Procarbazine, Lomustine And Vincristine Chemotherapy Research Articles

PCV ALONE IN GRADE 2 AND GRADE 3 OLIGODENDROGLIOMA – LONG-TERM RESULTS FROM A UK TERTIARY CARE CENTRE

Abstract AIMS Oligodendroglioma is a subgroup of gliomas which affects young adults and has a favourable overall survival (OS) ranging between 31.5 to 56.6.% at 10 years. Standard management of these tumours is maximal safe resection followed by adjuvant radiotherapy and systemic chemotherapy with Procarbazine, Lomustine and Vincristine (PCV), or surveillance where appropriate. PCV alone is an option that helps defer or avoid radiotherapy and its neurocognitive side effects in a selected group of patients. Our retrospective study analyses outcomes with PCV alone in Oligodendroglioma. METHOD We screened patient records between 1999 to 2021 and identified 31 patients who had a histological diagnosis of grade 2/3 oligodendroglioma (with confirmation of 1p19qcodeletion on molecular testing) and received PCV alone after surgery (biopsy/ tumour resection). RESULTS Out of 31 patients, twenty-six patients were grade 2 and five patients were grade 3 oligodendroglioma. Median age was 44 years and male: female was 15:16. Median follow up was 9.5 years. Twenty-five patients (80%) presented with seizures. 80% of patients had tumour resection & twenty four patients received 5 or more cycles of PCV alone as first-line oncological treatment. There was no significant difference in outcomes for grade2/3 tumours. Eighteen patients (58%) had local tumour relapse. Fourteen patients (45%) underwent salvage radiotherapy. Median time to radiotherapy was 7 years. Median OS was 19.4 years and median progression free survival (PFS) was 13.3 years. 9 deaths were reported. CONCLUSION PCV chemotherapy alone is an effective adjuvant treatment option for selected patients with oligodendroglioma, with a favourable PFS and OS shown in our series. Its use may allow deferral of radiotherapy and avoidance of associated neurocognitive side effects which can have a detrimental effect of quality of life for these young patients.

T2-Fluid-attenuated inversion recovery (FLAIR) pseudoprogression in patients with anaplastic oligodendrogliomas treated with procarbazine, lomustine and vincristine (PCV) chemotherapy alone.

Pseudoprogression in gliomas has been extensively described after radiotherapy with or without chemotherapy, but not after chemotherapy alone. Here we describe the occurrence of pseudoprogression in patients with anaplastic oligodendrogliomas treated with postoperative procarbazine, lomustine and vincristine (PCV) chemotherapy alone. We retrospectively reviewed the medical and radiological files of patients with 1p/19q codeleted, IDH-mutant anaplastic oligodendrogliomas treated with PCV chemotherapy alone who presented magnetic resonance imaging (MRI) modifications suggestive of tumour progression and in whom the final diagnosis was a pseudoprogression. We identified six patients. All patients underwent a surgical resection and were treated with PCV chemotherapy without radiotherapy. After a median of 11 months following the initiation of chemotherapy (range: 3-49 months), the patients developed asymptomatic white matter MRI modifications around the surgical cavity leading to the suspicion of a tumour progression. These modifications appeared as hyperintense on T2-fluid-attenuated inversion recovery (FLAIR) sequence, hypointense on T1 sequence, and lacked mass effect (0/6), contrast enhancement (0/6), restriction on diffusion-weighted imaging (0/4), relative cerebral blood volume (rCBV) increase on perfusion MRI (0/4), and hypermetabolism on 18 F-fluoro-L-dopa positron emission tomography (18 F-DOPA PET) scan (0/3). One patient underwent a surgical resection demonstrating no tumour recurrence; the five other patients were considered as having post-therapeutic modifications based on imaging characteristics. After a median follow-up of 4 years all patients were progression-free. Anaplastic oligodendroglioma patients treated with postoperative PCV chemotherapy alone occasionally develop T2/FLAIR hyperintensities around the surgical cavity that can wrongly suggest tumour progression. Multimodal imaging and close follow-up should be considered in this situation.

Clinical feasibility of modified procarbazine and lomustine chemotherapy without vincristine as a salvage treatment for recurrent adult glioma.

