Comparison of Efficacy and Safety of a Bevacizumab Biosimilar, in Combination with Chemotherapies, in Nonresectable Metastatic Colorectal Cancer and in Advanced Nonsquamous Non-Small Cell Lung Cancer: A Randomized, Double-Blind, Phase III Study.

Ranjith K.The objective of this study was to compare the efficacy, safety, pharmacokinetics, and immunogenicity of a proposed bevacizumab biosimilar (DRL_BZ) with the innovator Avastin (reference medicinal product [RMP]) in patients with nonresectable metastatic colorectal cancer (mCRC) over a period of 9 months and advanced nonsquamous non-small cell lung cancer (NSCLC) over 6 months. The study was planned as a randomized, double-blind trial. In part A, a total of 117 mCRC patients were intended to receive 5 mg/kg of bevacizumab every 2 weeks along with mFOLFOX6 chemotherapy for a maximum of 18 cycles. In part B, 60 NSCLC patients were to receive 15 mg/kg of bevacizumab every 3 weeks along with pemetrexed and carboplatin for the initial four cycles, followed by pemetrexed for another four cycles. The primary endpoint was the progression-free survival rate at 6 months (PFS6) in both subparts. The anticipated sample size was 106 evaluable mCRC patients to achieve 85% statistical power for concluding noninferiority with a margin of half the difference (18.8%) between DRL_BZ and Avastin, along with a pilot study involving 60 evaluable NSCLC patients. Safety comparison included assessing adverse events (AEs), infusion reactions, and lab abnormalities. Immunogenicity comparison involved the incidence of antidrug antibodies (ADAs) and neutralizing antibodies (NAbs). Pharmacokinetic comparison was planned after the first and fourth dosing cycles of treatment in 24 NSCLC patients. The PFS6 for mCRC patients treated with DRL_BZ and RMP was 57.8% and 50% respectively, with a difference in efficacy of 7.8 (-8.7, 23.7). The PFS9 was 31.1% and 22.9%, with a difference of 8.2% (-6.9%, 22.9%). The objective response rate (ORR) for DRL_BZ and RMP was 28.8% and 22.4%, while the disease control rate (DCR) was 44.2% and 37.9% respectively. For NSCLC patients, the PFS6 was 44% and 45%, showing a difference of -1.0 (-4.2, 22.1). The ORR was 41.4% and 48.1%, and the DCR was 62.1% and 63%. The frequency, type, and severity of AEs were similar in both indications. Blood levels during the first and fourth dosing cycles exhibited comparable values. All NSCLC patients tested negative for ADA, while no mCRC patients on DRL_BZ tested positive for ADA. Low incidences of ADA (8%) and NAbs (4.0%) were reported in patients on RMP. Overall, the efficacy, safety, immunogenicity, and pharmacokinetic parameters of DRL_BZ and RMP were found to be comparable. Clinical Trial Registration For BZ-01-002: CTRI/2016/01/006481.

Interfraction variations in doses at OARs during three-dimensional high dose rate brachytherapy planning of cervix cancer.

