A surveillance study of clinical stage I nonseminomatous germ cell tumors of the testis: 10-year followup

PURPOSE: We evaluate the 10-year results of a surveillance study of clinical stage I nonseminomatous germ cell tumors of the testis. MATERIALS AND METHODS: Between 1981 and 1984 we recruited 85 consecutive evaluable patients with nonseminomatous germ cell tumors of the testis and normal post-orchiectomy physical examination, chest x-rays, bipedal lymphangiography, abdominal scans and serum tumor markers. The patients were followed for at least 10 years after orchiectomy alone, which was performed elsewhere in 90% of the cases. RESULTS: The interval between visits was twice as long as it was scheduled. Relapses occurred in 25 patients (29.4%) after a median disease-free interval of 7 months (range 2 to 68). Five patients had further relapses and 3 (3.5%) died of cancer. Retroperitoneal relapses (19%) occurred later than lung relapses, and they were diagnosed when larger than 5 cm. in 7 patients. The percentage of embryonal carcinoma within the tumor associated with relapse (p = 0.008), T category (p = 0.023), scrotal violation (p = 0.042) and vascular invasion (p = 0.063) had a weak correlation but data on T category and vascular invasion were available for only some patients. CONCLUSIONS: Surveillance is a difficult type of study and missing data may compromise the therapeutic program based on prognostic factors.     

The management of stage I testis cancer

For clinical stage I seminoma, conventional management consists of adjuvant RT after orchiectomy. Only 5% of patients relapse. The majority can be salvaged by chemotherapy. The overall survival of 98% is excellent. Seminoma is radiosensitive. A lower dose of RT is required than for NSGCT. Standard therapy presently is 30 Gy in 3 weeks, as suggested by the MRC study. RT is generally well tolerated. There have been recent concerns about second malignancies after 10 to 15 years. Surveillance studies have shown that 18% of patients relapse, the majority in para-aortic lymph nodes. About 15% require salvage RT and 5% salvage chemotherapy. Second relapses are seen in patients treated with RT at first relapse, and occur outside of the radiation field. The main advantage of surveillance is that 80% of patients can be spared slightly toxic overtreatment. The main disadvantage is the need for long-term follow-up, which is expensive and stressful to the patient. Good patient compliance, mandatory to an observation policy, is often difficult on a long-term basis. Seminoma is clearly responsive to chemotherapy. Adjuvant carboplatin in clinical stage I has only been evaluated in two studies. Because reliable prognostic factors have not been established, a high-risk group cannot be identified, and chemotherapy must be given to all patients. Whether or not one cycle of chemotherapy is sufficient requires further confirmation, particularly in view of the results with carboplatin as compared with cisplatin in patients with advanced NSGCT. Results of the randomized MRC trial comparing RT with carboplatin are of interest.     

A rational approach to managing stage I nonseminomatous germ cell cancer

Four studies examined the effects of divided attention in younger and older adults. Attention was divided at encoding or retrieval in free recall (Experiment 1), cued recall (Experiments 2 and 3), and recognition (Experiment 4). Dividing attention at encoding disrupted memory performance equally for the two age groups; by contrast, for both age groups, dividing attention at retrieval had little or no effect on memory performance. Secondary task reaction times (RTs) were slowed to a greater extent for the older adults than for the younger adults, especially at retrieval. Age-related differences in RT costs at retrieval were largest in free recall, smaller in cued recall, and smallest in recognition. These results provide evidence for an age-related increase in the attentional demands of encoding and retrieval.     

