Seema Gulia

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.

Oligometastatic breast cancer: A mini review.

With few exceptions such as germ cell tumors, trophoblastic neoplasms and colonic cancers, metastatic solid tumors are considered largely incurable. It is increasingly appreciated that oligometaststic cancer differs from multi-metastatic disease in prognosis and survival. Oligometastatic breast cancer (OMBC) is, therefore, sometimes considered as an intermediate biological state between localized and widely metastatic disease. There is no strict definition of OMBC with studies using different criteria. Treatment of OMBC is still controversial in view of sparse data that is retrospective. However, there is an increasing shift toward individualized, multidisciplinary management of OMBC with the intent to cure some patients. This article will concisely review the subject of OMBC from points of view of biology and practical management recommendations.

Induction chemotherapy in technically unresectable locally advanced oral cavity cancers: Does it make a difference?

BACKGROUND Locally advanced and unresectable oral cavity cancers have a poor prognosis. Induction might be beneficial in this setting by reducing tumor bulk and allowing definitive surgery. AIM To analyze the impact of induction chemotherapy on locally advanced, technically unresectable oral cavity cancers. MATERIALS AND METHODS Retrospective analysis of patients with locally advanced oral cavity cancers, who were treated with neoadjuvant chemotherapy (NACT) during the period between June 2009 and December 2010. Data from a prospectively filled database were analyzed for information on patient characteristics, chemotherapy received, toxicity, response rates, local treatment offered, patterns of failure, and overall survival. The statistical analysis was performed with SPSS version 16. RESULTS 123 patients, with a median age of 42 years were analyzed. Buccal mucosa was the most common subsite (68.30%). Three drug regimen was utilized in 26 patients (21.10%) and the rest received two drug regimen. Resectability was achieved in 17 patients treated with 3 drug regimen (68.00%) and 36 patients receiving 2 drug regimen. Febrile neutropenia was seen in 3 patients (3.09%) receiving 2 drug regimen and in 9 patients (34.62%) receiving 3 drug regimen. The estimated median OS was not reached in patients who had clinical response and underwent surgery as opposed to 8 months in patients treated with non-surgical modality post NACT (P = 0.0001). CONCLUSION Induction chemotherapy was effective in converting technically unresectable oral cavity cancers to operable disease in approximately 40% of patients and was associated with significantly improved overall survival in comparison to nonsurgical treatment.

Outcome of Gestational Trophoblastic Neoplasia: Experience from a Tertiary Cancer Centre in India

AIMS Gestational trophoblastic neoplasms (GTN) comprise a spectrum of interrelated conditions originating from the placenta. With sensitive assays for human chorionic gonadotropin (β-hCG) and current approaches to chemotherapy, most women with GTN can be cured with preservation of reproductive potential. The purpose of this analysis was to address the outcome of GTN from a developing country, as data are largely sparse from this region. MATERIALS AND METHODS We undertook a retrospective review of GTN cases treated at our centre from 2001 to 2008. Patients of GTN were assigned to low-risk (score ≤ 6) or high-risk (score ≥ 7) categories as per the modified World Health Organization scoring system. The low-risk group was treated with single-agent methotrexate (MTX) and the high-risk group received the EMA/CO regimen. Salvage therapies were EMA/EP or BEP. Treatment was continued until serum β-hCG values were normal for three consecutive chemotherapy cycles, after which the patients were kept on follow-up. RESULTS In total, 70 GTN patients were treated at our institution during this period; 48 (68%) were low-risk and 22 (32%) were in the high-risk category. The median β-hCG level was 50 000 IU/l. The lung was the most common site of metastasis, seen in 15 (21%) patients. Among 48 low-risk patients, 37 (77%) received chemotherapy, of whom 25 (68%) were treated with MTX and 24 (96%) achieved a complete response. Twelve low-risk patients (32%) received EMA/CO therapy; 10 (83%) achieved a complete response. The 22 high-risk patients received EMA/CO and of these 16 (73%) achieved a complete response, two (9%) progressed, two (9%) died of progressive disease and two (9%) were lost to follow-up. Grade 3/4 toxicities with MTX included mucositis in two (8%) and neutropenia in five (21%) patients. At a median follow-up of 16.6 months, overall survival in the low- and high-risk groups was 100 and 88.8%, respectively. CONCLUSION Risk-stratified treatment of GTN was associated with acceptable toxicity and resulted in outcome that was comparable with international standards.

