Design and synthesis of spiro derivatives of parthenin as novel anti-cancer agents.

Several novel spiro derivatives of parthenin (1) have been synthesized by the dipolar cycloaddition using various dipoles viz; benzonitrile oxides, nitrones and azides with exocyclic double bond of C ring (α-methylene-γ-butyrolactone). Majority of the compounds exhibited improved anti-cancer activity compared to the parthenin, when screened for their in vitro cytotoxicity against three human cancer cell lines viz., SW-620, DU-145 and PC-3. In vivo screening of select analog revealed improved anti-cancer activity with low mammalian toxicity as compared to parthenin. The results of the cytotoxicity pattern of these derivatives reveals the SAR of these sesquiterpinoid lactones and possible role of α,ß-unsaturated ketone of parthenin in inhibiting NF-kB. A mechanistic correlation of anti-cancer activity along with in vivo and western blotting experiments has been described.

Adjuvant sequential chemotherapy and radiotherapy in uterine papillary serous carcinoma.

PURPOSE: To evaluate the efficacy and toxicity of adjuvant combination of sequential chemotherapy followed by radiotherapy in uterine papillary serous carcinoma (UPSC). METHODS AND MATERIALS: From April 1994 to June 2003, 26 patients (median age 61.7 years, range 46.9-78.4) with UPSC were treated with a platinum-based chemoradiation protocol after definitive surgery. 9 patients were assigned as stage I (35%), 4 were stage II (15%), 11 were stage III (42%), and 2 were stage IV (8%) according to the FIGO staging for gynecological cancers. All patients underwent total hysterectomy, salpingo-oophorectomy, pelvic +/- perioartic lymph nodes dissection/sampling, omentectomy, and peritoneal washing. The adjuvant chemoradiation protocol consists of 4 cycles of platinum-based chemotherapy followed by pelvic irradiation and vaginal vault brachytherapy. In selected stage I patients with no or minimal myometrial invasion, only vault brachytherapy was given after adjuvant chemotherapy. RESULTS: After a median follow-up of 28 months (range 9-113 months), 14 (54%) patients were alive and free of disease. 12 out of these 14 patients were FIGO stage I/II. 9 patients (35%) had died (8 from distant metastases). The Kaplan-Meier 2-year and 5-year survival estimates were 69.5% and 57%, respectively. Only 4 (15%) patients had pelvic recurrence. None of the patients developed local vault recurrence. The treatment was well tolerated, only 1 patient developed congestive cardiac failure from the chemotherapy and 6 patients had grade 2 peripheral neuropathy on follow-up. CONCLUSION: In our series of UPSC patients treated with adjuvant chemotherapy followed by radiotherapy, local control can be achieved in a majority of patients. Distant failure remains the major cause of mortality. Further investigations into finding a more effective systemic therapy are required if improvement in outcome for this form of uterine cancer is to be achieved.

Intracranial germ cell tumour: experience of a Singaporean institution over 11-year period.

BACKGROUND: Intracranial germ cell tumours (IGCT) are rare. We present our experience in Therapeutic Radiology Department, National Cancer Centre, Singapore. METHODS: A retrospective study was conducted through case notes review on 25 patients with IGCT referred between January 1988 and January 1999. RESULTS: The median age at diagnosis was 13 years (range 6-22). The tumours were mainly pineal germinoma (72%). Median follow-up for living patients was 2.57 years (range 0.12-10.8). Median radiotherapy (RT) dose to whole brain, primary site and spine was 35.3,54 and 30 Gys respectively. Four to six cycles of BEP or JEB chemotherapy (CM) were given in 10 patients. As for the whole study group, the seven-year overall survival (OS) and recurrence-free survival (RFS) were 86% (95% CI 72-100) and 78% (95% CI 60-100) respectively. The 10-year OS and RFS were 65% (95% CI 36-100) and 78% (95% CI 60-100) respectively. The germinoma group had 75% 10-year OS and 86% 10-year RFS. Mixed germinoma and non-germinoma germ cell tumours (NGGCT) group had 50% one-year RFS and 44% two-year OS. Acute side-effects of RT and CM were minimal. There was no statistically significant difference in side-effects when treatment modalities were compared. CONCLUSION: In the treatment of intracranial germinoma, we recommend biopsy and CSRT. Primary chemotherapy (+/- low-dose cranial RT) should be used in the protocol or clinical trial settings. Chemo-radiotherapy is recommended for mixed germinoma and NGGCT. A multicentre trial is needed to address various controversial issues.

