Rajendra Kerkar

A cluster randomized, controlled trial of breast and cervix cancer screening in Mumbai, India: methodology and interim results after three rounds of screening

Cervix and Breast cancers are the most common cancers among women worldwide and extract a large toll in developing countries. In May 1998, supported by a grant from the NCI (US), the Tata Memorial Hospital, Mumbai, India, started a cluster‐randomized, controlled, screening‐trial for cervix and breast cancer using trained primary health workers to provide health‐education, visual‐inspection of cervix (with 4% acetic acid‐VIA) and clinical breast examination (CBE) in the screening arm, and only health education in the control arm. Four rounds of screening at 2‐year intervals will be followed by 8 years of monitoring for incidence and mortality from cervix and breast cancers. The methodology and interim results after three rounds of screening are presented here. Good randomization was achieved between the screening (n = 75360) and control arms (n = 76178). In the screening arm we see: High screening participation rates; Low attrition; Good compliance to diagnostic confirmation; Significant downstaging; Excellent treatment completion rate; Improving case fatality ratios. The ever‐screened and never‐screened participants in the screening arm show significant differences with reference to the variables religion, language, age, education, occupation, income and health‐seeking behavior for gynecological and breast‐related complaints. During the same period, in the control arm we see excellent participation rate for health education; Low attrition and a good number of symptomatic referrals for both cervix and breast.

Diffusion-weighted Imaging of Gynecologic Tumors: Diagnostic Pearls and Potential Pitfalls

Conventional magnetic resonance (MR) imaging has an established role in gynecologic imaging. However, increasing clinical demand for improved lesion characterization and disease mapping to optimize patient management has resulted in the incorporation of newer sequences, such as diffusion-weighted (DW) imaging, into routine protocols for pelvic MR imaging. DW imaging provides functional information about the microenvironment of water in tissues, hence augmenting the morphologic information derived from conventional MR images. It can depict shifts of water from extracellular to intracellular compartments, altered cell membrane permeability, disruption of cell membrane depolarization, and increased cellular density. Such changes may be associated with tumors. DW imaging has emerged as an important cancer biomarker and takes the role of the radiologist from the level of mere macroscopic diagnosis to more active participation in determining patient prognosis and management through a better understanding of the tumor microenvironment. With the growing acknowledgment of DW imaging as a pivotal tool in the radiologists armamentarium, radiologists must be familiar with the appearances of various gynecologic tumors at DW imaging and understand the implications of this sequence for improving diagnostic accuracy and predicting and monitoring treatment response. Although positron emission tomography/computed tomography is extremely useful for detecting tumor recurrence in cervical and ovarian carcinomas, it has a limited specificity in the immediate posttreatment setting. DW imaging may aid in detection of residual or recurrent tumors in such situations. DW imaging is a potentially useful adjunct to conventional MR imaging for evaluation of gynecologic tumors, thus improving overall diagnostic accuracy, tumor staging, prediction of response to therapy, and treatment follow-up.

Determinants of Compliance in a Cluster Randomised Controlled Trial on Screening of Breast and Cervix Cancer in Mumbai, India

Objectives: This study aims to investigate the efficacy of screening by low-cost technology in down-staging and reducing mortality due to breast and cervix cancer. Methods: The present trial is a community-based, cluster randomised controlled cohort study on screening for breast and cervix cancers (clinical breast examination and visual inspection of the cervix after application of 4% acetic acid). Univariate and multivariate logistic regression analyses are conducted to identify the predictors of participation in screening. Results: The average compliance is 71.43 and 64.93% for breast and cervix cancer screening, respectively, with the highest compliance in round 1. At the end of 3 screening rounds, 94 and 84% of the eligible women were screened at least once for breast and cervix cancer, respectively. Younger women, women from other than Hindu and Muslim communities, school level-educated women, women belonging to lower-income families, Marathi-speaking women, married women and women who had previously consulted for any breast or gynaecological complaints had higher compliance to participation in screening. Conclusions: Good compliance rates to screening have been demonstrated in the trial, reflecting acceptance of the study by the society, which has implications while translating the trial into a programme.

Spectrum of neuroendocrine carcinomas of the uterine cervix, including histopathologic features, terminology, immunohistochemical profile, and clinical outcomes in a series of 50 cases from a single institution in India.

