Rakesh Jalali

Clinical studies for improving radiotherapy with 2-deoxy-D-glucose: Present status and future prospects

Higher rates of glucose usage generally correlate with poor prognosis in several types of malignant tumours. Experimental studies (both in vitro and in vivo) have shown that 2-deoxy-D-glucose (2-DG), a glucose analog and glycolytic inhibitor, enhances radiation-induced damage selectively in tumor cells while protecting normal cells, thereby suggesting that 2-DG can be used as a differential radiomodifier to improve the efficacy of radiotherapy. Clinical trials undertaken to study the feasibility, safety, and validity of this suggested approach will be described. Based on 2-DG-induced radiosensitization observed in primary organ cultures of cerebral glioma tissues, clinical trials were designed taking into consideration the radiobiology of gliomas and pharmacokinetics of 2-DG. Phase I/II clinical trials have unequivocally demonstrated that a combination of 2-DG (200-300 mg 2-DG per kg body weight orally administered after overnight fasting, 20 min before irradiation) with large weekly fractions (5 Gy/fraction) of low-LET radiotherapy is well tolerated without any acute toxicity or late radiation damage to the normal brain tissue. Nonserious transient side effects similar to hypoglycemia induced disturbances like restlessness, nausea, and vomiting were observed at the 2-DG doses used. Data from these trials involving more than 100 patients have clearly indicated a moderate increase in the survival, with a significant improvement in the quality of life with clinicopathological evidence of protection of normal brain tissue. A phase III multicentric trial to evaluate the efficacy of the combined treatment is in progress. Directions for future studies are discussed.

Factors Influencing Neurocognitive Outcomes in Young Patients With Benign and Low-Grade Brain Tumors Treated With Stereotactic Conformal Radiotherapy

PURPOSE To present the effect of radiotherapy doses to different volumes of normal structures on neurocognitive outcomes in young patients with benign and low-grade brain tumors treated prospectively with stereotactic conformal radiotherapy (SCRT). METHODS AND MATERIALS Twenty-eight patients (median age, 13 years) with residual/progressive brain tumors (10 craniopharyngioma, 8 cerebellar astrocytoma, 6 optic pathway glioma and 4 cerebral low-grade glioma) were treated with SCRT to a dose of 54 Gy in 30 fractions over 6 weeks. Prospective neuropsychological assessments were done at baseline before RT and at subsequent follow-up examinations. The change in intelligence quotient (IQ) scores was correlated with various factors, including dose-volume to normal structures. RESULTS Although the overall mean full-scale IQ (FSIQ) at baseline before RT remained unchanged at 2-year follow-up after SCRT, one third of patients did show a >10% decline in FSIQ as compared with baseline. Logistic regression analysis demonstrated that patients aged <15 years had a significantly higher chance of developing a >10% drop in FSIQ than older patients (53% vs. 10%, p = 0.03). Dosimetric comparison in patients showing a >10% decline vs. patients showing a <10% decline in IQ revealed that patients receiving >43.2 Gy to >13% of volume of the left temporal lobe were the ones to show a significant drop in FSIQ (p = 0.048). Radiotherapy doses to other normal structures, including supratentorial brain, right temporal lobe, and frontal lobes, did not reveal any significant correlation. CONCLUSION Our prospectively collected dosimetric data show younger age and radiotherapy doses to left temporal lobe to be predictors of neurocognitive decline, and may well be used as possible dose constraints for high-precision radiotherapy planning.

Prospective Evaluation of Radiotherapy With Concurrent and Adjuvant Temozolomide in Children With Newly Diagnosed Diffuse Intrinsic Pontine Glioma

PURPOSE To present outcome data in a prospective study of radiotherapy (RT) with concurrent and adjuvant temozolomide (TMZ) in children with diffuse intrinsic pontine gliomas (DIPGs). METHODS AND MATERIALS Pediatric patients with newly diagnosed DIPGs were prospectively treated with focal RT to a dose of 54 Gy in 30 fractions along with concurrent daily TMZ (75 mg/m(2), Days 1-42). Four weeks after completing the initial RT-TMZ schedule, adjuvant TMZ (200 mg/m(2), Days 1-5) was given every 28 days to a maximum of 12 cycles. Response was evaluated clinically and radiologically with magnetic resonance imaging and positron emission tomography scans. RESULTS Between March 2005 and November 2006, 20 children (mean age, 8.3 years) were accrued. Eighteen patients have died from disease progression, one patient is alive with progressive disease, and one patient is alive with stable disease. Median overall survival and progression-free survival were 9.15 months and 6.9 months, respectively. Grade III/IV toxicity during the concurrent RT-TMZ phase included thrombocytopenia in 3 patients, leucopenia in 2, and vomiting in 7. Transient Grade II skin toxicity developed in the irradiated fields in 18 patients. During the adjuvant TMZ phase, Grade III/IV leucopenia developed in 2 patients and Grade IV thrombocytopenia in 1 patient. Patients with magnetic resonance imaging diagnosis of a high-grade tumor had worse survival than those with a low-grade tumor (p = 0.001). Patients with neurologic improvement after RT-TMZ had significantly better survival than those who did not (p = 0.048). CONCLUSIONS TMZ with RT has not yielded any improvement in the outcome of DIPG compared with RT alone. Further clinical trials should explore novel treatment modalities.

