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Further evaluation of this regimen, alone or as a 'backbone' for other agents, needs to be considered. Rationale for combining immunotherapy with chemotherapy. Immunotherapy has usually been considered as an alternative to more traditional modalities.
Moreover, it has previously been felt that chemotherapy is inherently immunosuppressive and not suitable for combining with immunotherapy. In this review, the concept of combining different modalities that result in cell death, such as radiotherapy and chemotherapy , with immunotherapy is explored.
Additionally, several chemotherapy agents at low doses selectively inhibit regulatory and suppressor cells. In phase 2, a total of 94 and 47 evaluable patients were assigned to arms 1 and 2, respectively. No difference in median progression-free survival was observed between arms 1 and 2 6. A total of 21 patients had a treatment-emergent adverse event leading to death 18 in arm 1 and 3 in arm 2 ; for 10 individuals, this was an infection pneumonia or sepsis deemed to be related to the study drug.
Published by Elsevier Inc. Dose-related nephrotoxicity of carboplatin in children. This study investigated changes and the time course of these changes in renal function in children following treatment with carboplatin , and identified risk factors for nephrotoxicity. Glomerular and proximal renal tubular function were investigated before and up to 2 years after treatment in 23 children who received carboplatin. The main findings were reduced glomerular filtration rate GFR , and increased renal tubular loss of magnesium, manifested by a low serum magnesium S Mg.
No patient had a clinically important reduction in GFR, and only one patient had symptomatic hypomagnesaemia. GFR and S Mg did not change over time after completion of treatment.
Dose intensity DI of carboplatin was not shown to be related to S Mg following treatment. High CDs of carboplatin may be associated with evidence of renal damage qualitatively similar to but less severe than that caused by cisplatin. GFR and SMg should be carefully monitored when high CDs of carboplatin are used, or if carboplatin is combined with other nephrotoxic chemotherapy. The epidermal growth factor receptor EGFR tyrosine kinase inhibitor gefitinib was initially approved in Japan in for the treatment of advanced or metastatic non-small-cell lung cancer NSCLC ; however, the optimal order of conventional cytotoxic chemotherapy carboplatin and paclitaxel and gefitinib administration has not been determined.
We conducted a randomized phase II study of carboplatin and paclitaxel followed by gefitinib vs. Carboplatin and paclitaxel were administered in 4 cycles every 3 weeks; gefitinib was continued until disease progression or development of unacceptable toxicity. The primary endpoint was overall survival; the secondary endpoints were response rate and adverse event prevalence.
The median overall follow-up was The major toxicities were hematological carboplatin and paclitaxel or skin rash, diarrhea and hepatic dysfunction gefitinib.
Interstitial lung disease was observed in 1 patient from each arm. In arms A and B, the carboplatin and paclitaxel response rate, gefitinib response rate, and median survival durations were Arm A was selected for a subsequent phase III study. In this clinical trial, researchers will test whether the addition of the drug combination vincristine, topotecan, and cyclophosphamide to a standard chemotherapy regimen improves overall survival in patients with extracranial Ewing.
Combination studies of platinum II -based metallointercalators with buthionine-S,R-sulfoximine, 3-bromopyruvate, cisplatin or carboplatin.
With current chemotherapeutic treatment regimes often limited by adverse side effects, the synergistic combination of complexes with anticancer activity appears to offer a promising strategy for effective cancer treatment.
Synergistic relationships were observed, indicating a potential to decrease dose-dependent toxicity and improve therapeutic efficacy. Feasibility of adjuvant chemotherapy with S-1 plus carboplatin followed by single-agent maintenance therapy with S-1 for completely resected non-small-cell lung cancer: This multicenter study evaluated the feasibility of novel adjuvant chemotherapy with S-1 plus carboplatin followed by single-agent, long-term maintenance with S-1 in patients with completely resected stage II-IIIA non-small-cell lung cancer NSCLC.
Patients unable to continue S-1 plus carboplatin because of severe toxicity converted to single-agent S-1 maintenance. Eighty-nine patients were enrolled, of whom 87 were eligible and assessable. The treatment completion rate was There were no treatment-related deaths.
The 2-year relapse-free survival rate was We concluded that adjuvant chemotherapy with S-1 plus carboplatin followed by single-agent maintenance therapy with S-1 is feasible and tolerable in patients with completely resected NSCLC. In the present work an attempt was made to gain greater therapeutic effect of diazane coupled with adriamycin and sarcolysin.
Leucemias L and La served as a model. In leucosis La diazane was injected once in 5 days. Either an additional injection of adriamycin two days prior to diazane injection or sarcolysin injected simultaneously with diazane enabled the authors to obtain a distinct synergestic effect. In leucemia L a simultaneous administration of diazane and sarcolysin also contributes to considerably longer survival of leucemic animals.
Such combinations are likely to be promising in their clinical use. We evaluated the prevalence of and risk factors for hypersensitivity reactions related to carboplatin , which is commonly used to treat gynecological malignancies.
All women with pathologically documented ovarian, fallopian tube, or primary peritoneal cancer treated with carboplatin alone or a carboplatin -based combination chemotherapy regimen at a single hospital between January and December were retrospectively recruited. We analyzed the incidence, characteristics, risk factors, management, and outcomes of carboplatin -related hypersensitivity reactions among these patients. Among eligible women, 75 The annual incidence of carboplatin -related hypersensitivity reactions gradually increased from 0.
