Multidrug Chemotherapy Protocol Research Articles

Outcome of serial cardiac evaluations during doxorubicin-based chemotherapy in small- to medium-sized dogs with multicentric lymphoma

Doxorubicin is an anthracycline antitumor antibiotic with dose-dependent and cumulative cardiotoxicity. However, the necessity for serial cardiac evaluation is unknown in dogs without risk factors for dilated cardiomyopathy (DCM). This study aimed to investigate serial changes in echocardiographic and electrocardiographic measures in small- and medium-sized dogs after four doxorubicin doses. We included 17 dogs, weighting < 20 kg, with multicentric lymphoma. All dogs received doxorubicin over 30 min every 4 weeks as part of a multi-drug chemotherapy protocol. The average doxorubicin dose was 3.8 times per dog. Clinical cardiotoxicity was not observed during the monitoring period. The incidence of developing arrhythmia was not significantly associated with the number of doxorubicin doses received (P = 0.600). The development of valvular regurgitations and mitral regurgitation in these dogs was not significantly associated with the number of doxorubicin doses (P = 0.363 and P = 0.779, respectively). The other echocardiographic results were not significantly different between each evaluation. In conclusion, our results showed no significant cardiotoxicity under echocardiogram and electrocardiogram in small- and medium-sized dogs without risk factors for DCM after four doses of doxorubicin in a 30-minute infusion method.

Successful Multidrug Chemotherapy for Rhabdomyosarcoma in a Seven-Year-Old Girl: A Case Report

The most frequent soft tissue cancer in children is rhabdomyosarcoma (RMS). A diagnosis typically occurs between the ages of 5 and 6 in women. We report a seven-year-old girl was referred to Hospitals with complaints of a protruding left eye. The swelling was presented in July 2021, which was small earlier but has increased and become more prominent. An examination of the left eyelid showed a 2.5 x 2.5 x 1.5 cm solid mass with edema, erythema, and secretion in the superior and inferior affected eyelid. A Head CT scan revealed a left superolateral lacrimal duct tumour with a normal intracerebral structure. The histopathology examination found dacryoadenitis with an RMS tumour. This patient was treated using the RMS multidrug chemotherapy protocol (vincristine, actinomycin, and cyclophosphamide) for three sessions, which decreased tumour progressivity five months later. Early and appropriate treatment of this patient with chemotherapy regimens according to the protocol for RMS has a good prognosis.

Metastatic Desmoplastic Small Round Cell Tumor - A Case Report and Review of the Literature

Desmoplastic small round cell tumour is a rare malignancy most often seen in the abdomen or pelvis of young men. Unfortunately, this disease is usually metastatic at diagnosis and has dismal outcomes. Since 1991, when it was first described as a distinct clinical entity by Gerald WL and Rosai J some 200 cases were reported. All cases are characterized by the chromosomal translocation t (11;22) (p13; q12), which results in a formation of EWSR1-WT1 fusion gene. The diagnosis of IDSRCT is often made with core-needle tissue biopsy specimens of laparoscopy or laparotomy. Immunohistochemical analyses have shown the co-expression of epithelial, neuronal, myogenic, and mesenchymal differentiation markers. Multimodal therapy is usually indicated with chemotherapy, surgery &amp; radiotherapy. We report a rare and unusual case of an extensive abdominopelvic desmoplastic small round cell tumour with liver &amp; lung metastases, in an adolescent male patient from Bangladesh who presented with abdominal mass, pain &amp; hepatomegaly. With various difficulties in diagnosis, we ultimately reached at diagnosis by open biopsy and immunohistochemistry as desmoplastic small round cell tutor. Now patient is on multidrug chemotherapy (modified p6) protocol.

