A double-blind placebo-controlled randomized study of Chinese herbal medicine as complementary therapy for reduction of chemotherapy-induced toxicity.

BACKGROUND: Chinese herbal medicine (CHM) is a common complementary therapy used by patients with cancer for reduction of chemotherapy-induced toxic effects. This study applied the highest standard of clinical trial methodology to examine the role of CHM in reducing chemotherapy-induced toxicity, while maintaining a tailored approach to therapy. PATIENTS AND METHODS: Patients with early-stage breast or colon cancer who required postoperative adjuvant chemotherapy were eligible for the study. Enrolled patients were randomly assigned to one of three Chinese herbalists who evaluated and prescribed a combination of single-item packaged herbal extract granules. Patients received either CHM or placebo packages with a corresponding serial number. The placebo package contained nontherapeutic herbs with an artificial smell and taste similar to a typical herbal tea. The primary end points were hematologic and non-hematologic toxicity according to the National Cancer Institute Common Toxicity Criteria Version 2. RESULTS: One hundred and twenty patients were accrued at the time of premature study termination. Patient characteristics of the two groups were similar. The incidence of grade 3/4 anemia, leukopenia, neutropenia, and thrombocytopenia for the CHM and placebo groups were 5.4%, 47.3%, 52.7%, and 1.8% and 1.8%, 32.2%, 44.7%, and 3.6%, respectively (P = 0.27, 0.37, 0.63, and 0.13, respectively). Incidence of grade 2 nausea was the only non-hematologic toxicity that was significantly reduced in the CHM group (14.6% versus 35.7%, P = 0.04). CONCLUSIONS: Traditional CHM does not reduce the hematologic toxicity associated with chemotherapy. CHM, however, does have a significant impact on control of nausea.

Hepatocellular carcinoma: is current therapy really altering outcome?

Progress in the management of hepatocellular carcinoma (HCC) has been slow and has limited impact on outcome. Most patients with HCC have two diseases--chronic liver disease and HCC--and complex interactions between the two have major implications for diagnosis and prognosis as well as the management of HCC. The disease is most prevalent in those areas of the world where the infrastructure for clinical trials is least developed. Also, the aetiology of the disease varies around the world and it is still not known whether HCCs of different aetiologies have different prognoses. Current treatment is making an impact on the management of HCC but further progress awaits not only the development of more effective treatments but also the development of adequate methodologies to assess the impact of these treatments.

Systemic chemotherapy of liver tumors.

Primary and secondary liver tumors have a reputation for being resistant to chemotherapy and, in the absence of surgical resection, rapidly fatal. Until recently, such a reputation was well justified: response rates above 20% were not seen, and complete responses were distinctly rare. Over the past 5 years, the mood of those in the field has become rather more optimistic and a pattern of effective therapy is emerging. This involves combination therapy in patients with unresectable disease to increase the operative rates, and postoperative adjuvant therapy to decrease the high relapse rate which is so characteristic of both primary and secondary liver tumors. In the case of hepatocellular carcinoma, the combination therapy involves cytotoxic drugs and interferon. With secondary colorectal cancer (CRC), the combination of 5-fluorouracil (FU) and leucovorin, together with one of the new cytotoxic agents such as oxaliplatin or irenotecan, is producing much higher response rates and prolonged survival, and permitting a higher resection rate. Postoperative treatment is also showing promise in decreasing the relapse rate. With CRC metastatic to the liver, this involves hepatic artery infusion (HAI), systemic 5-FU, and leucovorin. Adjuvant systemic therapy of HCC has not yet been widely tested, but success with locoregional lipiodol iodine131 is proof of principle. The coming decade should see a significant improvement in the outlook of patients with malignant liver tumors as multimodality treatment becomes more widely investigated and practiced.

Adjuvant intra-arterial iodine-131-labelled lipiodol for resectable hepatocellular carcinoma: a prospective randomised trial.