Therefore, disease severity, histological type, malignant ascites, past drug allergies, and cumulative carboplatin dose are risk factors for carboplatin -related hypersensitivity reactions. Such reactions could potentially be reduced or prevented by slowing the infusion rate and using a desensitization protocol involving anti-allergy medications. However, its applicability is restricted mostly to patients responding to salvage chemotherapy.
Optimal salvage regimen for these patients is unclear. In this study, our aim was to compare the efficacy profiles of ifosfamide, carboplatin , and etoposide ICE and etoposide-steroid-cytarabine-cisplatin ESHAP cytosine arabinoside, cisplatin, and dexamethasone regimens in the salvage treatment of relapsed or refractory HD. Of patients, 47 Response could be evaluated in patients. Carboplatin is in a class of medications Metastatic seminoma is a highly curable disease.
Standard treatment comprises of combination chemotherapy. The short- and long-term toxicities of this treatment are increasingly recognised and the possibility of over treatment in such a curable disease should be considered. We have therefore assessed the use of single agent carboplatin at a dose of AUC 10 in patients with good prognosis metastatic seminoma.
Patients with good prognosis metastatic seminoma treated with carboplatin AUC 10 were identified at our institution and affiliated institutions. Treatment was three weekly for a total of three or four cycles. Outcome and toxicities were analysed. Three-year survival was There were no treatment related deaths. Single agent carboplatin at a dose of AUC 10 is an effective treatment for good prognosis metastatic seminoma.
The outcome compares favourably to previously published outcomes of combination chemotherapy. Although haematological toxicity is a concern, single agent carboplatin treatment for good prognosis metastatic seminoma could be considered a treatment option and is associated with less toxicity than combination regimens currently used.
Overview of different available chemotherapy regimens combined with radiotherapy for the neoadjuvant and definitive treatment of esophageal cancer. Neoadjuvant chemoradiotherapy CTRT is the current standard of care for treatment of locally advanced cancer of the esophagus or gastroesophageal junction. Many efforts have been made over the last years to identify the best chemotherapy and radiotherapy combination regimen, but specific randomized trials addressing this issue are still lacking.
A systematic review of the literature was performed searching in PubMed all published studies of combinations CTRT regimens for operable or unresectable esophageal cancer to describe activity and toxicity. Studies considered were prospective series or clinical phase II-III trials including at least 40 patients and published in English language.
Long-term results of CROSS trial have established RT combined with carboplatin plus paclitaxel chemotherapy as the preferred neoadjuvant treatment option for both squamous and adenocarcinoma of the esophagus. More effective multimodal treatment strategies integrating novel biological agents including immunotherapy and based on an extensive molecular tumor characterization are eagerly awaited.
EMP combination chemotherapy and low-dose monotherapy in advanced prostate cancer. Many chemotherapeutic regimens combined with estramustine phosphate EMP have been elaborated for the treatment of hormone-refractory prostate cancer over 30 years. In addition, an interim report in 83 patients was presented. They were not consecutively enrolled but were treated on low-dose EMP monotherapy for previously untreated advanced prostate cancer in Department of Urology of Tokyo University and our 21 affiliated hospitals.
Overall PSA response rate was as high as However, overall toxicity rate was abnormally high The reason of low drug compliance may be attributed to gastrointestinal symptoms. To overcome the low drug compliance, appropriate patients for EMP administration should be selected by using gene analysis on the basis of sophisticated tailor-made medicine.
Background Sorafenib, a multikinase inhibitor of cell proliferation and angiogenesis, inhibits the mitogen-activated protein kinase pathway that is activated in most uveal melanoma tumors. This phase II study was conducted by the SWOG cooperative group to evaluate the efficacy of sorafenib in combination with carboplatin and paclitaxel CP in metastatic uveal melanoma. Methods Twenty-five patients with stage IV uveal melanoma who had received 0—1 prior systemic therapy were enrolled.
The primary endpoint was objective response rate ORR ; a two-stage design was used with the study to be terminated if no confirmed responses were observed in the first 20 evaluable patients. Conclusion In this study, the overall efficacy of CP plus sorafenib in metastatic uveal melanoma did not warrant further clinical testing when assessed by ORR, although minor tumor responses and stable disease were observed in some patients.
Efficacy of preoperative transcatheter arterial chemoembolization combined with systemic chemotherapy for treatment of unresectable hepatoblastoma in children. The purpose of this study was to evaluate, retrospectively, the clinical efficacy of preoperative transcatheter arterial chemoembolization TACE combined with systemic chemotherapy for unresectable hepatoblastoma.
Five boys and three girls mean age Mean tumor diameter and mean alfa-fetoprotein AFP level were For all patients, preoperative systemic chemotherapy was administered before TACE. At each TACE, carboplatin and adriamycin mixed with iodized oil were infused into the feeding arteries. Tumor response and prognosis after treatment were evaluated. Mean tumor shrinkage was In all cases TACE combined with systemic chemotherapy enabled subsequent safe and complete surgical resection.
Preoperative TACE combined with systemic chemotherapy was effective in inducing surgical resectability of unresectable hepatoblastoma. The genetic and clinical heterogeneity of breast cancer makes the identification of effective therapies challenging.
