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BACKGROUND Patients with International Union Against Cancer (UICC) Stage I–II nasopharyngeal carcinoma (NPC) appear to have a relatively favorable prognosis and generally are excluded from trials of combined modality treatment. More recently, plasma/serum cell-free Epstein-Barr virus (EBV) DNA has been shown to be measurable in the majority of NPC patients at the time of diagnosis, and appears to have prognostic significance. However, within Stage I-II disease, in which failure events are infrequent, the prognostic impact of the pretreatment EBV DNA level has not been addressed to our knowledge. This issue has management implications because different therapeutic strategies currently are employed for patients with good-risk and those with poor-risk NPC. METHODS A cohort of 90 patients with UICC Stage I-II NPC (World Health Organization Grade 2/3 histology) had their pretherapy plasma/serum EBV DNA levels determined by a quantitative polymerase chain reaction assay and correlated with the probability of posttherapy failure. All patients received radiation therapy only, except for three patients who also received concurrent chemotherapy. Kaplan–Meier plots of the probability of locoregional failure, distant failure, and cancer-specific survival were compared with reference to clinical stage and EBV DNA levels. RESULTS With a median follow-up time of 45 months, 12 patients and 7 patients, respectively, had developed locoregional and distant failures, including 2 patients with both local and distant failures. Patients with distant failure had significantly higher pretherapy EBV DNA levels than those without failure (a median of 13,219 copies/mL [interquatile-range, 274,635 copies/mL] vs. a median of 423 copies/mL [interquatile-range, 2753 copies/mL]). The probability of distant failure was significantly higher in patients with high (> 4000 copies/mL plasma) compared with low EBV DNA levels (P = 0.0001, log-rank test) and for Stage IIB disease compared with Stage I and Stage IIA disease combined (P = 0.0149, log-rank test), but was not significantly different between patients with Stage II and those with Stage I disease. The risks of locoregional failure were not significantly different between patients with high and those with low EBV DNA levels, and also was not significantly different between clinical substages. Approximately 35% of patients with Stage IIB disease were in the at-risk group for distant failure, as identified by high EBV DNA levels. CONCLUSIONS Within a group of patients with UICC Stage I-II NPC, the pretherapy plasma EBV DNA level was found to identify a poor-risk group with a probability of distant failure similar to that of patients with advanced stage disease. This group of patients may warrant management considerations currently applicable only to cases of Stage III-IV disease. The prognostic significance of designating Stage IIB disease as per the 1997 UICC staging was confirmed, although the pretherapy EBV DNA level appears to be a more powerful prognostic discriminator in patients with early-stage NPC. Cancer 2003;98:288–91. © 2003 American Cancer Society. DOI 10.1002/cncr.11496

BACKGROUND Elevated levels of soluble intercellular adhesion molecules (sICAM)-1 in serum have been shown to be associated with poor prognosis in Hodgkin disease and non-Hodgkin lymphomas. However, little is known about the significance of serum sICAM-1 levels in extranodal lymphomas. The objective of this study was to examine the sICAM-1 levels in patients with extranodal lymphomas and the correlation with clinical features and outcome. METHODS The serum levels of sICAM-1 were measured in stored serum samples of 88 patients with primary extranodal lymphomas at presentation using enzyme-linked immunoassay. The correlation between serum sICAM-1 levels and clinical characteristics, pathologic features, and disease outcome were retrospectively analyzed. RESULTS Serum sICAM-1 levels in patients with extranodal lymphomas (mean, 372 ± 198.8 ng/mL; interquartile range, 252–466 ng/mL) were significantly higher than that of healthy control subjects (mean, 214 ± 78.5 ng/mL; interquartile range, 160–241 ng/mL; P < 0.0001). High serum sICAM-1 levels (≥ 371 ng/mL) were significantly associated with B-symptoms, elevated lactate dehydrogenase level, advanced stage (III/IV; Ann Arbor Staging System), and poor response to therapy. Univariate analysis demonstrated a significantly poorer 5-year disease free (41% vs. 64%; P = 0.01) and overall (44% vs. 73%; P = 0.003) survival in patients with high serum sICAM-1 as compared with those with normal sICAM-1. In multivariate analysis, both disease free (P = 0.0085) and overall (P = 0.0003) survival were independently associated with high serum sICAM-1 levels. CONCLUSIONS Serum sICAM-1 levels are elevated in patients with extranodal lymphomas. In these individuals, high serum sICAM-1 levels are associated with adverse disease features and poor outcome. Cancer 2000;89:1387–95. © 2000 American Cancer Society.

