-7 mammary tumor xenografts mice demonstrated that tumor could be clearly visualized by 99mTc-DTPA-DG. The efficacy of combined chemotherapy treatment in this xenograft model was assessed by scintigraphy of tumor/muscle ratios. 99mTc-DTPA-DG is a targeted molecular imaging agent, promising in the evaluation of early response of tumors to chemotherapy.

Chemotherapeutic Management of Small Bowel Adenocarcinoma Associated with Crohn's Disease

Four patients with metastatic primary small bowel adenocarcinoma associated with Crohn's disease were successfully treated with low dose combination chemotherapy consisting of 5-fluorouracil, leucovorin and irinotecan with or without gemcitabine. Benefits included prolonged survival, objective responses, response of resistant tumors, downstaging, and a successful secondary complete resection (Ro) with a durable remission.

Laboratory based low dose combination chemotherapy + bevacizumab for recurrent refractory and unresectable gastric cancer

14133 Twenty consecutive prospectively registered patients with refractory or Stage IV gastric cancer were treated with GFLIP (Bruckner el al ASCO 2002;2005). The last 10 upon relapse were treated with GFL[OX]T and Bevacizumab, substituting oxaliplatin (OX) 30→40 mg/M2, taxotere (T) 30→40 mg/M2 for cisplatin in the q2wk schedule. One or both regimens produced; objective responses for 15 patients including 5 complete (radiologic, tumor markers, PET responses) and 2 surgical downstaging resulting in resection or successful completion surgery; 3 patients had stable disease greater than 4 months with subjective benefit, gemcitabine was given at 400→500 mg/M2 as tolerated (→), 2 failed both regimens. One-year actuarial survival was 75%, two-year survival was 25%. All 20 lived more than six months. The level of activity, multiple crossover responses, responses with both regimens, a number of long remissions (long survival after 5FU cisplatin and GFLIP failed) and clinical downstaging allowing further surgery identify both regimens either individually or in sequence as deserving systematic investigation. The utility of low doses (responses), unusual clinical benefits, quality of life and safety offer possible advantages compared to standard dose regimens.This strategy appears to reduce and delay the limiting toxicity of the irinotecan (I) 80 mg/M2, cisplatin (P) 40 mg/M2 OX/T which are conventionally treatment limiting drugs. The regimens were designed based on laboratory evidence of low dose drug interaction including reversal of resistance to conventional drugs (applicable to both pancreatic and gastric cancer (Janat et al, Amer Asso Cancer Res 1999). After clinical demonstrations of high response rates and reversal of resistance against refractory pancreatic cancer (Bruckner et al, AntiCancer Res and ASCO 2005). The regimens were offered to patients with recurrent previously treated and refractory gastric cancer and then based on initial exceptional responses to high risk patients with poor prognosis due to clinical complications of their gastric cancer. No significant financial relationships to disclose.

Novel Therapeutic Approach Yields Excellent Results in Minimally Differentiated Acute Myeloid Leukemia (AML-M0): Time To Think out of the Box.