Procarbazine, lomustine and vincristine (PCV) chemotherapy is considered a salvage option for adult glioma; however, its significant toxicities frequently lead to dose reduction or discontinuation in patients with recurrent glioma. The current study evaluated the safety and efficacy of modified procarbazine and lomustine (PC) chemotherapy that omits vincristine and reduces the lomustine dose compared with those of conventional PCV chemotherapy. Using electronic medical records, all patients with adult recurrent glioma who received PC or PCV chemotherapy between 2009 and 2020 at Seoul St. Mary's Hospital or St. Vincent's Hospital were examined retrospectively. A total of 59 patients met the eligibility criteria. Among them, 15 patients received modified PC chemotherapy (PC group) and 44 patients received PCV chemotherapy (PCV group). The PC group presented a significantly lower hematology toxicity (anemia, 6.7 vs. 45.5%, P=0.02; thrombocytopenia 20.0 vs. 70.4%, P<0.001). Additionally, the clinical impacts of PC chemotherapy, including delay of a cycle, dose reduction, discontinuation of drug(s) or total cessation of chemotherapy, were significantly less frequent compared with the PCV group (26.7 vs. 68.2%, P=0.012). The overall survival of the PC group was also significantly longer than that of PCV group (396 vs. 232 days, P=0.042), while there was no significant difference in progression-free survival between the two groups (284.5 vs. 131 days, P=0.077). The results suggested that modified PC chemotherapy may be an alternative chemotherapeutic regimen with tolerable toxicity and without loss of clinical efficacy in patients with recurrent adult glioma. Further prospective and larger studies are required to validate our findings.

One year of procarbazine lomustine and vincristine is poorly tolerated in low grade glioma: a real world experience in a national neuro-oncology centre

BackgroundFollowing optimal local therapy, adjuvant Procarbazine, Lomustine and Vincristine (PCV) improves overall survival (OS) in low-grade glioma (LGG). However, 1 year of PCV is associated with significant toxicities. In the pivotal RTOG 9802 randomised control trial, approximately half of the patients discontinued treatment after 6 months. As patients on clinical trials may be fitter, we aimed to further explore the tolerability of PCV chemotherapy in routine clinical practice.MethodsWe conducted a retrospective study between 2014 and 2018 at a National Neuro-Oncology centre. Patients who had received PCV during this time period were included. The primary objective was to assess tolerability of treatment. Secondary objectives included evaluation of treatment delays, dose modifications and toxicities.ResultsOverall, 41 patients were included, 24 (58%) were male and 21 (51%) aged ≥40 years. 38 (93%) underwent surgical resection and all patients received adjuvant radiotherapy prior to chemotherapy. The median number of cycles completed was 3,2,4 for procarbazine, lomustine and vincristine respectively. Only 4 (10%) completed all 6 cycles of PCV without dose modifications. There was a universal decline in dose intensity as cycles of chemotherapy progressed. Dose intensity for cycle 1 versus cycle 6 respectively: procarbazine (98% versus 46%), lomustine (94% versus 48%) and vincristine (93% versus 50%). Haematological toxicities were common. Six (14%) patients experienced Grade III-IV thrombocytopaenia and 13 (31%) experienced Grade III-IV neutropaenia.ConclusionToxicities are frequently observed with the PCV regimen in clinical practice. It might be preferable to adjust doses from the start of chemotherapy to improve tolerability or consider alternative chemotherapy, particularly in older patients with LGG.

Toxicity Profile of Procarbazine Lomustine and Vincristine Chemotherapy in Low-Grade Glioma - Retrospective Review.

BackgroundThe role of Procarbazine Lomustine and Vincristine (PCV) chemotherapy is already established in terms of improving survival in low-grade glioma (LGG). This improved survival has led to the increasing administration of PCV to LGG patients over the past years. However, like other chemotherapies, serious hematological and non-hematological toxicities may occur. The purpose of this study was to evaluate the toxicity profile of PCV and its clinical relevance in our practice. Materials and MethodsWe reviewed 63 patients of LGG retrospectively who received chemotherapy PCV between January 2015 and January 2018 at Shaukat Khanum Memorial Cancer Hospital & Research Centre, Lahore.ResultsSignificant hematological toxicity as grade 3 anemia, thrombocytopenia, and neutropenia occurred in 19%, 27%, and 46% respectively with PCV. Other toxicities such as neurotoxicity, vomiting and derangement of liver enzymes occurred in 3.2%, 19%, and 19% respectively. Patients who were on concurrent anticonvulsants had no increase in PCV toxicity. Survival was not impacted by hematological toxicities up to grade 3.ConclusionPCV chemotherapy is associated with major hematological, hepatic, and clinical toxicities (vomiting, constipation, and neuropathy). Hematological toxicities influenced the course of treatment in terms of delays and interruptions.