BACKGROUND The authors have designed a non-cisplatin-based chemotherapy regimen for the treatment of patients with advanced nonsmall cell lung carcinoma (NSCLC). This regimen capitalizes on the mild toxicity of gemcitabine, a novel nucleoside analog. METHODS A total of 46 chemotherapy-naive patients with histologically confirmed Stage IIIB or IV NSCLC were enrolled. Eligible patients were treated with gemcitabine 1000 mg/m2 on Days 1, 8, and 15, plus oral etoposide 50 mg daily for 14 days, which was increased to 21 days if there was no World Health Organization (WHO) Grade 3 or 4 toxicity in the 1st 2 cycles (each cycle was 28 days long). All patients were included for analysis of response and survival according to an intention-to-treat principle. RESULTS The overall response rate was 43.5% (95% confidence interval [CI], 30.7–60.2%). There was 1 complete response (2.2%) and 19 partial responses (41.3%). The median survival was 48.0 weeks (95% CI, 38.1–75.9 weeks) and the 1-year survival rate was 45% (95% CI, 29–62%). The median time to progression for all patients was 39.2 weeks (95% CI, 35.7–49.7 weeks). World Health Organization (WHO) Grade 3 and 4 anemia, neutropenia, and thrombocytopenia was reported in 29%, 32%, and 18% of patients, respectively. Two patients had reactivation of hepatitis B viral infection that resulted in WHO Grade 4 hepatic dysfunction. Other nonhematologic toxicities were uncommon. CONCLUSIONS This non-cisplatin-based regimen of gemcitabine and oral etoposide achieved a high response and survival rate. Toxicity appeared to be less severe than that associated with existing cisplatin-based regimens. A randomized study of this regimen versus a cisplatin-based regimen is indicated. Cancer 2000;89:543–50. © 2000 American Cancer Society.

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 reveiwed 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 131I-Lipiodol, 3) intraarterial infusion of 90Y microspheres, or 4) parenteral administration of radiolabeled monoclonal antibodies. RESULTS High dose rate interstitial irradiation with afterloading of 192Ir 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 131I-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 90Y 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, 131I-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. Cancer 1998;83:1894-1907. © 1998 American Cancer Society.

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. Cancer 1998;83:925-929. © 1998 American Cancer Society.

BACKGROUND Chemotherapy containing anthracycline is the standard initial treatment for aggressive non-Hodgkin's lymphoma (NHL), and the International Prognostic Index (IPI) is widely accepted as the standard tool for determining the prognosis of patients with this disease. However, the data on which the IPI was based primarily came from studies conducted in Western countries. It may not be directly applicable to Asian populations, in which the incidence of primary extranodal lymphoma (PENL) is known to be high. METHODS The authors conducted a retrospective study of 218 patients with aggressive NHL who were treated with chemotherapy. They analyzed the distribution of stage and pathology, prognostic factors, toxicity, and treatment outcome. The IPI was then applied and its ability to identify distinct prognostic groups tested. RESULTS Eighty-six patients (39.4%) had lymph node lymphoma (LNL) and 132 (60.6%) had primary extranodal lymphoma (defined as non-Hodgkin's lymphoma with primary presentation, bulk of disease, and histologic confirmation at an extranodal site). The most common primary extranodal sites were the stomach (22%) and Waldeyer's tonsillar ring (18.9%). The complete response rate of PENL patients to chemotherapy containing anthracycline was 52%, as compared with 64% of the LNL group. The 5-year survival rates for patients with LNL and PENL were 57.4% and 52.1%, respectively. The toxicity in the two patient groups was similar. Four of the prognostic factors in the IPI–age, serum LDH, performance status, and disease stage–predicted significantly different survival for PENL and LNL patients. However, the number of extranodal sites involved was not a significant predictive variable in PENL. CONCLUSIONS The IPI was applicable to this Chinese population in which the incidence of PENL was high, although the number of extranodal sites did not achieve statistical significance as a risk factor. A proposal for modification was made. Chemotherapy containing anthracycline was an effective treatment for both PENL and LNL patients. Cancer 1998;82:2439-2448. © 1998 American Cancer Society.

