Bidhu Kalyan Mohanti

IMPROVING CANCER RADIOTHERAPY WITH 2-DEOXY-D-GLUCOSE: PHASE I/II CLINICAL TRIALS ON HUMAN CEREBRAL GLIOMAS

PURPOSE Evaluation of tolerance, toxicity, and feasibility of combining large fraction (5 Gy) radiotherapy with 2-deoxy-D-glucose (2DG), an inhibitor of glucose transport and glycolysis, which has been shown to differentially inhibit repair of radiation damage in cancer cells. METHODS AND MATERIALS Twenty patients with supratentorial glioma (Grade 3/4), following surgery were treated with four weekly fractions of oral 2DG (200 mg/kg body weight) followed by whole brain irradiation (5 Gy). Two weeks later, supplement focal radiation to the tumor (14 Gy/7 fractions) was given. Routine clinical evaluation, x-ray computerized tomography (CT), and magnetic resonance (MR) imaging were carried out to study the acute and late radiation effects. RESULTS All the 20 patients completed the treatment without any interruption. The vital parameters were within normal limits during the treatment. None reported headache during the treatment. Mild to moderate nausea and vomiting were observed during the days of combined therapy (2DG + RT) in 10 patients. No significant deterioration of the neurological status was observed during the treatment period. Seven patients were alive at 63, 43, 36, 28, 27, 19, and 18 months of follow-up. In these patients, the clinical and MR imaging studies did not reveal any late radiation effects. CONCLUSIONS Feasibility of administering the treatment (2DG + 5 Gy) is demonstrated by the excellent tolerance observed in all 20 patients. Further, the clinical and MR studies also show the absence of any brain parenchymal damage.

Best Supportive Care Compared With Chemotherapy for Unresectable Gall Bladder Cancer: A Randomized Controlled Study

PURPOSE We designed this study to evaluate efficacy of modified gemcitabine and oxaliplatin (mGEMOX) over best supportive care (BSC) or fluorouracil (FU) and folinic acid (FA) in unresectable gall bladder cancer (GBC). PATIENTS AND METHODS Patients with unresectable GBC were enrolled for single center randomized study. Arm A, BSC; arm B, FU 425 mg/m(2) and FA 20 mg/m(2) intravenous (IV) bolus weekly for 30 weeks (FUFA); arm C, gemcitabine 900 mg/m(2) and oxaliplatin 80 mg/m(2) IV infusion on days 1 and 8 every 3 weeks for maximum of six cycles. Eighty-one patients were randomly assigned, arms A (n = 27), B (n = 28), and C (n = 26). RESULTS Complete response plus partial response in the three groups was 0 (0%), four (14.3%), and eight (30.8%) respectively (P < .001). Two patients in the mGEMOX arm and one patient in the FUFA arm underwent curative resection after chemotherapy. One patient in the mGEMOX arm had complete pathologic response. Median overall survival (OS) was 4.5, 4.6, and 9.5 months for the BSC, FUFA, and mGEMOX arms (P = .039), respectively. Progression-free survival (PFS) was 2.8, 3.5, and 8.5 months for the three groups (P < .001). There was no difference in grade 3/4 toxicities in the chemotherapy arms except transaminitis, which was more prevalent in mGEMOX arm (P = .04). Two patients in the FUFA arm and 10 patients in the mGEMOX arm had grade 3 or 4 myelosuppression. Two patients in the mGEMOX group had neutropenic fever that resolved with antibiotics. CONCLUSION This randomized controlled trial confirmed the efficacy of chemotherapy (mGEMOX) compared with BSC and FUFA in improving OS and PFS in unresectable GBC.

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.

Chemotherapy alone vs. chemotherapy plus high dose multiple antioxidants in patients with advanced non small cell lung cancer.