Neuroendocrine carcinomas of the cervix are uncommon, characterized by a histomorphological spectrum and, mostly, an aggressive clinical course. There are only few substantial studies on such cases documented from our country, where cervical cancer is the second most common cancer affecting women. Herein, we present a spectrum of 50 cervical neuroendocrine carcinomas, including histopathologic features, terminology, immunohistochemical (IHC) profile, and clinical outcomes, wherever available. Fifty tumors occurred in women, with their age ranging from 23 to 69 years (mean, 48.6 years; median, 46.5 years). Stagewise, among 25 cases, most cases (6, or 24%) presented with stage IB. Average tumor size was 4.7 cm. On histopathologic review, 26 tumors (52%) were classified as small cell carcinoma (SMCA); 14 (28%), as large cell neuroendocrine carcinomas (LCNECs); 4 (8%), as SMCA+LCNECs; and 6, as mixed carcinomas, including 3 tumors (6%) with SMCA and squamous cell carcinoma (SCC), 2 tumors (4%) with LCNEC and adenocarcinoma, and a single tumor (2%) with LCNEC and squamous cell carcinoma. On IHC performed in 41 tumors (82%), 36 tumors (87.8%) were positive for at least a single neuroendocrine marker, and 22 (53.6%) expressed 2 neuroendocrine markers. Synaptophysin was positive in 22 (59.4%) of 37 tumors; chromogranin, in 27 (72.9%) of 37; CD56, in 8 (100%) of 8; and neuron-specific enolase in 7 (87.5%) of 8 tumors. Treatment wise, among 30 patients (60%), 6 (20%) underwent surgery, including Wertheim hysterectomy (5) and simple hysterectomy (1); 8 (26.6%) underwent surgery with adjuvant treatment, and 10 patients (33.3%) were offered chemotherapy and/or radiotherapy. On follow-up (27 patients, or 54%) over 1 to 144 months, 16 patients (59.2%) were alive with disease over median duration of 9 months, and 7 (25.9%) were free of disease over median duration of 26.5 months. There were 5 recorded deaths. Thirteen tumors (48.1%) metastasized, most commonly to liver. In cases with early stage disease and adjuvant treatment, including radiotherapy, LCNEC histology fared well. This study forms the largest documented series on cervical neuroendocrine carcinomas from our country, testifying the current histopathologic classification system. Although SMCAs can be recognized on morphology, LCNECs need to be correctly identified because these can be misdiagnosed in the absence of neuroendocrine markers. Synaptophysin, chromogranin, and CD56 are optimal IHC markers. Small cell carcinomas, pure or mixed, are relatively more aggressive. All these tumors are best treated with multimodal therapy. Early stage disease treated with radical surgery and adjuvant treatment seems to increase survival. Despite aggressive treatment, prognosis is dismal.

Determinants of compliance in a cluster randomised controlled trial on screening of breast and cervix cancer in mumbai, India. 2. Compliance to referral and treatment.

Objectives: The study aims to investigate the efficacy of screening by low-cost technology in down-staging and reduction of mortality due to breast and cervix cancer. Methods: The present trial is a community-based, cluster randomised controlled cohort study on screening for breast and cervix cancers (clinical breast examination and visual inspection of the cervix after application of 4% acetic acid). Univariate and multivariate logistic regression analyses are conducted to identify the predictors of compliance to referral among screen-positive women and to treatment among cancer cases. Results: The compliance to diagnostic investigations is 73% among screen-positive women referred for breast cancer and 79% among women referred for cervix cancer. Younger women, women working in service or being self-employed, school level-educated women, mother tongue Marathi, participation in screening in all 3 rounds and women referred as screen positive for cervix cancer had higher compliance to diagnostic investigations. The compliance to treatment completion is higher in women diagnosed with breast cancer, at 95%, compared to 86% for cervix cancers and 81% for cervix pre-cancers. Conclusions: Good compliance rates along with a proper system of referral, further investigations, confirmation of diagnosis and treatment as demonstrated in this trial are crucial for successful screening programmes.

