Prediction of outcome in locally advanced breast cancer by post-chemotherapy nodal status and baseline serum tumour markers.

In spite of the apparent improvement in outcome in locally advanced breast cancer, the prognosis remains dismal in many patients. The aim of this study was to define prognostic subgroups within this heterogeneous entity. Between 1990 and 1999, 104 consecutive patients with locally advanced breast cancer were treated by a multimodality programme consisting of 4-6 courses of CAF induction chemotherapy followed by surgery, breast-conserving when feasible. In most cases, chemotherapy was then resumed, up to a total of eight courses, followed by locoregional radiation therapy. Patients with hormone receptor-positive tumours received tamoxifen (20 mg day(-1)) for 5 years. At a median follow-up of 57 months, the 5-year overall survival for the entire group and the disease-free survival for the 94 operated patients were 65% and 53%, respectively. Univariate analysis identified 10 prognostic factors of overall and disease-free survival, of which four retained significance on multivariate analysis: inflammatory breast cancer (P=0.0000, P=0.0004, respectively), baseline tumour markers (P=0.003 for both), post-chemotherapy number of involved nodes (P=0.003; P=0.017) and extracapsular spread (P=0.052; P=0.014). In conclusion, besides inflammatory features, baseline tumour markers and post-chemotherapy nodal status are strong predictors of outcome in locally advanced breast cancer.

Liver metastases from colorectal cancer: regional intra-arterial treatment following failure of systemic chemotherapy.

This study was designed to determine response rate, survival and toxicity associated with combination chemotherapy delivered intra-arterially to liver in patients with hepatic metastases of colorectal origin refractory to standard systemic treatment. A total of 28 patients who failed prior systemic treatment with fluoropyrimidines received a median of 5 cycles of intra-arterial treatment consisting of 5-fluorouracil 700 mg/m(2)/d, leucovorin 120 mg/m(2)/d, and cisplatin 20 mg/m(2)/d for 5 consecutive days. Cycles were repeated at intervals of 5-6 weeks. A major response was achieved in 48% of patients: complete response in 8% and partial response in 40%. The median duration of response was 11.5 months. Median survival was 12 months at a median follow up of 12 months. On multivariate analysis, the only variables with a significant impact on survival were response to treatment and performance status. Toxicity was moderate: grades III-IV neutropenia occurred in 29% of patients. Most of the patients complained of fatigue lasting for a few days following each cycle. There were no cases of hepatobiliary toxicity. These findings indicate that regional intra-arterial treatment should be considered in selected patients with predominantly liver disease following failure of standard treatment.

Early development of vaginal shortening during radiation therapy for endometrial or cervical cancer.

Vaginal necrosis can occur following radiation therapy for gynecological malignancies. The distal vaginal mucosa has a poorer radiation tolerance than the mucosa in the upper region. We examined the extent of vaginal shortening in patients treated by intravaginal brachytherapy with or without pelvic irradiation. Maximal extension of the vaginal cylinder above the pubis was measured for each insertion. We found that the difference in mean values between insertions (2.3 vs. 1.7 cm) was highly statistically significant (P < 0.0001). Our study shows that vaginal shortening can occur during the course of intracavity and external irradiation. These alterations in vaginal anatomy can have important consequences on doses received by the distal vaginal mucosa.

Prognosis of patients with recurrent laryngeal carcinoma.

BACKGROUND: Although recurrent laryngeal carcinoma is a common clinical problem, the data regarding its natural history and prognostic factors are limited. The aim of the study was to describe the clinical course of patients with recurrent laryngeal carcinoma and determine the impact of various factors on their survival. METHODS: The medical files of 65 patients with recurrent laryngeal cancer treated at the Rabin Medical Center between 1975 and 1996 were reviewed. The possible risk factors for survival were analyzed using univariate and multivariate models. RESULTS: The estimated 2- and 5-year survival rates of the patient population were 67% and 56%, respectively. On univariate analysis, primary tumor site, T stage and nodal status, duration of disease-free interval, site of recurrence, and operability of recurrent tumor were all powerful prognostic factors for survival. On multivariate analysis, three variables retained statistical significance: primary tumor site (p < .001), site of recurrence (p < .001), and its operability (p = .005). CONCLUSIONS: We found several disease-related factors to be predictive of poor outcome in patients with recurrent laryngeal cancer. Our data emphasize the need for early detection not only of primary tumors but also of their recurrences.