En bloc nephrectomy in patients undergoing post-chemotherapy retroperitoneal lymph node dissection for nonseminomatous testis cancer: indications, implications and outcomes

PURPOSE: We review the indications for nephrectomy at post-chemotherapy retroperitoneal lymph node dissection, identify patients at risk for nephrectomy and assess the impact of nephrectomy on outcome. MATERIALS AND METHODS: Using a computerized data base and chart review we retrospectively reviewed the records of 848 patients who underwent retroperitoneal lymph node dissection after chemotherapy. RESULTS: En bloc nephrectomy was performed at retroperitoneal lymph node dissection after chemotherapy in 162 of the 848 patients (19%). The indications for nephrectomy included contiguous involvement of perirenal structures in 73% of the cases, renal vein thrombosis in 6%, a poorly functioning or nonfunctioning renal unit in 5% and a combination of these conditions in 16%. Pathological studies of the hilum revealed cancer in 20% of the cases, teratoma in 49% and fibrosis in 31%. Patients requiring nephrectomy had significantly more advanced disease and larger disease volume at presentation and after chemotherapy. There were no significant differences in perioperative morbidity or mortality compared with patients who did not undergo nephrectomy. Only 3 patients required perioperative dialysis and none required long-term renal support. CONCLUSIONS: These findings support en bloc nephrectomy at post-chemotherapy retroperitoneal lymph node dissection in select patients with large volume perihilar retroperitoneal disease.     

Primary chemotherapy for stage 2 testis cancer

To evaluate the efficacy and toxicity of primary chemotherapy in patients with stage 2 (retroperitoneal lymph node metastases) testis cancer, 20 consecutive patients referred to Groote Schuur Hospital between September 1992 and March 1994 were reviewed. There were 10 patients with non-bulky non-seminomatous germ cell tumour (NSGCT), 5 with bulky NSGCT and 5 with bulky seminoma. The treatment regimen consisted initially of 4 cycles of cisplatin, etoposide and bleomycin. Patients with NSGCT and a residual mass after chemotherapy subsequently underwent retroperitoneal lymph node dissection (RPLND) and those with seminoma underwent a low dose of irradiation to the mass. In 7 (70%) of the 10 patients with non-bulky NSGCT, there was a complete response to chemotherapy and 3 patients underwent limited RPLND. One patient relapsed at follow-up but remains clear of disease after salvage therapy. The survival rate is 100% at a median follow-up of 60 months (range 12-143 months). In 5 patients with bulky NSGCT there was no complete response to chemotherapy. Three have undergone limited RPLND. The survival rate is 52% at a median follow-up of 130 months (range 108-152 months). In 5 patients with bulky seminomas, the survival rate is 100% at a median follow-up of 55 months (range 29-92 months). Toxicity has been modest except for 1 patient who died postoperatively in the early part of the study. Four patients have fathered children after treatment. We conclude that primary chemotherapy is the treatment of choice for patients with stage 2 testis cancer.     

Laparoscopic retroperitoneal lymph node dissection for clinical stage I nonseminomatous testicular tumor

In Japan, a nationwide mass screening system for neonatal metabolic diseases was established in 1977. This system consisted of screening programs for five main congenital metabolic diseases, including phenylketonuria (PKU). To evaluate the efficiency of the mass screening system, a cost-benefit analysis of the screening program for PKU (as a typical case in Japan) was carried out. The costs of the detection and the treatment program were compared with the projected benefit (avoided costs) that results from prevention of the mental retardation associated with the disorders due to PKU. Costs and benefits were discounted at an annual rate of 7%. Assuming that the incidence of PKU was 1/80,500 and the total number of infants screened was 1.2 million, net benefits for the screening program were $283,000, and the cost-benefit ratio was 1:2.5. The sensitivity analysis for the incidence of PKU showed that the cost-benefit ratios exceeded one.     