Clinical Trial Ethics: One Standard Does Not Fit All

TO THE EDITOR: In their recent commentary on the ethics of clinical trials in low-resource settings, Joffe and Miller have raised several pertinent points and questioned some established norms. Their core argument—that choice of control arm treatment in lowresource settings should be considered in the context of local standards—has considerable merit. Imposition of uniform, some would say artificial, control arm standards on clinical trials conducted in various economic settings can impede this invaluable component of health care activity. However, two further considerations deserve attention before this viewpoint can be unequivocally endorsed. First, in many lowto middle-income countries, the host community is not a homogeneous monolith; rather, it is a complex collection of individuals and groups with widely varying privileges. In India, for example, potential patients for a trial of systemic therapy in human epidermal growth factor receptor 2 (HER2) –positive early breast cancer will range from the majority in whom the nontrial standard would be only anthracycline-taxane based chemotherapy to a minority in whom the full recommended course of trastuzumab would be eminently feasible. What would be an ethical control arm for a systemic therapy trial in this subtype of breast cancer that will preserve the balance of risks and benefits for all patients? Would a trial with a no-trastuzumab control arm, justified on consideration of local standards, be open only to underprivileged patients? Joffe and Miller seem to have oversimplified the situation when they assert that “every participant has an ex ante chance of receiving an intervention that is potentially beneficial as compared with the local standard of care.” Second, in an era rife with new standards in oncology practice, it is time to establish some sort of hierarchy within these standards. For example, imatinib in chronic myeloid leukemia, rituximab in CD20 aggressive lymphomas, and trastuzumab in HER2-positive early breast cancer have conferred unprecedented benefits on patients, including lives saved from cancer-related death. It could be argued that to conduct systemic therapy clinical trials in these diseases without the corresponding agents in the control arm would be ethically unjustified regardless of local standard considerations. The same cannot be said for many other targeted therapies in metastatic cancers that have, at best, been shown to result in only modest gains, often in the form of improvement in progression-free survival unaccompanied by overall survival or quality-of-life benefits. We believe that a careful appraisal of each clinical trial setting, including the efficacy and feasibility of standard therapeutic choices, will lead to appropriate design of the control arm in most instances. It is about time that the medical ethics community acknowledged that a one-standard-fits-all approach approach to conducting trials has outlived its usefulness, and a more nuanced personalized approach will be in the best interests of all stakeholders.

Intrathecal trastuzumab for leptomeningeal carcinomatosis in patients with human epidermal growth factor receptor 2 positive breast cancer

There has been recent increase in incidence of leptomeningeal carcinomatosis, possibly due to widespread use of adjuvant trastuzumab and its known poor CNS penetration. Currently there are limited therapeutic options for these patients and outcome is poor. We report two cases of women with HER2 positive breast cancer who developed leptomeningeal carcinomatosis for which they were treated with intrathecal trastuzumab in combination with systemic therapy. Both patients had rapid symptomatic benefit and radiological response and remained progression free for at least seven months. Intrathecal trastuzumab can be considered a reasonable therapeutic option for these difficult to treat patients.

Everolimus in heavily pretreated metastatic breast cancer: Is real world experience different?

BACKGROUND Drugs targeting mammalian target of rapamycin signaling pathway have been recently approved for treatment of hormone receptor (HR) positive metastatic breast cancer (MBC). However, there is lack of real world data from India on the use of this therapeutic strategy. MATERIALS AND METHODS A retrospective analysis of MBC patients who had recurrence or progression while receiving aromatase inhibitors (AIs) and further treated with everolimus and either tamoxifen/AI/fulvestrant between March 2012 and June 2014, was undertaken. RESULTS There were 41 patients with median age 55 years, 73% with visceral metastasis, and 73% with ≥2 sites of metastases. Thirty (73%) patients had received 3 prior lines of therapy including AI (100%), tamoxifen (94%), fulvestrant (39%), and chemotherapy (100%) while the remaining had received <3 lines of prior therapy. The commonest Grade 3/4 adverse events were stomatitis (19%), hyperglycemia (new/worsening, 17%), fatigue (14.5%), nonneutropenic infections (14%), anemia (12%) and pneumonitis (7%). Everolimus dose reductions were required in 31% patients. There were 30% partial responses, 38% prolonged disease stabilizations and 32% disease progression as best responses to everolimus. The median progression-free survival was 22 weeks (5 months). CONCLUSIONS Everolimus based treatment has meaningful activity in heavily pretreated patients with HR-positive MBC but is associated with considerable toxicity and requirement for dose adjustment.

Acute renal failure secondary to ingestion of alternative medication in a patient with breast cancer.