We designed I-SPY 2, a phase 2, multicenter, adaptively randomized trial to screen multiple experimental regimens in combination with standard neoadjuvant chemotherapy for breast cancer. The goal is to match experimental regimens with responding cancer subtypes. In this ongoing trial, women are eligible for participation if they have stage II or III breast cancer with a tumor 2. Patients undergo adaptive randomization within each biomarker subtype to receive regimens that have better performance than the standard therapy.
Regimens are evaluated within 10 biomarker signatures i. Veliparib- carboplatin plus standard therapy was considered for HER2-negative tumors and was therefore evaluated in 3 signatures.
The primary end point is pathological complete response. Tumor volume changes measured by magnetic resonance imaging during treatment are used to predict whether a patient will have a pathological complete response. Regimens move on from phase 2 if and when they have a high Bayesian predictive probability of success in a subsequent phase 3 neoadjuvant trial within the biomarker signature in which they performed well. A total of 72 patients were randomly assigned to receive veliparib- carboplatin , and 44 patients were concurrently assigned to receive control therapy; at the completion of chemotherapy , the estimated rates of pathological complete.
High-dose chemotherapy with haemopoietic stem-cell rescue improves event-free survival in patients with high-risk neuroblastoma; however, which regimen has the greatest patient benefit has not been established.
We aimed to assess event-free survival after high-dose chemotherapy with busulfan and melphalan compared with carboplatin , etoposide, and melphalan. We did an international, randomised, multi-arm, open-label, phase 3 cooperative group clinical trial of patients with high-risk neuroblastoma at institutions in 18 countries that included an open-label randomised arm in which high-dose chemotherapy regimens were compared.
Patients age years with neuroblastoma were eligible to be randomly assigned if they had completed a multidrug induction regimen cisplatin, carboplatin , cyclophosphamide, vincristine, and etoposide with or without topotecan, vincristine, and doxorubicin and achieved an adequate disease response.
Patients were randomly assigned 1: Doses of busulfan and melphalan were modified according to bodyweight. Stem-cell rescue was given after the last dose of.
Carboplatin -induced immediate hypersensitivity reactions are relatively common among patients with gynecological malignancies. Once this occurs, the patient might be at risk for future carboplatin -induced reactions.
This study evaluated the efficacy of allergic consultation, carboplatin skin testing and desensitization as a single intervention strategy in this population. Patients with a well-documented immediate reaction to carboplatin were offered allergy consultation, carboplatin skin testing and a desensitization plan in a single visit between scheduled chemotherapy sessions.
Fifty-five patients with an immediate reaction were evaluated. A total of carboplatin desensitization cycles were administered to 49 women. Among them, 10 patients had a mild immediate hypersensitivity reaction during desensitization. Five patients subsequently tolerated carboplatin administered in the prolonged desensitization protocol. In the data presented, we propose a strategy that is both cost effective and very convenient for the patient.
The diagnostic procedure, including allergist consultation and skin test, can be completed in less than 2 h. In most cases where carboplatin is indispensable, desensitization can be administered without overnight hospitalization. The toxicity of radiotherapy RT combined with weekly carboplatin and adjuvant carboplatin and etoposide was prospectively assessed in a group of patients with high-risk Stage I and II Merkel cell carcinoma of the skin.
Patients were eligible if they had disease localized to the primary site and lymph nodes, with high-risk features. This was followed by three cycles of carboplatin and etoposide. A total of 18 patients were entered into the study, and their data were compared with the data from 53 patients entered into the Trans-Tasman Radiation Oncology Group Treatment was completed as planned in 16 patients. The weekly carboplatin dose was delivered in 17 patients, and 15 were able to complete all three cycles of adjuvant carboplatin and etoposide.
Grade 3 and 4 neutrophil toxicity occurred in 7 patients, but no cases of febrile neutropenia developed. The results of our study have shown that weekly carboplatin at this dosage is a safe way to deliver synchronous chemotherapy during RT for MCC and results in a marked reduction of febrile neutropenia and Grade 3 skin toxicity compared with the three weekly regimen.
Oxaliplatin-capecitabine OxCap and carboplatin -paclitaxel CarPac based neo-adjuvant chemoradiotherapy nCRT have shown promising activity in localised, resectable oesophageal cancer. A non-blinded, randomised 1: Surgery was performed weeks after nCRT. Primary end-point was pathological complete response pCR. Eighty five patients were randomised between October and February from 17 UK centres.
Three of 85 3. Twelve of 41 Both regimens were well tolerated. Only CarPacRT passed the predefined p. Carboplatin versus alternating carboplatin and doxorubicin for the adjuvant treatment of canine appendicular osteosarcoma: Despite numerous published studies describing adjuvant chemotherapy for canine appendicular osteosarcoma, there is no consensus as to the optimal chemotherapy protocol.
The purpose of this study was to determine whether either of two protocols would be associated with longer disease-free interval DFI in dogs with appendicular osteosarcoma following amputation. Dogs with histologically confirmed appendicular osteosarcoma that were free of gross metastases and underwent amputation were eligible for enrollment. Dogs were randomized to receive either six doses of carboplatin or three doses each of carboplatin and doxorubicin on an alternating schedule.
Fifty dogs were included. Toxicity was similar between groups. These results suggest that six doses of carboplatin may be associated superior DFI when compared to six total doses of carboplatin and doxorubicin. Most patients are diagnosed at an advanced stage, palliative chemotherapy therefore being the only treatment option.
This study was aimed at evaluating the health-related quality of life HRQoL of advanced-stage NSCLC patients receiving palliative chemotherapy with carboplatin and paclitaxel.