Surveillance study for clinical stage I testicular seminomas and nonseminomatous germ cell tumors

Intravenous immunoglobulin (IVIG) (Octagam), was used to determine the effect on hyperacute rejection in an ex vivo xenograft model. Six pig kidneys were perfused with IVIG and fresh human AB blood, and six control pig kidneys were simultaneously perfused with albumin and blood from the same donation. The survival of the IVIG-perfused xenografts (median, 6.5 h) was significantly (P = 0.03) longer than the albumin-perfused xenografts (median, 3.5 h). Complement was activated in both groups. The administration of IVIG to the perfused blood resulted in immediate and significantly higher complement activation in the fluid phase as compared with the albumin group. At rejection the fluid phase complement activation was higher in the IVIG group than in the albumin group for C1rs/C1inh complexes, C4bc, Bb and TCC. At the time of rejection both the albumin and the IVIG group demonstrated interstitial tubular haemorrhage, vasculitis or necrosis of glomerular capillaries and glomerular microthrombi. IgM, C1q, C3c, C4 and fibrin were located in arteries and glomeruli and IgG in the interstitium in both groups at rejection. The fluid phase findings are consistent with a modulatory effect of IVIG on complement activation by deviating the classical pathway activation towards the fluid phase. The prolonged survival of the IVIG-perfused kidneys suggests that IVIG may be useful to dampen hyperacute rejection.     

Molecular pathologic substaging in 244 stage I non-small-cell lung cancer patients: clinical implications

PURPOSE: To retrospectively construct a comprehensive multivariate model of cancer recurrence and to design a molecular pathologic substaging system in stage I non-small-cell lung cancer (NSCLC). METHODS: All patients with stage I NSCLC resected at Brigham and Women's Hospital (Boston, MA) between 1984 and 1992 with adequate clinical follow-up were studied. The importance of three demographic characteristics, surgical extent, 11 pathologic features, and seven molecular factors on cancer-free survival was examined. RESULTS: Two hundred forty-four patients were studied, with 25 noncancer deaths and 80 patients with recurrent disease. Significant univariate predictors (P < .05) of cancer recurrence were age older than 60 years, male sex, wedge resection, World Health Organization (WHO) adenocarcinoma subtype solid tumor with mucin, lymphatic invasion, and p53 expression. Multivariate analysis identified nine independent predictors of recurrence: solid tumor with mucin, a wedge resection, tumor diameter of 4 cm or greater, lymphatic invasion, age older than 60 years, male sex, p53 expression, K-ras codon 12 mutation, and absence of H-ras p21 expression. Multivariate cancer-free survival (CFS) analysis in the 180 patients who underwent lobectomy or pneumonectomy led to the elimination of sex and age, which left six independent factors. CONCLUSION: Lobectomy or pneumonectomy should be performed in stage I NSCLC. Using the six independent factors for recurrent disease, we propose a pathologic molecular substaging system. Patients with two factors or less are graded Ia, with a 5-year CFS rate of 87%; those with three factors are graded Ib, with a 5-year CFS rate of 58%; and those with four factors or more are graded Ic, with a 5-year CFS rate of 21%.     

Risk-adapted treatment of clinical stage 1 non-seminoma testis cancer

250 patients with clinical stage 1 non-seminomatous germ cell tumours of the testis (NSGCT 1) were included into a prospective multicentre protocol during 1990-1994 and treated according to three risk strata: patients without tumour cell invasion of vascular structures in the testis (VASC-) and elevated serum AFP levels (AFP+) at orchiectomy were considered low risk (LR) and only observed closely. VASC- and AFP- or VASC+ and AFP+ patients were presumed intermediate risk (IR) and pathologically staged (PS) by retroperitoneal lymph node dissection (RPLND). VASC+ and AFP-patients were regarded as high risk (HR) and received adjuvant chemotherapy (PEB x 3). At a median observation time of 40 (7-68) months, all patients were alive and without evidence of active germ cell cancer. The actuarial relapse rate in the 106 LR patients was 22%, and 70% (14/20) had elevated serum tumour markers at relapse. One of 32 (3%) HR patients relapsed with a resectable retroperitoneal mature teratoma despite adjuvant chemotherapy. Only 14% of the 99 IR patients who underwent RPLND had PS2 disease, and the actuarial relapse rate in 85 PS1 patients was 18%. This multicentre study demonstrated that excellent therapeutic outcome is possible when 18 comparatively small urological and oncological centres follow a strict and formal cancer care programme. The useful prognostic effect of VASC was once again verified. Pathological staging by RPLND in NSGCT1 is, in our opinion, not necessary, with presumed low-risk patients offered surveillance and high-risk patients offered adjuvant chemotherapy.     

