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The levels for serum protein bound neutral carbohydrates (fucose, mannose, and galactose) were determined at specific intervals for 40 patients with small cell carcinoma of the lung and compared to the corresponding carcinoembryonic antigen (CEA) levels. In pretreatment samples, the frequency of elevation was 92.5% for fucose and 77.5% each for mannose and for galactose. CEA determined in these same samples was elevated (greater than 5 ng/ml) in 45.0%. One or more of the three carbohydrate levels were elevated in pretreatment serum of 95.0% of the patients. The individual frequency of elevation for each carbohydrate was significantly related to initial stage of disease (P less than 0.01). Median survival was significantly longer for patients based on a discriminant of less than 3 carbohydrates elevated in pretreatment samples (25 months) to all 3 elevated (11 months) with P = 0.0302. A single value, termed the biomarker index, was calculated to represent the summation of the individual carbohydrate levels per individual serum sample. The biomarker index was found to be directly correlated with extent of primary disease, number of metastic sites, tumor burden, and clinical response categories assessed at serial time points. For patients with both low Biomarker Index values and normal CEA levels in pretreatment samples, an initial rise in both determinations occurred frequently corresponding to partial or complete tumor response. The occurrence of such discordant results must be considered as a likely possibility for those patients with low or normal pretreatment biological marker levels and subsequent response to primary chemotherapy.

BACKGROUND Cisplatin has minimal antitumor activity when used as second- or third-line treatment of metastatic breast carcinoma. Older reports suggest an objective response rate of 8% when 60–120 mg/m2 of cisplatin is administered every 3–4 weeks. Although a dose–response effect has been observed with cisplatin, the dose-limiting toxicities associated with cisplatin (e.g., nephrotoxicity, ototoxicity, and neurotoxicity) have limited its use as a treatment for breast carcinoma. WR-2721 or amifostine initially was developed to protect military personnel in the event of nuclear war. Amifostine subsequently was shown to protect normal tissues from the toxic effects of alkylating agents and cisplatin without decreasing the antitumor effect of the chemotherapy. Early trials of cisplatin and amifostine also suggested that the incidence and severity of cisplatin-induced nephrotoxicity, ototoxicity, and neuropathy were reduced. METHODS A Phase II study of the combination of cisplatin plus amifostine was conducted in patients with progressive metastatic breast carcinoma who had received one, but not more than one, chemotherapy regimen for metastatic disease. Patients received amifostine, 910 mg/m2 intravenously over 15 minutes. After completion of the amifostine infusion, cisplatin 120 mg/m2 was administered over 30 minutes. Intravenous hydration and mannitol was administered before and after cisplatin. Treatment was administered every 3 weeks until disease progression. RESULTS Forty-four patients were enrolled in the study of which 7 (16%) were ineligible. A median of 2 cycles of therapy was administered to the 37 eligible patients. Six partial responses were observed for an overall response rate of 16%. Most patients (57%) stopped treatment because of disease progression. Neurologic toxicity was reported in 52% of patients. Seven different life-threatening toxicities were observed in patients while receiving treatment. CONCLUSIONS The combination of cisplatin and amifostine in this study resulted in an overall response rate of 16%. Neither a tumor-protective effect nor reduced toxicity to normal tissues was observed with the addition of amifostine to cisplatin in this trial. Cancer 2001;92:2517–22. © 2001 American Cancer Society.

BACKGROUND A Phase II study was performed evaluating the disease free and overall survival rates associated with a dose-intensive, 16-week, doxorubicin-based adjuvant chemotherapy regimen in women with breast carcinoma and ≥ 10 involved axillary lymph nodes. METHODS Eligible patients underwent staging with computed tomography and bone scanning and were treated with a 16-week, dose-intensive chemotherapy regimen, comprised of 8 2-week courses of cyclophosphamide, 100 mg/m2 orally, on Days 1–7; doxorubicin, 40 mg/m2 intravenously (i.v.), on Day 1; methotrexate, 100 mg/m2 i.v., on Day 1 with leucovorin rescue, 10 mg/m2, every 6 hours for 6 doses orally on Day 2; vincristine, 1 mg i.v. on Day 1; 5-fluorouracil (5-FU), 600 mg/m2 i.v., on Day 2 over 2 hours; and 5-FU, 300 mg/m2/day continuous i.v. on Days 8 and 9. Tamoxifen, 20 mg daily, was administered to patients with estrogen receptor positive tumors treated after October 1988. All patients were offered locoregional radiation therapy. RESULTS Sixty-four women were treated on protocol. The median follow-up of 27 surviving patients was > 8 years at last follow-up. Three patients were lost to follow-up. The median time to progression was 54 months, the Kaplan–Meier estimate of event free survival at 5 years was 44% (95% confidence interval [CI], 31–56%), and the Kaplan–Meier estimate of overall survival at 5 years was 57% (95% CI, 44–69%). At 98 months the Kaplan–Meier estimate of freedom from recurrence was 31% (95% CI, 19–43%) and the Kaplan–Meier estimate of survival at 111 months was 36% (95% CI, 23–49%). CONCLUSIONS Despite the use of dose-intensive, doxorubicin-based, adjuvant chemotherapy, and intensive staging prior to study entry, the results of the current study are similar to those of previous reports for standard dose chemotherapy and appear inferior to those reported for high dose therapy. Cancer 1999;85:899–904. © 1999 American Cancer Society.