Objective: In vitro and animal studies suggest that antitumor effect of chemotherapeutic agents may be enhanced by antioxidants. Therefore, we initiated a clinical study to test the efficacy of high-dose multiple antioxidants (vitamins C, E and beta carotene) as an adjunct to chemotherapy (paclitaxel and carboplatin) in non-small-cell lung cancer. Methods: 136 patients of stage IIIb and stage IV NSCLC were randomized to receive chemotherapy (paclitaxel and carboplatin) alone (chemotherapy arm, n = 72) or chemotherapy in combination with ascorbic acid 6100 mg/day, dl-alpha-tocopherol (vitamin E) 1050 mg/day and beta-carotene 60 mg/day (combination arm, n = 64). Survival were calculated by the Kaplan-Meier method and compared using the log-rank test. Results: An overall response rate (RR) of 33% was observed in chemotherapy arm with 24 patients showing a partial response (PR) and none showing a complete response (CR). In combination arm the overall RR was 37% with 24 patients showing PR and two showing CR. The median survival times in chemotherapy arm and combination arm were nine and 11 months respectively. The overall survival (OS) rates in chemotherapy arm and combination arm at one year were 32.9% and 39.1%, and at two years, 11.1% and 15.6% respectively. None of these differences were statistically significant (p = 0.20). Toxicity profiles were similar in both arms. Conclusions: These results do not support the concern that antioxidants might protect cancer cells from the free radical damage induced by chemotherapy. Larger trials are needed to demonstrate whether high-dose multiple antioxidants in conjunction with chemotherapy increase the response rates and/or survival time in advanced lung cancer.

Intrarectal formalin application, an effective treatment for grade III haemorrhagic radiation proctitis

Haemorrhagic radiation proctitis (HRP) is infrequently seen amongst the patients who are either undergoing or have undergone radiotherapy to the pelvis. We treated 16 documented cases of HRP, who did not respond to conventional steroid retention enemas, with 4% formalin application. It was observed that the rectal bleeding was controlled completely in 81% cases in median follow up of 11 months (range 6-17 months) and diversion colostomy could be avoided in all the cases. The effectiveness of local formalin application in severe HRP is described in this article.

Disregulated expression of the Th2 cytokine gene in patients with intraoral squamous cell carcinoma.

It has been seen that advanced stage oral squamous cell carcinoma is associated with impaired T‐cell function and higher antibody response. In order to find out if such immune disregulation is associated with alteration of T‐helper (Th) type CD4+ T‐cell phenotype leading to altered cytokine production, we studied the Th‐like cytokine profile in 35 oral squamous cell carcinoma patients and 21 normal controls. Concomitant expression of both Th1 and Th2 cytokine genes was studied by reverse transcription and Polymerase Chain Reaction (PCR) based amplification (RT‐PCR) of mRNA extracted from freshly isolated peripheral blood mononuclear cells (PBMC) using specific primers for Interferon (IFN)‐γ, Interleukin (IL)‐2, IL‐4 and IL‐10. Almost 63% of oral cancer patients showed polarization of a Th‐like cytokine response as compared to 33 % of the normal controls while 66.6% of normal controls showed a predominantly non‐polarized Th0 response. Expression of IFN‐γ and IL‐2 genes was more commonly seen in the early stage of the disease (p < 0.02) whereas majority of advanced stage tumours was associated with enhanced expression of IL‐4 and IL‐10 but not IFN‐γ and IL‐2 genes. Patients with lymphnode metastases and poorly differentiated tumours expressed IL‐4 and IL‐10 more frequently with concomitant suppression of IFN‐γ and IL‐2 genes. It seems therefore, that the development of oral squamous cell carcinoma leads to polarization of cytokine gene expression that is skewed towards the Th1‐like response in the early stage. However, increasing tumour load and lymphnode invasion suppresses Th1 cytokine genes, thus skewing it toward a Th2‐like cytokine response.

Radiation related morbidities and their impact on quality of life in head and neck cancer patients receiving radical radiotherapy

Although 50–70% of head and neck cancer patients in India receive radiotherapy (RT), radiation-related acute and late morbidities and their impact on quality of life (QOL) are infrequently reported. Acute and late radiation morbidities and QOL were assessed in a prospective longitudinal study of 45 patients with head and neck cancers receiving radical RT to a dose of 7000 cGy in conventional fractionation. Grade II acute morbidities experienced by the largest percent of the sample during the course of RT pertained to the mucosa (66.4%), salivary gland (84%), and oesophagus (53%). These morbidities led to an increase in the symptom scores of appetite loss (76.46), fatigue (65.75) and pain (44.77). This increase in the symptom scores consequently led to a significant decline in physical, social and emotional functioning as well as global health status score during the course of RT (p < 0.001). Scores improved after 1 month of RT but did not reach the pre-RT value. Future studies may consider correlating QOL assessment to significant patient and disease related parameters such as performance status, weight loss, stage and site of disease.

Weight loss during radiotherapy for head and neck malignancies: what factors impact it?