T-cell lymphoma involving the rectum of a dog

A mediastinal mass was diagnosed in a 7-year-4-month-old neutered female mixed breed dog following a 3-week history of lethargy, hyporexia and pyrexia. Bi-cavitary imaging, needle aspirate cytology and flow cytometry confirmed WHO clinical stage IVb, intermediate to large T-cell lymphoma involving the mediastinum, liver and spleen. The dog initially responded to a multidrug chemotherapy protocol but clinical deterioration occurred 3 months later. The dog presented with anorexia, vomiting and diarrhoea, associated with marked faecal tenesmus and haematochezia, initially believed by the primary care practitioner to be related to chemotherapy toxicity. However, rectal examination revealed multiple sessile and pedunculated masses. Further diagnostic imaging, cytology and flow cytometry confirmed progressive disease, including T-cell lymphoma of the rectum. Histology and immunohistochemistry confirmed an infiltrate of intermediate-sized CD3-positive neoplastic cells that expanded the rectal mucosa. Rectal lymphoma is uncommon in dogs and previous cases have been B cell in origin. In this report we describe the clinical presentation and macro- and microscopic findings of a case of canine T-cell lymphoma involving the rectum.

Procarbazine, prednisolone and cyclophosphamide oral combination chemotherapy protocol for canine lymphoma.

Orally administered daily chemotherapy offers a novel treatment approach for canine lymphoma in a population of dogs that have failed or not tolerated maximum tolerable dose chemotherapy. A multidrug oral chemotherapy protocol was designed and implemented for the treatment of 50 dogs with multicentric lymphoma with minimal side effects. The protocol consisted of oral procarbazine, prednisolone and cyclophosphamide (PPC) administered daily. Efficacy and toxicity were evaluated by clinical and laboratory evaluation. An overall response rate of 70% was achieved, with 24% and 46% of dogs having a partial and complete response, respectively, to treatment with the PPC protocol. Response to the PPC protocol (complete or partial) and age were the only factors identified as prognostic for time from initiation of the PPC chemotherapy until death. Overall, the protocol was very well tolerated with only one dog requiring protocol discontinuation due to grade 4 thrombocytopenia. Eight dogs recorded gastrointestinal toxicities, seven grade I and one grade II toxicity. These findings demonstrate that the administration of a continuous oral combination chemotherapy can provide comparable survival times in the rescue setting in dogs with multicentric lymphoma with minimal side effects.

Surgery for locally advanced pancreatic ductal adenocarcinoma-is it only about the vessels?

Pancreatic ductal adenocarcinoma (PDAC) is an oligosymptomatic disease, that is usually diagnosed in an advanced tumor stage. Traditionally, only the small subset of patients with tumors that showed no signs of vascular infiltration and distant metastases proceeded to surgery-still the only curative therapeutic modality to date. The remaining majority of patients received palliative chemotherapy or chemoradiation, usually with gemcitabine monotherapy. While gemcitabine monotherapy results in improved survival compared to best supportive care, most patients still succumb to the disease under therapy in a relatively short amount of time. Over the last years and decades, paradigms have shifted in PDAC treatment and potent multidrug chemotherapy protocols, including gemcitabine plus nab-paclitaxel and FOLFIRINOX, result in sufficient downstaging of advanced tumors in many patients. In this context, more and more patients are eligible for exploration and often resection. In this review we discuss the current state of the art in the clinical management and surgical treatment of patients with locally advanced pancreatic cancer, including classifications of locally advanced and borderline disease and surgical strategies for extended resections. An emphasis is put on arterial and venous resections and their outcome. In the end, we discuss current gaps in the literature and propose directions future research endeavors should focus on.

Quality of life assessment in cancer patients receiving single-agent versus multidrug chemotherapy protocols.

Background:Quality of life (QoL) is an essential factor in therapeutic decision-making for human patients and is commonly used as an endpoint in clinical trials of cancer treatments. Aim:To compare owners’ perception of QoL in canine and feline patients affected by different tumor histotypes treated with single-agent or multidrug protocols. Methods:Owners were asked to assess the impact on QoL of their pets undergoing chemotherapy treatment by answering a questionnaire and assigning a score to different health-related parameters reported to affect QoL. Results:Questionnaires of 101 patients (85 dogs and 16 cats), collected at different time points, were analyzed. Fifty-seven patients were given single-agent chemotherapy (carboplatin, doxorubicin, lomustine, melphalan, mitoxantrone, vinblastine, and vinorelbine), whereas 44 were given multiple-agent treatment. When diverse factors including chemotherapy treatment type (single-agent vs. multidrug regimens) and the onset and kind of adverse effects were considered, no significant variations in owners’ perceptions of their pets’ QoL were discovered.Conclusion:Chemotherapy type (single-agent vs. multidrug protocol) and related adverse events are shown, which did not influence owners’ perception of their pet’s QoL.Future prospective studies should look into clinical characteristics that might affect QoL, such as the patient’s age, tumor stage, and protocol purpose (curative vs. palliative).

