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.

Adjuvant postoperative 5-fluorouracil chemotherapy combined with pelvic radiation for rectal cancer: results from an Asian population.

Prospective randomized clinical trials have shown the effectiveness of combined adjuvant 5-fluorouracil-based chemotherapy and radiotherapy after surgical resection of rectal cancer. To assess toxicity of this therapy, prospective data were collected from 236 Asian rectal cancer patients treated with combined 5-fluorouracil-based chemotherapy and radiotherapy after surgery. Almost 82% of patients completed planned therapy. Grade 3 and 4 diarrhea, stomatitis, and granulocytopenia occurred in approximately 18-21% of patients. There were two treatment-related deaths from granulocytopenia and sepsis. With median follow-up of 3.5 years, median disease-free and overall survival was 75 and 88 months, respectively. In conclusion, combined adjuvant 5-fluorouracil-based chemotherapy and radiotherapy after surgical resection of rectal cancer is tolerable in Asian patients with moderate toxicity.

Concurrent chemoradiotherapy in patients with locally advanced nasopharyngeal carcinoma of the undifferentiated type.

The result with radiotherapy alone in patients with locally advanced nasopharyngeal carcinoma (NPC) was disappointing. Encouraging results have been reported with the use of concurrent chemoradiotherapy in patients with locally advanced squamous cell carcinoma of the head and neck. Hence, we decided to explore the use of this treatment schedule in patients who presented with locally advanced disease (UICC/AJCC classification system). Between July 1995 and March 1996, 14 patients with locally advanced NPC were treated with the following schedule: radiation therapy was given conventionally to a total of 66 to 70 Gy to both the nasopharynx and neck with or without parapharyngeal/intracavitary boost; chemotherapy consisted of intravenous cisplatin at 20 mg/m2/day and intravenous 5-flurouracil 1000 mg/m2/day, infused over 8 hours on days 1 to 4 during the first and fifth week of radiation therapy. Depending on the patient's tolerability and clinical assessment of toxicity, a third cycle of chemotherapy was planned 4 to 5 weeks after the second cycle, upon the completion of the radiotherapy. Twelve patients completed all intended treatment. Two patients failed to do so due to treatment-related mortality. The median follow-up duration was 30 months. Limiting toxicities were myelosuppression and oropharyngeal mucositis. The overall response rate was a 100% at both the primary and nodal sites of disease. The median disease-free survival was 21 months. Forty per cent of the patients were alive at 3 years. This treatment schedule was associated with an unacceptable treatment-related death rate. As a result, this protocol was terminated.

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.

Temporal lobe necrosis following radiation therapy for nasopharyngeal carcinoma: 1H MR spectroscopic findings.

PURPOSE: To observe the patterns of radiation-induced temporal lobe necrosis (TLN) following radiation therapy for nasopharyngeal carcinoma (NPC). METHODS AND MATERIALS: Twenty-five proton magnetic resonance spectroscopic (1H MRS) examinations were acquired from 13 healthy adult volunteers for comparison with data from the patient population. There were 18 patients (28 spectra) with radiologic evidence of TLN and all patients were confirmed cases of NPC treated with radiation therapy. Six patients (33%) had a single treatment while 12 (67%) patients had two treatments. All 1H MRS examinations were performed on a 2-T whole body system (Bruker) using the point-resolved spectroscopy (PRESS) method with TE = 135 ms, TR = 3000 ms, and data processed automatically using the LCModel software package for metabolite quantification. RESULTS: The N-acetyl-aspartate (NAA) levels were reduced in all except one spectrum (96%). Choline (Cho) was increased in 3 (11%), normal in 4 (14%), and reduced in 21 (75%) spectra. The creatine (Cr) level was normal in 8 (29%) spectra and reduced in 20 (71%) spectra. In four patients with normal imaging findings 1H MRS was abnormal. CONCLUSION: 1H MRS can characterize radiation-induced TLN. Spectra with increased Cho can be mistaken for neoplasm. Spectroscopy can also identify metabolic derangement before imaging.