Objective: The American Brachytherapy (BT) Society recommends that BT must be included as a component of the definitive radiation therapy for cervical carcinoma because recurrences and complications are decreased when BT is used in addition to external beam radiotherapy. The aim of this study is to quantify the interfraction dose variations (VARacts) during high dose rate (HDR) BT, the effect of variation in dose in terms of excess "unrecognized" dose to OAR and to conclude the reason of the variation in reference of applicator position/geometry versus deformation of the organ at risk (OAR) concerned. Materials and Methods: Total 30 patients of carcinoma cervix, biopsy proven, between June 2018 and May 2019, were taken for the study. All patients were treated with external beam radiation therapy to a dose of 50 Gy in 25 fractions over 5 weeks, followed by three fractions of HDR intracavitary brachytherapy (ICBT) (7.5 Gy to point A in each fraction) by two-dimensional (2D) X-ray-based planning. Before treatment in the first and last fraction of BT, computed tomography (CT) scan was done for every patient. Then, a 3D-based planning was performed with CT images on our HDR Plus software with image sequence option. VARact was calculated. Rigid image registration of consecutive fraction images was used for quantification of the hypothetical variation in dose (VARhypo) arising exclusively due to changes in applicator placement and geometry. Results: The mean contoured rectal volumes for the first and third fractions were 41.49 cc and 44.72 cc, respectively, while the respective volumes for bladder were 9.33 cc and 9.35 cc cm. These differences were statistically insignificant (P value: 0.263 and 0.919 for rectum and bladder, respectively). The mean equivalent dose in 2 Gy fraction (EQD2) bladder D2cc was 5.68 Gy and 5.79 Gy in the first and third fraction ICBT, respectively. The mean EQD2 for the rectal D2cc was 11.63 Gy and 12.85 Gy in the first and third fraction ICBT, respectively. None of the patients had an actual cumulative EQD2 more than 90 Gy for bladder, but 36.66% of the patients had a rectal dose exceeding the tolerance (75 Gy). Regression plots showed that VARhypo alone could predict about 42.2% of the VARact in the rectum and 19.2% of the VARact in the bladder. Thus, the remaining variation was due to the organ deformation-related dose variations between the two fractions. Conclusions: There were no statistically significant variations in the volumes or doses of OAR between the two fractions. However, a significant proportion of patients may have a higher dose to the OAR in the third fraction in the absence of individualized planning. This increase is likely to be more detrimental where higher doses per fraction are used. Variations in OAR doses may be caused by organ deformation and/or changes in applicator placement/geometry.

Triple combination of palliative oral metronomic chemotherapy in recurrent and metastatic epithelial ovarian cancer: A retrospective study.

Background: Ovarian cancer is a leading cause of death from gynecological cancer in the world and in India. This study aims to evaluate the efficacy and toxicity profile of oral metronomic chemotherapy (MCT) in the form of etoposide, cyclophosphamide, and tamoxifen in recurrent and metastatic ovarian cancer. Methods: This was a retrospective observational study that included those post-treatment patients who had the recurrent or metastatic disease after completion of treatment in 2018 at Regional Cancer Centre, Bikaner, Rajasthan. Forty patients who were unfit for further intensive intravenous chemotherapy were included. The oral MCT constituted etoposide, cyclophosphamide, and tamoxifen. Descriptive statistics and Kaplan-Meier analyses were performed. Progression-free survival (PFS) and overall survival (OS) were assessed. Results: Forty women with a median age of 62 (range: 35-80) years were enrolled in the study to receive oral MCT. The Eastern Cooperative Oncology Group-Performance Status (ECOG-PS) was 0-1 in 28 patients and 2-3 in 12 patients. The best clinical response rate post-oral MCT was seen in the first 4 months. Objective response was observed in 24 (60%) of patients in the form of stable disease (19, 47.5%) and partial response (5, 12.5%). Disease progression was observed in 10 (25%) of patients. The median follow-up was 6.4 months (4.5-9.2 months). The median estimated OS was 6.5 months. The median estimated PFS was 3.7 months. Nineteen (47.5%) patients had grade-I/II mucositis. Grade-III/IV mucositis were observed in 9 (22.5%) patients. Thirty-seven (92.5%) patients died at the end of the study at 1 year. Dose reduction was required in 15 (37.5%) patients. Conclusion: Oral MCT was found to be an effective and well-tolerated regime with good symptomatic control and low-moderate toxicity profile in patients with relapsed and metastatic ovarian cancer. However, 22% of patients showed grade-III/IV thrombocytopenia.

Clinical impact of extended field radiation therapy in Stage III carcinoma cervix versus conventional field techniques: A comparative study.