Prognostic factors in 677 patients in Singapore with nondisseminated nasopharyngeal carcinoma.

BACKGROUND: The objective of the current study was to describe the survival of nasopharyngeal carcinoma (NPC) patients in Singapore, verify the prognostic value of the revised 1997 TNM staging system, and develop a multivariate prognostic model for NPC. In addition, the authors also examined the prognostic value of characteristics of lymph node spread and parapharyngeal involvement. METHODS: A prospectively maintained database containing clinical and computed tomography scan data was used to reclassify 677 NPC patients treated between 1992 and 1994 according to the new staging system. Records were linked with the death registry to ascertain the patient's vital status and date of death. Overall and stage specific survival were analyzed using the Kaplan-Meier method and the log rank test. Univariate and multivariate Cox proportional hazards regression analysis were used to obtain prognostic models. RESULTS: Two hundred seventy-four deaths (40.5%) occurred. The 5-year survival rate was 56.6% (95% confidence interval [95% CI], 52.3%, 60.7%). The stage specific 5-year survival rates were: Stage I, 88%; Stage IIA, 75%; Stage IIB, 74%; Stage III, 60%; Stage IVA, 35%; and Stage IVB, 28%. TNM stage was found to be a statistically significant prognostic factor (P < 0.0001). Cranial nerve (hazard ratio [HR]: 2.77), orbit (HR: 5.71), and intracranial involvement (HR: 2.46) conferred a particularly bad prognosis in univariate analysis. Independently significant prognostic factors were age; lymph node status; and paraoropharyngeal, cranial nerve, orbit, and nasal involvement. Among lymph node positive patients, independently significant prognostic lymph node characteristics were Ho level and laterality. Although parapharyngeal involvement appeared to be prognostically unimportant, paraoropharyngeal involvement distinguished a subgroup with a poorer prognosis (HR: 1.84; 95% CI, 1.45, 2.34; P < 0.0001). Lateral spread to the medial infratemporal fossa and beyond also was found to confer a poorer prognosis. CONCLUSIONS: The results of the current study show that the revised 1997 TNM staging system is prognostically useful. Subdivision into paraoropharyngeal involvement and using the medial infratemporal fossa to delineate prognostically significant lateral spread should be considered in future revisions.

Concurrent chemoradiotherapy followed by adjuvant chemotherapy in Asian patients with nasopharyngeal carcinoma: toxicities and preliminary results.

PURPOSE: Nasopharyngeal carcinoma (NPC) is endemic in Singapore. Nearly 60% of the patients diagnosed with NPC will present with locally advanced disease. The North American Intergroup study 0099 reported improved survival outcome in patients with locally advanced NPC who received combined chemoradiotherapy when compared to radiotherapy alone. Hence we explored the feasibility and efficacy of a similar protocol in our patients. METHODS AND MATERIALS: Between June 1996 and December 1997, 57 patients were treated with the following schedule as described. Radical radiotherapy (RT) of 66-70 Gy to the primary and neck with cisplatin (CDDP) 25 mg/m2 on days 1-4 given by infusion over 6-8 hours daily on weeks 1, 4, and 7 of the RT. This is followed by a further 3 cycles of adjuvant chemotherapy starting from week 11 from the first dose of radiation (CDDP 20 mg/m2/d and 5-fluorouracil [5-FU] 1 gm/m2/d on days 1-4 every 28 days). RESULTS: The majority of patients (68%) had Stage IV disease. About 54% of patients received all the intended treatment; 75% received all 3 cycles of CDDP during the RT phase and 63% received all three cycles of adjuvant chemotherapy. The received dose intensity of CDDP and 5-FU of greater than 0.8 was achieved in 58% and 60% of the patients respectively. Two treatment-related deaths due to reactivation of hepatitis B and neutropenic sepsis respectively, were encountered. At median follow-up of 16 months, 14 patients had relapsed, 12 systemically and 2 loco-regionally. CONCLUSION: Due to the acceptable tolerability of such a protocol in our cohort of patients, we have embarked on a Phase III study to confirm the results of the 0099 Intergroup study in the Asian context.

Primary non-Hodgkin's lymphoma of the uterine cervix: case report of long-term survival of two patients treated with surgery and radiotherapy.

Two patients with Stage 1EA primary non-Hodgkin's lymphoma of the uterine cervix were treated by surgery and radiotherapy in 1986 and 1987. On follow-up, over a period of 10 years, both are well and remain free of recurrence.

A review of patients with high-risk carcinoma of the cervix treated with combined surgery and postoperative radiotherapy.