Second neoplasms in patients with Merkel cell carcinoma.

BACKGROUND: Merkel cell carcinoma (MCC) has been associated with a high incidence of other skin tumors and hematological malignancies. The purpose of this study was to analyze data from the Israel Cancer Registry regarding the incidence of second neoplasms in patients with MCC and their impact on survival. METHODS: Sixty-seven patients in whom MCC was diagnosed between 1983 and 1999 were included. Data were collected on age, gender and ethnic origin, dates of diagnosis of MCC and any other neoplasm, and date and cause of death, if applicable. Comparison of MCC-specific survival, estimated by the Kaplan-Meier product limit method, between patients with no other neoplasm and those with second primary tumors was performed by log rank test. Age-specific standardized incidence ratio (SIR) was calculated using 5751 age- and ethnic-matched malignant melanoma patients as a control group. RESULTS: Seventeen patients (25%) had a second neoplasm before, concomitant with, or after the diagnosis of MCC; 2 of them also had a third primary tumor. The SIR was 2.8 (95% CI; range, 1.38-4.22), significantly higher than the control group. Almost half the tumors were squamous cell carcinomas, either skin or head and neck, and most of the remainder were hematological malignancies or breast and ovarian adenocarcinomas. On univariate analysis, the presence of another neoplasm, regardless of its chronology, was associated with higher MCC-specific mortality (65% vs. 40% for patients with MCC only; P = 0.022). Analysis of only those patients in whom a second neoplasm developed during follow-up after treatment for MCC yielded an estimated actuarial risk of developing a second primary of 2.1% for each year of observation. CONCLUSIONS: There is a high incidence of second neoplasms, including noncutaneous solid tumors, in patients with MCC. The presence of these neoplasms, whether they appear before, after, or simultaneously with MCC, is associated with a higher MCC-specific mortality.

Laryngeal carcinoma--epidemiological and clinical features: experience of the Rabin Medical Center in Israel.

We sought to compare the epidemiological and clinical features of patients with carcinoma of the larynx treated at a major Israeli tertiary facility with other series in the literature. The charts of 361 consecutive patients from 1974 to 1995 were reviewed. Our population was distinguished from other series by a low rate of alcohol abuse (12%), high incidence of second malignancies in sites other than the upper aerodigestive tract (53%) and high rate of early-stage tumors (82%). Overall 5-year survival and local control rates were 88% and 85%, respectively. Our study suggests that the low alcohol consumption and high proportion of early-stage tumors at diagnosis, characteristic of the Israeli population of patients with laryngeal carcinoma, may explain, in part, the relatively high survival and local control rates.

Tailoring treatment for classical Kaposi's sarcoma: comprehensive clinical guidelines.

Classical Kaposi's sarcoma (CKS) is a rare indolent proliferative disease which is particularly prevalent among Jews of Ashkenazi and Mediterranean origin. To define guidelines for its comprehensive management, we conducted a retrospective analysis of 123 patients, focusing mainly on treatment modalities. The CKS-related mortality was 4% (5 patients). Of the 39 patients for whom observation only was the primary approach, 15 (38%) remained progression-free for 1-83 months (median, 4 months). Twenty-nine of the 52 (56%) patients who underwent surgery as the primary approach remained recurrence-free for 1-162 months (median, 15 months). Radiotherapy achieved an objective response in 74 courses (85%), including 50 (58%) complete responses. Symptomatic relief was reported in 95% of the patients. Vinblastine (27 series) achieved an objective response in 73% of series, including 22% complete responses. Multivariate analysis of time to progression with observation alone identified immunosuppression as the only significant independent factor that predicted disease progression. Our study suggests that observation alone may be sufficient for immunocompetent asymptomatic patients; symptomatic resectable lesions are suitable for simple excision; and more advanced disease or unresectable lesions require radiotherapy. If disease is extensive or the other approaches fail, chemotherapy is appropriate. Tailoring the treatment for CKS is an integrative process, requiring good understanding of the role of each available modality in the different clinical disease settings.