Complementary and alternative medicine (CAM) use among cancer patients is widely prevalent and often underreported. Advanced stage of disease is significantly associated with CAM use. The concurrent use of alternative medicines and chemotherapy drugs has the potential to lead to toxicities as well as altered therapeutic activity due to unknown interactions. We report a case of early breast cancer who presented to us with non-oliguric acute renal failure related concurrent use of Ayurvedic medicines and adjuvant anthracycline based.

Prevalence and patterns of cytomegalovirus DNAemia in adult patients with acute lymphoblastic leukemia on chemotherapy.

Th e use of immunosuppressive agents such as high-dose steroids and anti-metabolites for prolonged periods can predispose patients with acute lymphoblastic leukemia (ALL) to develop cytomegalovirus (CMV) reactivation and disease, more so in countries with a background of high CMV seropositivity ( 90%) such as India [1]. Th ere are abundant data on the pattern and time course of CMV reactivation or primary infection in allogeneic stem cell transplant recipients, and well-defi ned strategies have been developed for prophylaxis, screening and pre-emptive treatment [2]. However, there is a remarkable paucity of data regarding CMV reactivation in ALL. Reactivation can lead to prolonged cytopenias, fever and other manifestations, which are often misdiagnosed and treated empirically with antimicrobials. Delays in diagnosis and therapy can compromise the dose intensity of chemotherapy, a key to achieving cure in ALL. Th ese facts underlie the importance of understanding the pattern, time of occurrence and clinical manifestations of CMV reactivation in ALL. To address this, we analyzed adult patients with ALL ( 14 years) who were treated with multi-agent chemotherapy (MCP-841) between July 2009 and July 2011 at Tata Memorial Hospital, India to understand the clinical features and pattern of CMV reactivation. CMV DNA was estimated in blood with real time quantitative polymerase chain reaction (PCR) (Roche; CMV DNA Quant Kit) in patients with clinical suspicion of CMV reactivation. Th is included the presence of persistent fever alone (fever of unknown origin), hepatomegaly and/or splenomegaly (relapse of ALL being ruled out), cytopenias (absolute neutrophil count less than 1000/mm 3 , platelet count less than 100 000/mm 3 , hemoglobin less than 8 g/dL) unexplained by the previous chemotherapy, respiratory symptoms (cough, coryza, infi ltrates on chest radiography), gastrointestinal symptoms (abdominal pain, anorexia, loose stools), unexplained liver dysfunction, signifi cant weight loss and skin rashes. Th e lowest detection limit with this method was 392 copies/mL. CMV serology was not done at baseline prior to ALL therapy given the high prevalence of CMV seropositivity in our population. We did not carry out active surveillance for CMV reactivation. Th ese patients were not given any antibacterial, antifungal or antiviral prophylaxis except co-trimoxazole. Patients with neutropenic and non-neutropenic fever were investigated with blood (bacterial/fungal), sputum and urine culture, computed tomography (CT) of the thorax, ultrasound scan of the abdomen and pelvis, bronchoscopy with culture of bronchoalveolar lavage in cases with pneumonia (if there was no response to antibacterial and antifungal therapy), and were included if no cause was found or if there was no response to therapy. Patients with deranged liver function tests were included if they had normal imaging, negative serology for hepatitis viruses and no history of hepatotoxic drug usage. None of the patients was subjected to biopsy to prove CMV disease due to low platelets and coagulopathy. Patients with raised CMV DNA copy numbers and clinical features suggestive of CMV infection (after excluding all other causes) were treated with ganciclovir. CMV DNA copy numbers were monitored until they became negative. Isolation of CMV DNA in whole blood along with clinical or laboratory features consistent with CMV infection, response to ganciclovir based therapy and temporal association of response to declining CMV DNA copy numbers was labeled as CMV reactivation. Case records were analyzed for demographics, chemotherapy details and the type of therapy prior to CMV reactivation, clinical features, laboratory parameters, viral load, antiviral therapy and response.

National Cancer Grid of India Consensus Guidelines on the Management of Cervical Cancer

Standard guidelines for the management of early and locally advanced cervical cancer are available from various academic consortiums nationally and internationally. However, implementing standard-of-care treatment poses unique challenges within low- and middle-income countries, such as India, where diverse clinical care practices may exist. The National Cancer Grid, a consortium of 108 institutions in India, aims to homogenize care for patients with cervical cancer by achieving consensus on not only imaging and management, but also in addressing potential solutions to prevalent challenges that affect the homogenous implementation of standard-of-care treatment. These guidelines therefore represent a consensus statement of the National Cancer Grid gynecologic cancer expert group and will assist in homogenization of the therapeutic management of patients with cervical cancer in India.