Analysis of dose intensity in doxorubicin-containing adjuvant chemotherapy in stage II and III breast carcinoma.

Three hundred thirty-six patients with stage II or stage III breast cancer were treated on an adjuvant protocol containing fluorouracil, doxorubicin, cyclophosphamide, vincristine, and prednisone (FACVP). Depending on the estrogen-receptor (ER) status, the patients were subdivided to receive maintenance chemotherapy with or without tamoxifen. The administered dose intensity of fluorouracil, doxorubicin, and cyclophosphamide (FAC) (mg/m2/wk) relative to the projected dose intensity (based on planned dose) was computed for each patient. The relative dose intensity of the first six cycles of chemotherapy (RDI6) was compared with disease-free survival (DFS). Of the 299 patients who completed at least six cycles of therapy, 83% received dose intensities within 20% of standard intensity (.8 less than or equal to RDI6 less than or equal to 1.2). The group with the highest dose intensity (RDI6 greater than or equal to 1.13) had the longest DFS, though there was not a clear trend of linear association between dose intensity and DFS after adjustment for prognostic factors (P = .16). The patients who received at least standard dose intensity (RDI6 greater than or equal to 1.0) had longer DFS than those whose therapy did not reach standard intensity (RDI6 less than 1.0). This difference was significant in patients with stage III disease (P = .01). The 37 patients who completed fewer than six cycles of chemotherapy had the shortest DFS (5-year DFS of 48% v 65% in the others). This retrospective analysis, in a heterogeneously treated group of patients, did not show the differences in outcome associated with dose intensity as demonstrated in the earlier studies comparing projected dose intensity of various cyclophosphamide, methotrexate-, and fluorouracil (CMF)-containing adjuvant trials. Improved DFS was noted in the stage III patients receiving higher dose intensity. Our failure to demonstrate the differences in stage II patients may be due to the narrow range of dose intensity in this study or to a difference in the dose-response curves depending on the stage of disease.

Fulminant hepatic failure in non-Hodgkin lymphoma patients treated with chemotherapy.

Chemotherapy is the mainstay of therapy for patients with non-Hodgkin lymphoma. Among side-effects associated with the use of chemotherapy, immunosuppression is one which can be potentially fatal. In hepatitis B carriers, immunosuppression permits widespread infection of the hepatocytes and its subsequent withdrawal causes an "immunological rebound" leading to massive necrosis of hepatocytes. 4 patients who died of fulminant hepatitis following chemotherapy are reported. These were patients with positive hepatitis B serology. Caution is advised when treating non-Hodgkin lymphoma in patients from hepatitis B endemic regions.

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 pulmonary lymphoma--clinical review from a single institution in Singapore.

Primary pulmonary lymphoma is a rare and vexing subset of extranodal non-Hodgkin's lymphoma. We report 11 cases and provide a brief literature review. We also highlight an unusual case of a relapsed peripheral T-cell primary lung lymphoma that underwent apparent spontaneous remission. Eleven cases of primary pulmonary lymphoma treated in our institution were studied for their clinical characteristics, behaviour, response to treatment and clinical outcome. The median duration of follow up was 26 months. The mean age was in the 50s and the presenting symptoms generally respiratory and non-specific. LDH levels did not correlate with either stage or grade of disease. Lower lobe involvement was most common and nodules and mass-like lesions the main radiologic feature. Small lymphocytic lymphoma accounted for the majority of cases and were indolent in behaviour. Good symptom control and radiologic response was achieved with chemotherapy in disseminated low grade lung lymphomas. Combination chemotherapy was effective in the aggressive lymphomas. In conclusion, Small lymphocytic lymphoma of the lung is an indolent disease with a long symptom-free survival even after recurrence. Our series confirms the clinical characteristics of primary pulmonary lymphoma. The role of Ling Zhi in effecting the spontaneous remission in the peripheral T-cell lymphoma is speculative.

MACOP-B in advanced non-Hodgkin's lymphoma.

