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PubMed2000

Cerebral metastases as first symptom of cancer: a clinico-pathologic study.

Symptomatic brain metastases of carcinomas in patients without a previously diagnosed malignancy are frequent in neurosurgical series. Such tumors often lack distinctive morphological characteristics so that the routine histological examination can be unsuccessful in identifying the site of origin. Objectives of the present study were to evaluate the frequency of brain metastases as the only manifestation of an unknown primary cancer by the retrospective analysis of a series of consecutively operated single cerebral metastases; to verify the efficacy of clinical investigations in detecting the site of origin; to investigate whether the primary site can be identified by the immunohistochemical study of the neurosurgical specimens. Antibodies to the following antigens were used: carcinoembryonic antigen (CEA), carbohydrate antigen (CA) 19.9, CA 125, BCA-225, cytokeratin 20, PSA, HMB-45. Out of 181 patients operated for single cerebral metastasis of carcinoma, 99 (54.7%) were in patients without any previously diagnosed systemic neoplasm. In 26.7% the primary remained undiagnosed after clinical investigations, in 9 cases even at autopsy. PSA and HMB45 antibodies specifically identified metastases from prostate carcinomas and skin melanomas, respectively. No other specific immunophenotype was identified; the immunoreactivity of the single cases was more or less suggestive for a primary site. Precocious metastases of lung carcinomas expressed CEA more frequently than late metastases. It has been hypothesized that CEA plays some role as a contact mediating device. CEA expression can have some link with the tendency to metastasize precociously to the brain. No major difference of p53 and k-ras expression has been found in precocious versus late brain metastases.

Adult↗
PubMed2002

Prognostic stratification in UPC: a role for assessing the value of conventional-dose and high-dose chemotherapy for unknown primary carcinoma.

High-dose chemotherapy has been advocated by some investigators as a means to circumvent drug resistance, thereby improving treatment results in patients with solid tumors. For patients with unknown primary tumors, this hypothesis has only recently undergone limited testing. Two groups (one from the USA and one from Europe) have published their experience with higher doses of chemotherapy in the treatment of UPC. The results are not superior to those reported by other investigators using more standard doses of chemotherapy. Most importantly, chemotherapy trials for UPC are usually conducted in small populations made up of heterogeneous patient subsets with varying sensitivity to chemotherapy. It seems likely that progress in the management of patients with unknown primary cancers will occur as a result of efforts to improve the understanding of the natural history of this disease coupled with the assessment of novel agents targeted against specific biochemical abnormalities that will be demonstrated to be important in the development and maintenance of these malignancies.

Adult↗
PubMed2000

A phase I study of prolonged ambulatory infusion carboplatin with oral etoposide showing activity in prostate cancer.

PURPOSE: This phase I study aimed to establish the dose for phase II trials of a dose-intense outpatient regimen of ambulatory carboplatin and oral etoposide. PATIENTS AND METHODS: Cohorts of three patients received escalating doses of carboplatin 15, 20, and 23 mg/m2/day as a 3-week continuous ambulatory infusion with oral etoposide initially at 50 mg/day. Patients entered had prostate, colon, head and neck, breast, unknown primary cancers and mesothelioma. RESULTS: At 23 mg/m2 of carboplatin, two patients had WHO grade 3 lethargy and myelosuppression, which were the dose-limiting toxicities. Six patients were entered at the dose recommended for phase II studies, carboplatin 20 mg/ m2/day and etoposide 50 mg/day for 21 days repeated every 6 weeks. This was well tolerated except for one patient with multiple bone metastases from prostate cancer experiencing grade 4 myelosuppression and a single patient with grade 3 constipation. Seven patients with hormone-resistant prostate cancer were entered into the study, one at 15 mg/m2, four at 20 mg/m2 and two at 23 mg/m2 of carboplatin, and received a median of four cycles of treatment. The only responses were seen in prostate cancer where there were two partial responses in patients with soft tissue predominant disease. Five patients who could be evaluated with initially elevated PSA exhibited falls of > or 50% after receiving the chemotherapy. All but one patient with prostate cancer experienced significant reduction in pain levels. The median time to progression of the patients with prostate cancer was 4 months. CONCLUSIONS: Ambulatory infusion carboplatin and oral etoposide is a tolerable dose-intense outpatient regimen which warrants further testing in phase II trials including hormone-resistant prostate cancer.