Colonic lymphoma causing colo-colonic intussusception and chronic intestinal obstruction in a four-year-old German shepherd dog

Gastrointestinal lymphoma accounts for approximately 7 per cent of all canine lymphomas. It is typically associated with a poor prognosis when localised to the gastrointestinal tract. This case report describes...

A randomized controlled trial of the effect of prednisone omission from a multidrug chemotherapy protocol on treatment outcome in dogs with peripheral nodal lymphomas.

OBJECTIVE To determine the effect of prednisone omission from a multidrug chemotherapy protocol on outcome in dogs with peripheral nodal lymphomas. DESIGN Single-center, nonblinded, parallel-group, randomized, controlled trial. ANIMALS 40 client-owned dogs with a histopathologically confirmed diagnosis of peripheral nodal lymphoma and an expected survival time of > 4 weeks with treatment. PROCEDURES Treatment consisted of a combination of L-asparaginase, cyclophosphamide, doxorubicin, vincristine, and prednisone (L-CHOP) or an identical protocol except for the omission of prednisone (L-CHO). The primary outcome of interest was progression-free survival time. Veterinary caregivers and assessors of outcome were not blinded to treatment assignment. Treatment assignment was concealed from the owners of study dogs prior to enrollment, but was revealed after written informed consent was provided. RESULTS The trial was terminated early because of slow enrollment. The 40 dogs successfully enrolled in the study were randomly assigned to the L-CHOP (n = 18) or L-CHO (22) group; results for all 40 dogs were analyzed with respect to the primary outcome. Median progression-free survival time was 142.5 days for dogs receiving L-CHO and 292 days for dogs receiving L-CHOP (hazard ratio, 1.79; 95% confidence interval, 0.85 to 3.75). Serious adverse events were more common among dogs receiving L-CHO. However, this difference was not significant. CONCLUSIONS AND CLINICAL RELEVANCE The exclusion of prednisone from the L-CHOP protocol did not appear to result in improved progression-free survival time for dogs with peripheral nodal lymphomas. However, the present trial was likely underpowered to detect a clinically meaningful difference in progression-free survival time between groups.

A retrospective evaluation of lomustine (CeeNU) in 32 treatment naïve cats with intermediate to large cell gastrointestinal lymphoma (2006-2013).

Multi-drug chemotherapy protocols for feline lymphoma have demonstrated variable efficacy and tolerability. In phase I trials, lomustine has demonstrated efficacy for cats with lymphoma though its use for treatment naïve feline intermediate/large cell gastrointestinal (GI) lymphoma remains unknown. This study evaluated the efficacy and tolerability of lomustine for the treatment of feline GI lymphoma. Thirty-two cats with histologically or cytologically confirmed intermediate/large cell GI lymphoma were evaluated retrospectively. Factors assessed included clinical signs, hematologic/biochemical parameters and use of l-asparaginase at induction. A response rate of 50% (16/32), with median duration of response of 302 days (range 64-1450 days), was found. Median progression-free interval was 132 days (range 31-1450 days), with overall median survival time of 108 days (range 4-1488 days). History of hyporexia, presence of anaemia and dose of lomustine were significantly associated with progression-free survival. Overall, lomustine is a well-tolerated and effective treatment for feline GI lymphoma.

The pharmacogenomics of osteosarcoma.

Osteosarcoma (OS), the most common malignant tumor of bone, is presently treated with multidrug neoadjuvant chemotherapy protocols, which allow to cure 60-65% of patients but also induce toxicity events that cannot be predicted or efficiently prevented. The identification and validation of pharmacogenomic biomarkers is, therefore, absolutely warranted to provide the bases for planning personalized treatments with the aim to increase the therapeutic benefits and to avoid or limit unnecessary toxicities. As several targeted therapies against molecular and immunological markers in OS are presently under clinical investigation, it may be speculated that some new agents for innovative treatments may emerge in the next years. However, the real improvement of therapeutic perspectives for OS is strictly connected to the identification of pharmacogenomic biomarkers that may stratify patients in responders or non-responders and identify those individuals with higher susceptibility to treatment-associated toxicity. This review provides an overview of the pharmacogenomic biomarkers identified so far in OS, which appear to be promising candidates for a translation to clinical practice, after further investigation and/or prospective validation.