Re-evaluating the Efficacy and Toxicity of Procarbazine, Lomustine and Vincristine (PCV) in Relapsed Glioblastoma in the Concurrent/Adjuvant Temozolamide Era

Background: Publication of the Stupp Trial in 2005 led to adoption of concurrent/adjuvant Temozolomide(TMZ) with radiotherapy as the standard of care for fit patients with newly diagnosed Glioblastoma. No accepted standard treatment exists for relapsed disease. However, nitrosurea based regimens are commonly used. Little published evidence exists for the use of such nitrosurea based regimens in the post-Stupp era. Patients and Method: We present a retrospective study of a cohort of patients between 2009 and 2014 treated with procarbazine, lomustine and vincristine (PCV) for disease progression after completing treatment with the Stupp regime. Result: 33 patients received PCV chemotherapy having previously been treated with the Stupp regime. Median age was 47 (range 23 to 74). The median number of cycles received was 2 (range 1 to 6). Patients underwent magnetic resonance imaging (MRI) to assess response: 19%, 23% & 58% showed Partial Response, Stable, and Progressive Disease respectively. The Median Overall Survival (OS) was 26 weeks. Median Progression Free Survival (PFS) was 17 weeks with Progression Free Survival at 6 months (PFS 6) of 20%. Grade 3/4 haematological toxicity was observed in 31% of patients, of these, 18% developed grade 3/4 thrombocytopenia. Non haematological toxicities included venous thromboembolism in 13% of cases. Treatment discontinuation due to toxicities occurred in 6% of patients. Conclusion: Our experience in this cohort of patients suggests that PCV in relapsed GBM following the Stupp regimen provides modest survival benefit but is relatively well tolerated with a low risk of serious toxicity.

Adjuvant treatment of anaplastic oligodendrogliomas and oligoastrocytomas.

Standard care of adjuvant treatment for anaplastic oligodendrogliomas (AO) and anaplastic oligoastrocytomas (AOA) is not yet well defined. The benefit of adjuvant chemotherapy and radiotherapy (RT), given as single modalities or sequentially, is still unclear. Furthermore, insight into the predictive and prognostic impact of various biomarkers is surging. To compare postoperative sequential RT and chemotherapy to RT alone in adults with newly diagnosed AO or mixed AOA. To evaluate the predictive and prognostic impact of the following biomarkers: codeletion of chromosomes 1p and 19q, O(6)-methylguanine-DNA methyltransferase (MGMT) promotor methylation and isocitrate dehydrogenase (IDH)-1 and -2 mutations. We searched the Cochrane Central Register for Controlled Trials (CENTRAL, Issue 1, 2014), MEDLINE (2006 to March week 2, 2014) and EMBASE (2006 to week 11, 2014). We scanned reference lists from relevant studies for any additional articles. We included randomized controlled trials (RCTs) of adults with AO, AOA or anaplastic astrocytoma (AA) comparing adjuvant treatment of chemotherapy, RT, or sequential chemotherapy and RT. We excluded no specific chemotherapy regimens. We critically appraised and extracted data from relevant studies. Based on the differences in participant selection with respect to the definition of AO (two versus three high-risk anaplastic features), the inclusion of AA and sequence of treatment (RT and chemotherapy), we could not consider the results from the three RCTs for meta-analysis. Three RCTs, with 931 participants, tested different neoadjuvant treatments: RT alone; sequential RT and procarbazine, lomustine and vincristine (PCV) chemotherapy; PCV chemotherapy alone; and temozolomide chemotherapy alone. None of the studies blinded participants or personnel, and, therefore, are considered at high risk of performance and detection bias. The studies were otherwise at low risk of bias. One study, the European Organisation for Research and Treatment of Cancer (EORTC) trial, demonstrated a statistically significant overall survival (OS) benefit for RT plus PCV, with a median OS of 3.5 years compared with 2.6 years in the RT alone arm (P value = 0.018). This result was reported 10 years after the conclusion of the enrolment, and was not apparent in the original 2008 Cochrane review. Furthermore, with retrospective evaluation of biomarkers, codeletion of complete chromosome arms 1p and 19q and IDH-1 or -2 mutation were independent prognostic factors for OS in two of the RCTs (Radiation Therapy Oncology Group (RTOG) and EORTC), and were predictive for OS in one trial (RTOG). The third trial (NOA-04) evaluated these biomarkers prospectively and found them prognostic for progression-free survival. Early PCV, either before or after RT, appears to improve OS of participants with AO or AOA. Use of biomarkers including codeletion of chromosomes 1p and 19q with or without IDH-1 or -2 mutation identify a subset of people with increased sensitivity to combined PCV and RT. The important role of biomarkers was supported in all of the RCTs examined, and prospective evaluation should be undertaken in future studies. However, PCV was associated with significant grade 3 and 4 toxicities, and whether temozolomide can be substituted for this remains unclear.