Adult↗
PubMed1992

Unusual MRI findings in metastatic carcinoma to the choroid and optic nerve: a case report.

A 51 year old man with biopsy proven pulmonary sarcoidosis and skin test positive for tuberculosis presented with features of an amelanotic flat choroidal mass suggestive of choroiditis. The mass enlarged despite corticosteroids and anti-tuberculous medications. A thorough systemic evaluation for possible primary tumor metastatic to the choroid was negative. Further clinical evaluation and magnetic resonance imaging suggested a diffuse primary choroidal malignant melanoma with optic nerve invasion. The eye was enucleated and the mass proved histopathologically to be a mucin secreting adenocarcinoma of unknown origin despite a repeat systemic work-up. The patient died three months after the onset of symptoms and three weeks after enucleation with diffuse metastases from an unknown primary cancer. Magnetic resonance imaging (MRI) is usually helpful in the differentiation of uveal melanoma from uveal metastasis. In this case, however, it suggested the diagnosis of a diffuse choroidal melanoma. The reason for the atypical MRI findings will be discussed.

Adenocarcinoma↗
PubMed2004

Recurrences near base of skull after IMRT for head-and-neck cancer: implications for target delineation in high neck and for parotid gland sparing.

PURPOSE: Locoregional (LR) failures near the base of the skull, and their relationships to the targets in the high neck, were examined in a series of patients who underwent intensity-modulated radiotherapy (IMRT) for head-and-neck cancer. METHODS AND MATERIALS: Between 1994 and 2002, 133 patients with non-nasopharyngeal head-and-neck squamous cell carcinoma completed a course of curative, parotid-sparing RT. Treatment was delivered until 1996 with conformal three-dimensional techniques and thereafter with multisegmental static IMRT. Of the 133 patients, 80 had oropharyngeal, 27 oral cavity, 12 hypopharyngeal, 11 laryngeal, and 3 unknown primary cancer. The AJCC stage was I in 1, II in 6, III in 26, IVA in 83, and IVB in 12; cancer was recurrent in 5. Sixty patients received primary and 73 postoperative IMRT. 86% of patients (n = 115) had ipsilateral neck metastasis. In all patients, the contralateral neck was clinically node negative but was judged to be at high risk of subclinical disease. Delineation of the superior-most extent of the nodal targets was consistent and corresponded with Rouviere's observations. In the contralateral clinically node-negative neck, the uppermost Level II nodal target was the subdigastric (SD) nodes. To ensure coverage, the uppermost clinical target volume was delineated at the axial CT image in which the posterior belly of the digastric muscle crossed the jugular vein. In the ipsilateral neck, which was node positive in most patients, the uppermost Level II clinical target volume was delineated through the base of the skull. The uppermost retropharyngeal (RP) nodal target was delineated at the level of the top of the C1 vertebral body, accommodating Rouviere's description of the location of the lateral RP nodes. The dose prescription was 70 Gy for the primary planning target volumes (PTVs); 64 Gy and 60 Gy for PTV of the postoperative beds with and without extracapsular extension, respectively; and 50-54 Gy for PTVs of nonoperated subclinical disease, at 1.8-2.0 Gy fractions. In-field or marginal recurrences were defined as those occurring when >95% or 20-95% of the recurrence volume, respectively, had received >95% of the prescribed dose. RESULTS: At a median follow-up of 32 months (range, 6-107 months), 21 patients (16%) had locoregional recurrence. Seventeen recurrences were in-field and four were marginal. The most prevalent nodal recurrence was in Level II bilaterally, where all failures were in-field. In-field failures were observed in the ipsilateral high neck cranial to the SD nodes (all in initially node-positive neck). No recurrences occurred in the contralateral high neck, cranial to the SD nodes, which was not included in the targets. The 95% confidence interval for the risk of recurrence in that region was 0-2.7%. Three RP nodal failures were observed; two were marginal, occurring ipsilateral and contralateral to the primary tumors, and centered cranial to the top of C1. After these recurrences, the RP nodal clinical target volumes were delineated bilaterally through the base of skull, without subsequent RP recurrence. These target delineation guidelines allowed the achievement of a mean contralateral parotid dose of < or =26 Gy (found previously to preserve salivary output significantly) in 82% of the patients. The 3-year actuarial LR recurrence-free survival rate of primary and postoperative IMRT patients was similar (81% and 84%, respectively). Oropharyngeal cancer patients had the greatest LR recurrence-free survival rate (94%, p <0.001). No statistically significant differences were found in the dose delivered to the PTVs or the in-field recurrence volume between patients who had or did not have LR failure. CONCLUSION: These results suggest that when the contralateral node-negative side of the neck has a high risk of subclinical metastasis, it is adequate to include the SD nodes as the cranial-most Level II nodal target in non-nasopharyngeal head-and-neck cancer. In the node-positive side of the neck, this nodal level should be delineated more cranially. The RP nodal targets should be delineated more cranially. The RP nodal targets should be delineated bilaterally and should extend to the base of the skull, rather than to the top of C1. These guidelines allowed substantial sparing of the contralateral parotid gland. The results of this series validate a consensus for target delineation adopted recently by cooperative radiotherapy groups.