A longitudinal study of ABC transporter expression in canine multicentric lymphoma

Canine lymphoma is typically treated with a doxorubicin-based multidrug chemotherapy protocol. Although this is often initially successful, tumour recurrence is common and frequently refractory to treatment. Failure to respond to chemotherapy is thought to represent drug resistance and has been associated with active efflux of cytostatic drugs by transporter proteins of the ATP-binding cassette (ABC) family, including P-glycoprotein (ABCB1), MRP1 (ABCC1) and BCRP (ABCG2). In this study, ABC transporter mRNA expression was assessed in 63 dogs diagnosed with multicentric lymphoma that were treated with a doxorubicin-based chemotherapy protocol. Expression of ABCB1, ABCB5, ABCB8, ABCC1, ABCC3, ABCC5 and ABCG2 mRNA was quantified in tumour samples (n = 107) obtained at the time of diagnosis, at first tumour relapse and when the tumour was no longer responsive to cytostatic drugs while receiving chemotherapy. Expression data were related to patient demographics, staging, treatment response and drug resistance (absent, intrinsic, acquired). ABC transporter expression was independent of sex, weight, age, stage or substage, but T cell lymphoma and hypercalcaemia were associated with increased ABCB5 and ABCC5 expression, and decreased ABCC1 mRNA expression. Drug resistance occurred in 35/63 (55.6%) dogs and was associated with increased ABCB1 mRNA expression in a subset of dogs with B cell lymphoma, and with increased ABCG2 and decreased ABCB8, ABCC1 and ABCC3 mRNA expression in T cell lymphomas. ABC transporter expression in the pre-treatment sample was not predictive of the length of the first disease-free period or overall survival. Glucocorticoids had no effect on ABC transporter mRNA expression. In conclusion, drug resistance in canine multicentric lymphoma is an important cause of treatment failure and is associated with upregulation of ABCB1 and ABCG2 mRNA.

Multi-drug resistance in a canine lymphoid cell line due to increased P-glycoprotein expression, a potential model for drug-resistant canine lymphoma

Canine lymphoma is routinely treated with a doxorubicin-based multidrug chemotherapy protocol, and although treatment is initially successful, tumor recurrence is common and associated with therapy resistance. Active efflux of chemotherapeutic agents by transporter proteins of the ATP-Binding Cassette superfamily forms an effective cellular defense mechanism and a high expression of these transporters is frequently observed in chemotherapy-resistant tumors in both humans and dogs.In this study we describe the ABC-transporter expression in a canine lymphoid cell line and a sub-cell line with acquired drug resistance following prolonged exposure to doxorubicin. This sub-cell line was more resistant to doxorubicin and vincristine, but not to prednisolone, and had a highly increased P-glycoprotein (P-gp/abcb1) expression and transport capacity for the P-gp model-substrate rhodamine123. Both resistance to doxorubicin and vincristine, and rhodamine123 transport capacity were fully reversed by the P-gp inhibitor PSC833. No changes were observed in the expression and function of the ABC-transporters MRP-1 and BCRP.It is concluded that GL-40 cells represent a useful model for studying P-gp dependent drug resistance in canine lymphoid neoplasia, and that this model can be used for screening substances as potential P-gp substrates and their capacity to modulate P-gp mediated drug resistance.

Pericardial lymphoma in seven cats.