Aim: The aim of the study was to examine tumor control and clinical outcomes of extended field irradiation and compare it with those treated with conventional field in same disease profile and also to determine toxicities associated with radiation treatment. Methods: This study included 50 biopsy-proven and registered International Federation of Gynecology and Obstetrics Stage III cases of carcinoma cervix treated with concurrent computed tomography (injection cisplatin 40 mg/m2 weekly) + external beam radiotherapy (EBRT) upto 50 Gy + high-dose-rate intracavitary brachytherapy (ICBT) (22.5 Gy). Twenty-five patients were randomized to each arm. Arm A: Conventional field EBRT 50 Gy with concurrent weekly chemotherapy followed by ICBT. Arm B: Extended field EBRT 50 Gy with concurrent weekly chemotherapy followed by ICBT. Results: At 12-month follow-up, 43 patients (86%) had attained CR. Overall, seven patients (14%) were in noncomplete response (CR) group (non-CR = patients with partial response, stable disease, or progressive disease). The non-CR rate was 16% for Arm A and 20% for Arm B. Among seven patients of non-CR group, six had local disease and one had failure at distant site. Five (10%) patients died in this study, 2 (8%) in Arm A and 3 (12%) patients in Arm B. Residual disease was seen in 2 (4%) patients. Grade III diarrhea was seen in eight patients (16%), 3 in Arm A (12%) and 5 in Arm B (20%). Fifteen patients (30%) developed Grade III skin toxicity. Seven patients in Arm A (28%) and 8 patients (32%) in Arm B developed Grade III toxicity. Twenty-five (50%) cases presented with varying stages of vaginal adhesions and stenosis. Conclusion: Majority of patients achieved CR with minimal acute and late toxicities with similar results in both arms. No patient had pelvic or para-aortic metastasis until recent follow-up.

Metronomic palliative chemotherapy in locally advanced, recurrent and metastatic head-and-neck cancer: A single-arm, retrospective study of a regional cancer center of North India (Asia).

BACKGROUND: Head-and-neck cancer is the most common cancer in developing countries of Southeast Asia. Most of the patients present to the hospital in advanced stage and have a poor prognosis. This study aims to evaluate the efficacy and toxicity profile of oral metronomic chemotherapy (MCT) in the form of methotrexate and celecoxib in locally advanced, recurrent and metastatic head-and-neck cancers. MATERIALS AND METHODS: This was a single-arm retrospective observational study that included posttreatment patients with locally advanced, recurrent and metastatic disease in the year 2016 (January 1, to December 31, 2016). A total of 84 patients warranting palliative chemotherapy but not willing to take intravenous chemotherapy were included in the study. The oral MCT schedule consisted of oral celecoxib (200 mg twice daily) and oral methotrexate (15 mg/m2/week). Response evaluation was done using the Response Evaluation Criteria in Solid Tumors criteria version 1.1, and toxicity profile was assessed using the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.03. Descriptive statistics and Kaplan-Meier analysis were performed. RESULTS: Eighty-four patients, 68 males and 16 females, with a median age of 62 years (range: 35-80 years), were enrolled in the study to receive oral MCT. The Eastern Cooperative Oncology Group performance status was 0-1 in 62 patients and 2-3 in 22 patients. The primary sites of disease were buccal mucosa (18), tongue (22), tonsil (24), lower alveolus (7), hypopharynx (10), and soft palate (3). The best clinical response rate in post oral MCT was seen in the first 4 months (120 days). Objective response was observed in 67% of patients in the form of stable disease (56%) and partial response (11%). Disease progression was observed in 27% of patients. The median follow-up was 192 (6.4 months) days. The median estimated overall survival was 195 (6.5 months) days. The median estimated progression-free survival was 110 (3.6 months) days. Symptomatic relief with respect to pain was reported in about 75% of patients. Eighteen (21%) patients had Grade I-II mucosal reactions. Grade III-IV mucosal reactions were observed in five (6%) patients. Seventy-eight (93%) patients died at the end of the study at 1 year. Dose reduction was required in 15 (18%) patients. CONCLUSION: Oral MCT using celecoxib and methotrexate is an effective, economical, and well-tolerated regimen with good pain control and low toxicity profile in patients with locally advanced, recurrent and metastatic head-and-neck cancer.