Between May 1986 and March 1991, 38 patients with previously untreated advanced intermediate and high-grade non-Hodgkin's lymphoma were treated with methotrexate, doxorubicin, cyclophosphamide, vincristine, prednisone, and bleomycin (MACOP-B): 73% of the patients had stages III and IV disease, 55% had "B" symptoms, and 55% had bulky disease (nodal masses > 10 cm). Histologic subtypes included diffuse large-cell and immunoblastic lymphoma. In 96% of patients clinical response was achieved (69% complete response and 27% partial response). Acturial disease-free survival and overall survival were 55% and 60%, respectively, at 2 years. Treatment-related mortality was 16%: 3 patients died from neutropenic sepsis and 3 (hepatitis B carriers) from fulminant hepatitis at the time of steroid withdrawal. The incidence of nonfatal neutropenic fever was 24% and mucocutaneous toxicity was common. The poorer overall results may be attributed to more advanced disease. Caution is advised in the use of MACOP-B among hepatitis B carriers.

A phase II trial of etoposide, leucovorin and 5-fluorouracil (ELF) in patients with advanced gastric cancer.

Etoposide, leucovorin and 5-fluorouracil (ELF) chemotherapy has been reported to be less toxic yet effective (response rates of 50%) in patients with advanced gastric cancer. A phase II study of ELF in 25 patients (11 males, 14 females, median age 53 years) with advanced adenocarcinoma of the stomach is reported. Patients received outpatient intravenous etoposide 120mg/m2 over 2 hours, folinic acid 300 mg/m2 over 2 hours, 5-fluorouracil 500 mg/m2 boluses daily for 3 days every 21 days. Of 17 measurable patients, there was one complete response (CR), 4 partial responses (PR) for a total response rate of 29.4%. Non-hematologic toxicity was modest (grade 0 vomiting 11/21, stomatitis 16/21, diarrhea 17/21). Grade 3/4 neutropenia was seen in 14/23, thrombocytopenia in 2/23, anemia in 5/23 patients. Median progression-free and overall survival was 4.1 and 7.1 months, respectively. In conclusion, ELF chemotherapy shows only modest activity in patients with advanced gastric cancer and is associated with severe hematologic toxicity.

Extract of astragalus membranaceus and ligustrum lucidum does not prevent cyclophosphamide-induced myelosuppression.

There is increasing evidence that many Chinese medicinal herbs are promising biological response modifiers in cancer treatment. The extract of some Chinese herbs have shown ability in stimulating the bone marrow and improving the peripheral white cell counts in rats. We studied the effect of a dried extract of two commonly used Chinese herbs, Astragalus membranaceus (AM) and Ligustrum lucidum (LL) on cytotoxic-induced myelosuppression. Wistar rats weighing 250-300g each were divided into two groups of 12. Both groups were given cyclophosphamide intravenously at 75 mg/kg on day 1 of the study. Rats in the study group were fed 240 mg of crude extract of AM and LL from day 1 to day 12 of study. The daily absolute neutrophil count (ANC) and the platelet count were monitored. There was no difference between the study and the control group in terms of nadir count, time to nadir and time to recovery for both the ANC and the platelet counts. The duration of neutropenia (ANC < 1.0 x 10(9)/L) was also similar in both groups. Our results showed that the extract of AM and LL does not prevent cyclophosphamide-induced myelosuppression.

Combination chemotherapy (dacarbazine, carmustine, cisplastin, and tamoxifen) in advanced melanoma.

Melanoma is rare in Singapore with an age-standardised rate (ASR) of 0.4-0.8 per 100,000 per year. Thirteen patients with metastatic or locally advanced melanoma were referred to the Department of Medical Oncology, Singapore General Hospital between Feb 1991 and Nov 1993. Ten patients were given combination chemotherapy comprising carmustine (BCNU), cisplatin, dacarbazine (DTIC) and tamoxifen. The remaining 3 patients either rejected chemotherapy or were too ill to receive chemotherapy. Patient characteristics were as follows: there were 6 males and 4 females; age range 29-75 years; all were Chinese; sites of primary disease: extremities 8, retroorbital 1, vagina 1; sites of metastases: lymph nodes 6, skin 2, pulmonary 3, liver 1. All received the same combination chemotherapy comprising iv BCNU 150 mg/m2 q8wk, iv DTIC 220 mg/m2 x 3 days q4 wk, iv cisplatin 25 mg/m2 x 3 days q4 wk and tab tamoxifen 40 mg daily. There were 6 partial responses and no complete responses, giving a response rate of 60% with a median survival of 11.5 months. Three patients with sites of disease in the vagina, retroorbital region and metastatic liver disease had progressive disease despite chemotherapy and one died of treatment related sepsis. The 6 responders include those with metastases to the skin, nodes and/or lung. Treatment was generally tolerable. Two patients experienced delays of their subsequent cycles of treatment by 1-2 weeks due either to neutropenia and/or thrombocytopenia. This regimen is a fairly active combination against metastatic melanoma, particularly those with metastases to the nodes, skin and the lung. Those with involvement of other sites tend to respond poorly.

