Unfavorable cancers of unknown primaries: presentation and prognostic factors. A population-based 8-year experience.

Cancer of unknown primary is a mostly disseminated malignancy where detailed investigations cannot reveal a probable origin. A few subsets may respond to specific therapy, but the large majority of cases have a median survival of 3-4 months in the few population-based reports, which, however, did not use current investigations and therapy. It is not known if survival can be prolonged by chemotherapy or if supportive care is preferable, especially in the most unfavorable cases in whom chemotherapy may impair the quality of life without prolonging it. We therefore studied prognosis of 134 recent population-based consecutive unfavorable patients. Multiple involvements of the liver, nodes, lungs and skeleton, polysymptomatology, and biochemical abnormalities were common. The median survival time was 103 days, and the 1-year survival was 19%. Hypoalbuminemia, weight loss, and anemia in this order were the strongest negative prognostic factors in multivariate analysis, but univariate analysis added involvement of multiple sites or of the liver, high age, male gender, adenocarcinoma histology, and tobacco use as unfavorable factors. About 10% of patients became long-term survivors, sometimes in the presence of one or more of negative prognostic factors but in particular those with limited nodal spread. A previously unreported finding was that nodal involvement of squamous cell carcinoma limited to the iliacoinguinal region could seemingly be cured by surgery ± radiotherapy. In the absence of efficient treatment and controlled therapeutic trials, supportive care alone seems justified for patients with the worst prognostic factors.

Gene expression profiling guiding diagnosis and therapy of rare mammary-like anogenital gland carcinomas.

Cancers derived from anogenital mammary-like glands are rare, and their identification and selection of treatment for dissemination may be difficult. We encountered two such tumors, which both presented as occult primaries with nodal and hematogenous metastases. They were studied by immunohistochemistry, HER2 receptor assay, and gene expression profiling. Both tumors had some microscopical and immunohistochemical features in common with breast cancer, but lacked estrogen and progesterone receptors. Taxane-platinum-based systemic chemotherapy did not stop progression in a male patient, in whom a developing inguinal skin lesion was the likely primary tumor. The same regimen gave partial remission in a later, female, patient. After the mammary-like, HER2 positive nature of her tumor was confirmed by gene expression profiling using CupPrint and TargetPrint assays, treatment with vinorelbine-trastuzumab induced complete remission that is maintained by trastuzumab alone for almost 4 years after initial diagnosis. Molecular and immunohistochemical characterization of these rare tumors may identify them and sometimes guide systemic chemotherapy away from a non-specific and "broad spectrum" regimen toward a targeted therapy, resulting in greater effectiveness with less side effects.

Undetectable late hepatic sequelae after hypofractionated stereotactic radiotherapy for liver tumors.

Hypofractionated liver stereotactic radiotherapy has produced long-term survival, but the hepatobiliary system is radiosensitive and may be severely damaged by the treatment. We have evaluated long-term radiation effects on hepatobiliary functions in the first long-term survivors reported after radiotherapy to the hepatobiliary system for liver tumors. Eleven patients were followed for up to 13 years after treatment of tumors≤9 cm in size. Conventional blood chemistry, clearance of indocyanine green and segmental uptake and excretion of radiolabeled mebrofenin were assayed. Slightly abnormal routine blood chemistry was found during the first 2 years in some patients with pre-existing liver damage. Other parameters were seemingly unaffected, and liver segments which received differing mean doses did not differ measurably with regard to parenchymal or ductal function. Late liver functions were therefore not demonstrably affected by the radiotherapy in most patients even in the presence of mild cirrhosis, after previous exposure to liver toxic agents, or after resection. However, slight to moderate late dysfunction occurred in one patient after three courses of irradiation, and in a cirrhotic patient after two major liver resections following radiotherapy. Our previous doses for irradiation of liver tumors gave no measurable chronic side effects and may be increased in order to control tumors more effectively. In selected patients, irradiation is possible even in the presence of liver dysfunction, and previous irradiation or resection does not absolutely contraindicate salvage treatment by re-irradiation or resection.

Surgical displacement of risk organs to improve stereotactic radiotherapy for liver tumors.

BACKGROUND AND OBJECTIVES: Precision irradiation may cure some liver malignancies, but adjacent stomach and colon may interfere with the delivery of the desired high doses due to the risk for serious side effects. METHODS AND RESULTS: Preferably laparoscopic distancing of the risk organs included their mobilization, omental interposition between them and the target, and gastropexy to the lateral abdominal wall. This enabled us to more than double the radiation doses that were permitted by native anatomy. CONCLUSION: Minimally invasive surgical displacement of risk organs may increase the prospect of local control of liver tumors after precision irradiation with little demand on the patients and resources.

Curative stereotactic body radiotherapy for liver malignancy.