Acute treatment-related toxicity in elderly patients with good performance status compared to young patients in locally advanced esophageal carcinoma treated by definitive chemoradiation: A retrospective comparative study.

INTRODUCTION: The benefit of definitive chemoradiotherapy (CRT) in elderly patients with locally advanced esophageal cancer is not well established. We perform a single institutional retrospective study of CRT in terms of toxicity in elderly patients (age more than 60 years) as compared with young cohort (age <60 years) in locally advanced nonmetastatic esophageal cancer. PATIENTS AND METHODS: A total 145 of patients, 79 in young age (Group A) and 66 patients of elder age (Group B) with Stage II and III squamous cell carcinoma of the esophagus with ECOG PS of 0-1, who had undergone definitive CRT at our institute from January 2015 to November 2018 were selected for this analysis. Chemotherapy was cisplatin (40 mg/m2) given concurrently on weekly basis with radiotherapy (RT). Total prescribed dose of RT was 50.4 Gy at the rate of 1.8 Gy per fraction. Median age was 40 years (25-60 years) and 65 years (60-75 years) in young and elderly group, respectively. Follow-up is done at median of 28 months (1-48 months) after treatment. RESULTS: Acute Grade 2-3 esophagitis was seen in 48.10% in young cohort, while it was 60.6% in older group. Grade 2-3 nausea and vomiting was seen in 32.91% in young age patients, while it was 45.5% in elder patients. No statistically significant difference is seen in acute treatment-related toxicity in young and elderly group. CONCLUSION: Our conclusion is that patients with adequate functional status should not be excluded from curative CRT based on age alone.

Induction Chemotherapy Followed by Concurrent Chemoradiation in the Management of Different Stages of Cervical Carcinoma: 5-year Retrospective Study.

AIM: The data of survival for Indian cervical cancer patients treated by indigenous modifications of the protocol are scarce. The objective of this retrospective study was to analyze the efficacy and tolerability in patients of cervical carcinoma treated by neoadjuvant chemotherapy followed by concurrent chemoradiation. MATERIALS AND METHODS: Three hundred and thirty two cases of squamous cell carcinoma of cervix who received 3 cycles of neoadjuvant chemotherapy followed concurrent chemoradiation were retrospectively analyzed for overall survival (OS), disease-free survival (DFS), and local pelvic control rate. RESULTS: The 3-year OS and DFS were 93.7 % for stage I-B, 88.0 and 84.0 % for stage II-A, 82.8 and 79.7 % for stage II-B, 70.0 and 64.9 % for stage III-A, 59.3 and 52.4 % for stage III-B, and 53.6 and 32.1 % for stage IV-A disease. The 5-year OS and DFS rates were 93.7 and 87.5 % for stage I-B, 84.0 % for Stage II-A, 79.7 and 76.6 % for stage II-B, 67.6 and 59.5 % for stage III-A, 48.4 and 41.9 % for stage III-B, and 28.6 and 14.3 % for stage IV-A disease. CONCLUSION: Neoadjuvant chemotherapy followed by concurrent chemoradiation is feasible and produces impressive disease-free and overall survival. This protocol is especially helpful for busy cancer centers with long waiting lists on radiotherapy machines.

Giant cell variant of malignant fibrous histiocytoma of male breast: A rare case report.

Malignant fibrous histiocytoma (MFH) is the most common form of soft tissue sarcoma during middle and late adulthood in the deep connective tissue of the extremities, abdominal cavity, and retroperitoneum. However, primary breast sarcoma is a rare disease entity, comprising less than 1% of all breast malignancies. MFH of the male breast is very rare. We present a case of MFH of giant cell variant of the right breast in a 50-year-old male who presented with a painless lump. Following cytological investigation, simple mastectomy was performed. Immunohistochemical staining confirmed the diagnosis.