Physical and cognitive functioning scale scores differed significantly among chemotherapy cycles, indicating improved and worsened HRQoL, respectively. A phase I trial of the novel farnesyl protein transferase inhibitor, BMS, in combination with paclitaxel and carboplatin in patients with advanced cancer.
This phase I study was conducted to determine the toxicities, pharmacokinetics, and pharmacodynamics of BMS, a farnesyl transferase inhibitor, in combination with paclitaxel and carboplatin , in patients with advanced solid tumors. Patients with solid tumors received one of six escalating dose levels of BMS infused over 1 hour given following paclitaxel and carboplatin on the first day of a day cycle.
Toxicities were graded by the National Cancer Institute common toxicity criteria and recorded as maximum grade per patient for each treatment cycle. Inhibition of farnesyl transferase activity in peripheral blood mononuclear cells PBMCs was evaluated.
Thirty patients received cycles of treatment through six dose levels. Dose-limiting toxicities were neutropenia, thrombocytopenia, nausea, and vomiting. There was no pharmacokinetic interaction between BMS and paclitaxel.
One measurable partial response was observed in a patient with taxane-resistant esophageal cancer. There was partial regression of evaluable disease in two other patients endometrial and ovarian cancer.
The combination of BMS with paclitaxel and carboplatin was well tolerated, with broad activity in solid tumors. Primary frontal sinus squamous cell carcinoma in three dogs treated with piroxicam combined with carboplatin or toceranib. To our knowledge, this is the first publication concerning canine pFS-SCC, diagnosed using histology or cytology and medical imaging, in three dogs. The tumours extended into the orbit or brain cavity, without nasal involvement.
Treatment was initiated with piroxicam- carboplatin. Prolongation of carboplatin delivery with a low dose intensity was performed on dogs with a favourable initial response. Dog 1 achieved a complete remission CR , but was euthanized days after start of therapy. Dog 2, still alive 3 years after start of therapy and in CR, received 14 carboplatin deliveries. In dog 3, after changing the treatment protocol into piroxicam-toceranib, a significant tumour reduction occurred, but the dog was euthanized after days because of a relapse.
Targeting chemotherapy -resistant leukemia by combining DNT cellular therapy with conventional chemotherapy. While conventional chemotherapy is effective at eliminating the bulk of leukemic cells, chemotherapy resistance in acute myeloid leukemia AML is a prevalent problem that hinders conventional therapies and contributes to disease relapse, and ultimately patient death.
We have recently shown that allogeneic double negative T cells DNTs are able to target the majority of primary AML blasts in vitro and in patient-derived xenograft models. Given the differences in the modes of action of DNTs and chemotherapy , we hypothesize that DNT therapy can be used in combination with conventional chemotherapy to further improve their anti-leukemic effects and to target chemotherapy -resistant disease.
Drug titration assays and flow-based cytotoxicity assays using ex vivo expanded allogeneic DNTs were performed on multiple AML cell lines to identify therapy-resistance. Primary AML samples were also tested to validate our in vitro findings. Further, a xenograft model was employed to demonstrate the feasibility of combining conventional chemotherapy and adoptive DNT therapy to target therapy-resistant AML.
Lastly, blocking assays with neutralizing antibodies were employed to determine the mechanism by which chemotherapy increases the susceptibility of AML to DNT-mediated cytotoxicity. Here, we demonstrate that KG1a, a stem-like AML cell line that is resistant to DNTs and chemotherapy , and chemotherapy -resistant primary AML samples both became more susceptible to DNT-mediated cytotoxicity in vitro following pre-treatment with daunorubicin.
Moreover, chemotherapy treatment followed by adoptive DNT cell therapy significantly decreased bone marrow engraftment of KG1a in a xenograft model. Our results demonstrate the feasibility and benefit of using DNTs as. Carboplatin binding to histidine. An X-ray crystal structure showing the binding of purely carboplatin to histidine in a model protein has finally been obtained.
This required extensive crystallization trials and various novel crystal structure analyses. Carboplatin is a second-generation platinum anticancer agent used for the treatment of a variety of cancers. Previous X-ray crystallographic studies of carboplatin binding to histidine in hen egg-white lysozyme; HEWL showed the partial conversion of carboplatin to cisplatin owing to the high NaCl concentration used in the crystallization conditions.
Here, it is reported that a partial chemical transformation takes place but to a transplatin form. Thus, to attempt to resolve purely carboplatin binding at histidine, this study utilized co-crystallization of HEWL with carboplatin without NaCl to eliminate the partial chemical conversion of carboplatin.
Tetragonal HEWL crystals co-crystallized with carboplatin were successfully obtained in four different conditions, each at a different pH value. The structural results obtained show carboplatin bound to either one or both of the N atoms of His15 of HEWL, and this particular variation was dependent on the concentration of anions in the crystallization mixture and the elapsed time, as well as the pH used.
The structural details of the bound carboplatin molecule also differed between them. Overall, the most detailed crystal structure showed the majority of the carboplatin atoms bound to the platinum centre; however, the four-carbon ring structure of the cyclobutanedicarboxylate moiety CBDC remained elusive. The potential impact of the results for the administration of carboplatin as an anticancer agent are.