Adult parameningeal rhabdomyosarcoma--a case report and literature review.

Although rhabdomyosarcoma is predominantly a malignant disease of children, it is also seen in adults. Since adults account for only 15% of rhabdomyosarcomas, the experience gathered for the treatment of the malignancy has been derived from treating children. The treatment of a case of adult extensive parameningeal rhabdomyosarcoma with CyVADlC chemotherapy and radiotherapy is described, together with a review of the literature.

Common toxicities of cancer chemotherapy.

Sixty cancer patients who were receiving chemotherapy at an outpatient Oncology Centre were surveyed for their views on a list of treatment-related toxicities. The severity of each toxicity was assessed using a visual analogue scale. Sixty percent of patients felt that the overall toxicity was acceptable. Ten percent felt like giving up. Problem with venous access was named the worst toxicity by 37% of patients, followed by nausea and vomiting (19%), and long waiting time (11%). Male patients tended to tolerate chemotherapy better. The female patients were significantly more affected by hair loss than their male counterpart. Better understanding of the toxicities of chemotherapy as perceived by the patients themselves allows them to take appropriate measures in improving their quality of life.

Mitomycin, ifosfamide and cisplatin in advanced non-small cell lung cancer.

BACKGROUND: Chemotherapy can be used to palliate the symptoms in patients with advanced non-small cell lung cancer. PATIENTS: Twenty-four chemo-naive patients with stage IIIB and IV non-small cell lung cancer were treated with the MIC regimen (mitomycin, ifosfamide and cisplatin). RESULTS: The overall response rate was 33% (partial response) and median duration of response was 7 months (range 5 to 10 months). At median follow-up of 26 months, the median survival was 8 months, and 1-year survival was 29%. Toxicities were tolerable. CONCLUSION: This appears to be a reasonable regimen for palliating advanced non-small cell lung cancer.

Use of ondansetron in the control of emesis in autologous peripheral blood stem cell transplant (APBSCT) for solid tumours.

AIM: The use of autologous peripheral blood stem cell transplant (APBSCT) for solid tumours have increased exponentially in the last 5 years. While the use of 5-hydroxytryptamine 3 (5HT3) receptor antagonists has been shown to improve control of emesis in patients receiving conventional dose chemotherapy, similar literature in APBSCT is more limited. We report our experience in the use of ondansetron in APBSCT. METHOD: Twenty-three patients with solid tumours receiving high-dose chemotherapy with APBSCT were studied. All were started on intravenous ondansetron at 24 mg/day before commencement of the conditioning regimen and continued till vomiting had ceased for 24 hours. The conditioning regimen used was dependent on the tumour type and the duration ranged from 4 to 6 days. Control of emesis was assessed by the number of vomiting episodes in each 24-hour period, monitored throughout conditioning till discharge from hospital. RESULTS: Complete or major protection from vomiting was achieved in 83% of patients on day 1. During the entire conditioning period, 52% of patients achieved complete or major response to ondansetron. After the conditioning period (delayed emesis), 44% of patients achieved complete or major response. CONCLUSIONS: The control of emesis for patients undergoing high-dose chemotherapy with APBSCT is fair with ondansetron. Research on more effective combinations to further improve emetic control in this selected group of patients is needed.

Management of chemotherapy-induced neutropenic sepsis--combination of cephalosporin and aminoglycoside.

In cancer patients undergoing combination chemotherapy, neutropenic febrile episode (NFE) is a life-threatening condition. Prompt initiation of empirical antibiotics is essential to limit morbidity and mortality. To understand the effectiveness of combination antibiotics consisting of a third-generation cephalosporin and an aminoglycoside, a retrospective review of all patients admitted for NFEs was conducted. Between August 1990 and December 1991, there were 34 NFEs in 26 cancer patients which were treated with a combination of aminoglycoside (gentamicin or amikacin) and a cephalosporin (ceftriaxone or ceftazidime). Initial antibiotic therapy included aminoglycoside plus ceftriaxone in 23 NFEs and ceftazidime in 11 NFEs. A change of antibiotics was required in 11 NFEs because of deteriorating clinical status or culture-proven drug resistance. Bacteria were isolated in 12 (35%) NFEs (blood 7, respiratory tract 2, skin 2, urine 1). Of these, eight (62%) were gram-negative bacteria and five were gram-positive bacteria. One blood specimen grew both gram-positive and gram-negative organisms. Broad spectrum antibiotics were effective in almost all NFEs. Thirty-one (91%) NFEs resolved with antibiotics. Three patients succumbed to their infection despite combination antibiotics. Aminoglycoside and cephalosporin is an effective antibiotic combination in the management of fever in neutropenic hosts. Randomised trials comparing this combination with newer antibiotics like monobactams and quinolones are needed in the search for more effective therapy.