BACKGROUND: Resection of hepatocellular carcinoma is potentially curative, but local recurrence is common. In this prospective randomised trial, we aimed to find out if one dose of postoperative adjuvant intra-arterial iodine-131-labelled lipiodol could reduce the rate of local recurrence and increase disease-free and overall survival. METHODS: Patients who underwent curative resection for hepatocellular carcinoma and recovered within 6 weeks were randomly assigned one 1850 MBq dose of 131I-lipiodol or no further treatment (controls). We compared rates of recurrence and disease-free and overall survival (the primary endpoints) between the two groups by intention to treat. We planned an interim analysis when 30 patients (both groups together) had been followed up for a median of 2 years, with the intention of stopping early if the between-group difference in disease-free survival was significant (p=0.029). FINDINGS: Between April, 1992, and August, 1997, we recruited 43 patients: 21 received intra-arterial 131I-lipiodol and 22 received no adjuvant treatment. During a median follow-up of 34.6 (range 14.1-69.7) months, there were six (28.5%) recurrences among the 21 patients in the adjuvant treatment, compared with 13 (59%) in the controls (p=0.04). Median disease-free survival in the treatment and control groups was 57.2 (0.4-69.7) and 13.6 (2.1-68.3) months, respectively (p=0.037). 3-year overall survival in the treatment and control groups was 86.4% and 46.3%, respectively (p=0.039). The interim analysis showed a significant increase in disease-free survival in the treatment group compared with the controls (p=0.01), so we closed the trial early. 131I-lipiodol had no significant toxic effects. INTERPRETATION: In patients with hepatocellular carcinoma, one 1850 MBq dose of intra-arterial 131I-lipiodol given after curative resection significantly decreases the rate of recurrence and increases disease-free and overall survival.

Enhancement of local control in locally advanced node-positive nasopharyngeal carcinoma by adjunctive chemotherapy.

PURPOSE: To determine the efficacy of chemotherapy adjunctive to radical radiotherapy (neoadjuvant +/- adjuvant) in patients with node-positive nasopharyngeal carcinoma (NPC). METHODS AND MATERIALS: All the node-positive patients given adjunctive chemotherapy between 1984-1989 (n = 209, CHEMO) were compared with all the node-positive patients treated by radical radiotherapy alone during the same period (n = 409, NCHEMO). The CHEMO group had significantly more bulky nodes, lower cervical/supraclavicular nodes, and more advanced overall stages than the NCHEMO group because nodal size (> or =24 cm) was used as a selection criterion for chemotherapy (1984-1988 departmental protocol and 1988-1989 prospective randomized trial). The chemotherapy consisted of two courses of neoadjuvant cisplatin (100 mg/m2 D1) and 5-fluorouracil (5-FU) (1 gm/m2 D1-D3) in 191 patients. In addition to the two courses of neoadjuvant, four courses of adjuvant chemotherapy, of the same combination, were given after radical radiotherapy in a further 18 patients. Radical radiotherapy delivered a nasopharyngeal dose of 60-62.5 Gy. In addition, parapharyngeal booster external radiotherapy (20 Gy) was given in the presence of parapharyngeal involvement, and intracavitary brachytherapy (24 Gy) was used to treat any local residual tumor diagnosed at 4-6 weeks after external radiotherapy. Both crude and actuarial rates were compared (survival, distant metastases, and local failures) between CHEMO and NCHEMO for all patients, for individual Ho's overall stage, for patients with nodes of different sizes (< or =3 cm, >3-< or =6 cm, >6 cm), for individual T-stage and individual N-stage, and for patients belonging to different gender and different age groups (<40 years, > or =40 years). Multivariate analyses using the Cox Regression Model were performed to identify significant prognostic factors. RESULTS: With a median follow-up of 5.5 years (range 0.7 to 10 years), CHEMO had significantly less local failures overall than NCHEMO; this was especially true for patients with advanced stages (III + IV). Additionally, in all nodal-size subgroups, in all node-positive T3, and in node-positive T3-Stage IV, there was a significant reduction in local failures after chemotherapy. There was a trend toward fewer local failures in favor of chemotherapy in Stage III, Stage IV, and T3-Stage III (0.05

Combating hepatocellular carcinoma with an integrated approach.