Pembrolizumab is a humanized monoclonal antibody which serves to enhance the antitumor immune response by targeting programmed cell death 1 receptor. However, numerous immune-mediated toxicities of pembrolizumab have been reported. Follow-up PET-CT scanning showed a very good response at the level of the tumor but new-onset activity in bilateral hilar and mediastinal lymph nodes. Biopsy of these lymph nodes revealed a benign pathology with noncaseating granulomas consistent with immune-mediated sarcoidosis.
The pathogenesis of immunotherapy-induced sarcoidosis is not yet known but has been reported in different cancers and using different checkpoint inhibitors.
To our knowledge, this case is the first in the literature displaying pulmonary sarcoidosis in a patient with NSCLC 4 months after having initiated chemotherapy plus pembrolizumab combination therapy. Background Pembrolizumab is a humanized monoclonal antibody which serves to enhance the antitumor immune response by targeting programmed cell death 1 receptor. Conclusion The pathogenesis of immunotherapy-induced sarcoidosis is not yet known but has been reported in different cancers and using different checkpoint inhibitors.
However, this regimen requires hospitalization to ensure proper hydration and continuous infusion of 5-FU, and causes severe nausea and anorexia. Primary end point was overall response rate. Secondary end points were safety, treatment completion rate, progression-free survival, overall survival, and clinical benefit rate.
Planned sample size was 45 patients. Forty-seven subjects were accrued from July to October Median overall survival was A potentially treatment-related death occurred in one patient with intestinal pneumonia. The PCE regimen shows promising. Consistent with the synergistic to additive antitumor activity the combination index ranging from 0. Removal of paclitaxel increased the repair of carboplatin -DNA adducts: Chemotherapy combinations for cancer treatments harbor immense therapeutic potentials which have largely been untapped.
Of all diseases, clinical studies of drug combinations are the most prevalent in oncology, yet their effectiveness is disputable, as complete tumor regressions are rare. Our research has been devoted towards developing delivery vehicles for combinations of chemotherapy drugs which elicit significant tumor reduction yet limit toxicity in healthy tissue. Current administration methods assume that chemotherapy combinations at maximum tolerable doses will provide the greatest therapeutic effect -- a presumption which often leads to unprecedented side effects.
Contrary to traditional administration, we have found that drug ratios rather than total cumulative doses govern combination therapeutic efficacy. In this thesis, we have developed nanoparticles to incorporate synergistic ratios of chemotherapy combinations which significantly inhibit cancer cell growth at lower doses than would be required for their single drug counterparts.
The advantages of multi-drug incorporation in nano-vehicles are many: To exploit these advantages for polychemotherapy delivery, two prominent nanoparticles were investigated: Liposomes represent the oldest class of nanoparticles, with high drug loading capacities and excellent biocompatibility. Polymer-drug conjugates offer controlled drug incorporations through reaction stoichiometry, and potentially allow for delivery of precise ratios.
Here, we show that both vehicles, when armed with synergistic ratios of chemotherapy drugs, significantly inhibit tumor growth in an aggressive mouse breast carcinoma model.
Furthermore, versatile drug incorporation methods investigated here can be broadly. Phase I study of the c-raf-1 antisense oligonucleotide ISIS in combination with carboplatin and paclitaxel in patients with previously untreated, advanced non-small cell lung cancer.
The carboplatin dose was then increased to AUC fp 6 mg. The maximum tolerated dose was established by toxicity during the first two day cycles of therapy. The pharmacokinetics of all three agents was determined before and during the ISIS infusion. Dose-limiting neutropenia occurred in two patients at dose level 3. Grade 3 and 4 nonhematologic toxicities were infrequent and limited to nausea and constipation. The maximum tolerated doses were carboplatin AUC fp 6 mg. There were no objective responses and the concurrent infusion of ISIS did not alter the plasma pharmacokinetics of paclitaxel or total platinum.
ISIS can be safely combined with standard doses of carboplatin and paclitaxel. Combining cytotoxic chemotherapeutic agents with inhibitors of aberrant signal transduction mediated by Raf proteins produced no objective responses in the dose and schedule administered in this study. Combination chemotherapy is widely exploited for enhanced cancer treatment in clinic.
However, the traditional cocktail administration of combination regimens often suffers from varying pharmacokinetics among different drugs. The emergence of nanotechnology offers an unparalleled opportunity for developing advanced combination drug delivery strategies with the ability to encapsulate various drugs simultaneously and unify the pharmacokinetics of each drug.
This review surveys the most recent advances in combination delivery of multiple small molecule chemotherapeutics using nanocarriers. The mechanisms underlying combination chemotherapy , including the synergistic, additive and potentiation effects, are also discussed with typical examples. We further highlight the sequential and site-specific co-delivery strategies, which provide new guidelines for development of programmable combination drug delivery systems.
Clinical outlook and challenges are also discussed in the end. To explore the feasibility and activity of a histology-based induction combination chemotherapy for elderly patients with clinical stage III non-small cell lung cancer NSCLC. The primary endpoint was the overall response rate ORR following induction. Grade 3 or 4 toxicity was reported for five patients Delinasios , All rights reserved. The use of carboplatin for the treatment of pediatric low grade gliomas PLGG is often limited by the development of carboplatin hypersensitivity.
Here we report the frequency of carboplatin hypersensitivity reactions depending on the treatment regimen used, and outcomes of carboplatin desensitization. The records of all patients in a single institution who were treated with carboplatin for PLGG were accessed and all patients receiving more than one dose of carboplatin are reported.