Prognostic factors for local control of early glottic cancer: the Rabin Medical Center retrospective study on 207 patients.

PURPOSE: Different radiation therapy schedules and devices have been used over the last 20 years at Rabin Medical Center in patients with early glottic cancer. The aim of the present retrospective analysis was to identify the subgroup of patients at high risk of failure of radiation treatment. MATERIALS AND METHODS: Between 1974 and 1994, 207 patients with squamous cell carcinoma of the glottis, 182 Stage T1 and 25 Stage T2, underwent definitive radiation therapy. During this period, treatment was administered with different radiation devices (60Co or 6-MV X ray), using different dose/fraction protocols (1.8 or 2 Gy per day, 5 or 6 fractions per week), total doses (42-77.4 Gy), overall radiation times, and delays. These treatment variables, in addition to certain patient and tumor characteristics, were correlated with local control at a median follow-up of 57 months (range 18-265 months). RESULTS: The 5-year local control rates for T1 and T2 tumors were 88% and 73%, respectively. Univariate analysis showed that smoking, diabetes mellitus, anterior commissure involvement, T stage, and extension of tumor to one third or more of the vocal cord were highly significantly correlated with decreased local control. None of the treatment variables, including dosage at which complete tumor regression was noted, were found to be predictive. By multivariate analysis, only anterior commissure involvement was found to be highly significant (risk ratio 1.9, 95% CI 1.2-3.0, p = 0.027), and T stage was borderline significant (risk ratio 1.6, 95% CI 1.0-2.5, p = 0.054). CONCLUSION: This study suggests that only two tumor characteristics are predictive of local failure of early glottic cancer: anterior commissure involvement and T stage. Treatment variables apparently do not influence local control.

Classic Kaposi sarcoma: experience at Rabin Medical Center in Israel.

Classic Kaposi sarcoma is an indolent cutaneous proliferative disease affecting mainly elderly people of Mediterranean and Jewish origin. The authors review the epidemiologic and clinical findings in Israeli patients with classic Kaposi sarcoma treated at the Institute of Oncology, Rabin Medical Center. A total of 123 patients were identified. The average age at diagnosis was 68 years (range, 20-90 years) and, as expected, there was a strong predominance of men (2.4:1). All but two patients were Jewish. The distribution of Ashkenazic Jews and Sephardic Jews was almost equal. Twenty-three patients (19%) had secondary malignancies that were mostly solid tumors. The clinical course was indolent and rarely fatal (4% disease-related mortality). Multivariate analysis revealed that non-Ashkenazic origin, age over 70 years, multiple lesions (>10), and immunocompromised conditions adversely affected survival. Radiotherapy for localized skin lesions yielded an 88% objective response, with symptomatic relief in 95% of patients. Chemotherapy was similarly effective (76% response rate) in patients with disseminated disease. These data demonstrate the indolent nature of classic Kaposi sarcoma which usually requires a less aggressive therapeutic approach than in the African and AIDS-related types of Kaposi sarcoma.

Initial TPS serum level as an indicator of relapse and survival in colorectal cancer.

BACKGROUND: Tissue polypeptide specific antigen (TPS) measures a soluble fragment of cytokeratine 18 and may be regarded as a proliferative marker. MATERIALS AND METHODS: TPS was measured in 173 consecutive patients with colorectal cancer. Median follow up time was 36 months. Of 137 evaluable patients 39 developed metastases (P.D.) and 98 remained with no evidence of disease (N.E.D.). RESULTS: Initial TPS levels were elevated in 75% of P.D. patients compared to 32% of N.E.D. patients (p < 0.001), CEA levels were elevated in 26% of P.D. patients had elevated initial TPS compared to 35.5% of N.E.D. patients (p < 0.001), CEA was elevated in 33.3% of the P.D. patients compared to 1.3% of N.E.D. patients (p < 0.001). Survival and disease free survival were significantly shorter for patients with initial high TPS level. TPS was more sensitive than CEA in predicting relapse. CONCLUSIONS: These preliminary data suggest that TPS may be a prognostic factor for relapse and may help to allocate Dukes'B2 patients for adjuvant chemotherapy.