Adult↗
PubMed2001

Evaluation of head and neck cancer with 18F-FDG PET: a comparison with conventional methods.

The aim of this study was to evaluate the usefulness of 18F-FDG PET in the diagnosis and staging of primary and recurrent malignant head and neck tumours in comparison with conventional imaging methods [including ultrasonography, radiography, computed tomography (CT) and magnetic resonance imaging (MRI)], physical examination, panendoscopy and biopsies in clinical routine. A total of 54 patients (13 female, 41 male, age 61.3+/-12 years) were investigated retrospectively. Three groups were formed. In group I, 18F-FDG PET was performed in 15 patients to detect unknown primary cancers. In group II, 24 studies were obtained for preoperative staging of proven head and neck cancer. In group III, 18F-FDG PET was used in 15 patients to monitor tumour recurrence after radiotherapy and/or chemotherapy. In all patients, imaging was obtained at 70 min after the intravenous administration of 180 MBq 18F-FDG. In 11 of the 15 patients in group I, the primary cancer could be found with 18F-FDG, yielding a detection rate of 73.3%. In 4 of the 15 patients, CT findings were also suggestive of the primary cancer but were nonetheless equivocal. In these patients, 18F-FDG showed increased 18F-FDG uptake by the primary tumour, which was confirmed by histology. One patient had recurrence of breast carcinoma that could not be detected with 18F-FDG PET, but was detected by CT. In three cases, the primary cancer could not be found with any imaging method. Among the 24 patients in group II investigated for staging purposes, 18F-FDG PET detected a total of 13 local and three distant lymph node metastases, whereas the conventional imaging methods detected only nine local and one distant lymph node metastases. The results of 18F-FDG PET led to an upstaging in 5/24 (20.8%) patients. The conventional imaging methods were false positive in 5/24 (20.8%). There was one false positive result using 18F-FDG PET. Among the 15 patients of group III with suspected recurrence after radiotherapy and/or chemotherapy, 18F-FDG was true positive in 7/15 (46.6%) and true negative in 4/15 (26.6%). The conventional imaging methods were true positive in 5/15 (33.3%) and true negative in 4/15 (26.6%). One false negative (6.6%) and three false positive findings (20%) on 18F-FDG PET were due to inflamed tissue. The conventional imaging methods were false positive in three (20%) and false negative in three cases (20%). It is concluded that in comparison to conventional diagnostic methods, 18F-FDG PET provides additional and clinically relevant information in the detection of primary and metastatic carcinomas as well as in the early detection of recurrent or persistent head and neck cancer after radiotherapy and/or chemotherapy. 18F-FDG PET should therefore be performed early in clinical routine, usually before CT or MRI.

Female↗
PubMed1985

Metastatic carcinoma from unknown primary site: the experience of a large oncology centre.