Resolution of superior vena cava obstruction in small cell lung cancer patients treated with chemotherapy.

Small cell lung cancer is a highly chemo-sensitive malignancy. As it often presents with a central lesion, superior vena cava obstruction (SVCO) is not an uncommon manifestation. From January 1990 to December 1993, 161 patients with small cell lung carcinoma were seen at our institution. Twenty (12.4%) of these patients presented with symptoms and signs of SVCO. Initial therapy consisted of radiotherapy in 4 patients and chemotherapy in 16 patients. Of those treated with chemotherapy, patient characteristics included 13 males, median age of 62.5 years (range 51 to 78 years), Eastern Co-operative Oncology Group (ECOG) performance status of 3 to 4 in 7 patients; 1 to 2 in 9 patients, and limited stage disease in 8 patients. The median period of follow-up was 5 months. Nine patients received a combination of cisplatin and etoposide (EP), 5 had cyclophosphamide, doxorubicin and vincristine, 1 had cyclophosphamide, etoposide and vincristine and 1 had monotherapy with oral etoposide. Overall response to chemotherapy was 81% (with 31% complete responses). All responders had resolution of SVCO. Only 3 patients did not respond (1 patient defaulted, 1 patient died of neutropenic sepsis at week one and 1 patient had stable disease). Resolution of SVCO was noted within the first 2 weeks after the first cycle; the earliest being 3 days. The only patient given single-agent oral etoposide responded within 10 days after initiation of treatment. Of the 7 patients with poor performance status (ECOG 3 to 4), 3 died from treatment-related complications. Chemotherapy is highly effective as a primary treatment of small cell lung carcinoma despite presentation with SVCO. However, caution is advised in the use of combination chemotherapy for those presenting with poor performance status. Initial therapy with oral etoposide or radiotherapy should be considered as possible alternatives for these patients.

Primary cerebral lymphoma--a case report and review of the management.

The brain is an uncommon extranodal site for the development of malignant lymphoma. There is an increased risk among immunocompromised patients. While the overall outcome is poor, innovative approaches with combination chemotherapy and radiotherapy can sometimes produce durable remissions. The treatment of a non-immunocompromised patient with cerebral lymphoma incorporating chemotherapy and radiotherapy is described with a review of the literature.

Primary mediastinal germ cell tumour.

Testicular germ cell tumour is said to be a model for curable neoplasm. However, the prognosis of primary extragonadal germ cell tumour does not appear to be as promising. Though similar in histology, the biology of primary extragonadal germ cell tumour is different as exemplified by the patients in this review. Eight patients with primary mediastinal germ cell tumours were treated with intensive cisplatin-based chemotherapy. All, except one, had non-seminomatous components. The poor prognosis of mediastinal germ cell tumour is due to a combination of poor treatment results with the cisplatin-based regimen and the development of non-germ cell and haematological malignancies.

A report of infusional 5-fluorouracil and subcutaneous alpha-2A-interferon in the treatment of advanced colorectal carcinoma.

Systemic chemotherapy with 5-fluorouracil (5-FU) has been the mainstay of treatment for patients with metastatic colorectal carcinoma. Administering the drug in a continuous low-dose schedule has produced better result than bolus therapy. Resistance to short-pulse treatment can also be overcome by prolonged exposure. Recent studies suggest the feasibility of biomodulation of 5-FU with recombinant interferon (rIFN alpha-2a) with improved response. Sixteen patients were treated with continuous 5-FU 250 mg/m2 and rIFN alpha-2a 10 x 10(6) u thrice weekly for a maximum of 24 weeks. Five of them had received bolus 5-FU previously. Nine (82%) of the chemonaive group and 1 (20%) previously treated patient had partial response. The median duration of response was 7 months. Grade II to III mucositis were seen in 44% of the patients and 2 patients developed neurological complications. Although the overall response appeared encouraging, the incidence of toxicity was high. In the absence of further phase III studies, rIFN alpha-2a biomodulation of 5-FU cannot be regarded as standard treatment for patients with metastatic colorectal carcinoma.