From May 1992 to October 1995, 57 patients with early stage cervical carcinoma were treated with hysterectomy and postoperative pelvic radiotherapy because of the presence of adverse histopathologic features. On prospective follow-up and analysis, the clinical outcome for 50 of these patients showed a pelvic disease control rate of 90.9%, a disease-free survival of 80.6% and an overall survival of 86.3%. Of the 8 relapses, half occurred in the pelvis i.e., 2 in the vaginal vault and 2 in the pelvic side walls. No severe complications were observed, but there was a 20% long-term Radiation Therapy and Oncology Group (RTOG) grade 1 to 2 urinary bladder dysfunctional problem and 28% incidence of suprapubic and/or leg oedema.

Radiotherapy as local adjuvant treatment for endometrial carcinoma--a review of 45 patients.

Forty-five patients with endometrial carcinoma were treated with local postoperative adjuvant radiotherapy during the period 1992 to 1995. Radiotherapy technique comprised both external beam irradiation as well as high-dose-rate vaginal vault brachytherapy. The 5-year overall survival and relapse-free survival rates were 74% and 73%, respectively and poorly differentiated histology grade was associated with poorer prognosis. Only 1 patient developed an isolated vaginal vault recurrence and another 9 patients relapsed mainly at the distal anatomical sites. The main radiotherapy-related complications were vaginal adhesion and stenosis. Radiotherapy is therefore effective as local adjuvant treatment in reducing risk of local-regional relapse in endometrial carcinoma.

Patient profile and survival in 270 computer tomography-staged patients with nasopharyngeal cancer treated at the Singapore General Hospital.

This is a report analysing the patient profile and survival results in 270 patients with nasopharyngeal carcinoma treated with radiation therapy between July 1987 and December 1988. The patients had a median age of 52.6 months, and a male-female ratio of 2.5:1. Ninety-four percent of patients were Chinese. The commonest presentation was that of a neck mass (found in approximately 65% of patients). Approximately two-thirds presented with disease more advanced than Ho's stage II. At a median follow-up of 52.6 months, the 5-year actuarial survival rate was 53% and the freedom from relapse rate was 57%. One hundred and seven patients died within the observation period. Of these, 46 patients had disease in the post nasal space, 41 in the neck and 60 in sites outside the head and neck.

Half body irradiation for palliation of widespread metastatic bone disease.

An analysis is made of 134 patients treated by a single dose half body irradiation at the Department of Therapeutic Radiology, Singapore General Hospital. A total of 149 fields were treated with 15 patients receiving both upper and lower half treatments. This technique achieved a more than 70% subjective pain relief in the patients who had widespread bony metastases. Side effects were minimal and this technique has been used on an outpatient basis since the first preliminary study in 1986. There was a dose response, more than 75% (75 out of 97 patients) with pain relief using doses of 700 cGy and above. Sensitive tumours also produced better results with nasopharyngeal carcinoma, prostate and breast having pain relief in more than 70% of patients. The largest group of patients (51 cases) treated was nasopharyngeal carcinoma, as this tumour is fairly common locally and often presents with bony metastases as the first site of spread.

Differentiated thyroid cancer: outcome of treatment in 80 cases.

The author carried out a retrospective analysis, with 6-13 years follow up, of 80 patients with differentiated thyroid cancer. The patients were treated with surgery, radioactive iodine, radiation therapy and suppression hormone therapy. The results, 5 year and 12 year survivals of 97% and 85%, are comparable with the results of much larger series with longer periods of follow up. The most significant prognostic factor was age at presentation. No patient below the age of 45 died from the cancer even if, at presentation, there was very advanced local disease or multiple distant metastases. In addition, sex, extent of local disease and presence of multiple metastases were also important in predicting survival. Cervical node involvement, by itself, did not worsen the prognosis and long survival with lung secondaries is possible.

Radiotherapy of early glottic cancer Singapore, 1978-1981.

This study analyses the results of primary radiotherapy for 44 patients with early glottic cancer (Tis, T1 stage) given at the Therapeutic Radiology Department, Singapore General Hospital during the 4-year period from 1978 to 1981. Irradiation was delivered using cobalt teletherapy with free set-ups, and without "air-gap" compensation. Total doses of 55Gy to 64Gy were given in daily fractions of 1.8Gy, treating five times a week. The crude 5-year survival rate for Tis/T1a tumours was 88.9% and for T1b lesions, 81%. On correcting for deaths from intercurrent disease, the survival rates improved to 95.5% and 92.6% respectively. In 33 cases where the quality of voice after radiation was assessed, 15 patients (45.4%) retained good voice quality with an additional 11 patients (33.3%) having acceptable voice quality. In seven cases the voice after radiation was rated as poor. Nine patients had local recurrence, giving a rate of 20.4%. One other patient had cervical node metastasis and subsequently developed lung secondaries. Surgery, solely or with re-irradiation, was an effective treatment for local recurrence. Re-irradiation alone failed to control any case with recurrence.