Background. Locoregional recurrences occur commonly in women with breast cancer and often have grave prognostic implications. Major controversies exist concerning the prophylaxis, implications, and treatment of such relapses and are the focus of this review. Methods. The relevant medical literature was reviewed and analyzed. Results. Locoregional recurrences may be prevented by postoperative radiation therapy; however, this has little impact on survival. Postoperative systemic therapy prevents locoregional relapse, but less efficiently than radiation therapy. When these modalities are combined, radiation therapy often is delayed until after several cycles of chemotherapy. Optimal sequencing remains controversial. Most patients with locoregional relapses have an exceedingly poor outlook. Radiation therapy provides excellent local control; however, the addition of combination chemotherapy should be considered for patients with defined poor prognostic features. The clinical impact of recurrence in the breast after breast-conserving primary treatment now is emerging. Such local relapses do not have the dreaded prognostic implications of locoregional relapse after mastectomy, but are a marker for an increased risk of dissemination. Standard therapy in this setting remains mastectomy. Additional breast-conserving surgery may be considered in the context of clinical trials for patients with certain favorable features. Conversely, some local relapses after breast-conserving surgery have a poorer prognosis, and the addition of adjuvant systemic therapy should be considered in addition to mastectomy. Conclusions. The heterogenous nature of locoregional relapses has made it difficult to conduct prospective randomized clinical trials. However, many retrospective data exist, making it possible to recommend rational treatment approaches for these patients.

An initial trail to determine whether the theoretical advantage of concurrent systemic chemotherapeutic protection and local control (by radiation) could be achieved has been applied to 16 patients with breast cancer (Stage 3 and 4). CMFP/CMF combination chemotherapy has been administered with external irradiation (5000 rad breast, 4000–4400 rad nodes). External irradiation was successfully accomplished with tangential fields to avoid combined modality esophagitis while achieving internal mammary node irradiation. Six patients subsequently received Iridium-192 interstitial implantation. Six patients treated preoperatively (4000 rad, breast) were able to have modified mastectomy within 3–6 weeks of completing radiation therapy without graft requirement or undue morbidity. Acute reactions during therapy included some amplification of epidermitis and myelosuppression. Prolongation of the radiation treatment course occurred in two patients and delay in chemotherapy cycles in four patients. In two patients, the leukocyte count nadir was below 1000 and one was hospitalized with fever. The majority of the patients achieved 75% of the designed chemotherapeutic doses in the ensuing year. Many of the patients with advanced disease were administered an Adriamycin-containing regimen upon completion of the radiation therapy. The current results suggest that it would be feasible to initiate a randomized prospective study using these techniques to compare sequential and concomitant chemo-radiation therapy in primary breast cancer to determine whether there is significant advantage in local control and duration of NED survival in either of the treatment regimens.

The adrenal glands are frequently metastatic sites of lung and other primary neoplasms. These metastases are usually clinically occult and secondary adrenal hemorrhage is extremely rare. Two patients who developed massive adrenal hemorrhage secondary to metastatic lung carcinoma to the adrenal glands are presented.

Metastatic carcinoma to the testis is unusual. There are only seven previously reported cases in which a testicular mass was the first clinical manifestation of an underlying malignancy. The authors review 127 cases in which the testis was involved by metastatic carcinoma, and describe an additional two patients in whom a malignant testicular mass was the presenting sign of an underlying nontesticular carcinoma. The tumors most commonly reported to metastasize to the testis are: prostate (45 cases), lung (25 cases), melanoma (12 cases), colon (11 cases), kidney (10 cases), stomach (6 cases), and pancreas (5 cases). Neuroblastoma, retinoblastoma, carcinoid tumor, and cancers of the bile duct, ureter, bladder, salivary gland, and thyroid have also involved the testis secondarily. Nineteen patients (15%) had bilateral testicular metastases. Patients with secondary testicular neoplasms were older in general than those with germ cell tumors (mean, 55 years; median, 57 years). Histologically, the presence of extensive lymphatic and vascular invasion and an interstitial pattern, in which the seminiferous tubules are spared, is suggestive of a metastasis. In four of the nine cases (44%) in which testicular enlargement was the first manifestation of an underlying carcinoma the correct pathologic diagnosis was initially missed. Serum alpha-fetoprotein (AFP) and human chorionic gonadotropin (HCG) are occasionally elevated in patients with nontesticular primary tumors, but markedly elevated levels in young patients suggest a nonseminomatous germ cell tumor, as does positive immunoperoxidase staining for AFP and HCG.