BACKGROUND Nasopharyngeal carcinoma (NPC) is a radiosensitive tumor for which there is a high local control rate after radical radiotherapy (RT). However, for patients with locoregionally advanced disease, the rate of distant metastasis is high and the 5-year overall survival rate is poor. METHODS A review of retrospective and prospective clinical studies was performed to assess the role of chemotherapy in three settings: metastatic disease; neoadjuvant and/or adjuvant; and concurrent chemotherapy with radiotherapy. RESULTS Cisplatin-based combination chemotherapy results in a high response rate in patients with metastatic NPC, and a subgroup may achieve long term disease free survival. The use of neoadjuvant and adjuvant chemotherapy to treat locoregionally advanced disease has resulted in consistently high response rates, but no randomized trial to date has demonstrated an improvement in overall survival. A recent Head and Neck Intergroup study randomized patients in the United States to receive concurrent chemotherapy (cisplatin) and radiotherapy or radiotherapy only. Although this approach demonstrated significant benefit in overall survival favoring the use of concurrent chemotherapy and radiotherapy, its applicability in geographic areas of high NPC incidence remains to be proven. CONCLUSIONS NPC is a chemosensitive tumor, and patients with metastatic disease have a high response rate. Further prospective studies will define the standard approach to treating locoregionally advanced NPC, which is likely to incorporate into the primary treatment some form of systemic chemotherapy. Cancer 1998;82:1003-12. © 1998 American Cancer Society.

BACKGROUND Distant metastases are common in patients with nasopharyngeal carcinoma (NPC), and their presence is the most important factor in limiting survival. We aimed to study the prognosticators determining survival subsequent to distant metastasis from NPC. METHODS A study by both mono- and multivariate analyses was carried out in 945 patients presenting between 1984 and 1989. Forty-two presented with metastases and 247 developed metastasis after primary radiotherapy. RESULTS Patients who presented with distant metastasis (M1-classification) had a significantly shorter survival than those who developed metastases after primary radiotherapy. The presence of hepatic metastases, short metastasis free interval, and older age at presentation significantly predicted short survival after the diagnosis of distant metastasis. Patients with metastases preceded by, and/or accompanied with, locoregional recurrence had comparable survival to those without, despite their association with a significantly longer metastasis free interval. A history of locoregional recurrence was however not compatible with long term, disease free survival, and, in its presence, advanced T-classification on presentation predicted poor survival subsequent to metastasis. Long term disease free survival (64–117 months) was attained in 4 young patients (age < 40 years) with isolated intrathoracic metastases in the absence of locoregional recurrence after achieving a complete response to aggressive treatment, with chemotherapy, radiotherapy, and/or surgery, usually multimodal. CONCLUSIONS Some of the clinical prognosticators have been identified and an attempt was made to subclassify distant metastases according to possible differences in prognosis. A subset of metastatic NPC was identified which is compatible with long term, disease free survival. Investigations during follow-up should be directed toward the early detection of such potentially salvageable cases. Cancer 1996;77:2423-31.