Radiotherapy (RT) is an important treatment modality in head and neck cancers. Loss of weight during RT due to various factors is a matter of concern. This study was conducted to see the pattern of weight loss and the causative factors involved. One hundred forty patients with head and neck cancer treated with radical RT, concurrent chemoradiation, or postoperative RT were retrospectively studied. A dose of 70 Gy was given in the radical and in the chemoradiation schedule. In postoperative RT, a dose of 60-64 Gy was delivered. During the weekly review of the patients, serial recording of their weight was done along with measurement of other parameters. Analysis was done to see which factors were causative in patients having a weight loss of >5 kg and of >10%. Three variables were found to be significant for the >5-kg weight loss. These were a low initial Karnofsky performance score (KPS; <0.001), use of chemoradiation (P < 0.001), and a total dose of >60 Gy (P = 0.04). For the >10% weight loss, the significant factors were low initial KPS (P < 0.001) and use of chemoradiation (P < 0.001). Therefore, it is important to take care of the nutrition of those patients who have a low KPS, are on chemoradiation, or will be delivered a dose of >60 Gy. The role of prophylactic Ryles tube placement or agents such as megestrol acetate in such patients should be further investigated.

Clinical features and prognostic factors of early breast cancer at a major cancer center in North India

BACKGROUND Data on the clinical profile of early breast cancer (EBC) from India is scant. Due to differences in genetics, environment, lifestyle, socio-demographic structure and ethnicity, the presentation and behavior of breast cancer in India may be different. AIMS To analyze the clinical presentation and outcome of EBC patients. SETTINGS AND DESIGN A single center retrospective study. MATERIALS AND METHODS Data from 487 EBC patients registered and treated at our institute from 1993 through 1999 were analyzed. Coxs multivariate regression test was used to determine prognostic factors for overall and disease-free survival (OS & DFS). RESULTS The median age was 47 years and 49.7% patients were pre-menopausal. Ninety-six per cent patients presented with a lump. Stages I, IIa, and IIb comprised 7.8%, 38.8%, and 47.6% respectively. Only 11.3% patients opted for breast-conserving surgery (BCS) while the remaining 88.7% underwent modified radical mastectomy (MRM). Adjuvant chemotherapy was administered to 275 (56.5%), and radiotherapy to 146 (29.9%). Estrogen receptor status was known in 173, of whom 93 (53.7%) were positive. Most patients were prescribed Tamoxifen for 5 years. At a median follow-up of 48 months, 126 (25.9%) patients had relapsed (systemic 107, loco-regional 19) and 94 (19.3%) had died. Five-year DFS and OS were 73% and 78%, respectively. On multivariate analysis, four positive nodes adversely influenced survival (P< 0.01). CONCLUSIONS The median age at presentation was 47 years, significantly lower than most Western figures. The majority (86.4%) had a lump size > two cm. BCS was done in only 11% and the rest underwent MRM. Nodal involvement was the significant prognostic factor.

Prophylactic beclomethasone spray to the skin during postoperative radiotherapy of carcinoma breast: a prospective randomized study.

BACKGROUND AND AIMS Radiation induced wet desquamation of skin in carcinoma breast patients is a painful condition. In this study topical beclomethasone dipropionate spray was used as prophylaxis with the purpose of reducing risk of the wet desquamation of skin in irradiated field. MATERIALS AND METHODS Sixty patients of carcinoma breast were planned for postoperative loco regional radiotherapy (50 Gy in 25 fraction over five weeks) were prospectively randomized into two groups (1) steroid group-patients were advised to use beclomethasone dipropionate spray in irradiated axilla from day one of radiotherapy, (2) control group-patients were not allowed to use any topical agent in irradiated area. Radiation induced skin reaction was noted in terms of erythema, dry desquamation and wet desquamation weekly till end of prescribed 50 Gy dose of the radiation therapy. STATISTICAL METHOD Chi-square test was used to see the statistical significance of the difference in wet desquamation between two arms of the study. Chi-square value and P-value was calculated for the difference of wet desquamation in two study arms. RESULT In steroid group 4/30 (13.33%) patients developed wet desquamation of the axillary skin at the end of the radiotherapy. For the control group, this figure was 11/30 (36.66%). The difference in wet desquamation of the axillary skin in the two groups was statistically significant (P-value = 0.0369). CONCLUSION Topical steroid (beclomethasone dipropionate spray) for skin during radiotherapy significantly reduces the risk of wet desquamation of the skin.