Adjuvant therapy for stage I testicular cancer

A variety of possible mechanisms for the loss of CD4+ T cells has been proposed, such as direct cytopathic effects by HIV-1 infection, and indirect induction of apoptosis. However, the fundamental picture of major and central pathogenic processes for the decay of immune systems is still missing in understanding the pathogenic mechanisms of HIV-1 infected humans. It is more appropriate to expand our focus onto entire organ systems involved in the development of immune system such as bone marrow and thymus. From the observations in the clinical studies, HIV-1 causes a variety of pathology on the T cell development pathway even from the hematopoietic progenitors and immature thymocytes, which should have a substantial impact on the failure of T cell homeostasis in the periphery. The SCID-hu mouse constructed by surgical implantation of human fetal hemato-lymphoid organs into the immunodeficient mouse has been used for the experimental evaluation of various parameters associated with HIV-1 infection and hematosuppression. Given the apparently normal structure and function of the human implants, the SCID-hu bone and Thy/Liv mice would appear to be potentially reliable models for the analysis of human physiology and patho-physiology.     

Unusual development of nonseminomatous germ cell tumors of the testis (NSGCT)

The authors describe a clinical case of metastatic testicular non-seminomatous germinal tumor with several recurrences treated by the association of chemotherapy and surgery for remaining lesions. Based on this case a review of the literature is done to illustrate the evolution of treatments, to highlight the evolutive potential of mature teratoma, the delayed recurrences.     

The value of prognostic factors in the management of stage I nonseminomatous germ cell testicular tumors (NSGCTT)

A patient with florid hypertrophic pulmonary osteoarthropathy (HPOA) associated with metastatic nasopharyngeal carcinoma is presented. Despite the presence of metastatic disease in the thorax and in bone, the patient's main symptom was severe pain from the HPOA, which was temporarily relieved by chemotherapy. Her disease subsequently progressed during chemotherapy and the pain became resistant to conventional treatment, including high dose morphine, non-steriodal anti-inflammatory agents and steriods. It was only with local radiation to the involved joints that the pain could be controlled. Our patient demonstrates that local radiotherapy is an option for the palliation of extreme HPOA.     

Immunohistochemical expression of Ki-67 to predict lymph node involvement in clinical stage I nonseminomatous germ cell tumors

PURPOSE: Primary archival tumor tissues of 89 patients with clinical stage I nonseminomatous germ cell tumors were analyzed for MIB-1 expression and histological parameters such as percentage embryonal carcinoma and presence of vascular invasion to determine the value of these parameters to predict absence or presence of occult lymph node disease. MATERIALS AND METHODS: A monoclonal antibody (MIB-1) developed for application in paraffin-embedded tissues was used to measure immunohistochemical expression of Ki-67 for the overall tumor (total MIB-1) and for each malignant cell type present. In addition, the primary tumors were examined for the presence of vascular invasion and determination of quantitative histology. Univariate and multivariate logistic regression models were used for statistical analysis. RESULTS: Univariate analysis neither revealed total MIB-1 score nor MIB-1 score in the highest area of staining of the different cell types to significantly predict pathological stage I or stage II disease. However, the presence of vascular invasion (p < 0.0001) and the percentage of embryonal carcinoma (p < 0.0001) were significant risk factors for occult nodal disease. Multivariate logistic regression analysis revealed the combination of vascular invasion and the percentage of embryonal carcinoma to be the best model to predict pathological stage II correctly (86.5%). DISCUSSION: The determination of immunohistochemical MIB-1 expression did not correlate with pathological stage in clinical stage I nonseminomatous germ cell tumors (NSGCT). We were not able to define high risk or low risk groups for occult nodal disease based on MIB-1 staining results. However, percentage of embryonal carcinoma and presence of vascular invasion accurately predicted absence or presence of lymph node metastasis in clinical stage I NSGCT. Our study underlines that a prospective multicenter trial is urgently needed to accurately assess the role of MIB-1 staining in management of clinical stage I NSGCT.     

