Patterns of relapse and treatment outcome after active surveillance or adjuvant carboplatin for stage I seminoma: a retrospective study of the Spanish Germ Cell Cancer Group

Purpose Active surveillance (AS) and adjuvant chemotherapy (AC) with carboplatin are valid alternatives for managing stage I seminoma, and most relapses can be cured with cisplatin-based chemotherapy. However, some reports suggest that AC may modify the classical pattern of recurrences. Methods We analyzed all relapses observed in a series of 879 patients with stage I seminoma included in 4 consecutive studies of the Spanish Germ Cell Cancer Group. After a median follow-up of 67 months, recurrences were detected in 56/467 (12%) low-risk cases on AS and 13/412 (3%) high-risk cases after AC (p < 0.001). The objective was to describe clinical features, treatment and outcome. Univariate comparisons were performed between both groups. Results No significant differences were found between relapses on AS and those after AC in terms of time to relapse (13 vs 17 months), size (26 vs 27 mm), location (retroperitoneum in 88% vs 85%), and method of detection (computed tomography in 77% vs 69%). Treatment consisted of chemotherapy (etoposide + cisplatin ± bleomycin) in 89% and 92%, respectively. Late relapses (after > 3 years) were seen in 11% vs 7.7% (p = NS) and second or successive recurrences in 1.8 vs 23% (p < 0.05). With a median follow-up of 130 moths, two patients died of seminoma-unrelated causes (AS group) and the rest are alive and disease-free. Conclusion In the setting of a risk-adapted treatment of stage I seminoma, the administration of two courses of AC in patients with tumor size > 4 cm and/or rete testis invasion is associated with a higher incidence of second recurrences but does not significantly modify the pattern of relapses or their outcome (AU)

Patterns of relapse and treatment outcome after active surveillance or adjuvant carboplatin for stage I seminoma: a retrospective study of the Spanish Germ Cell Cancer Group.

PURPOSE: Active surveillance (AS) and adjuvant chemotherapy (AC) with carboplatin are valid alternatives for managing stage I seminoma, and most relapses can be cured with cisplatin-based chemotherapy. However, some reports suggest that AC may modify the classical pattern of recurrences. METHODS: We analyzed all relapses observed in a series of 879 patients with stage I seminoma included in 4 consecutive studies of the Spanish Germ Cell Cancer Group. After a median follow-up of 67 months, recurrences were detected in 56/467 (12%) low-risk cases on AS and 13/412 (3%) high-risk cases after AC (p < 0.001). The objective was to describe clinical features, treatment and outcome. Univariate comparisons were performed between both groups. RESULTS: No significant differences were found between relapses on AS and those after AC in terms of time to relapse (13 vs 17 months), size (26 vs 27 mm), location (retroperitoneum in 88% vs 85%), and method of detection (computed tomography in 77% vs 69%). Treatment consisted of chemotherapy (etoposide + cisplatin ± bleomycin) in 89% and 92%, respectively. Late relapses (after > 3 years) were seen in 11% vs 7.7% (p = NS) and second or successive recurrences in 1.8 vs 23% (p < 0.05). With a median follow-up of 130 moths, two patients died of seminoma-unrelated causes (AS group) and the rest are alive and disease-free. CONCLUSION: In the setting of a risk-adapted treatment of stage I seminoma, the administration of two courses of AC in patients with tumor size > 4 cm and/or rete testis invasion is associated with a higher incidence of second recurrences but does not significantly modify the pattern of relapses or their outcome.

Prognostic factors for relapse in stage I seminoma: a new nomogram derived from three consecutive, risk-adapted studies from the Spanish Germ Cell Cancer Group (SGCCG).

BACKGROUND: We aimed to analyze prognostic factors for relapse in stage I seminoma managed by either active surveillance or adjuvant chemotherapy, and to describe the long-term patterns of recurrence in both groups. PATIENTS AND METHODS: From 1994 to 2008, 744 patients were included in three consecutive, prospective risk-adapted studies by the Spanish Germ Cell Cancer Group. Low-risk patients were managed by surveillance and high-risk patients were given two courses of adjuvant carboplatin. Relapses were treated mainly with chemotherapy. Patient age, tumor size, histological variant, pT staging, rete testis invasion, and preoperative serum BHCG levels were assessed for prediction of disease-free survival (DFS). RESULTS: After a median follow-up of 80 months, 63 patients (11.1%) have relapsed: 51/396 (14.8%) on surveillance and 12/348 (3.2%) following adjuvant carboplatin. Actuarial overall 5-year DFS was 92.3% (88.3% for surveillance versus 96.8% for chemotherapy, P = 0.0001). Median time to relapse was 14 months. Most recurrences were located at retroperitoneum (86%), with a median tumor size of 26 mm. All patients were rendered disease-free with chemotherapy (92%), radiotherapy (5%), or surgery followed by chemotherapy (3%). A nomogram was developed from surveillance patients that includes two independent, predictive factors for relapse: rete testis invasion and tumor size (as a continuous variable). CONCLUSION: Long-term follow-up confirms the risk-adapted approach as an effective option for patients with stage I seminoma. The pattern of relapses after adjuvant chemotherapy is similar to that observed following surveillance. A new nomogram for prediction of DFS among patients on surveillance is proposed. Rete testis invasion and tumor size should be taken into account when considering the administration of adjuvant carboplatin. Prospective validation is warranted.