A sequential four-drug chemotherapy and biotherapy with interferon alpha and GM-CSF--an innovative protocol for the treatment of metastatic melanoma.

We present the results of our chemo-biotherapy protocol for patients with metastatic melanoma. The rationale for the design of the combined therapy was induction of systemic anti-tumor immunity by: (a) priming with IFN-alpha for enhancement of tumor and histocompatibility antigen expression, (b) therapy by the 4-drug regimen (BCNU, DTIC, cisplatin and tamoxifen) for maximal tumor destruction, followed by (c) an immunomodulatory, low dose of GM-CSF. Treatment was given in cycles of three weeks: first IFN-alpha (3 x 10(6) U/day on days 1, 3, and 5); then the 4-drug regimen given according to Del Prete et al., (4); followed by GM-CSF (20 micrograms/m2/day on days 15 to 21). All patients were previously untreated by chemotherapy, and had a performance status of ECOG 0-2. Treatment was discontinued upon severe toxicity or disease progression. In responding patients--once maximal response was achieved-IFN alpha treatment (3 x 10(6) U/day, three times weekly) was continued for a period of two years or until disease progression. All 40 patients (28 males and 12 females) who received the above program were evaluable for response and toxicity and received at least two cycles of therapy. At a median follow-up of one year, 50% had achieved an objective response, with 22.5% complete responses (CR), and 27.5% partial remissions (PR). Median duration of response is 11 months (12 for CR and 9 for PR patients). Median survival for all patients is 14 months (range, 7-21), increasing to 22 months (range, 15-29) in responding patients. Activation of patients' peripheral blood Macrophages and Dendritic Cells was observed following GM-CSF treatment. The chemo-biotherapy protocol presented above--while associated with acceptable toxicity--resulted in a relatively high response rate with an increase in the number of durable responses in patients with metastatic melanoma.

The effect of irradiation on expression of HLA class I antigens in human brain tumors in culture.

The immunosuppressive effects of irradiation are well known; however, under certain circumstances irradiation also augments the local immune response by as yet undefined mechanisms. Because of the importance of HLA class I antigen in immune regulation and the fact that killing of tumor cells by cytotoxic T cells is HLA antigen-restricted, the authors studied HLA class I antigen expression in eight glioblastomas multiforme, four meningiomas, and four medulloblastomas. Twenty fragments of each tumor specimen were placed in short-term cultures immediately after resection. For each tumor, control Sample 1 was not irradiated. Sample 2 was irradiated on Day 1, and two groups of the remaining pieces of each tumor (specimens 3 to 10) were irradiated on two consecutive days. Escalating radiation doses were given, starting at 200 cGy/day for Sample 2 up to 1000 cGy/day for Sample 10. The total dose range was 200 to 2000 cGy. Corresponding nonirradiated tumor fragments served as controls. Four hours after irradiation, each sample was processed and stained for HLA class I antigen using the immunoperoxidase technique. The tumor cells were intensely stained in nonirradiated glioblastomas and meningiomas, whereas no staining was observed in medulloblastomas. In four of the eight glioblastomas and in all four meningiomas, irradiation augmented HLA class I antigen expression compared to controls. This effect was dose-dependent and was maximum in the 1200 cGy-treated specimens. No change was observed in the other four glioblastomas or in the medulloblastomas. The data suggest that irradiation does not decrease and may even induce HLA class I antigen expression in some brain tumors. This may be one of the mechanisms by which immunotherapy operates after irradiation. Further studies are required to elucidate optimum radiation doses and fractionation as well as optimum timing of immunotherapy.

Orbital and adnexal involvement in systemic non-Hodgkin's lymphoma.