Laparoscopic retroperitoneal lymphadenectomy for cancer of the testis

Laparoscopic retroperitoneal lymph node dissection (RPLND) is a technically advanced procedure that has been undertaken for the management of low-stage nonseminomatous germ cell testis tumor. Although it has been shown to be an effective staging technique, its role as a therapeutic operation is currently unknown. Laparoscopic RPLND requires longer operative times but offers the patient all the advantages of minimally invasive surgery, such as less postoperative pain and shorter hospitalization and convalescence. The role of laparoscopic RPLND for the evaluation of residual abdominal masses following chemotherapy is currently being examined.     

Immunocytochemical markers in stage I lung cancer: relevance to prognosis

PURPOSE: This study investigated the frequency of the expression and prognostic significance of a panel of immunocytochemical markers in resected non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: A total of 515 cases of pathologic stage I NSCLC were analyzed. The median follow-up time of surviving patients was 102 months. The following immunocytochemical markers were tested: blood group A and precursors of blood antigens; laminin receptor; c-erbB1/epidermal growth factor receptor (EGFR) and c-erbB2/Neu; BCl2; p53; and angiogenesis. Kaplan-Meier estimates of survival and time to recurrence were calculated for clinical variables and biologic markers using the Cox model for multivariate analysis. RESULTS: The pathologic tumor extension (pT) represented the most powerful prognostic factor for survival (P = .0008) and time to recurrence (P = .0007). None of the immunocytochemical markers emerged as an independent predictive factor for survival. Bcl2-positive tumors showed a better time to recurrence (P = .03), but the difference lost statistical significance in the multivariate analysis. Of interest, in the group of 137 patients classified as pT1N0, both EGFR expression and nonangiogenic type of vascular pattern were associated with a poorer survival (P = .02). However, data derived from subset analysis must be interpreted cautiously. CONCLUSION: Our findings do not support a relevant prognostic role of immunocytochemical markers in NSCLC. The evidence is not sufficient to alter clinical practice or even to restrict clinical trials of adjuvant treatments to predefined biologic subsets of patients.     

A rational treatment of stage I epithelial ovarian cancer

OBJECTIVE: To evaluate the incidence of lymph node metastasis and the role of lymphadenectomy in stage I epithelial ovarian cancer. METHODS: Forty patients with stage I epithelial ovarian cancer treated from 1985 to 1990, were divided into two groups and retrospectively analyzed. First group of 20 patients were treated by routine surgery and cis-platinum based chemotherapy. Second group of 20 patients were treated by routine surgery and cis-platinum based chemotherapy plus retroperitoneal lymphadenectomy, and on the basis of with normal ovary and uterus preserved in the younger stage I a patients. A comparison was made between the five-year survival rates of the two groups. RESULTS: Four patients in the second group were found to have retroperitoneal lymph node metastasis and should be staged as II c postoperatively. In three of the four patients aortic lymph node metastasis were diagnosed. The chances of metastasis to the pelvic and to the aortic lymph nodes were nearly equal. There is a significant difference in the 5-year survival rates between the two groups (85% vs 100%, P < 0.05). Ten patients with their ovaries and uteri preserved are living and well. CONCLUSION: It is suggested that to obtain accurate FIGO staging and to improve survival and its quality, retroperitoneal lymphadenectomy should be performed in all patients with stage I eipthelial ovarian cancer, and younger patients with stage I a cancer may preserve their gestational functions if desired.     