Phase II trial of a paclitaxel and carboplatin combination in Asian patients with metastatic nasopharyngeal carcinoma.

PURPOSE: An earlier phase II trial of paclitaxel in patients with metastatic nasopharyngeal carcinoma (NPC) demonstrated a response rate of 22%. Hence we proceeded to study the combination of paclitaxel and carboplatin in these patients. PATIENTS AND METHODS: The 21-day regimen was as follows: i.v. paclitaxel 175 mg/m2 over three hours preceded by standard premedications, followed by i.v. carboplatin dosed at AUC of six infused over one hour. Only chemotherapy-naive patients with histological diagnoses of undifferentiated carcinoma of the nasopharynx, systemic metastases and radiologically measurable lesions were eligible. RESULTS: Thirty-two patients were accrued to this study. Twenty patients (62%) had at least two sites of metastasis. The main grade 3-4 toxicity was neutropenia (31%). Nine patients (28%) developed neutropenic sepsis, which caused the demise of one of them. Twenty-four patients (75%) responded to treatment, with one (3%) attaining a complete response. The median time to progression of disease was seven months and the median survival was 12 months. At one year, 52% of the patients were alive. CONCLUSIONS: The combination of paclitaxel and carboplatin is an active regimen in NPC. Its convenience of administration and good tolerability make it an attractive alternative regimen to consider for patients with metastatic disease.

Induction chemotherapy followed by concurrent chemoradiotherapy in stage III unresectable non-small cell lung cancer.

The favourable experience with the combination regimen of vinorelbine, ifosfamide and cisplatin (NIP) in patients with metastatic non-small cell lung cancer (NSCLC) has led to a protocol assessing this regimen as an induction treatment in patients with stage III unresectable NSCLC, followed by thoracic radiotherapy with concurrent daily cisplatin as a radiosensitizer. Two cycles of NIP were administered 21 days apart; each cycle comprised i.v. vinorelbine 25 mg/m2 on days 1 and 8, i.v. ifosfamide 3 g/m2 on day 1 with MESNA as uroprotection, and i.v. cisplatin 50 mg/m2 on day 1. Radical thoracic radiotherapy commenced on day 43 to a total dose of 64 Gy and i.v. cisplatin 6 mg/m2 was given concurrently prior to each fraction of radiation as a sensitiser. Two more cycles of NIP were given to patients who responded favourably to the induction treatment about 2 weeks after completion of radiation. Between July 1995 and July 1997, 44 patients were treated with this protocol. This treatment schedule was generally well tolerated. Grade 3-4 neutropenia occurred in 50% of the patients and neutropenic sepsis was seen in 8. Grade 3-4 oesophagitis was uncommon. Most of the patients were able to complete the induction and concurrent chemoradiotherapy phase. Major response occurred in 75% of the patients with 2 (4.5%) complete responses (CR). A total of 6 patients achieved CR after chemoradiotherapy. At a median follow-up of 35 months, the median overall survival for all patients was 15 months with a 3-year survival rate of 24%. The median overall survival for stage IIIA patients was 19 months with a 3-year survival rate of 39% in contrast to 13 months' median overall survival and only 15% 3-year survival rate for stage IIIB. The NIP regimen results in a high response rate in NSCLC and this treatment programme seems to benefit selected patients with stage III disease.

Orbital lymphoma: results of radiation therapy.

Orbital lymphoma is a rare presentation of non-Hodgkin's lymphoma. Treatment with radiotherapy is well-established. Twenty cases of orbital lymphoma treated at the Singapore General Hospital with radiation therapy were reviewed. All patients had improvement of their initial presenting symptoms and complete remission after radiation. Long-term local control was achieved in 17 of 20 (85%) of the treated orbits.

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.

Gastrointestinal lymphoma--a review of 54 patients in Singapore.