A presumed primary pericardial lymphoma was diagnosed in seven cats. Clinical findings at presentation included poor body condition, dehydration and dyspnoea. Thoracic diagnostic imaging was performed in six cases and revealed pleural effusion and a diffuse thickening of the pericardium. A cytological diagnosis of lymphoma was obtained in six cases; in four cases the diagnosis was confirmed at necropsy. Immunophenotyping was performed in six cases: three cases were classified as T-cell and three as B-cell lymphoma. Four cats did not receive any treatment. One cat received only prednisone and two cats received chemotherapy. Six cats lived 7-11 days, except for one cat that received a multi-drug chemotherapy protocol and was still alive at the time of writing (750 days after diagnosis). Primary pericardial lymphoma is a rare extranodal feline lymphoma that has never been described previously.

Prednisolone inclusion in a first-line multidrug cytostatic protocol for the treatment of canine lymphoma does not affect therapy results

Chemotherapy protocols for canine lymphoma include the routine use of glucocorticoids for their lympholytic effect. However, glucocorticoids are associated with side effects (e.g. polyphagia, polyuria, and weight gain), limit the use of non-steroidal anti-inflammatory drugs, and can induce drug transporter expression that could lead to drug resistance. Despite these negative effects, there are no data to support the use of glucocorticoids as part of a multidrug chemotherapy protocol for the treatment of canine lymphoma.A prospective, randomized clinical trial was conducted in 81 dogs with multicentric lymphoma and no history of recent glucocorticoid use. All dogs were staged and treated with the same chemotherapy protocol (L-asparaginase, cyclophosphamide, doxorubicin, vincristine, and prednisolone) with half of the dogs receiving prednisolone. Both treatment groups were similar with respect to demographics, immunophenotype, and clinical stage, except for a higher number of substage b patients in the prednisolone group (5 vs. 14; P=0.015). Treatment results obtained with the initial treatment (complete response rate 75%, disease-free period 176days) and rescue treatment (complete response rate 45%, disease-free period 133days), overall survival (283days) and adverse events (number and grade) were similar for both groups. In conclusion, prednisolone, as part of a multidrug chemotherapy protocol, has no additional effect on treatment results and can be omitted from first-line multidrug protocols used for the treatment of canine lymphoma.

Functional organ preservation in patients with locoregionally advanced head and neck squamous cell carcinoma treated by platinum-based multidrug induction chemotherapy and concurrent chemoradiotherapy

BackgroundThe objective of this study was to evaluate the feasibility, safety, and efficacy in terms of functional organ preservation of multidrug induction chemotherapy and concurrent chemoradiotherapy (IC–CCRT) protocol in patients with locoregionally advanced head and neck squamous cell carcinoma (LA-HNSCC). Patients and methodsPatients with previously untreated, inoperable, histologically proven nonmetastatic stage III or IV HNSCC were eligible. Following one cycle of IC, two cycles of cisplatinum and 5-fluorouracil CCRT with conventional fractionated radiotherapy up to a dose of 66–70 Gy were administrated. ResultsBetween January 2000 and July 2007, a total of 139 patients were candidates to receive IC–CCRT for LA-HNSCC. Overall, 83% of the patients completed the treatment. Three-year overall survival estimate was 68% [95% confidence interval (CI) 57% to 79%]. Three-year progression-free survival (PFS) estimate was 62% (95% CI 50% to 74%). Three-year functional PFS was 57% (95% CI 44% to 69%). There were no cases of treatment-related deaths. The most frequent severe acute toxicity was pharyngeal mucositis. ConclusionsCisplatinum-based multidrug IC–CCRT can result in functional organ preservation and curative treatment in most patients with LA-HNSCC. The toxicity profile and patients’ compliance to treatment confirmed the safety and tolerability of this approach.

Paclitaxel-induced Neutrophilic Adverse Reaction and Acral Erythema

Paclitaxel, a microtubule-stabilizing anti-neoplastic agent that belongs to the family of taxanes, is used in the treatment of advanced and/or refractory lung, breast, head, neck and other epithelial cancers. Site-specific reactions, such as inflammation at injection sites or cellulitis after extravasation (1), have been reported. Adverse cutaneous reactions associated with paclitaxel treatment include bullous fixed drug eruption (2), erythema multiforme (3), pustular eruption (4), scleroderma-like cutaneous lesions (5), onycholysis (6), and acral erythema (one case) (7). Of note, acral erythema (erythrodysesthesia) has been reported with multi-drug chemotherapy protocols that included paclitaxel (8, 9). We report here the first case of paclitaxel-induced neutrophilic adverse reaction with concomitant acral erythema, and highlight the mechanisms that may be involved.