Nine patients with 11 primary or secondary liver non-neuroendocrine malignancies with mean and maximum diameters of 4.0 and 7.7 cm became long-term survivors after precision irradiation in a stereotactic body frame. Doses varied from 20 to 45 Gy split at 2-4 occasions a few days apart, with higher doses in the target centers. Occasional chemotherapy was stopped well before irradiation. No hospitalizations were needed because side effects, regional pain and nausea, were mild. All patients have now survived 5-14 years without recurrences. Two verified and one suspected secondary cancers occurred in organs close to the irradiated targets, and two of them could be resected for cure. Precision irradiation can thus cure selected liver malignancies. It is the first non-invasive method to achieve this, and the present patients are its first long-term survivors. A prolonged follow-up period is, however, necessary, because we have in other patients seen local tumor regrowth as late as four years after irradiation. The approach may cure some tumors, which are technically unsuited for other treatment modalities, and can be used for patients at high surgical risk. The success rate for local control seems good, but has to be defined by formal studies after optimization of radiation doses.

Liver embolizations in oncology: a review. Part I. Arterial (chemo)embolizations.

Arterial embolization of the liver often temporarily retards the growth of liver tumors which are mainly nourished arterially. The use of degradable agents avoids collateral formation which would prohibit repeat procedures and permit tumor regrowth. The effect of embolizations is largest in small hypervascular lesions, e.g., many hepatocellular or neuroendocrine cancers. Toxic chemicals can be added, chemoembolization, with unproven effects on responses and survival rates. Institutional differences in indications and procedures make evaluation of embolizations difficult. However, intermediate-term survival increases in selected cases of unresectable hepatocellular cancers and hormonal symptoms from neuroendocrine tumors often improve. Scant experience supports embolization for anti-tumoral effects in some pediatric tumors, to control bleeding from ruptured tumors, for symptomatic hemangiomas, and for downstaging of hepatocellular cancers before transplantation.

Liver embolizations in oncology. A review. Part II. Arterial radioembolizations, portal venous embolizations, experimental arterial embolization procedures.

Arterial embolization of the liver may temporarily retard the growth of its primary and secondary tumors which are both mainly nourished arterially. Addition of radioisotopes, mostly (131)I or (90)Y, results in radioembolizations which predominantly act by radiation and less by ischemia. They may therefore be utilized in the absence of portal venous flow when conventional embolization is hazardous. (131)I-oily radioembolization seems to prolong short-term survival in such patients with unresectable hepatocellular cancers, and to improve the prognosis after resection of hepatocellular cancer. The procedure does however not palliate better than "cold" chemoembolization in patients with preserved portal flow, except for having milder side effects. Embolization with (90)Y-coupled microspheres may shrink primary and secondary liver tumors but has so far unproven effects on survival. Embolization of portal venous branches gives compensatory hypertrophy of the non-embolized liver and can increase the volume of the future remnant liver before resection. This diminishes the risk for postoperative liver failure after extensive resection and/or in the presence of chronic liver disease, and permits wider surgical indications. Tumor growth may however be accelerated, and the hypertrophy is inhibited by severe liver parenchymal disease in which situation the method would be most needed. Experimental use of liver arterial embolizations includes combined arterial and portal embolizations, i.e. "chemical hepatectomy," arterial embolizations before external radiotherapy, administration of boron for neutron capture therapy, immunoembolizations, and future gene therapy.

Molecular and virological studies on a rare case of biliary papillomatosis.

In a recurrence of a rare case of biliary papillomatosis, a disease that often becomes malignant, the presence of human papillomavirus (HPV), Cytomegalovirus (CMV) and Epstein-Barr virus (EBV), as well as DNA ploidy and markers of proliferation and invasion, were examined. No such viruses were identified by polymerase chain reactions. Moreover, markers of invasion, such as laminin, and of proliferation, MIB1 and cyclin A, were absent or at normal levels despite progressive superficial growth of the tumour. The tumour was aneuploid, but the p53-p21 tumour growth suppressor system was not mutated. It was concluded that the presented case of tumour relapse, despite an anamnesis of seven years and its expanding but non-invasive growth, did not contain the viruses that were examined for, and had not become malignant.

Radiosurgery for recurring liver metastases after hepatectomy.

BACKGROUND/AIMS: Most resected liver metastases from colorectal cancer recur. A minority of liver recurrences have been re-resected, but most re-resections fail and they decrease the postoperative performance status for a longer time than the initial resections, so that less demanding potentially curative treatments need evaluation. METHODOLOGY: Four out of 5 liver-only recurrences after 18 consecutive liver resections were limited and suitable for radiosurgery. The patients were fixed in a frame and stereotactic irradiation with 20 Gy twice or 15 Gy three times was delivered to the tumors. RESULTS: Limited side effects were seen, without medical need for hospital admission. Thirteen--101 months later, all treated tumors were locally controlled with complete radiologic remission of two of them. Only one patient recurred in the liver, with bilobar lesions preceded by extrahepatic spread. Neither recurrence would have been prevented by a rehepatectomy instead of irradiation. One patient died later tumor-free from stroke, two died from generalized tumors, and one remains in remission 101 months after radiosurgery. CONCLUSIONS: Radiosurgery of liver tumors merits further study, and may offer a less demanding alternative to resection for selected liver tumors with the prospect of long-term survival.