Thirty four patients with PLGG were treated with carboplatin according to one of the two different regimens. Desensitization showed limited effectiveness in this cohort. Gemcitabine plus cisplatin versus gemcitabine plus carboplatin as first-line chemotherapy in advanced transitional cell carcinoma of the urothelium: No differences between arms were noted in the overall toxicity profiles and any parameter of toxicity.
The most frequent grade hematologic toxicity was neutropenia in The most frequent grade nonhematologic toxicity was nausea and vomiting GP: Grade nephrotoxicity occurred in 14 GP-treated patients Per an intent-to-treat analysis, overall response, evaluated on 80 patients, was Median time to progression was 8.
Median survival was Chemotherapy in advanced ovarian cancer: Advanced Ovarian Cancer Trialists' Group. The purpose of this systematic study was to provide an up to date and reliable quantitative summary of the relative benefits of various types of chemotherapy non-platinum vs platinum, single-agent vs combination and carboplatin vs cisplatin in the treatment of advanced ovarian cancer.
Also, to investigate whether well-defined patient subgroups benefit more or less from cisplatin- or carboplatin -based therapy. Meta-analyses were based on updated individual patient data from all available randomized controlled trials published and unpublished , including 37 trials, patients and deaths.
The results suggest that platinum-based chemotherapy is better than non-platinum therapy, show a trend in favour of platinum combinations over single-agent platinum, and suggest that cisplatin and carboplatin are equally effective. There is no good evidence that cisplatin is more or less effective than carboplatin in any particular subgroup of patients. Randomized phase II trial of carboplatin versus paclitaxel and carboplatin in platinum-sensitive recurrent advanced ovarian carcinoma: The aim of this study was to determine whether the response rate for the paclitaxel- carboplatin combination is superior to carboplatin alone in the treatment of patients with platinum-sensitive recurrent ovarian carcinoma.
The primary end point was objective response, following a 'pick up the winner' design. Secondary end points included time to progression TTP , overall survival, tolerability and quality of life QoL. Eighty-one patients were randomized and included in the intention-to-treat analysis. The response rate in arm B was No significant differences were observed in grade hematological toxicity.
Median TTP was No significant differences were found in the QoL analysis. Paclitaxel- carboplatin combination is a tolerable regimen with a higher response rate than carboplatin monotherapy in platinum-sensitive recurrent ovarian carcinoma. Successful treatment of ovarian cancer with apatinib combined with chemotherapy. The standard treatment for ovarian cancer is chemotherapy with 2 drugs taxanes and platinum drugs. However, the traditional combination of the 2 drugs has many adverse effects AEs and the cancer cells will quickly become resistant to the drugs.
Apatinib is a small-molecule antiangiogenic agent which has shown promising therapeutic effects against diverse tumor types, but it still remains unknown whether apatinib has an antitumor effect in patients with ovarian cancer.
Herein, we present a successfully treated case of ovarian cancer using chemotherapy and apatinib, in order to demonstrate the effectiveness of this new combined regimen in ovarian cancer. The disease and the cancer antigen CA had been controlled well by surgical treatment and following chemotherapy.
However, the drugs could not control the disease anymore as the CA level was significantly increasing. The patient was treated with apatinib combined with epirubicin.
Then, the oral ulcer disappeared and the HFS was controlled by dose adjustment, oral vitamin B6, and hand cream application. The CA reverted to the normal value after treatment with the new regimen. Magnetic resonance imaging showed that the original tumor lesions had disappeared. Apatinib monotherapy as maintenance therapy was then used to successfully control the cancer with a complete response.
Our study is the first, to our knowledge, to report the therapeutic effects of apatinib and epirubicin on ovarian cancer. Apatinib combined with chemotherapy and apatinib monotherapy as maintenance therapy could be a new therapeutic strategy for ovarian cancer, especially. Dose escalation of the hypoxic cell sensitizer etanidazole combined with ifosfamide, carboplatin , etoposide, and autologous hematopoietic stem cell support.
Multiple mechanisms of drug resistance contribute to treatment failure. Although high-dose therapy attempts to overwhelm these defenses pharmacologically, this approach is only successful in a fraction of treated patients. Many drug resistance mechanisms are shared between malignant and normal cells, but the expression of various drug resistance mechanisms associated with hypoxia is largely confined to tumor tissue.
Thus, reversal of this mechanism is likely to provide a therapeutic advantage to the host. This study was designed to define the dose-limiting toxicities and maximum tolerated dose of etanidazole when it is given concurrently with high-dose ifosfamide, carboplatin , and etoposide ICE , with hematopoietic stem cell support. The maximum tolerated doses of high-dose ICE were administered concurrently with dose escalations of etanidazole, a hypoxic cell sensitizer. All agents were given by h continuous i.
Mesna uroprotection was provided. Autologous marrow and cytokine mobilized peripheral blood progenitor cells were reinfused on day 0. Fifty-five adults with advanced malignancies were enrolled in cohorts of five to nine patients.
Four dose levels of etanidazole between 3 and 5. Five deaths occurred at the top dose level. One additional patient suffered a witnessed cardiorespiratory arrest from ventricular fibrillation and was resuscitated.
Dose-dependent and largely reversible peripheral neuropathy was observed consisting of two syndromes: Increasing the radiotherapy dose can result in improved local control for non-small-cell lung cancer NSCLC and can thereby improve survival. Accelerated hypofractionated radiotherapy can expose tumors to a high dose of radiation in a short period of time, but the optimal treatment regimen remains unclear.