The case records of patients presenting with metastases from an unknown primary cancer (MUP) have been reviewed. Important prognostic variables were performance status and the presence of disease in more than one system. Patients of poor performance status and disease in multiple organs had a median survival of one month and 87% were dead within three months. Those patients of good performance status and disease apparent in only one organ had a median survival of seven months. Patients with carcinoma confined to lymph nodes in the high cervical region who received treatment with radiotherapy had 3- and 5-year survival rates of 26% and 17% respectively.

Aged↗
PubMed2005

Dynamical interactions between multiple cancers.

Multiple tumors in a patient have the possibility to interact with each other, through the competition for new blood supply which is required for growth and progression (angiogenesis). The multiple tumors can be independent, multiple primary cancers. Alternatively, they can be metastases which originate from one primary tumor. This paper uses mathematical models to investigate such dynamical interactions between multiple cancers. We start with a model which describes the growth of a single angiogenic tumor, and then generalize this model to include multiple tumors which compete for circulating endothelial progenitor cells in order to build new blood vessels. We explore under which conditions multiple tumors can coexist, and when one tumor can exclude other tumors from growing. Based on this framework, we discuss the circumstances under which independent multiple primary tumors can arise. We further discuss the inefficiency of metastatic cells to grow successfully, and suggest an explanation for the occurrence of multiple metastases with an unknown primary cancer.

Humans↗
PubMed2006

PET-CT vs contrast-enhanced CT: what is the role for each after chemoradiation for advanced oropharyngeal cancer?

PURPOSE: The aim of our study was to assess the utility of positron emission tomography (PET) and 2 fluoro-2-deoxy-D-glucose coupled with neck CT compared with contrast-enhanced CT in predicting persistent cancer either at the primary site or cervical lymphatics in patients with oropharyngeal cancer treated with concurrent chemoradiation METHODS: Thirty consecutive patients underwent clinical examination, PET-CT, and contrast-enhanced CT to assess response after the completion of the treatment. The outcome variable was positive tissue diagnosis or negative disease at 6 months. Sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy were calculated for the primary site as well as cervical disease. RESULTS: Contrast-enhanced CT alone showed the best accuracy in detecting disease at the primary site after treatment (85.7%). Accuracy in evaluating residual tumor in the cervical lymphatics for contrast-enhanced CT and PET-CT was 59.3% and 74.1%, respectively. For evaluating the neck, PET-CT and contrast-enhanced CT demonstrated 100% NPV, but the PPV was 36.3% and 26.6%, respectively. CONCLUSIONS: In this preliminary study, PET-CT seems to be superior to contrast-enhanced CT in predicting persistent disease in the neck after chemoradiation for oropharyngeal or unknown primary cancer, but not at the primary site. However, the possibility of a false-positive result in the neck remains high, and thus overtreatment may result. Even more concerning are the false-negative results. Larger, prospective studies will be important in defining the role of PET-CT in obviating the need for salvage neck dissections after chemoradiation.

Adult↗
PubMed2004

Multi-platform, multi-site, microarray-based human tumor classification.

The introduction of gene expression profiling has resulted in the production of rich human data sets with potential for deciphering tumor diagnosis, prognosis, and therapy. Here we demonstrate how artificial neural networks (ANNs) can be applied to two completely different microarray platforms (cDNA and oligonucleotide), or a combination of both, to build tumor classifiers capable of deciphering the identity of most human cancers. First, 78 tumors representing eight different types of histologically similar adenocarcinoma, were evaluated with a 32k cDNA microarray and correctly classified by a cDNA-based ANN, using independent training and test sets, with a mean accuracy of 83%. To expand our approach, oligonucleotide data derived from six independent performance sites, representing 463 tumors and 21 tumor types, were assembled, normalized, and scaled. An oligonucleotide-based ANN, trained on a random fraction of the tumors (n = 343), was 88% accurate in predicting known pathological origin of the remaining fraction of tumors (n = 120) not exposed to the training algorithm. Finally, a mixed-platform classifier using a combination of both cDNA and oligonucleotide microarray data from seven performance sites, normalized and scaled from a large and diverse tumor set (n = 539), produced similar results (85% accuracy) on independent test sets. Further validation of our classifiers was achieved by accurately (84%) predicting the known primary site of origin for an independent set of metastatic lesions (n = 50), resected from brain, lung, and liver, potentially addressing the vexing classification problems imposed by unknown primary cancers. These cDNA- and oligonucleotide-based classifiers provide a first proof of principle that data derived from multiple platforms and performance sites can be exploited to build multi-tissue tumor classifiers.