BACKGROUND: The orbit is rarely a secondary site of lymphoma dissemination, and only few reports exist on the course and characteristics of involvement in these sites. METHODS: The authors retrospectively reviewed the records of 187 consecutive patients with systemic non-Hodgkin's lymphoma (NHL) diagnosed and treated at Beilinson Medical Center between 1986 and 1992. RESULTS: Ten patients (5.3% of those with NHL) had orbital or adnexal involvement or both. Histologically, six had intermediate-grade lymphoma, three had diffuse small cleaved cell lymphoma, and one had nodular small cleaved cell lymphoma. In all 10 patients, the lymphoma was widespread, and in 6, there were two or more other extranodal sites of involvement, mainly, bone marrow (six) and skin (three). The orbital involvement was found either at presentation or as late as 53 months after primary diagnosis. Various therapeutic approaches were chosen, from local orbital irradiation to different mild to aggressive chemotherapeutic protocols. Complete regression of the orbital or adnexal involvement or both was observed in 9 of 10 patients, but in 6 the systemic disease either persisted or recurred at other sites. CONCLUSIONS: Orbital or adnexal involvement or both by NHL may appear at any time during the course of the disease. It responds well to either chemotherapy or radiation therapy with prolonged local remission. The results of this study strongly suggest that every patient with NHL in whom any periorbital or orbital mass, ptosis, proptosis or lid edema develops should be suspected of having orbital lymphoma involvement until proven otherwise.

Current developments in breast cancer.

Interest in the prevention and early detection of breast cancer (BC) is increasing. Prevention studies are under way, and new data from mass screening trials are being evaluated. Improvement of the quality of mammography films and their proper interpretation are regarded as essential for effective early detection. With screening encompassing an increasing number of women, the rising proportion of suspicious breast findings had led to renewed efforts to improve the accuracy of cytologic diagnosis. Basic research continues to contribute to a better understanding of BC biology. Improved discrimination between subsets of patients with different prognosis is expected to optimize results of therapy in operable BC. Reports on taxol and suramin, new types of antitumoral drugs, as well as progress in monoclonal antibody therapy, may constitute preliminary steps towards novel therapeutic strategies.

Prognostic factors in node-positive operable breast cancer patients receiving adjuvant chemotherapy.

A retrospective analysis of prognostic factors in 214 consecutive node-positive (N+) operable breast cancer patients, receiving Melphalan + 5-fluorouracil adjuvant chemotherapy between 1980 and 1984 was performed. Median follow-up was 95 months. Actuarial disease-free interval (DFI) and survival (S) were determined according to age, menopausal status, histology, size of primary tumor (T), multifocality, tumor location, hormonal receptor status, number of N+, size of N+, tumor spread in axillary fat, and interval between surgery and onset of adjuvant chemotherapy. On univariate analysis two factors were prognostic for DFI and S: number of N+ and T size. A comparison between traditionally classified T1 and T2 patients revealed no significant difference, but when the cut-off point was shifted from 2 cm to 3 cm, T size represented a highly significant prognostic factor. In patients with T less than or equal to 3 cm 5-year DFI was 54% and 5-year S was 76%, while in patients with T greater than 3 cm the respective values were 23% (p less than 0.001) and 41% (p less than 0.001). These significant DFI and S differences persisted after adjustment for number of N+ by bivariate analysis. Multivariate analysis supported the importance of T greater than 3 cm as a strong adverse predictor. Four adverse variables, T greater than 3 cm, number of N+ greater than or equal to 4, multifocality, and tumor spread in axillary fat were used to divide our patients into three subsets with significantly different DFI: Group I, with none of the above factors; Group II, with only one factor present; and Group III, with more than one factor present (5 years DFI 66%, 45%, and 21%, respectively; p less than 0.001).

A clinical evaluation of nuclear estrogen receptors combined with cytosolic estrogen and progesterone receptors in breast cancer.

Breast cancer tissue from 95 women was simultaneously assayed for three receptors: cytosolic estrogen (CER), cytosolic progesterone (CPR), and nuclear estrogen (NER). The main objective was to determine whether the addition of NER assay to the currently accepted practice with only CER and CPR could improve the predictive capacity of receptors. Forty-two patients were studied for response to hormone therapy and 95 patients were studied for survival; the median follow-up period was 73 months (range, 8 to 300 months). The incidence of CER+, CPR+, and NER+ was 74%, 70%, and 52%, respectively. Each receptor appeared more frequently, although not significantly so, in higher age groups. Forty percent of tumors had all three receptors positive and 14% had all negative; the remaining tumors showed all possible combinations of receptors. Both the rate of response and survival curves among 70 patients with CER+ did not show any significant difference whether NER was positive or negative. Also, among 38 patients with CER+, CPR+, and NER+, there was no significant difference in the clinical outcome as compared to 17 patients with CER+, CPR+, and NER-. Among 25 patients with CER- the rare occurrence of NER+ in only three patients did not suggest any clinical implication. It is concluded, therefore, that on overall clinical grounds the current series does not support the addition of NER assay whenever data is available on both CER and CPR.