Endoscopic surveillance of Barrett's esophagus: a cost-effectiveness comparison with mammographic surveillance for breast cancer

OBJECTIVE: Endoscopic surveillance of Barrett's esophagus is commonly practiced to detect malignancy in an early and curable stage. However, the cost-effectiveness of this practice has been questioned. To clarify this issue, we undertook a cost analysis of endoscopic surveillance to detect adenocarcinoma in Barrett's esophagus compared with mammography used to detect occult carcinoma of the breast, a widely accepted cancer surveillance technique. METHODS: The rate of esophageal adenocarcinoma detected by endoscopic surveillance was calculated for Duluth Clinic patients with Barrett's esophagus seen from 1980 to 1995 and compared with published rates. The rate of occult breast cancer detection was calculated for all women undergoing surveillance mammography at the Duluth Clinic for the year 1994 and compared with published rates. Costs for screening studies and therapy for cancer treatment for both cancers were calculated based on clinical results and assumptions regarding outcomes derived from published reports, and the costs were compared. RESULTS: Endoscopic surveillance of 149 patients with benign Barrett's esophagus was performed for a total of 510 patient-yr, during which time seven patients developed adenocarcinoma, an incidence of one case per 73 patient-yr of follow-up. Occult breast cancer was detected in 50 of 12,537 mammograms, a detection rate of 0.4%. The incidences in both cases were comparable to published figures. The costs of detecting a case of adenocarcinoma in Barrett's esophagus and occult breast cancer were $37,928 and $54,513, respectively, and those for treatment resulting in cure were $83,340 and $83,292. Cost per life-yr saved was $4,151 for adenocarcinoma in Barrett's esophagus and $57,926 for breast cancer. CONCLUSION: Endoscopic surveillance of patients with Barrett's esophagus compares favorably with the common practice of surveillance mammography to detect early breast cancer, and should therefore be considered to be as cost-effective as surveillance mammography.     

Deferred treatment of locally advanced nonmetastatic prostate cancer: a long-term followup

PURPOSE: We prospectively investigated long-term survival in select men with locally advanced, nonmetastatic prostate cancer managed with deferred treatment. MATERIALS AND METHODS: A total of 50 patients with prostate cancer clinically outside the prostatic capsule and without distant metastases were included in a surveillance protocol. The men were treated if and when symptoms occurred or upon request. The series was followed until December 1994. No patient was lost to followup. RESULTS: Median patient age at diagnosis was 71 years. All patients were followed more than 144 months or died before then. Actual (cumulative incidence) overall and disease specific survival rates at 5, 10 and 12 years were 68 and 90, 34 and 74, and 26 and 70%, respectively. A third of the patients had not received antitumor treatment at followup or before death. CONCLUSIONS: When managed with deferred treatment nonpoorly differentiated, locally advanced nonmetastatic prostate cancer seems to have a poorer survival outcome than similarly managed clinically localized prostate cancer. However, compared with other treatments and in terms of survival deferred treatment may be an option for select patients with such tumors and a life expectancy of 10 years or less.     

Impact on survival by method of recurrence detection in stage I and II cutaneous melanoma

Immunoaffinity columns were made with specific egg yolk immunoglobulin (Ig) Y against bovine IgG1 and IgG2 and were used to isolate pure IgG1 and IgG2 from Cheddar cheese whey or colostrum. About 10% of the IgY was specific for IgG, and 3% of the IgY was subclass-specific after hyperimmunization of laying hens with either IgG1 or IgG2. Up to 38% of the potential binding capacity of IgY was obtained after immobilization by reductive amination. The IgY columns were stable, and one column could be reused for more than 50 times for over a year with minimal loss in binding capacity. Milk that was free of either IgG subclass was successfully produced by the selective removal of IgG1 or IgG2 subclasses. Double-immunodiffusion analysis confirmed the isolation of subclasses from whey and colostrum and also confirmed that their removal from milk was specific.