This short review summarizes an integrated approach to new methods of managing hepatocellular carcinoma (HCC) developed at our centre. HCC-specific isoforms of alpha-fetoprotein were detected by isoelectric focusing and their value in the differential diagnosis of early HCC on a background of chronic liver disease has been shown. Selective internal radiation therapy using yttrium-90 (90 Y) microspheres has been shown to be an effective treatment for inoperable HCC in a phase I and II study. A partition model for estimating the radiation doses from the 90 Y microspheres to the tumour and the non-tumorous liver during the therapy was then formulated, verified by correlating with intraoperative dosimetry, and evaluated in clinical settings. This permits 90 Y microspheres to be administered safely without the need of an open surgery and a randomized therapeutic controlled trial is in progress. Another randomized controlled trial using iodine-131 Lipiodol as a post-operative adjuvant therapy, aiming at reducing the recurrence rate is also on-going. HCC may be more effectively combated with a better understanding of its pathogenesis from chronic liver disease.

Internal radiation therapy for patients with primary or metastatic hepatic cancer: a review.

BACKGROUND: The limited efficacy of current approaches to the treatment of patients with hepatic cancer, including external beam radiation therapy and cytotoxic chemotherapy, has reawakened interest in the use of internal radiation therapy. METHODS: The authors reviewed series of patients with liver metastases or hepatocellular carcinoma (HCC) treated with 1) interstitial irradiation and direct intratumoral injection of 90Y microspheres, 2) intraarterial infusion of (131)I-Lipiodol, 3) intraarterial infusion of 90Y microspheres, or 4) parenteral administration of radiolabeled monoclonal antibodies. RESULTS: High dose rate interstitial irradiation with afterloading of (192)Ir resulted in local control of hepatic metastases for a median of 8 months and complete tumor eradication in 2 patients. Direct intratumoral injection of 90Y microspheres reduced the size of 90.6% of tumors and completely destroyed them in 8 patients. Treatment with arterial (131)I-Lipiodol resulted in a 17-92% response rate as well as a case of complete remission of unresectable HCC. It was found to be most effective against small tumors. No response was observed with liver metastases from colorectal carcinoma. Partial response was commonly achieved when patients with unresectable liver metastases or HCC were treated with intraarterial 9OY microspheres. Among four patients whose HCC became resectable following treatment with 90Y microspheres, two cases of complete remission were documented. In a prospective randomized trial, (131)I-antiferritin combined with chemotherapy was no more effective than chemotherapy alone. CONCLUSIONS: The different approaches to internal radiation therapy that are reviewed in this article represent several ways in which radiation can be selectively targeted to hepatic tumors without undue radiation to the nontumorous liver. However, the efficacy of each of these therapies still needs to be evaluated in randomized controlled trials.

Multimodality treatment of primary lymphoepithelioma-like carcinoma of the lung.

BACKGROUND: Lymphoepithelioma-like carcinoma (LELC) of the lung occurs at a higher frequency in Asian compared with Western patients. Its association with Epstein-Barr virus varies among different ethnic groups. METHODS: Nine patients with primary LELC of the lung treated at a single institution with a multimodality approach comprised of surgery, chemotherapy, and radiotherapy are reported. Chemotherapy was comprised of cisplatin, 100 mg/m2, on Day 1 and 5-fluorouracil, 1 g/m2, on Days 2, 3, and 4. RESULTS: Five male and 4 female patients were treated over a 3-year period. Eight patients were non-smokers. Three patients had operable disease. Two of these patients received adjuvant radiotherapy or chemotherapy and remained free of recurrence at 18 and 20 months, respectively; 1 patient received no adjuvant treatment, and palliative chemotherapy was given for subsequent recurrent disease. Six patients had inoperable disease and received palliative chemotherapy +/- radiotherapy. Five patients had distant metastatic disease at presentation. Of the 7 patients who were evaluable for response to chemotherapy, 71.4% had a partial response and 28.6% had progressive disease. One patient who was evaluable for response to radiotherapy achieved a partial response. CONCLUSIONS: Primary LELC of the lung has a high rate of systemic metastasis and is highly chemosensitive. A multimodality approach to the management of this disease is recommended.

Nasopharyngeal carcinoma with metastatic disease to mediastinal and hilar lymph nodes: an indication for more aggressive treatment.