The total dose was greater than or equal to 60 Gy. In addition to radiotherapy, the patients also received at least 1 cycle of a concurrent two-drug chemotherapy regimen of NVB and CBP. A total of 26 patients 19 previously untreated cases and 7 cases of recurrent disease received 60GyGy radiotherapy with concurrent chemotherapy.
All of the patients underwent evaluations for toxicity and preliminary therapeutic efficacy. There were no treatment-related deaths within the entire patient group. The major acute adverse reactions were radiation esophagitis Hematological toxicities were common and did not significantly affect the implementation of chemoradiotherapy after supportive treatment. Grade III and above late lung toxicity did not occur. Background Increasing the radiotherapy dose can result in improved local control for non-small-cell lung cancer NSCLC and can thereby improve survival.
Results A total of 26 patients 19 previously untreated cases and 7 cases of recurrent disease received 60GyGy radiotherapy with concurrent chemotherapy. Variations in lean body mass LBM have been suggested to explain variations in toxicity from systemic cancer treatment. Patients received carboplatin AUC [area under the plasma concentration vs.
LBM was estimated from the cross-sectional muscle area at the third lumbar vertebra on computed tomographic scans.
Administered doses on day 1, first cycle, were recalculated as milligram of drug per kilogram of LBM. Data from patients were analyzed. Computed tomography-defined LBM may provide a future basis for better dose individualization.
A recent phase III trial compared the efficacy of cisplatin-topotecan a topoisomerase I inhibitor followed by carboplatin -paclitaxel Arm 1 versus paclitaxel- carboplatin Arm 2 in women with newly diagnosed stage IIB or greater ovarian cancer. There was a significantly lower response rate in the experimental arm compared to standard treatment, and less likelihood of normalized CA within the first 3 months.
At 43 months follow-up, there were no significant group differences in progression-free survival. There were also significantly more side effects in the experimental arm. Global QoL, physical symptoms, fatigue, and role, emotional, cognitive and social function all from the EORTC QLQ-C30 significantly improved in both treatment arms, with no significant between-arm differences.
Between-group differences in pain, insomnia, and peripheral neuropathy reported while on treatment did not differ at follow-up. Nausea and vomiting improved more with standard treatment both during and after treatment. Body image significantly differed between the groups only at cycle 5 more deterioration in Arm 2 but group differences disappeared at follow-up. A stratified analysis of global QoL by debulking surgery status found no greater effect indicating that overall improvements in QoL were unrelated to surgical recovery.
There was no significant QoL advantage of cisplatin-topotecan. This finding, combined with no progression-free survival conferred by this combination , reaffirms carboplatin -paclitaxel as the standard of care for women with newly diagnosed ovarian cancer. A phase II study of nab-paclitaxel plus carboplatin in combination with thoracic radiation in patients with locally advanced non-small-cell lung cancer.
Progression-free survival and overall survival were estimated using the Kaplan-Meier method. A total of 10 patients were enrolled in this trial between September and January from three institutes.
The overall response rate was Treatment-related death occurred in two patients. A phase II study of nab-paclitaxel plus carboplatin in combination with thoracic radiation in patients with locally advanced non—small-cell lung cancer.
Progression-free survival and overall survival were estimated using the Kaplan—Meier method. Optimal chemotherapy treatment for women with recurrent ovarian cancer. Question What is the optimal chemotherapy treatment for women with recurrent ovarian cancer who have previously received platinum-based chemotherapy? Perspectives Currently, standard primary therapy for advanced disease involves a combination of maximal cytoreductive surgery and chemotherapy with carboplatin plus paclitaxel or with carboplatin alone.
Despite initial high response rates, a large proportion of patients relapse, resulting in a therapeutic challenge. Because these patients are not curable, the goal of therapy becomes improvement in both quality and length of life.
The search has therefore been to find active agents for women with recurrent disease following platinum-based chemotherapy. Outcomes Outcomes of interest included any combination of tumour response rate, progression-free survival, overall survival, adverse events, and quality of life. Methodology The medline, embase, and Cochrane Library databases were systematically searched for primary articles and practice guidelines.
The resulting evidence informed the development of clinical practice recommendations. The practice guideline was externally reviewed by a sample of practitioners from Ontario, Canada. Results Thirteen randomized trials compared various chemotherapy regimens for patients with recurrent ovarian cancer. Only two of these randomized trials compared the same chemotherapy regimens: Platinum based combination chemotherapy has been associated with a high response rate in patients with cervical carcinoma.
To determine whether the toxicity could be reduced but the efficacy maintained carboplatin mg m-2 was substituted for cisplatin in a regimen that was repeated two weekly and also contained vincristine, methotrexate and bleomycin. Twenty-four patients with squamous cell carcinoma of the cervix of whom 17 had relapsed following radiotherapy were studied.
Carboplatin as given in the COMB regimen appears less effective than cisplatin containing combinations for squamous cell carcinoma of the cervix. The study was designed to examine the efficacy and safety of nintedanib administered with carboplatin plus nab-paclitaxel versus carboplatin plus nab-paclitaxel alone in chemotherapy -naive patients with advanced NSCLC associated with IPF. The goal of the study is to demonstrate that nintedanib combined with carboplatin plus nab-paclitaxel prolongs the interval to acute exacerbation of IPF compared with carboplatin plus nab-paclitaxel alone.