Background. Primary non-Hodgkin's lymphoma of the liver is rare. In this study, the presentation, pathologic features, and outcome of seven Chinese patients with primary hepatic lymphoma are described. Methods. From 1984 to 1994, the clinical records of 14 Chinese patients with non-Hodgkin's lymphoma and histologically proven liver involvement were reviewed. Seven (four males, three females; median age, 54 years) were considered to have primary hepatic lymphoma. Histologic and immunohistochemical studies were performed on paraffin embedded liver tissue. Results. “B” symptoms including fever (86%) and weight loss (57%) were the most striking presenting features. Hepatomegaly was present in all patients, splenomegaly in three (43%), and thrombocytopenia in six (86%). Only one patient was hepatitis B surface antigen-seropositive. None had preexisting liver disease. Histologic subtypes, though heterogenous, were mostly unfavorable and consisted of diffuse large cell lymphoma (two patients), small lymphocytic lymphoma (one patient), lymphoblastic lymphoma (one case), mantle cell lymphoma (one patient), anaplastic large cell Ki-1 lymphoma (one patient), and hepatosplenic T-cell lymphoma (one patient). Three patients expressed B-cell and 2 expressed T-cell phenotypes. Six patients received cytotoxic chemotherapy. One had resection and one had splenectomy, but none achieved complete remission, and only one remained alive as of this writing. The median survival was 3.7 months (range, 8 days to 47.7 months). Conclusion. Chinese patients with primary non-Hodgkin's lymphoma of the liver have prominent “B” symptoms, disease with a highly aggressive course, a poor response to local and systemic treatment, and short survival. Hepatitis B virus infection is not a major etiologic factor for these patients.

Background. Many nonseminomatous germ cell tumors (NSGCTs) express elevated levels of serum alpha-fetoprotein (AFP), which is widely used for diagnosis and monitoring therapy. Alpha-fetoprotein is also expressed in patients with hepatocellular carcinoma (HCC). In these sera, several variants, some highly specific, recently have been detected by isoelectric focusing. Methods. Sera were collected from nine patients with NSGCTs, five pregnant women, and five patients with HCC. After isoelectric focusing, the proteins were transferred to nitrocellulose membrane by blotting and incubated with polyclonal rabbit antihuman AFP conjugated with horseradish peroxidase. The enhanced chemiluminescence detection system and Hyperfilm-ECL were used to render the protein bands visible and each was quantified as a percentage of the total AFP using a densitometer. Results. Isoelectric focusing of serum alpha-fetoprotein from the patients with NSGCTs (four testicular, five mediastinal) revealed a consistent pattern characterized by a specific band (band +III). A second band (band +II) that is also seen in sera from patients with hepatocellular carcinoma was present in all patients. The overall pattern was distinct from that of AFP from HCC and that produced during late pregnancy. The two characteristic bands (AFP +II and +III) were responsible for the great majority of total AFP in these patients ; estimation of serial sera in patients undergoing treatment showed that total and malignant AFP changed in parallel. Banding patterns, apart from one patient, were identical in patients with testicular and mediastinal NSGCTs. Conclusion. NSGCTs tumors express a highly consistent and specific pattern of AFP variants. More detailed analysis of AFP patterns in larger numbers of patients may provide further insight into the cellular heterogeneity of germ cell tumors. Cancer 1995 :75 :1663-8.

Background. Serum alpha-fetoprotein (AFP) is elevated in up to 80% of patients with hepatocellular carcinoma (HCC). Modestly raised AFP levels (10-400 ng/ml) are also found in patients with nonmalignant liver diseases. In the present study, isoelectric focusing of AFP was used to differentiate the AFP found in patients with HCC. Methods. To establish the assay conditions, isoelectric focusing waas performed on sera from 14 patients with HCC and 13 with nonmalignant liver diseases. Sera was also analyzed under coded conditions from 16 patients with HCC. 14 with chronic active hepatitis (CAH), and b with cirrhosis to determine the specificity and sensitivity of the assay in the diagnosis of HCC. Results. Isoelectric focusing of sera from patients with HCC and various non malignant liver diseases identified AFP variants (AFP I-IV). All 14 patients with HCC had AFP varians I and III, and 7 of the 14 patients with HCC had AFP variants I and III, and 7 of the 14 pateints with HCC had AFP variants I and III, and 7 and 14 also had variant IV. When analyzed in the coded study 13 of the 16 cases of HCC were prediced correctly by the presence of AFP variants III of IV. AFP bands III and IV were not discernible in 12 of the 14 patients with CAH and 4 of the 6 with cirrhosis. Conclusion. Isoelectric focusing of sera from patients with HCC and nonmalignant liver disease identified two AFP variants apparently specific for HCC. In the setting of borderline elevation of AFP, this technique has a sensitivity of 81% and specificity of 85% for detecting the presence of bands III of IV and may prove suitable for use in a routine laboratory as a screening asay.