Small cell carcinoma of the lung is the tumor most commonly associated with ectopic ACTH production and hypercortisolism. The relationship between this paraneoplastic endocrine syndrome and the clinical course of the tumor is examined in this review of patients with the ectopic ACTH syndrome and small cell carcinoma seen at The Johns Hopkins Oncology Center between 1973 and 1979. Five of 157 (3.2%) patients with small cell carcinoma were clinically diagnosed as having the ectopic ACTH syndrome. The onset of this endocrine syndrome appeared to coincide with a more aggressive phase of the course of small cell carcinoma. Further analysis of these cases suggests that the development of the ectopic ACTH syndrome may reflect changes in cell populations within the tumor and/or alterations in tumor behavior with time and perhaps with the effects of drug therapy.

The monitoring utility of serial patterns of a single marker (carcinoembryonic antigen) level and multiple marker (three carbohydrates-fucose, mannose and galactose) levels in patients with small cell carcinoma of the lung was investigated using a quantitative approach. A serial multiple regression (SMR) model was formulated to assess the disease response following the first to the tenth course of therapy and resulted in the multiple correlations ranging from 0.183 (NS)-0.706 (P less than 0.005) for CEA, and 0.502 (P less than 0.250)-0.760 (P less than 0.025) for three carbohydrates, respectively. The appraisal of these markers utilizing the SMR model points out that: (1) the serial levels of CEA greater than 5.0 ng/ml are significantly correlated with the disease course whereas the serial levels less than 5.0 ng/ml reflect the trend of variation in the disease course, but with less accuracy; and (2) the levels of three carbohydrates, any one elevated before and during therapy, are significantly correlated with the disease course.

A chemotherapeutic regimen consisting of BCNU, cyclophosphamide, vincristine, and procarbazine was evaluated in 43 patients with small cell carcinoma of the lung. The majority of patients received radiation therapy of the primary tumor, but chemotherapy alone was utilized in a group of patients with widely disseminated disease. In addition to thorough staging with radioisotope scans and bone marrow biopsies, a study of calcitonin and histaminase as biochemical markers was performed. The BCVP chemotherapy resulted in a complete and partial response rate of 53% when given alone or in conjunction with radiotherapy. The survival data are preliminary, but the complete responders do have a statistically significant better survival (mean of + -95 days) than the partial responders and nonresponders. Hypercalcitonemia was not detected in our patients, but elevated histaminase activity was found in eight of 24 patients with small cell carcinoma and in only one of 19 patients with squamous and large cell carcinoma.

Four patients developed abnormal liver function tests and focal defects on liver scan while receiving cyclophosphamide, methotrexate and 5-fluorouracil as adjuvant chemotherapy following mastectomy for breast cancer. Liver biopsies showed severe focal inflammation. The biopsy findings and the subsequent clinical course of the patients strongly suggest that these abnormalities were due to hepatic toxicity of the chemotherapy and not metastic breast cancer. A review of serial liver function tests performed on 24 patients in that chemotherapy program revealed that four out of eight patients with elevated alkaline phosphatase prior to therapy developed early metastatic cancer. Elevated alkaline phosphatase occurring during chemotherapy on the other hand was quite common but more likely due to hepatic toxicity of the drugs. The development of abnormal liver function tests even in association with focal defects on liver scan is not sufficient to diagnose metastatic breast cancer in patients receiving adjuvant chemotherapy.

Clinical correlates with urinary excretion of polyamines were evaluated for 29 newly diagnosed and 35 previously treated patients with small cell carcinoma of the lung (SCC). The frequencies of pretreatment abnormalities were 12 (41%) for putrescine, 18 (62%) for spermidine, and 20 (69%) for spermine. In assessing disease parameters, the combined use of the abnormalities of spermidine and spermine as a discriminant was more effective than that of all three polyamines; it correlated significantly with extent of limited and extensive disease (P less than 0.001), and also resulted in significant separation of survival curves, the median survival of 11 months for both elevated compared to 19 months for neither or only one elevated (P = 0.062). No significant difference was seen in the abnormalities between no metastasis and one metastasis, whereas the frequencies of the abnormalities was highly increased in two or more metastases. The distribution of polyamines determined at regular treatment intervals showed distinctively more elevated patterns in progressive disease than in stable disease or partial and complete responses (P less than 0.01). In order to evaluate therapeutic effects on the relationship between polyamine excretion and tumor regression, correlations between urinary putrescine and spermidine were determined. The values of the ratio of spermidine to putrescine were significantly smaller in responders than in nonresponders (P less than 0.01); and these may be related to smaller tumor mass and higher tumor proliferative activity in responders, and larger tumor mass and lower tumor proliferative activity in nonresponders.