Algorithms↗
PubMed1988

Leucovorin and 5-fluorouracil as a treatment for disseminated cancer of the pancreas and unknown primary tumors.

Chemotherapy with leucovorin (100 to 200 mg) and 5-fluorouracil (30 mg/kg) every 2 wk produced four (three complete) objective responses among a group of eight patients with early metastatic pancreatic primary and unknown cancers. Complete remissions were associated with exceptionally long durations of survival, one in a patient failing prior combination chemotherapy. This treatment warrants testing because of its ease, scientific rationale, and the large population of patients with early metastatic pancreatic cancer for whom there is no accepted treatment. Early metastatic disease is defined as small metastatic lesions not immediately life threatening found in a physiologically intact patient. Controlled trials, demonstrating benefit associated with other 5-fluorouracil-containing regimens for patients with nonmetastatic stages of pancreatic cancer, provide a rationale for extending testing of leucovorin and 5-fluorouracil to other early stages of pancreatic cancer.

Adult↗
PubMed1983

Metastatic malignant disease of unknown origin.

The charts of 106 patients with metastasis from an unknown primary cancer were reviewed to formulate a more appropriate investigative strategy than is presently employed. The spinal column was the most common site for initial presentation of metastatic disease (26.5 percent). The primary tumor was identified before death in 31.3 percent of patients and after death in 6.6 percent. Lung cancer was found in 40 percent of patients with identified primary tumors. Diagnostic studies directed at specific symptoms had a significantly greater yield. Electroencephalograms, gallium scans, thyroid scans, and mammograms were not useful as screening studies. Conversely, bone scans were positive in 46.5 percent of asymptomatic patients and in 88 percent of symptomatic patients. Chest roentgenograms were suggestive of malignant tumors in 43.6 percent of patients. Results of liver scans were predictable on the basis of changes in the alkaline phosphatase level and clinical liver examination. History and physical examination should clearly document the stage of disease, evaluate possible primary sites, and rule out impending acute complications. Chest roentgenograms and bone scans should be obtained early and open biopsy of accessible lesions scheduled promptly. Efforts should be directed at ruling out the more treatable malignant tumors. Further work-up is then indicated only by the development of specific symptomatology. Since median patient survival after initial presentation is only 6.6 months, prolonged hospitalization for numerous nonproductive diagnostic tests seems inappropriate.

Adult↗
PubMed2006

Pharmacogenetics of paclitaxel metabolism.

Paclitaxel is one of the most widely used and effective anticancer drugs. Paclitaxel's clinical utility spans many tumor sites, including treatment of ovarian, breast, lung, head and neck, and unknown primary cancers. As is the case with most chemotherapy drugs, paclitaxel is administered empirically with little individualization of dose other than adjustment for body surface area. Metabolism of the drug is predominantly by the liver by cytochromes P450 2C8 and 3A4. Recent evidence points to the presence of polymorphisms in these enzymes. The clinical relevance of these polymorphisms is not yet fully explored, though they are expected to be key in fulfilling the ultimate goal of individualized dosing of paclitaxel. Here we review the pharmacology of paclitaxel and consider the possible effects pharmacogenetics may have on paclitaxel therapy.

Antineoplastic Agents, Phytogenic↗
PubMed1986

Pulmonary metastases. Pathological anatomy.

In 88 operative specimens topography, size and histopathological findings of lung metastases were analyzed. The stages of formation of metastases as the phase of invasion, embolization and implantation were differentiated by postmortem angiographies investigating the neo-vascularization of the metastases by 20 to 60 micron vessels. Analyses of metastases by morphological quantification of tumor regression after cytostatic therapy and immune histochemical examinations of lung metastases in unknown primary cancer have gained clinical importance.