A 20-year experience with 112 patients with cholangiocarcinoma was reviewed with reference to the demographic, etiologic, and clinical features and prognosis in the following two types: peripheral (originating from the intrahepatic small duct radicles) and hilar (originating from the major hepatic ducts at or near the junction of the right and left hepatic ducts). Seventy of the 112 patients were in the hilar group, and 42 were in the peripheral group. Prolonged high alcohol consumption was a prominent feature in both categories (45% and 37%, respectively). Among the women, 35% of those with the peripheral tumor had used oral contraceptive preparations. The major identifiable etiologic factor among the hilar tumors was ulcerative colitis, with or without sclerosing cholangitis, which was documented in 20 of 70 cases (28.6%), with an additional 4 patients having Crohn's disease. The hilar group mainly had obstructive jaundice initially, whereas abdominal pain and weight loss were the predominant symptoms in the peripheral type. Tumor recurrence was frequent in those undergoing resection or transplantation, and none of those undergoing chemotherapy or radiation therapy showed any objective evidence of response. Overall median survival time was poor in both groups at 12 months.

The reactivity of serum alpha-fetoprotein (AFP) from 20 patients with hepatocellular carcinoma (HCC) with immobilized lentil lectin was examined and found to be significantly greater (39% +/- 18%) than that of the same protein from seven patients with chronic liver disease (CLD, 11.2% +/- 3.3%), seven with fulminant hepatic failure (FHF, 10% +/- 8.4%), and eight normal pregnant women (4.1% +/- 2.7%). The reactivity with Concanavalin A (Con A) was also significantly greater for AFP from HCC patients (44.5% +/- 12.5%) than that from FHF patients (7.7% +/- 4%) and normal pregnant women (5.3% +/- 3.3%), but not from patients with CLD. The reactivity with lentil lectin permitted distinction between those with HCC (31.3% +/- 14.1%) and those with uncomplicated CLD (11.2% +/- 8.4%) even when the absolute levels of serum AFP were in the same range (80-400 ng/ml). Evaluation of the alterations by lectin binding methodology may be useful in overcoming problems associated with distinguishing between malignant and CLD, particularly at moderate serum AFP elevations.

We assessed the frequency of silent (i.e., clinically asymptomatic) cirrhosis among 305 patients with hepatocellular carcinoma (HCC) and cirrhosis in relation to the patients' country of birth, the cause of the cirrhosis, clinical features, and hepatitis B surface antigen (HBsAg) status. Overall, 56% of the patients had silent cirrhosis, but this occurred significantly more frequently among those born in areas of the world where HCC is common (64% compared with 36%), those who were HBsAg-seropositive (75% compared with 25%), and those who had cryptogenic cirrhosis (71% compared with 29%). Previously recognized ("known") cirrhosis was more common among those from low-incidence areas (52% compared with 36%) and the cause of the cirrhosis was more often alcoholic (44% compared with 10%). The clinical features at the time of presentation with HCC did not differ between the two groups. During the 10-year period of the study (1978 to 1988), 448 patients with HCC were seen (including those without cirrhosis and those in whom the presence or absence of cirrhosis could not be determined). Overall, therefore, cirrhosis was recognized before presentation with tumor in only 30% of the patients. The screening of cirrhotic patients can only have a limited impact on the early detection of HCC.