Five minor base ribonucleosides, primarily degradation products of transfer ribonucleic acid (tRNA), were evaluated as potential biological markers for patients with small cell carcinoma of the lung. The urinary concentration for pseudouridine, 1-methyladenosine, 1-methylinosine, N2-methylguanosine, and N2,N2-dimethylguanosine was determined by means of reversed-phase high performance liquid chromatography and quantitatively expressed as a function of creatinine excretion. Comparisons were made with carcinoembryonic antigen (CEA) plasma levels. The total frequency of elevated values for the five nucleosides in pretreatment urine samples was directly related to stage of disease with 24/60 (40%) determinations increased in 12 patients with limited disease and 69/85 (81%) in 17 patients with extensive disease. For these same patients, CEA levels were elevated respectively in 2/11 (18%) of the former and 9/17 (53%) of the latter group. The frequency and degree of elevation of the nucleoside/creatinine ratios in pretreatment samples from patients with extensive disease was correlated directly with increasing number of metastatic sites. Of the five nucleosides, the mean number elevated was two for limited disease, 3-4 for extensive disease with one metastatic site, 4 for two or three, and 5 for four or more sites of metastases. Based on a summation of pretreatment nucleoside/creatinine ratios, a discriminant for survival was derived giving curves separating patients (P = 0.086) similar to the discriminant based on stage of disease. Although discordant results were noted, an overall correlation of 75% agreement with clinical assessment was estimated in response categories when monitoring changes associated with therapy.

During the last decade, there has been an intense search for biological markers for breast carcinoma. Many different types of materials have been found that may be elevated in the body fluids of patients with this disease. However, no markers specific for breast cancer have been discovered and those currently available lack the sensitivity and specificity for early detection of the disease or for determining when the tumor burden is low. Problems may also occur in the interpretation of marker data due to apparent biological variations in synthesis or secretion. Plasma carcinoembryonic antigen (CEA), elevated in 60%-70% of patients with metastases, has had the most extensive evaluation. For the latter patients with increased plasma CEA, the levels in general are proportional to tumor burden. Changes in level with therapy correlate with measurable clinical parameters of response or progression in the majority of these patients. Specific patterns of serial CEA measurements after mastectomy may be helpful for predicting those patients most likely to develop recurrent disease. More recent attention has focused on trials of combinations of markers and on tissue measurement. The search for a specific marker for breast cancer using monoclonal antibody techniques is a promising area of considerable research interest.

A 58-year-old patient with metastatic prostatic carcinoma had two well-documented episodes of disseminated intravascular coagulation (DIC) occurring 1 year apart and resolving without heparin therapy. This case illustrates that DIC need not have a poor prognosis and may resolve spontaneously despite progressive cancer. The efficacy of heparin therapy is discussed.

Fifty white patients with small cell carcinoma of the lung (SCCL) were typed for histocompatibility antigens (HLA) to assist in providing platelet support for intensive induction therapy. An analysis of the HLA types in this population was undertaken to determine if there was an influence of HLA type on this disease. Patients with the HLA-Bw44 (HLA-B12) allele were found to be significantly over-represented in our patient population compared to a control population (52% versus 26%, P less than 0.001). In addition, patients possessing the HLA-A1 phenotype were found to have a significantly poorer 1-year survival rate (15%) than individuals who did not possess this allele (60% 1-year survival rate) (P less than 0.025). These findings will need to be confirmed by other groups working with large numbers of patients with SCCL.

Preliminary data suggesting synergistic activity of cisplatinum and doxorubicin and the expected poor prognosis of women with breast cancer who progress on treatment with cyclophosphamide, methotrexate and 5-fluorouracil (CMF), led to a trial of monthly doxorubicin (50 mg/M2), vincristine (1.4 mg/M2) and cisplatinum (50 mg/M2) in such patients. Overall partial response rate to this regimen was 42%; 37% progressed and 21% could not complete two cycles of therapy because of gastrointestinal (three or renal (one) toxicity. This study does not support the use of cisplatinum, 50 mg/M2, in combination with doxorubicin and vincristine in patients with breast cancer which has proven refractory to CMF therapy.