Humans↗
PubMed1993

A pilot clinical and pharmacological study of intra-arterial infusion of thiotepa.

Fourteen patients with progressive localized tumors were treated on a clinical and pharmacological study with intra-arterial Thiotepa. A transfemoral percutaneous catheter was inserted into the major artery supplying the tumor. A venous catheter was inserted into the vein draining the tumor area for blood sampling. Doses of Thiotepa ranged from 0.3 mg/kg to 1.0 mg/kg. Courses were repeated monthly and doses of drug escalated as tolerated. Toxicity was mild and doses of drug at least up to 0.9-1.0 mg/kg were tolerable. Pharmacokinetic parameters suggest increasing binding of Thiotepa to tissue when the drug is administered by the intra-arterial route. Clinical responses were observed in a patient with melanoma and in another patient with unknown primary cancer.

Dose-Response Relationship, Drug↗
PubMed1996

Malignant ascites: demographics, therapeutic efficacy and predictors of survival.

Demographics, treatment patterns, treatment efficacy and clinical predictors of survival were studied in 76 consecutive patients with malignant ascites. Sixty-four percent of patients were female, and mean age was 63 years. The most common primary malignancies were ovarian cancer, carcinoma of unknown primary, breast cancer, colorectal carcinoma and lymphoma. Ascites was present at the time of diagnosis of malignancy in 39%. Diuretics were administered in 22% of patients with a 22% response in ascites; all responding patients had hepatic metastases. Systemic anticancer therapy was administered in 38%, with a 38% objective response in ascites. Five peritoneovenous shunts were placed, with one shunt functional at 2 weeks. Paracentesis was performed in 71% of patients with complications potentially due to paracentesis occurring in 24% of these patients. Median survival was 78 days from the clinical diagnosis of ascites. Multivariate analysis revealed significantly shortened survival in patients with liver metastases and elevated serum bilirubin, while ovarian cancer was a significant independent predictor of prolonged survival.

Ascites↗
PubMed1980

Diagnostic persistence in working up metastatic cancer with an unknown primary site.

Following initial diagnostic work-up and histological confirmation of a metastatic lesion, an extensive search may fail to locate a primary cancer site. Two case reports are presented. A retrospective analysis was done of 255 patients with metastases of unknown origin; 231 patients (over 90%) have since died. Of 34 patients with autopsy information, no primary lesion was found in 20. In the remaining 14 cases, prior knowledge of the primary site would not have influenced either therapy or proganosis. A plea is made for judicious restraint in the use of diagnostic imaging procedures to search exhaustively for a primary cancer site.

Adult↗
PubMed2001

Use of cytokeratins 7 and 20 in determining the origin of metastatic carcinoma of unknown primary, with special emphasis on lung cancer.

Metastatic carcinoma of unknown primary is a common problem, accounting for up to 10-15% of all solid tumours at presentation. Proper identification of the site of origin has prognostic and therapeutic significance. Prior immunohistochemical methods to identify the site of origin have been useful in a limited number of cases. Differential cytokeratin staining may be useful in this setting, particularly in identifying metastases from lung cancer. We have identified 144 cases of metastatic carcinoma of unknown primary to bone, lung or liver at Brigham and Women's Hospital between 1 January 1997 and 1 July 1998. Cytokeratin (CK) 7 and CK20 were used in 75 of these cases to narrow down the possible sites of the primary tumours. All of these cases were ambiguous as to the site of the primary tumour. Forty-five cases were CK7+/CK20-, 15 cases were CK7-/CK20-, 9 cases were CK7-/CK20+ and 6 cases were CK7+/CK20+. Three of the cases were selected for detailed presentation and discussion as well as a discussion of the pertinent literature. Overall, the CK7+/CK20- phenotype favours a lung primary, the CK7+/CK20+ phenotype strongly favours transitional cells (urothelial) carcinoma, the CK7-/CK20+ phenotype favours colorectal carcinoma, while the CK7-/CK20- profile is not helpful.

Biomarkers↗