Background: AML M0 has dismal complete remission (CR) rates (<50% in most series) and poor long term survival with conventional combination chemotherapy (CT). Thus it is considered a candidate for allogenic bone marrow transplantation (BMT) in first remission and also for other novel therapeutic approaches. There is increasing recognition of angiogenesis as a pathogenic and prognostic factor in AML. The objective of our study was to evaluate the efficacy of low-dose oral metronomic CT in patients with AML-M0.Materials and methods: Eleven patients fulfilling the diagnostic criteria for AML-M0 and ineligible for standard CT and/or BMT were accrued in this pilot protocol between June 1998 and Feb 2005. The treatment consisted of Prednisolone 40 mg/m2/d, Etoposide 50 mg/m2/d and 6-TG 40 mg/m2/d (PET), given orally on out-patient basis continuously for 21 days every month. Post-induction high dose Ara-C (HD-Ara-C) was given whenever possible.Results: The median age was 17 yrs (range 1.5 to 52); 9 were males and 2 females. The median leukocyte count at presentation was 15.4 x 109/L (range 0.9 to 142) and platelet count was 62 x 109/L (range 21 to 442). CD56 and CD7 were positive in 3/5 and 8/11 of those evaluated. Cytogenetic studies were done in 7 patients. Ten of the eleven patients received at least 1 cycle of PET CT of which 9 (90%) achieved CR. The eleventh patient received only 1 week of CT before being lost to follow up, however by then she had already cleared all blasts (57%) in the peripheral blood. Importantly the whole induction was given on out patient basis with only 2 patients requiring admission. There was minimal to nil blood, platelet and antibiotic support required during the entire Induction therapy. Four of them received HD-Ara-C after achieving CR; two of them died in remission at 6 and 11 months. The other two are alive in CR at 36 months and 14 months. Others who could not get HD-Ara-C because of socio-economic reasons were continued on PET or ET chemotherapy for up to maximum of 12 cycles. The median overall survival was 20 months for those who continued treatment. So far no relapses are noted in those who received PET x 2 followed by HD-Ara-C.Conclusions: The dramatic remission rates, excellent tolerability, minimal cost and morbidity with this protocol provide proof of principle that metronomic approach may be a superior alternative to conventional induction chemotherapy in the treatment of AML-M0. Additionally, incorporation of HD-Ara-C consolidation and metronomic maintenance may improve the long term outcome of this disease with dismal prognosis.

Acute myeloblastic leukaemia in the elderly: biology, prognostic factors and treatment.

Elderly patients (> 60 years) with acute myeloblastic leukaemia (AML) have significantly inferior remission rates (around 50%) and median survival times (5-6 months) despite intensive therapy, compared with younger AML patients. This observation emanating from several large clinical studies has made treatment of elderly AML patients a highly controversial issue, with clinicians largely polarizing to one extreme viewpoint or the other. This article summarises the current understanding of the biology and the resultant justification for the assertion that AML in elderly patients is a distinct clinical entity; provides a useful list of prognostic factors to enable a rational therapeutic decision in individual patients; reviews the encouraging results with low-dose combination chemotherapy in small, non-randomized studies from four different centres; and draws attention to the possible significance of drug scheduling and pharmacokinetics in the treatment of elderly patients.

Current Issues in Cancer: Multiple myeloma

Multiple myeloma occurs in over 2000 new patients in England and Wales each year. It presents most frequently as bone pain and patients tend to become dehydrated and may develop renal failure. No available treatment is curative, but about two thirds of patients achieve a stable response with low dose combination chemotherapy. Combination chemotherapy including doxorubicin and carmustine with the alkylating agents cyclophosphamide and melphalan achieve a higher stable response rate than conventional treatment with melphalan and prednisone without additional haematological toxicity. These responses are associated with loss of bone pain and patients remain symptom free for months without further treatment. Relapse occurs on average in a little under two years and, though second responses are frequently obtained, the disease eventually becomes refractory. This paper looks at who should be treated and the benefits that may be expected from the treatments available.

Results of a low-dose combination chemotherapy with vincristine, bleomycin and methotrexate (V-B-M) based on cell kinetics in the palliative treatment of head and neck squamous cell carcinoma

A low dose combination chemotherapy with VCR, BLM and MTX (V-B-M) in a theoretically double synchronizing sequence was administered for palliative purpose to 84 patients with advanced squamous cell carcinoma of the head and neck. The treatment started with a weekly 3 days regimen (VCR 1 mg i.v., BLM 15 mg i.m. after 6 and 24 hr, MTX 20 mg/m 2 p.o. after 48 hr for 4 weeks). BLM was then reduced according to two different regimens in order to protract the treatment avoiding cumulative toxicity of the drug. In 60 assessable patients, a good response was observed in 46 patients ( 76%), with 62% of regressions greater than 50% and 32% of complete responses; regressions greater than 50% were more frequent in patients not previously treated ( 88 v 51%). The duration of response was correlated with the degree of the regression: in the responders its median duration was 4.1 months. V-B-M was effective in reducing or eliminating pain in the great majority of the cases, and this result was often protracted after interruption of the chemotherapeutic treatment. No important toxicity was observed and no patient required hospitalization or specific treatment to control side effects.