Large cell neuroendocrine carcinoma of the endometrium: An extremely uncommon diagnosis, but worth the efforts

Neuroendocrine carcinomas (NEC) of the female genital tract are aggressive and uncommon tumors. They usually involve the cervix and ovary, and are seen very rarely in the endometrium. The overwhelming majority of endometrial NECs are of conventional small cell type (up to 60 cases). Only seven cases of large cell type NEC of the endometrium have been reported. We report a case of large-cell neuroendocrine carcinoma (LCNEC) of the endometrium in a 70-year-old female. The case is described for its rarity and shows that a high index of suspicion can help the pathologist to use immunohistochemistry and in turn help in selection of appropriate chemotherapy.

Uterine smooth muscle tumors of uncertain malignant potential and atypical leiomyoma: A morphological study of these grey zones with clinical correlation

OBJECTIVES To study the histological features in uterine STUMP, and atypical leiomyomas (AL), and to correlate with clinical outcome. MATERIALS AND METHODS From January 2004 to August 2010, a total of 21 cases were retrieved from records, labeled as STUMP(7), AL (5), AL with low risk of recurrence (2), smooth muscle tumor of low malignant potential (STLMP) (2), and symplastic leiomyoma (5). The slides were reviewed for coagulative tumor cell necrosis (CTCN), hyaline necrosis/ infarction type necrosis, presence and degree of cytological atypia, mitotic activity, epithelioid morphology and myxoid features. The other characteristics (such as size, circumscription, individual tumor cell necrosis), were noted, wherever available. RESULTS The mean age was 45 years (median 46; range 24-67 yrs). CTCN was seen in 2 cases on examination of additional material; wherein a revised diagnosis of leiomyosarcoma had been given. Infarction type necrosis and individual cell necrosis was seen in 2 and 3 cases, respectively. Mitoses were less than 5/10 hpf in all the cases. One of the tumours labeled as STUMP also had concurrent endometrial adenocarcinoma. Follow up: Follow-up was available in 11 cases (52.3%). One patient had died. (cause not known). In 10 patients, the follow-up ranged from 4 to 56 months (mean 20.9 months; median 15 months) nine patients were alive and well. One patient (labeled STLMP) had metastatic liver disease 3 yrs after the primary surgery, at the last follow-up. CONCLUSIONS 1) There is an overlap in using the terminologies as STUMP, AL, AL with low risk of recurrence, AL with low malignant potential. A designation of STUMP does convey a category of borderline malignancy to the gynecological surgeons. Most behave in a benign fashion and follow-up without adjuvant therapy is currently recommended. Critical evaluation of coagulative tumor necrosis is essential. Follow-up remains a challenge in our setting.

Neoadjuvant Chemotherapy Followed by Radical Surgery Versus Concomitant Chemotherapy and Radiotherapy in Patients With Stage IB2, IIA, or IIB Squamous Cervical Cancer: A Randomized Controlled Trial

Purpose We compared the efficacy and toxicity of neoadjuvant chemotherapy followed by radical surgery versus standard cisplatin-based chemoradiation in patients with locally advanced squamous cervical cancer. Patients and Methods This was a single-center, phase III, randomized controlled trial ( ClinicalTrials.gov identifier: NCT00193739). Eligible patients were between 18 and 65 years old and had stage IB2, IIA, or IIB squamous cervical cancer. They were randomly assigned, after stratification by stage, to receive either three cycles of neoadjuvant chemotherapy using paclitaxel and carboplatin once every 3 weeks followed by radical hysterectomy or standard radiotherapy with concomitant cisplatin once every week for 5 weeks. Patients in the neoadjuvant group received postoperative adjuvant radiation or concomitant chemotherapy and radiotherapy, if indicated. The primary end point was disease-free survival (DFS), defined as survival without relapse or death related to cancer, and secondary end points included overall survival and toxicity. Results Between September 2003 and February 2015, 635 patients were randomly assigned, of whom 633 (316 patients in the neoadjuvant chemotherapy plus surgery group and 317 patients in the concomitant chemoradiation group) were included in the final analysis, with a median follow-up time of 58.5 months. The 5-year DFS in the neoadjuvant chemotherapy plus surgery group was 69.3% compared with 76.7% in the concomitant chemoradiation group (hazard ratio, 1.38; 95% CI, 1.02 to 1.87; P = .038), whereas the corresponding 5-year OS rates were 75.4% and 74.7%, respectively (hazard ratio, 1.025; 95% CI, 0.752 to 1.398; P = .87). The delayed toxicities at 24 months or later after treatment completion in the neoadjuvant chemotherapy plus surgery group versus the concomitant chemoradiation group were rectal (2.2% v 3.5%, respectively), bladder (1.6% v 3.5%, respectively), and vaginal (12.0% v 25.6%, respectively). Conclusion Cisplatin-based concomitant chemoradiation resulted in superior DFS compared with neoadjuvant chemotherapy followed by radical surgery in locally advanced cervical cancer.