Nasopharyngeal carcinoma (NPC) is a highly chemo- and radiosensitive tumour, distinctive from other head and neck squamous cell carcinomas. Distant metastatic rates correlate directly with T and N stages. The prognosis of metastatic NPC is grave and long term survivors are anecdotal. We encountered an 18-year-old man with locoregionally advanced NPC, who was initially treated with neoadjuvant chemotherapy and radiotherapy, but subsequently relapsed 6 months later in the superior mediastinal and right hilar nodal regions. Further chemotherapy and consolidation radiotherapy resulted in complete remission. He is currently alive and free of disease 5 years and 6 months after the completion of salvage treatment. We recommend aggressive treatment of NPC with isolated intrathoracic nodal relapse and imaging of the mediastinum for non-metastatic Ho's Stage N3 NPC patients.

A prospective randomized study of chemotherapy adjunctive to definitive radiotherapy in advanced nasopharyngeal carcinoma.

PURPOSE: A prospective randomized trial was conducted to compare chemoradiotherapy against radiotherapy alone in the treatment of locoregionally advanced nasopharyngeal carcinoma. METHODS AND MATERIALS: Eighty-two patients with histologically proven nasopharyngeal carcinoma who had either Ho's N3 staging or any N stage with a nodal diameter of > or = 4 cm were entered. Seventy-seven patients were evaluated for tumor response and survival. The patients were randomized to receive two cycles of cisplatin 100 mg/m2 Day 1,5-fluorouracil 1000 mg/m2 24-h infusion Days 2, 3, and 4 before radical radiotherapy, and four cycles of postradiotherapy chemotherapy (37 patients) or radiotherapy alone (40 patients). All patients received radical radiotherapy to the nasopharynx and neck. The nasopharynx and upper neck were treated to 66 Gy by conventional fractionation and the lower neck to 58 Gy. Booster radiotherapy (7.5 Gy/two fractions/week) was given to any residual nodes after standard radiotherapy. RESULTS: The patient characteristics, including staging, were similar in both arms. The overall response rate to neoadjuvant chemotherapy was 81% (19% complete response, 62% partial response). The rates of radiotherapy for boosting parapharyngeal disease or residual lymph nodes were not significantly different in the two arms. The overall complete response rate to chemoradiotherapy was 100%, and to radiotherapy alone, 95%. Toxicities in the chemoradiotherapy arm were mainly myelosuppression, nephrotoxicity, and nausea and vomiting. The degree of mucositis was not significantly different in the two arms. There was no treatment-related death. The median follow up was 28.5 months. The 2-year overall survival was 80% in the chemoradiotherapy arm and 80.5% in the radiotherapy arm. The 2-year disease-free survival was 68% in the chemoradiotherapy arm and 72% in the radiotherapy arm, without significant difference between the two arms. The locoregional relapse rate, distant metastatic rate, and median time to relapse were also not significantly different between the two arms. CONCLUSION: Despite promising tumor response rates from Phase II trials, this prospective randomized trial has demonstrated no benefit from adjunctive chemotherapy to radiotherapy in the treatment of locoregionally advanced nasopharyngeal carcinoma.

Selective internal radiation therapy with intra-arterial iodine-131-Lipiodol in inoperable hepatocellular carcinoma.

UNLABELLED: From August 1990 to June 1993, 26 patients with inoperable hepatocellular carcinoma were treated with intra-arterial iodine-131-Lipiodol (131I-L). METHODS: Iodine-131-Lipiodol was given through either an implantable arterial port (9 patients) or during hepatic angiography (17 patients). All 26 patients had multiple lesions, 3 had involved resection margin after surgical resection and 1 had diffuse infiltrative lesions. The median size of the largest tumor among 22 patients with a measurable lesion was 4.5 cm (2-9.5 cm). The end points are tumor response in terms of tumor size, change in serum alpha-fetoprotein level, toxicity of treatment and overall survival. RESULTS: Twenty-three patients received a single treatment of 1.11-2.22 GBq (30-60 mCi)131I-L. Three patients received 2.22-4.44 GBq (60-120 mCi)131I-L in three fractions. Considering both radiological regression and reduction in serum alpha-fetoprotein level as objective response criteria, the overall response rate was 52% (13 out of 25 patients with evaluable disease). Ten out of 15 patients who had raised alpha-fetoprotein levels had more than 50% reduction and 8 patients had more than 90% reduction in alpha-fetoprotein level. Since analysis, 19 patients have died and 7 remain alive, giving a minimum median survival of 6 mo (range 1.2-16.6 mo), with 4 surviving more than 1 yr calculated from the day of treatment. There was only one patient who had late deterioration of liver function compatible with radiation hepatitis. There was no bone marrow toxicity documented in any patients. CONCLUSION: Treatment with intra-arterial 131I-L was well tolerated in patients with inoperable hepatocellular carcinoma and produced an objective response of 52% with median survival of 6 mo. A fractionated dose of 131I-L was feasible and the radiation dose could be escalated safely.