BACKGROUND Topotecan (9-dimethylaminomethyl-10-hydroxycampthothecin) is a new topoisomerase I inhibitor with promising efficacy in the treatment of patients with small cell lung carcinoma (SCLC). Combination with a topoisomerase II inhibitor may potentate the therapeutic effect of topotecan, although there has been conflicting preclinical information on the combination. The objectives of this study were to establish the maximum tolerated dose and to determine the efficacy of the sequential combination of intravenous topotecan and oral etoposide in the treatment of patients with SCLC. METHODS Patients with histologically confirmed, limited or extensive stage SCLC were eligible. The dose escalation scheme of three cohorts (six patients per cohort) started at intravenous topotecan 0.5 mg/m2 per day for 5 days and oral etoposide 50 mg twice daily for 7 days (21-day cycles). Subsequent dose levels involved escalation of topotecan to 0.75 mg/m2 per day and 1.0 mg/m2 per day for 5 days. A Phase II study was conducted at one dose level below the maximum tolerated dose. The authors alternated the drug sequence with each consecutive cycle and compared the hematologic toxicity between the two sequences. RESULTS Thirty-six patients (21 patients with limited disease and 15 patients with extensive disease) received a total of 173 courses of sequential combination chemotherapy (topotecan etoposide, 88 courses; etoposide topotecan, 85 courses). The authors identified dose levels for the Phase II study as follows: topotecan, 0.75 mg/m2 per day for 5 days; and etoposide, 50 mg twice daily for 7 days. The dose-limiting toxicity was neutropenia. At this dose level, the incidence of Grade 3–4 neutropenia and the incidence of Grade 3–4 thrombocytopenia were 25% and 10.9%, respectively. Two patients died from neutropenic sepsis. There was no significant difference in hematologic toxicities between the two sequences. Complete and partial response rates were 5.6% and 55.6%, respectively (limited disease, 9.5% and 66.75%; extensive disease, 0% and 40%, respectively). The median progression free survival was 31.9 weeks (limited disease, 36.1 weeks; extensive disease, 28.9 weeks; 95% confidence interval, 25.6–36.0 weeks), and the median overall survival was 52.4 weeks (limited disease, 54.9 weeks; extensive disease, 30.1 weeks; 95% confidence interval, 39.6–57.7 weeks). CONCLUSIONS Combination therapy with topoisomerase I and II inhibitors is a safe and effective regimen for patients with SCLC. Future research on this combination should focus on an oral regimen for patients with extensive disease and poor tolerance to cisplatin. The authors recommend an oral dosage of topotecan at 1.2 mg/m2 per day (equivalent to intravenous topotecan at 0.75 mg/m2 per day) for 5 days followed by etoposide 50 mg twice daily for 7 days. Cancer 2002;95:1511–9. © 2002 American Cancer Society. DOI 10.1002/cncr.10836

BACKGROUND The current TNM staging system for patients with hepatocellular carcinoma (HCC) does not include liver function parameters and does not provide a precise prognosis for patients in different risk groups. The objectives of this study were to construct a new prognostic index for patients with hepatocellular carcinoma, the Chinese University Prognostic Index (CUPI), and to compare it with existing staging systems in terms of their ability to classify patients into different risk group. METHODS From 1996 to 1998, 926 ethnic Chinese patients who were diagnosed with HCC (mainly hepatitis B-associated) at a single institution were recruited prospectively into this study. A multivariate analysis on 19 patient characteristics was performed using a Cox regression model to identify independent prognostic factors. Weights were derived from the regression coefficients of various factors to construct the CUPI. Patients were classified according to different staging systems. Survival curves were plotted with the Kaplan–Meier method and were compared by using a log-rank test. RESULTS Both the TNM staging system and the Okuda staging system had prognostic significance, but the significance was lower for the Cancer of the Liver Italian Program (CLIP) prognostic score among the patients in the study population. The CUPI was constructed by adding the following factors into the TNM staging system: total bilirubin, ascites, alkaline phosphatase, α fetoprotein, and asymptomatic disease on presentation. The new CUPI characterized three risk groups with highly significant differences in survival during the whole period of follow-up (P < 0.00001) and was more discriminant than the other systems. CONCLUSIONS In the study population of patients with mainly hepatitis B-associated HCC, the CUPI was more discriminant than the TNM staging system, the Okuda staging systems, or the CLIP prognostic score in classifying patients into different risk groups and was better at predicting survival. The CUPI needs to be validated by different cohorts of patients before it can be recommended for general use. Cancer 2002;94:1760–9. © 2002 American Cancer Society. DOI 10.1002/cncr.10384