Primary gastrointestinal (GI) lymphoma accounts for 2% to 5% of all GI malignancies. Primary therapy in uncomplicated GI lymphoma remains controversial. Fifty-four patients (male to female ratio of 4:3, median age 56 years) with GI lymphoma were studied to evaluate complications and results of therapy. The sites involved were the stomach (31), small bowel (12), large bowel (4), gallbladder (1) and multifocal (6). Distribution by stage and grade (Working Formulation or Kiel) were: IE-30%, IIE-43%, IIIE-6%, IV-20% and unknown-1%; low grade-33%, intermediate grade-59% and high grade-8%. Majority (54%) had diffuse large cell lymphoma. Twenty-three patients (43%) underwent primary resection of the tumour followed by chemotherapy in 14 or radiotherapy in 3. Seventeen patients (31%) had primary chemotherapy and 3 (6%) had primary radiotherapy. Of the 48 patients who underwent therapy, 52% had complete response. At the last follow-up (median 21 months), 25 patients were disease-free. Overall survival was 67% at two years. Treatment strategies employing surgery, radiotherapy and chemotherapy, alone or in combination, do not appear to influence outcome. Surgical resection plus chemotherapy appear to be effective in the control of local and distant disease.

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.

Localised nodal non-Hodgkin's lymphoma--a study of 42 cases treated by radiotherapy.

The records of 42 patients with stage I and II nodal non-Hodgkin's lymphoma treated by radiotherapy with and without chemotherapy were analysed with regards to clinical presentation, investigations, treatment, radiotherapy techniques and results. The 5-year overall survival rates for all, low grade, intermediate grade and high grade histology types are 69.5%, 100%, 64.4% and 46.9% respectively. The 5-year relapse-free survival rates of those treated by initial radiotherapy alone for all, low grade and intermediate-high grade histology types are 54.8%, 46.9% and 59.4% respectively.

Testicular seminoma--the results of treatment by radiotherapy in Singapore.

A retrospective analysis was done of 49 patients treated for testicular seminoma over a 15-year period between January 1980 and April 1995 at the Department of Therapeutic Radiology, Singapore General Hospital. Their mean age was 39 years and their median period of follow-up was 67 months. Using the Royal Marsden Staging classification, 35 (71.4%) were stage I, 10 (20.4%) were stage II, I (2%) was stage III, and 3 (6.1%) were stage IV. Five (10.2%) arose in undescended testes. Thirty-six patients were treated with inguinal orchidectomy and postoperative radiotherapy to the para-aortic and ipsilateral iliac nodes. Eight had para-aortic and bilateral iliac irradiation, and 2 had ipsilateral pelvic, para-aortic, mediastinal and supraclavicular lymph node irradiation. Six of the patients had, in addition, irradiation of the inguinal-scrotal area. Nine received both chemotherapy as well as radiotherapy. The median dose of radiation given was 30.67 Gy and where a boost was required, the median total tumour dose was 35.75 Gy. The actuarial relapse-free survival at 10 years was 88.9% and the actuarial overall survival at 10 years was also 88.9%. Long-term treatment toxicities were uncommon.

Radical radiotherapy for carcinoma of the uterine cervix using high dose rate brachytherapy--a preliminary report.

From April 1992 to December 1994, a total of 61 patients with carcinoma of the cervix were treated with curative intent using initially external beam therapy followed by high dose rate brachytherapy. On reviewing 57 patients with adequate follow-up data, the local failure rate was found to be 12.3% and metastatic failure rate was 15.8%. Local pelvic failure rates for stage II and III patients were 10% and 13.6% respectively, but for stage I disease, there was one local failure out of 5 patients, at a rate of 20%. This is probably due to the small number in this subgroup. Complication rate was low with only one patient with grade IV problems, giving a serious complication rate of 1.7% only. Overall actuarial rate in this group was 50.1%. These results are encouraging but further review on achieving adequate follow-up is needed before firm conclusions can be drawn.

Nasopharyngeal cancer treated in Singapore.

With effect from July 1987 CT-scans of the nasopharynx became routinely available in the staging of nasopharyngeal cancer (NPC) in our department. Eighty-four evaluable cases during these first six months were studied and the results at a median follow-up period of 34 months revealed that 74% were alive at 2 years. The local relapse rate were 4% for T1; 10% for T2 and 35% for T3 tumours.

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.