5-Fluorouracil continuous infusion in metastatic colorectal cancer.

5-Fluorouracil (5-FU) remains the most active therapeutic agent in advanced colorectal cancer. This drug has demonstrated differing levels of activity dependent on the schedule of administration in experimental and clinical models. Twenty-six patients were treated with prolonged continuous infusion of 5-FU at 250 mg/m2/day via a portable infusion pump and Hickman's central venous catheter in this study. Twelve patients (46%) experienced a major response (complete response-1, partial response-11). Median duration of response was 5 months. Seventeen patients were chemotherapy-naive on accrual to this study. Ten patients from this group had partial responses (59%) and four were minor responders (24%). Hence 82% of patients who had no prior chemotherapy showed tumour responses to 5-FU continuous infusion. Two of nine patients (22%) with prior chemotherapy achieved major response. Favourable toxicity profile was noted with this regimen. Two patients discontinued therapy due to treatment-related toxicities (severe palmar-plantar erythrodysesthesia and superior vena cava thrombosis secondary to the central venous catheter). Prolonged continuous infusion of 5-FU could well be the standard treatment of advanced colorectal cancer in view of its favourable activity and toxicity profile. The serial serum carcino-embryonic antigen (CEA) trend was shown to correlate well to the objective response; a decline of more than 50% from baseline CEA level correlated with a major response and a rise of more than 50% correlated with progressive disease. Hence the use of serum CEA is suitable for monitoring response to chemotherapy which is advantageous with respect to patient convenience and cost-effectiveness.

Treatment of small cell lung cancer: a single institutional experience.

Forty-three patients with either limited or extensive small cell lung carcinoma were treated with either etoposide and cisplatin (EP) regimen or EP alternating with cyclophosphamide, doxorubicin and vincristine. Patients with limited disease were consolidated with radiotherapy. Responses were 96% (44% complete response) and 71% (6% complete response) in the patients with limited and extensive diseases, respectively. The 2-year disease-free and overall survival in the limited disease patients were 19% and 27%, respectively. None of the patients with extensive disease survived beyond 2 years. Toxicity of the therapy was acceptable. Forty percent developed grade 2 vomiting. Two patients had neutropenic fever of which one was fatal. One of the two-year survivors developed a second malignancy (oesophageal carcinoma). Despite consolidative radiotherapy in all responding patients with limited disease, 73% of the failure included a locoregional component. In the entire group, one-third of the patients developed brain metastases. Hence, more effective drugs and local treatment modalities are needed to improve this result.

Chemotherapy in non-small cell lung cancer: a review.

Lung cancer, of which non-small cell carcinoma is the most common, has been a significant therapeutic challenge for decades and will remain so for decades to come. Despite its prevalence, progress in the management of non-small cell lung cancer has been relatively slow. This is in part due to the pessimism of most physicians treating this disease, which has resulted in a relatively lackadaisical attitude with regards to clinical trials when compared to other solid tumours like breast or colorectal cancers. Nevertheless, the past decade has seen significant progress, specifically with regards to the management of locally advanced disease. Chemotherapy, though shown to be biologically active in non-small cell lung cancer, is considered an ineffective palliative tool in the setting of metastatic disease due to its toxicities and the "less than encouraging" response rates generated by the cisplatin-based combination regimen which is generally considered to be the most active currently available. The advent of new active agents such as paclitaxel and vinorelbine which are potentially less toxic may change this view. Conversely, the response rate of locally advanced disease to chemotherapy is significantly higher and this has resulted in numerous multimodality trials of neoadjuvant chemotherapy prior to surgery and/or radiation. To date, a number of randomised trials have shown that this approach can result in significant survival benefit for patients with locally advanced disease. An alternative approach makes use of the potential synergism between certain chemotherapeutic agents (such as cisplatin) and radiation when used concurrently. However, data on concurrent chemoradiotherapy in locally advanced disease have been largely based on single-arm studies and are inconclusive. Three randomised trials on concurrent chemoradiotherapy have been shown benefit for the use of combined modality in locally advanced disease. Hence, treatment of locally advanced disease should include chemotherapy as part of the combined modality approach. However, the optimal sequencing of these modalities would require well-designed randomised trials to determine.