Factors Influencing Cosmetic Outcome in Breast Conservation

With more than 1 million new cases each year, female breast cancer is the second most common cancer in the world and the most common cancer among women. Breast cancer involves a multimodality treatment and a co-ordinated approach from various specialties. Breast-conserving therapy (BCT) is increasingly being integrated into the management of breast cancer. The obvious advantages of BCT are equivalent local and distant control rates as compared with mastectomy and the preservation of the breast. However, the key to a successful BCT is achieving a cosmetic outcome that is acceptable to the patient and the physician. Cosmesis in breast cancer is the end result of a range of factors that fall under the broad heads of surgery, radiotherapy, chemotherapy and hormonal treatment. All of these modalities can play a role in compromising breast cosmesis. This overview discusses the factors that are critical in affecting the final cosmetic outcome in patients with BCT.

Single-Injection Depot Progesterone Before Surgery and Survival in Women With Operable Breast Cancer: A Randomized Controlled Trial

PURPOSE Many nonrandomized studies have suggested better outcome for patients with breast cancer who undergo surgery during the luteal (progestogenic) phase of their menstrual cycle, but this is controversial. We investigated the effect of a single preoperative injection of hydroxyprogesterone in women with operable breast cancer (OBC) in a randomized controlled trial (ClinicalTrials.gov identifier, NCT00123669). PATIENTS AND METHODS One thousand patients with OBC were randomly assigned to receive surgery or an intramuscular injection of depot hydroxyprogesterone 500 mg 5 to 14 days before surgery. Primary and secondary end points were disease-free survival (DFS) and overall survival (OS), respectively. An analysis by axillary lymph node status was preplanned. RESULTS At a median follow-up of 65 months among 976 eligible patients, 273 recurrences and 202 deaths were recorded. In the progesterone group versus control group, 5-year DFS and OS rates were 73.9% v 70.2% (hazard ratio [HR], 0.87; 95% CI, 0.68 to 1.09; P = .23) and 80.2% v 78.4% (HR, 0.92; 95% CI, 0.69 to 1.21; P = .53), respectively. In 471 node-positive patients, the 5-year DFS and OS rates in the progesterone group versus control group were 65.3% v 54.7% (HR, 0.72; 95% CI, 0.54 to 0.97; P = .02) and 75.7% v 66.8% (HR, 0.70; 95% CI, 0.49 to 0.99; P = .04), respectively. In multivariate analysis, DFS was significantly improved with progesterone in node-positive patients (adjusted HR, 0.71; 95% CI, 0.53 to 0.95; P = .02), whereas there was no significant effect in node-negative patients (P for interaction = .04). CONCLUSION A single injection of hydroxyprogesterone before surgery did not improve outcomes in all women with OBC. This intervention showed significant improvement in node-positive women that may be considered hypothesis generating. If replicated in other studies, this could be a simple and inexpensive intervention, especially in developing countries where the incidence of lymph node metastasis is high.

Molecular targeted therapy in recurrent glioblastoma: current challenges and future directions

Introduction: The survival of patients with glioblastoma (GBM), which is the most common primary brain malignancy, remains poor with current treatment modalities. However, an enhanced understanding of gliomagenesis is supporting the development of targeted molecular therapies with the potential for improving clinical outcomes. Areas covered: Epidermal growth factor receptor (EGFR) and vascular endothelial growth factor receptor (VEGFR) initiate key signaling pathways in GBM; however, trials with anti-EGFR agents have failed to show improved outcomes. Bevacizumab, a monoclonal antibody targeting VEGF, remains the only FDA-approved molecular drug in GBM; yet its use has only improved progression-free survival without any improvement in overall survival. We review the evidence supporting the continued evaluation of targeted molecular therapies in recurrent GBM. In addition, newer potential therapies targeting other signaling pathways, heat shock proteins and proteosomes, as well as the concept of targeting glioma stem cells are discussed. Expert opinion: The complex genetic origin of GBM makes it challenging to identify molecular subsets that may benefit from specific targeted therapies. Pathway inhibition, via multisite kinase inhibitors or a carefully selected combination of molecular drugs with or without cytotoxic agents, is currently undergoing evaluation in clinical trials and may improve outcomes in these patients.