Patterns of early treatment failure in non-metastatic nasopharyngeal carcinoma: a study based on CT scanning.

Six hundred and twenty-eight patients with non-metastatic nasopharyngeal carcinoma were staged by CT scanning and treated with radical locoregional radiotherapy. Parapharyngeal boost radiation for bulky parapharyngeal involvement, neoadjuvant chemotherapy for bulky nodal metastases, and intracavitary 192Ir treatment for local persistence of tumour after external radiotherapy were also used as appropriate. Forty-eight patients had Ho's (1978) Stage I disease (7.6%), 167 Stage II (26.6%), 312 Stage III (49.7%) and 101 Stage IV (16.1%). At 2 years after treatment, 185 patients (29.5%) had developed recurrence; 112 had distant metastases (60.5%), and 75 had local failure (40.5%). Eighty-three patients had developed distant metastases alone, 73 patients locoregional failure alone and 29 patients had both locoregional and metastatic failure. The overall 2-year actuarial distant and local failure rates were 18.4% and 12.7% respectively. Distant metastasis is the major form of treatment failure which limits early survival. Seventy-four per cent of distant metastases were not associated with locoregional recurrence and had probably arisen from pre-existing occult foci. Our data also suggest that the advent of CT scanning has improved local tumour delineation and radiotherapy planning, and hence local control.

Pharmacokinetics and toxicity of intraarterial adriamycin for hepatocellular carcinoma: effect of coadministration of lipiodol.

To determine the effect of coadministration of lipiodol on the pharmacokinetics and systemic toxicity of intraarterial Adriamycin in patients with hepatocellular carcinoma, nine patients were studied in detail. Each received two courses of a bolus injection of Adriamycin (60 mg/m2), in one of which the Adriamycin was mixed with 10 ml of lipiodol. Analysis of the paired data, and additional 'non-paired' data from a further seven patients, showed that there was no significant difference in the area under the concentration-time curve for Adriamycin or adriamycinol or, in the case of Adriamycin, the terminal half-life. Likewise the fall in haemoglobin concentration, white cell count and platelet count following treatment, and the degree of nausea and vomiting were not significantly different. Comparison with a series of 12 patients receiving intravenous Adriamycin, in the same dose schedule, revealed no difference in terms of pharmacokinetic parameters or toxicity with intraarterial administration of Adriamycin, with or without lipiodol.

Intraarterial adriamycin and lipiodol for inoperable hepatocellular carcinoma: a comparison with intravenous adriamycin.

The technique of 'targeting' cytotoxic drugs by mixing them with the contrast medium lipiodol is now widely used in Japan and the Far East where it has been reported to enhance response rates in patients with hepatocellular carcinoma. In the present study 19 patients with this tumour were treated with intra-(hepatic) arterial adriamycin (60 mg/m2), at least one course of which was combined with lipiodol (10-20 ml). Two patients (11%) had a remission as indicated by a significant fall in serum alphafetoprotein and there was a reduction of tumour size in one of these. The median survival period was 3 months (range 1-18) with the two responding patients surviving 8 and 12 months. This response rate was no better than the figure of 14% seen in 31 consecutive patients treated with intravenous adriamycin at the same dose, and the survival curves of the two groups of patients were not significantly different. Lipiodol in combination with adriamycin is not superior to intravenous adriamycin administered alone.