Combination cancer chemotherapy with one compound: Lung and prostate cancers are major health problems worldwide. Treatments with standard chemotherapy agents are relatively ineffective.
Combination chemotherapy gives better treatment than a single agent because the drugs can inhibit the cancer in different pathways, but new therapeutic agents are needed for the treatment of both tumor types.
Bradykinin BK antagonists offer advantages of combination therapy in one compound. These promising multitargeted anti-cancer compounds selectively stimulate apoptosis in cancers and also inhibit both angiogenesis and matrix metalloprotease MMP action in treated lung and prostate tumors in nude mice.
In certain combinations , they act synergistically with standard anti-cancer drugs. Due to its structure and biological activity, BKM is an attractive lead compound for derivatization and evaluation for lung and prostate cancer drugs.
Background Epidermal growth factor receptor tyrosine kinase inhibitors significantly prolong the progression-free survival of patients with non-squamous non-small cell lung cancer NSCLC. However, most patients develop tumor regrowth and their prognosis remains poor. Methods In phase I, eligible patients were administered oral erlotinib daily and intravenous pemetrexed, carboplatin , and bevacizumab every 3 weeks for four cycles with maintenance of pemetrexed and bevacizumab until progressive disease was observed.
The dose of erlotinib was mg for dose level 1 and mg for dose level 2. During the induction phase, grade 3 neutropenia without fever was observed in one patient at dose level 1 and two patients at dose level 2. Grade 3 anemia was reported in one patient at dose level 1 and grade 3 thrombocytopenia was reported in two patients at dose level 1 and dose level 2, respectively.
Conclusion Four-drug combination therapy is a feasible and promising. Antitumor immunity relies on the ability of the immune system to recognize tumor cells as foreign and eliminate them.
An effective immune response in this setting is due to surveillance of tumor-specific antigens that induce an adaptive immune response resulting in T-cell mediated cytotoxicity. However, there remains a crucial need for better treatment strategies for the majority of patients with advanced NSCLC, particularly in the frontline setting. Chemotherapy can increase antigenicity via immunogenic cell death ICD of tumor cells as well as also reduce "off target" immunosuppression in the tumor microenvironment TME.
Combining chemotherapy with PD-1 blockade harnesses the potential synergy between these agents and has led to encouraging results in the up-front treatment of NSCLC. In this review, we summarize the preclinical rationale behind these combinations and review recent trial data demonstrating their efficacy. Combined carboplatin plus ifosfamide and cisplatin in patients with advanced ovarian carcinoma. A phase I-II study. Because of the relative lack of overlapping toxicity, carboplatin PPL and cisplatin CDDP can be easily combined for treatment of ovarian cancer to increase total platinum dose intensity.
Ifosfamide IFO , one of the most effective single agents in ovarian cancer, has a low hematological toxicity when administered in continuous infusion. With a minimum follow-up of 32 months median 40 months , median progression-free survival and overall survival were 21 and 39 months, respectively. Brain metastases are rare in patients with colorectal cancer, but the incidence is expected to rise due to prolonged survival resulting from more effective regimens including anti-EGF-receptor and anti-angiogenic antibodies.
Because of the potential fear of intracranial hemorrhage, patients with colorectal brain metastases have been excluded from clinical trials involving bevacizumab or aflibercept.
Five patients with colorectal brain metastases treated with bevacizumab-containing chemotherapy regimen following either neurosurgery, radiosurgery, or whole-brain radiotherapy were identified between and The clinicopathological data and outcomes for these patients were reviewed.
Mean time to disease progression concerning brain metastases was Overall survival was Best response was a partial response in two and a stable disease in three patients.
Treatment-related adverse events were mild hypertension grade 1 , diarrhea grade 1 , and fatigue grade 1. No intracranial hemorrhage was observed. Bevacizumab in combination with chemotherapy is a feasible option for palliative treatment of patients with colorectal brain metastasis with a good safety profile.
Cancer forms exhibiting poor prognosis have been extensively researched for therapeutic solutions. One of the conventional modes of treatment, chemotherapy shows inadequacy in its methodology due to imminent side-effects and acquired drug-resistance by cancer cells. However, advancements in nanotechnology have opened new frontiers to significantly alleviate collateral damage caused by current treatments via innovative delivery techniques, eliminating pitfalls encountered in conventional treatments.
Properties like reduced drug-clearance and increased dose efficacy by the enhanced permeability and retention effect deem nanoparticles suitable for this application. Optimization of size, surface charge and surface modifications have provided nanoparticles with stealth properties capable of evading immune responses, thus deeming them as excellent carriers of chemotherapeutic agents. Biocompatible and biodegradable forms of polymers enhance the bioavailability of chemotherapeutic agents, and permit a sustained and time-dependent release of drugs which is a characteristic of their composition, thereby providing a controlled therapeutic approach.
Studies conducted in vitro and animal models have also demonstrated a synergism in cytotoxicity given the mechanism of action of anticancer drugs when administered in combination providing promising results.
Combination therapy has also shown implications in overcoming multiple-drug resistance, which can however be subdued by the adaptable nature of tumor microenvironment. Surface modifications with targeting moieties can therefore feasibly increase nanoparticle uptake by specific receptor-ligand interactions, increasing dose efficacy which can seemingly overcome drug-resistance.
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