Clinico-pathological spectrum of primary ovarian malignant mixed mullerian tumors (OMMMT) from a tertiary cancer institute: A series of 27 cases

AIMS AND OBJECTIVES To study the clinico-pathological characteristics of primary ovarian malignant mixed mullerian tumor (OMMMT) and assess the prognostic factors associated with treatment outcome and survival. MATERIALS AND METHODS The pathology database was searched for primary ovarian carcinosarcoma diagnosed and/or managed at our institute from period of January 2004 to July 2010. The histological sections were reviewed, with emphasis on type and grade of epithelial and sarcomatous components. The medical records were retrospectively analyzed for clinical details and follow up. RESULTS A total of 27 cases of primary ovarian carcinosarcoma were identified. The median age at diagnosis was 51 years. Fourteen patients had advanced stage (stage III and IV) at presentation. Cytoreductive surgery was done in 18 cases, and 7 had received upfront chemotherapy. Histologically, 10 cases had epithelial predominance (> 50% epithelial component) and 11 had sarcoma predominance. The most frequent epithelial component was endometroid type, and most common sarcoma component was rhabdomyosarcomatous. Hyaline droplets within sarcomatous stroma were seen prominently in 15 cases. Three cases showed germ cell /yolk sac-like areas. Eighteen cases had follow up with a median of 15 months (4-40 months). The recurrence-free survival in advanced stage and sarcoma predominant was 10.5 months in comparison to 13 months in early stage and epithelial predominant OMMMT. CONCLUSION Primary ovarian carcinosarcoma is a rare biphasic malignancy with variable proportions of epithelial and spindle elements. Presence of hyaline droplets within spindle sarcoma in a biopsy from ovarian mass should alert the pathologists regarding MMMT. Advanced stage, suboptimal cytoreduction, and sarcoma predominant tumors are likely to have a worse outcome in ovarian MMMT.

Protocol for a phase III randomised trial of image-guided intensity modulated radiotherapy (IG-IMRT) and conventional radiotherapy for late small bowel toxicity reduction after postoperative adjuvant radiation in Ca cervix

Introduction External beam radiation followed by vaginal brachytherapy (±chemotherapy) leads to reduction in the risk of local recurrence and improves progression-free survival in patients with adverse risk factors following Wertheims hysterectomy albeit at the risk of late bowel toxicity. Intensity Modulated Radiotherapy (IMRT) results in reduction in bowel doses and has potential to reduce late morbidity, however, needs to be confirmed prospectively in a randomised trial. The present randomised trial tests reduction if any in late small bowel toxicity with the use of IMRT in postoperative setting. Methods and analysis Patients more than 18 years of age who need adjuvant (chemo) radiation will be eligible. Patients with residual pelvic or para-aortic nodal disease, history of multiple abdominal surgeries or any other medical bowel condition will be excluded. The trial will randomise patients into standard radiation or IMRT. The primary aim is to compare differences in late grades II–IV bowel toxicity between the two arms. The secondary aims of the study focus on evaluating correlation of dose–volume parameters and late toxicity and quality of life. The trial is planned as a multicentre randomised study. The trial is designed to detect a 13% difference in late grades II–IV bowel toxicity with an α of 0.05 and β of 0.80. A total of 240 patients will be required to demonstrate the aforesaid difference. Ethics and dissemination The trial is approved by institutional ethics review board and will be routinely monitored as per standard guidelines. The study results will be disseminated via peer reviewed scientific journals, conference presentations and submission to regulatory authorities. Registration The trial is registered with clinicaltrials.gov (NCT 01279135).