Effect of the Addition of Chemotherapy to Radiotherapy on Cognitive Function in Patients With Low-Grade Glioma: Secondary Analysis of RTOG 98-02

The addition of PCV (procarbazine, lomustine, and vincristine) chemotherapy to radiotherapy (RT) for patients with WHO grade 2 glioma improves progression-free survival (PFS). The effect of therapy intensification on cognitive function (CF) remains a concern in this population with substantial long-term survival. A total of 251 patients with WHO grade 2 glioma age ≥ 40 years with any extent of resection or age < 40 years with subtotal resection/biopsy were randomly assigned to RT (54 Gy) or RT plus PCV. We observed 111 patients age < 40 years with gross total resection. CF was assessed by Mini-Mental State Examination (MMSE) at baseline and years 1, 2, 3, and 5. Overall, few patients experienced significant decline in MMSE score. There were no significant differences in the proportion of patients experiencing MMSE score decline between the randomized study arms at any time point. Both study arms experienced a significant gain in average MMSE score longitudinally over time, with no difference between arms. The MMSE is a relatively insensitive tool, and subtle changes in CF may have been missed. However, the addition of PCV to RT did not result in significantly higher rates of MMSE score decline than RT alone through 5 years of follow-up. Patients in both randomly assigned arms experienced a statistically significant average MMSE score increase over time, with no difference between arms. The addition of PCV chemotherapy to RT improves PFS without excessive CF detriment over RT alone for patients with low-grade glioma.

The Role of Chemotherapy in Anaplastic Astrocytoma Patients

ObjectiveThis retrospective study was performed to evaluate the role of chemotherapy in the management of patients with anaplastic astrocytoma (AA).MethodsWe compared the survival outcome among the 3 different treatment protocol groups in a single institution. A total of 86 patients (39 men and 47 women) with newly diagnosed AA after surgery were analyzed. Among them, 31 patients (36.0%) were treated with radiotherapy only (RT Group), 30 patients (34.9%) were treated with nimustine-cisplatin chemotherapy before RT (ACNU-CDDP group), and 25 patients (29.1%) were treated with procarbazine, lomustine and vincristine (PCV) chemotherapy after radiotherapy (PCV group).ResultsThe median survival was 14.0, 30.0 and 72.0 months in RT, ACNU-CDDP, and PCV group, respectively and showed significant differences (RT vs. ACNU-CDDP; p=0.039, RT vs. PCV; 0.002, ACNU-CDDP vs. PCV; 0.045). PCV group showed less toxicity rate (5 patients; 20%) than ACNU-CDDP group (12 patients; 40%), while only 3 patients (9.6%) in RT group experienced grade 3 or 4 toxicities.ConclusionAn application of chemotherapy before or after radiotherapy is beneficial in prolonging the survival of patients with AA. Adjuvant PCV chemotherapy after radiotherapy is recommendable.

Retrospective analysis of treatment outcome in 315 patients with oligodendroglial brain tumors

Although chemotherapy with procarbazine, lomustine and vincristine (PCV) is considered to be well tolerated, side effects frequently lead to dose reduction or even discontinuation of treatment of oligodendroglial brain tumors. The primary objective of the analysis was to retrospectively compare progression-free survival (PFS) after PCV vs. PC chemotherapy (without vincristine to avoid side effects). Patients were retrospectively identified from a database containing our patients between 1990 and 2003. For the selected cases, all histopathology reports were re-evaluated by a local neuropathologist. Based on the updated histology data, patients were included in the study if they had at least one histological diagnosis of an oligodendroglial tumor. PFS after start of PCV (n = 61) and PC (n = 84) chemotherapy identical (median 30 months). Multivariate analysis adjusting for prognostic imbalances favouring the PC group showed a minor, statistically non-significant benefit for PCV (hazard ratio 0.81, 95% confidence interval 0.53–1.25; p = 0.346). Younger age (< 50 y) was a statistically significant predictor of longer PFS. Significant advantages in terms of overall survival after first diagnosis of oligodendroglial tumor (OS, n = 315) were found for patients < 50 y (p < 0.001), oligodendrogliomas versus oligoastrocytomas (p = 0.002), and WHO°II vs. °III (p < 0.001). Three risk groups regarding OS were identified. Findings support the hypothesis that PC may be as effective as PCV chemotherapy, while avoiding the additonal risks of vincristine. Younger age, lower tumor grade and histology of an oligodendroglioma were identified to be favorable prognostic factors.