Advanced colorectal carcinoma--5 year survival of 76 cases treated at the Department of Therapeutic Radiology, Singapore General Hospital.

The results of 76 cases of advanced colorectal carcinoma treated at the Department of Therapeutic Radiology, Singapore General Hospital, from 1977 to 1978, are presented. All cases had "Curative" Surgery and were given adjuvant radiotherapy or chemotherapy or both. All were adenocarcinoma and had lymph node involvement as well as tumour infiltration through the bowel wall. 44 cases of rectal carcinoma were given radiotherapy to the pelvis followed by I/V 5-fluorouracil for at least one year. 32 cases of colon cancer were given I/V 5-fluorouracil for at least one year. 20 of these cases had cancer of the sigmoid colon and were given pelvic irradiation as well. The five year actuarial survival rates were 27.8% for rectal cancer and 24.3% for colon cancer.

Serum thyroglobulin (Tg) and thyroglobulin antibodies (TgAb) in thyroid cancer.

Serum thyroglobulin antibodies (TgAb) and serum thyroglobulin (Tg) levels were measured in 28 normal controls and 32 patients with differentiated thyroid cancer. The TgAb and Tg levels were measured in the patients when they were on replacement thyroxine therapy prior to the whole body radioiodine I-131 scan (WBS), using immunoradiometric assay kits. The TgAb level in normal controls was from 0-4.8 micrograms/ml, with a mean of 0.6 microgram/ml, while the Tg level in these controls was from 0.0-48.0 ng/ml, with a mean of 4.2 ng/ml. In the patients with thyroid cancer, the TgAb levels were normal except for a few patients who had residual thyroid or tumour in the neck and had raised levels of TgAb. Their Tg levels were normal except for 7 patients who had elevated values. 2 of these 7 had no evidence of disease on X-ray, bone scan, or WBS (I-131) while the other 5 had evidence of metastases. However, 4 patients had metastatic disease with normal Tg levels, and 2 of these patients had residual thyroid in the neck and raised TgAb levels, while in the remaining 2 patients, both Tg and TgAb were low. Serum Tg is a useful tumour marker for recurrent or metastatic thyroid cancer, but the presence of residual normal thyroid would interfere with the results.

Differentiated thyroid carcinoma--long term survival at the Singapore General Hospital.

The results of 48 cases of differentiated thyroid carcinoma treated at the Singapore General Hospital in the 5-year period 1977 to 1981 are presented. The peak incidence was in the 4th decade of life. Surgery, radiotherapy, radioactive iodine and hormones were the treatment modalities that were combined. 25% of the patients received radiotherapy while 74% were given at least one dose of radioactive iodine. The overall 5-year and 9-year actuarial (uncorrected) survival rates were 94.5% and 82.2% respectively. The 4 patients who died were in the older age group while younger patients had a good prognosis.

Radiotherapy of carcinoma of the uterine cervix in Singapore, 1973-1975.

The results of 322 patients with uterine cervix carcinoma treated by radiotherapy at the Singapore General Hospital in the 3-year period from 1973 to 75 are presented. Two hundred seventy-nine patients were treated with a combination of intracavitary radium, using Fletcher-Suit applicators and cobalt teletherapy; the remaining 43 patients received only cobalt teletherapy. One hundred thirty-four patients (41.6%) presented with FIGO Stage III disease. Only 46 patients (14.3%) presented with Stage I disease, showing that patients tended to present late in the disease course. Five-year actuarial (uncorrected) survival rates of 86.7% for Stage I, 65.0% for Stage II, 41.4% for Stage III and 4.9% for Stage IV were obtained with corresponding 10 year rates of 79.6%, 60.2%, 35.2% and 0%. The overall 5 and 10 year survival rates were 54.0% and 48.2%, respectively. The survival rates "flattened off" at about 7-8 years, reflecting late deaths after the fifth anniversary of treatment. Non-severe complications consisted mainly of chronic proctitis (41.3%) and vaginal stenosis (20.8%). Major complications were intestinal stricture (1.2%) and fistula formation (1.6%).