Methotrexate-induced leukoencephalopathy is treatable with high-dose folinic acid: a case report and analysis of the literature.

An episode of leukoencephalopathy is reported in a 13-year-old girl who, after standard radiotherapy for a posterior fossa medulloblastoma, received 8 treatments with a protocol containing a 4-hour infusion of 500 mg/m2 methotrexate and 12 mg intrathecal methotrexate. The leukoencephalopathy, documented clinically and by CT and EEG, cleared after 2350 mg of leucovorin (citrovorum factor, folinic acid) was given in addition to the 135 mg given as part of the therapy. A review of the literature suggests that leukoencephalopathy may be prevented by high doses of leucovorin and can be treated by high doses, if lower doses were used initially. When high dose leucovorin was not used, residual neurological damage is not unusual.

Activity of porphobilinogen deaminase in peripheral blood mononuclear cells of patients with metastatic cancer.

Porphobilinogen deaminase (PBGD), one of the enzymes in the pathway of heme synthesis, was found to be elevated in peripheral mononuclear cells of 60% of patients with epithelial tumors and metastatic spread, but only in 14% of patients with tumor and no evidence of metastases. The combination of both high lactic dehydrogenase and high PBGD afforded a sensitivity of 40%, but a specificity of 96% in diagnosing metastatic spread.

Leiomyosarcoma of kidney.

The case of a seventy-one-year-old woman with leiomyosarcoma of the kidney capsule is presented. Despite lack of invasion into surrounding tissues and few mitoses, the tumor recurred thirteen months after nephrectomy. A full subjective response and an almost complete objective regression lasting eight months were achieved using a short course of combination chemotherapy. The literature on leiomyosarcoma of the kidney is reviewed.

Significance of specific Epstein-Barr virus IgA and elevated IgG antibodies to viral capsid antigens in nasopharyngeal carcinoma patients.

The feasibility of using elevated Epstein-Barr virus (EBV) specific-IgG antiviral capsid antigen (VCA) and IgA anti-VCA antibody levels as an aid in diagnosis of nasopharyngeal carcinoma (NPC) was analyzed by determination of serum antibody titers to EBV in 54 NPC patients, 114 healthy blood donors, and 40 family members by the immunoperoxidase assay (IPA). No significant difference was found in the prevalence rate of EBV IgG anti-VCA antibodies (titer greater than or equal to 20) between the patient group and the control and family groups (100% vs 92% and 90%, respectively). The prevalence rate of elevated EBV IgG anti-VCA titers (greater than or equal to 80, greater than or equal to 160, greater than or equal to 320, greater than or equal to 640) was significantly higher in the NPC patients than in controls. For example, at an IgG titer of greater than or equal to 320, the prevalence rate was 82% in the NPC patient group and 1.7% in the controls (P less than 0.0001). The prevalence of EBV IgA anti-VCA antibodies (greater than or equal to 10) was significantly higher in the NPC patients than in control and family groups (82% vs 6.1% and 0%, respectively). The prevalence rate for elevated EBV IgA anti-VCA (greater than or equal to 20) was found to be significantly higher (P less than 0.0001) in NPC patients than in the control group (70% vs. 1.7%). A significantly high proportion (P = 0.0004) of NPC patients who had serum EBV IgA anti-VCA titers of less than 20 had elevated IgG titers to VCA greater than or equal to 320 (21% vs 1.7% among controls). It appears that testing for IgG antibodies at a serum dilution of 1:320 and for IgA antibodies at a dilution of 1:20 by the IPA technique comprises the best combination for the differentiation between NPC patients and health controls (91% vs 3.4%), and it is suggested that these be used as screening markers for NPC patients.