The diagnostic dilemma of primary central nervous system melanoma

Melanomas are malignant neoplasms of melanocytes developing predominantly in the skin, but occasionally arising from eyes, mucous membranes, and the central nervous system (CNS). The CNS can be affected by a spectrum of melanocytic lesions ranging from diffuse neurocutaneous melanosis, to a focal and benign neoplasm (melanocytoma), and to an overtly malignant tumor (melanoma). Primary melanocytic lesions involving the CNS are typically concentrated in the perimedullary and high cervical region. Primary CNS melanoma cannot be reliably distinguished from metastatic melanoma on neuroimaging and histopathological characteristics alone: its diagnosis is established only after exclusion of secondary metastatic disease from a cutaneous, mucosal or retinal primary. We present two patients with primary CNS melanoma and discuss relevant issues, available treatment options, and expected outcomes. Awareness of disease spectrum and clinico-biological differences may be used to guide therapeutic decision-making for a patient with a proven or suspected primary CNS melanoma.

Management of locally advanced breast cancer: Evolution and current practice

Locally advanced breast cancer (LABC) accounts for a sizeable number (30-60%) of breast cancer cases and is a common clinical scenario in developing countries. The treatment of LABC has evolved from single modality treatment, consisting of radical mutilating surgery or higher doses of radiotherapy in inoperable disease to multimodality management, which along with the above two included systemic therapy. Neoadjuvant chemotherapy (NACT) has made a tremendous impact on the management of LABC. NACT was initiated to institute systemic therapy upfront at the earliest in this group of patients with a high risk of micrometastasis burden. While NACT did not yield a survival advantage, it has however made breast conservation possible in selected group of cases. Large number of studies and many randomised trials have been done in women with LABC in order to improve the therapeutic decisions and also the local control and survival. With this background we have reviewed various treatment options in patients with LABC which should possibly help in guiding the clinicians for optimal management of LABC.

Real-time PCR assay based on the differential expression of microRNAs and protein-coding genes for molecular classification of formalin-fixed paraffin embedded medulloblastomas

BACKGROUND Medulloblastoma has recently been found to consist of 4 molecularly and clinically distinct subgroups: WNT, Sonce hedgehog (SHH), Group 3, and Group 4. Deregulated microRNA expression is known to contribute to pathogenesis and has been shown to have diagnostic and prognostic potential in the classification of various cancers. METHODS Molecular subgrouping and microRNA expression analysis of 44 frozen and 59 formalin-fixed paraffin embedded medulloblastomas from an Indian cohort were carried out by real-time RT-PCR assay. RESULTS The differential expression of 9 microRNAs in the 4 molecular subgroups was validated in a set of 101 medulloblastomas. The tumors in the WNT subgroup showed significant (P < .0001) overexpression of miR-193a-3p, miR-224, miR-148a, miR-23b, and miR-365. Reliable classification of medulloblastomas into the 4 molecular subgroups was obtained using a set of 12 protein-coding genes and 9 microRNAs as markers in a real-time RT-PCR assay with an accuracy of 97% as judged by the Prediction Analysis of Microarrays. Age at diagnosis, histology, gender-related incidence, and the relative survival rates of the 4 molecular subgroups in the present Indian cohort were found to be similar to those reported for medulloblastomas from the American and European subcontinent. Non-WNT, non-SHH medulloblastomas underexpressing miR-592 or overexpressing miR-182 were found to have significantly inferior survival rates, indicating utility of these miRNAs as markers for risk stratification. CONCLUSIONS The microRNA based real-time PCR assay is rapid, simple, inexpensive, and useful for molecular classification and risk stratification of medulloblastomas, in particular formalin-fixed paraffin embedded tissues, wherein the expression profile of protein-coding genes is often less reliable due to RNA fragmentation.

Estrogen, progesterone and HER2 receptor expression in breast tumors of patients, and their usage of HER2-targeted therapy, in a tertiary care centre in India

BACKGROUND This study was undertaken to document the pattern of expression of estrogen (ER), progesterone (PR) and human epidermal growth factor receptor-2 (HER2) and the usage of HER2-targeted therapy in a large tertiary care hospital in India in the year 2008. MATERIALS AND METHODS The histopathology reports of all breast cancer patients registered in the hospital in 2008 were extracted from the electronic medical record system. All the cases were immunohistochemically evaluated for estrogen and progesterone receptor status (ER and PR), and c-erbB-2 protein (HER2) expression using standard immunoperoxidase method. The use of HER2-targeted therapies was evaluated by extracting relevant information from the database of the hospital pharmacy and case charts of patients enrolled in ongoing approved trials. RESULTS A total of 2001 new patients of invasive breast cancers with available pathology reports were registered in the hospital in the year 2008. ER and/or PR expression was positive in tumors of 1025 (51.2%) patients. HER2 3+ expression by immunohistochemistry (IHC) was found in 335 (16.7%) and HER2 2+ in 163 (8.1%). The triple negative phenotype was found in 596 (29.8%) patients. An estimated 441 patients were eligible to receive HER2-targeted therapy based on their HER2 status. Of these 38 (8.6%) patients received some form of HER2-targeted therapy; 20 patients (4.5%) as part of ongoing clinical trials and 18 (4.1%) as part of routine care. CONCLUSIONS The overwhelming majority of patients eligible for HER2-targeted therapy in our institution are unable to receive it because of financial constraints and limited access to health insurance. There is a higher fraction of patients with the triple negative phenotype compared to the Western population.