BACKGROUND The objective of the current study was to identify patient and disease related factors that influence response and survival for patients with unresectable hepatocellular carcinoma (HCC) who received a systemic combination chemotherapy consisting of cisplatin, alpha-interferon, doxorubicin, and 5-fluorouracil (PIAF). METHODS From July 1996 to February 1999, 149 patients with unresectable HCC were treated with PIAF: cisplatin (20mg/m2 intravenously, Days 1–4), doxorubicin (40mg/m2 intravenously, Day 1), 5-fluorouracil (400mg/m2 intravenously, Days 1–4), and alpha-interferon (5MU/m2 subcutaneously, Days 1–4), once every 3 weeks up to a maximum of six cycles. Univariate and multivariate analyses of patient and disease characteristics were used to identify factors predicting response and survival. RESULTS The objective response rate according to conventional criteria was 16.8% (complete response in 3 out of 149 patients, or 2%, 95% confidence interval [CI] 0–4.3%; partial response in 22 out of 149 patients, or 14.8%, 95% CI 9–20%). The median survival time was 30.9 weeks (95% CI 22.1 to 40). Significant independent predictors of an objective response were: absence of cirrhosis (P = 0.006), low bilirubin level (P = 0.006), and positive hepatitis C serology (P = 0.025). The following factors were related to a shorter survival time: high Okuda stage (P = 0.001), vascular involvement (P = 0.018), and cirrhosis (P = 0.008). Good risk patients (absence of cirrhosis and total bilirubin ≤ 0.6mg/dL) had an objective response rate of 50%. CONCLUSIONS Patients with unresectable HCC who also have normal total bilirubin and non-cirrhotic livers have a better chance of response and prolonged survival after treatment with systemic PIAF. Cancer 2002;94:421–7. © 2002 American Cancer Society.

The serum ferritin level was raised in 34 of 35 (97%) patients with hepatocellular carcinoma and in 20 of 23 (87%) with uncomplicated cirrhosis. Levels rose following therapeutic embolisation in 14 of 15 patients and continued to rise in 85% of all tumor patients who showed no clinical response to chemotherapy (intravenous Adriamycin) whereas in those who did respond the serum ferritin level fell. By contrast, there was a fall in serum alphafetoprotein immediately after embolisation but like serum ferritin, alphafetoprotein levels rose with disease progression and only fell in those achieving clinical remission. Serum ferritin has no role in the differential diagnosis of hepatocellular carcinoma but may be a useful marker in monitoring response to chemotherapy particularly in the alphafetoprotein-negative patient.

The value of serial carcinoembryonic antigen (CEA) measurements as a marker of disease progression or in monitoring treatment was investigated in patients with hepatocellular carcinoma. Of 40 patients, including 16 with normal serum alpha-fetoprotein (AFP) concentrations, 29 (72.5%) had abnormal plasma CEA at presentation. Although this was more common in patients with pre-existing cirrhosis, the mean and range of plasma CEA were similar in patients with and without pre-existing hepatic disease. There was no correlation between plasma CEA and any biochemical parameter of hepatic function, although plasma CEA concentrations were significantly lower in patients with well-differentiated tumors. CEA concentrations increased in 71% of patients who had no response to cytotoxic drugs, but CEA also increased in 62.5% of those patients who did respond. Plasma CEA concentrations were elevated in 62.5% of patients with normal and 79% of patients with raised serum AFP on admission to the hospital. There was no correlation between individual AFP and CEA concentrations. Although elevated plasma CEA levels may be of diagnostic value in patients with hepatocellular carcinoma in the absence of pre-existing hepatic disease, and in those with normal serum AFP, our findings indicate that it does not behave as a true tumor marker.

Following a pilot study of VP-16.213 (180 mg/m2 on 3 consecutive days at 2 weekly intervals) in the treatment of patients with hepatocellular carcinoma, the efficacy of the drug was compared with that of adriamycin in another 35 patients in a randomized crossover trial. Each drug gave a similar response rate (18 and 28%, respectively) but the duration of response was significantly longer in those receiving Adriamycin. Some patients who had not responded to treatment with Adriamycin had worthwhile remission with VP 16.