Monitoring of Minimal Residual Disease (MRD) after Multidrug Chemotherapy and Its Correlation to Outcome in Dogs with Lymphoma: A Proof-of-Concept Pilot Study

Tumor cell burden in dogs with lymphoma cannot be assessed accurately by diagnostic evaluation during clinical complete remission (CR). Recent advances in polymerase chain reaction (PCR)-based methods enabled us to quantify minimal residual disease (MRD) in canine lymphoma. To quantify MRD in dogs with lymphoma treated with multidrug chemotherapy and to correlate it with remission duration after chemotherapy. Seventeen dogs with lymphoma that achieved CR by multidrug chemotherapy. Rearranged immunoglobulin heavy chain or T-cell receptor gamma chain gene fragments from lymphoma cells were PCR amplified and sequenced to prepare clone-specific primers and probes for real-time PCR to quantify MRD. MRD in the peripheral blood was monitored during and at the end of a 25-week multidrug chemotherapy protocol. Correlation between MRD at the end of chemotherapy and remission duration after chemotherapy was analyzed. MRD gradually decreased after initiation of multidrug chemotherapy, reached a nadir as low as <0.019-1.0 cells/microL at weeks 4-17, and remained low or slightly increased until week 25. MRD at the end of chemotherapy was negatively correlated with remission duration from the end of chemotherapy to relapse. MRD could be an objective marker to indicate tumor cell burden in dogs with lymphoma even in clinical CR. MRD at the end of chemotherapy could be a prognostic factor to predict remission duration after chemotherapy.

Gastrointestinal and Hematologic Adverse Events after Administration of Vincristine, Cyclophosphamide, and Doxorubicin in Dogs with Lymphoma that Underwent a Combination Multidrug Chemotherapy Protocol

The present study aimed to objectively evaluate the adverse events after the administration of chemotherapeutic agents used in the University of Wisconsin (UW)-Madison chemotherapy protocol (UW-25) for canine lymphoma, using the Veterinary Co-operative Oncology Group common terminology criteria for adverse events (VCOG-CTCAE). The medical records of 40 dogs with multicentric high-grade lymphoma that underwent UW-25 were reviewed. Gastrointestinal adverse events of grade 2 and above and blood/bone marrow adverse events of all grades were evaluated. Gastrointestinal adverse events occurring at least once during the entire period of UW-25 were observed in 50% (20/40), 17.9% (7/39), and 8.1% (3/37) of the dogs after the administration of vincristine (VCR), cyclophosphamide (CPA), and doxorubicin (DXR), respectively. Blood/bone marrow adverse events occurring at least once during UW-25 were observed in 57.5% (23/40), 41% (16/39), and 8.1% (3/37) of the dogs after the administration of VCR, CPA, and DXR, respectively. The rate of patients that experienced gastrointestinal adverse events was higher after the first administration of VCR than after the first administration of DXR. Findings obtained in this study will be helpful in predicting the adverse events that could occur when dogs with lymphoma are treated with UW-25.

Evaluation of a multidrug chemotherapy protocol with mitoxantrone based maintenance (CHOP-MA) for the treatment of canine lymphoma

The purpose of this study was to evaluate the efficacy of adding mitoxantrone to a cyclophosphamide, doxorubicin, vincristine, L-asparaginase and prednisone containing protocol. Sixty-five dogs with multicentric lymphoma were evaluated for overall remission and survival times. Remission and survival time versus stage, substage, pretreatment hypercalcaemia and pretreatment steroid administration were also evaluated. Overall median remission for dogs with multicentric lymphoma was 302 days and overall median survival was 622 days. Of the dogs with multicentric lymphoma, 23 (35%) received all scheduled mitoxantrone doses. Only median survival versus substage was found to be significant (substage a median survival was 679 days and substage b median survival was 302 days, P = 0.025). Increasing the total combined dose of doxorubicin and mitoxantrone may improve remission times when compared with historical controls, and further studies are needed to determine how best to utilize mitoxantrone in multidrug chemotherapy protocols for canine multicentric lymphoma.