Cerebral blood volume, genotype and chemosensitivity in oligodendroglial tumours

IntroductionThe biological factors responsible for differential chemoresponsiveness in oligodendroglial tumours with or without the −1p/−19q genotype are unknown, but tumour vascularity may contribute. We aimed to determine whether dynamic susceptibility contrast (DSC) magnetic resonance imaging (MRI) could distinguish molecular subtypes of oligodendroglial tumour, and examined the relationship between relative cerebral blood volume (rCBV) and outcome following procarbazine, lomustine and vincristine (PCV) chemotherapy.MethodsPretherapy rCBV was calculated and inter- and intraobserver variability assessed. Allelic imbalance in 1p36, 19q13, 17p13, 10p12–15, and 10q22–26 and p53 mutation (exons 5–8) were determined. rCBV was compared with genotype and clinicopathological characteristics (n=37) and outcome following PCV chemotherapy (n=33).Results1p/19q loss was seen in 6/9 grade II oligodendrogliomas, 6/14 grade II oligoastrocytomas, 4/4 grade III oligodendrogliomas, and 3/10 grade III oligoastrocytomas. rCBV measurements had good inter- and intraobserver variability, but did not distinguish histology subtype or grade. Tumours with 1p/19q loss had higher rCBV values (Student’s t-test P=0.001). Receiver operating characteristic analysis revealed a cut-off of 1.59 for identifying genotype (sensitivity 92%, specificity 76%). Tumours with high and low rCBV showed response to chemotherapy. The −1p/−19q genotype, but not rCBV, was strongly associated with response, progression-free and overall survival following PCV chemotherapy. Tumours with high rCBV and intact 1p/19q were associated with shorter progression-free and overall patient survival than those with intact 1p/19q and low rCBV or high rCBV and 1p/19q loss.ConclusionrCBV identifies oligodendroglial tumours with 1p/19q loss, but does not predict chemosensitivity. The prognostic significance of rCBV may differ in oligodendroglial tumours with or without the −1p/−19q genotype.

Second-line chemotherapy with temozolomide in recurrent oligodendroglioma after PCV (procarbazine, lomustine and vincristine) chemotherapy: EORTC Brain Tumor Group phase II study 26972

Oligodendroglial tumors are chemosensitive, with two-thirds of patients responding to PCV combination chemotherapy with procarbazine, lomustine (CCNU) and vincristine. Temozolomide (TMZ), a new alkylating and methylating agent has shown high response rates in recurrent anaplastic astrocytoma. We investigated this drug in recurrent oligodendroglial tumors (OD) and mixed oligoastrocytomas (OA) after prior PCV chemotherapy and radiation therapy. In a prospective non-randomized multicenter phase II trial patients were treated with TMZ 150 mg/m(2) on days 1-5 in cycles of 28 days for 12 cycles. Eligible patients had a recurrence after prior PCV chemotherapy, with measurable and enhancing disease as shown by magnetic resonance imaging. Pathology and all responses were centrally reviewed. Thirty-two eligible patients were included. In four patients the pathology review did not confirm the presence of an OD or OA. Twelve of 24 patients [50%, 95% confidence interval (CI) 29% to 71%] evaluable for response to first-line PCV chemotherapy had responded to PCV. Temozolomide was in general well tolerated; the most frequent side-effects were hematological. One patient discontinued treatment due to toxicity. In seven of 28 patients (25%, 95% CI 11% to 45%) with histologically confirmed OD an objective response to TMZ was observed. Median time to progression for responding patients was 8.0 months. After 6 and 12 months from the start of treatment, 29% and 11% of patients, respectively, were still free from progression. TMZ may be regarded as the preferred second-line treatment in OD after failure of PCV chemotherapy. Further studies on TMZ in OD are indicated.