The PDGFRß-AKT pathway contributes to CDDP-acquired resistance in testicular germ cell tumors.

PURPOSE: We examined whether PI3K-AKT or extracellular signal-regulated kinase (ERK) signaling pathways could play a role in the development of cisplatin (CDDP) resistance in testicular germ cell tumor (TGT) cells. EXPERIMENTAL DESIGN: We compared AKT and ERK activation levels in CDDP-sensitive testicular tumor cells and in their corresponding CDDP-resistant-derived cells. We also analyzed these pathways in orthotopic testicular tumors and human patient samples. RESULTS: Our results indicated that there was overactivation of AKT in CDDP-resistant cells compared with sensitive cells, but no effect on activated ERK levels. We observed an increase in mRNA and protein levels for platelet-derived growth factor (PDGF) receptor ß and PDGF-B ligand. These were responsible for AKT overactivation in CDDP-resistant cells. When PDGFRß levels were decreased by short hairpin RNA (shRNA) treatment or its activation was blocked by pazopanib, CDDP-resistant cells behaved like sensitive cells. Moreover, CDDP-resistant cells were more sensitive to incubation with PDGFRß inhibitors such as pazopanib or sunitinib than sensitive cells, a finding consistent with these cells being dependent on this signaling pathway. We also found overexpression of PDGFRß and pAKT in CDDP-resistant choriocarcinoma orthotopic tumor versus their CDDP-sensitive counterparts. Finally, we found high PDGFRß levels in human testicular tumors, and overexpression in CDDP-resistant testicular choriocarcinomas compared with the CDDP-sensitive and nontreated tumors. CONCLUSIONS: The PDGFRß-AKT pathway plays a critical role in the development of CDDP resistance in testicular tumoral cells.

ErbBs inhibition by lapatinib blocks tumor growth in an orthotopic model of human testicular germ cell tumor.

In this work, we have analyzed the expression of different members of the ErbB family in human samples of testicular germ cell tumors (GCTs). We observed expression of ErbB1 or ErbB2 in different tumor subtypes, but we also found high expression of ErbB3 in all GCTs tested. This pattern of expression was maintained when primary tumors were orthotopically implanted in nude mice. We have chosen a choriocarcinoma model characterized by high levels of ErbB1, but also of ErbB2 and ErbB3, to assay the in vivo effect of ErbB inhibitors on tumoral growth. Our results showed a complete lack of effect (refractoriness) to the pure ErbB1 receptor inhibitors cetuximab and gefitinib. While these inhibitors blocked ErbB1 phosphorylation, ErbB2 phosphorylation was not affected, suggesting an ErbB1-independent activation of this receptor. To confirm the importance of ErbB2 activation, animals were treated with lapatinib, a dual ErbB1 and ErbB2 inhibitor. Lapatinib treatment caused a 50% inhibition in tumor growth, an effect correlated with a blockade of both ErbB1 and ErbB2 phosphorylation levels, and of downstream signaling pathways (Akt, ERKs and Stat3). ErbB2 activation could still occur due to the formation of ErbB2/ErbB3 heterodimers, and ErbB3 activation was completely inhibited by lapatinib. Finally, combined inhibition of ErbB1 (gefitinib) and ErbB3 activities (knockdown expression by shRNA) inhibited tumoral testicular cells proliferation in a similar way to lapatinib. Our results explain why lapatinib but not anti-ErbB1 agents might be effective for treatment of testicular GCT patients.

Clinicopathological risk factors of Stage II colon cancer: results of a prospective study.

AIM: Adjuvant 5-fluorouracil based chemotherapy has demonstrated benefit in Stage III colon cancer but still remains controversial in Stage II. The aim of this study was to analyse the prognostic impact of clinicopathological factors that may help guide treatment decisions in Stage II colon cancer. METHOD: Between 1996 and 2006 data from patients diagnosed with colorectal cancer at Hospital Universitari Bellvitge and its referral comprehensive cancer centre Institut Català d'Oncologia/L'Hospitalet were prospectively included in a database. We identified 432 patients with Stage II colon cancer operated on at Hospital Universitari Bellvitge. The 5-year relapse-free survival (RFS) and colon-cancer-specific survival (CCSS) were determined. RESULTS: The 5-year RFS and CCSS were 83% and 88%, respectively. Lymphovascular or perineural invasion was associated with RFS [hazard ratio (HR) 1.84; 95% CI 1.01-3.35]. Gender (women, HR 0.48; 95% CI 0.23-1) and lymphovascular or perineural invasion (HR 3.51; 95% CI 1.86-6.64) together with pT4 (HR 2.79; 95% CI 1.44-5.41) influenced CCSS. In multivariate analysis pT4 and lymphovascular or perineural invasion remained significantly associated with CCSS. We performed a risk index with these factors with prognostic impact. Patients with pT4 tumours and lymphovascular or perineural invasion had a 5-year CCSS of 61%vs the 93% (HR 5.87; 95 CI 2.46-13.97) of those without any of these factors. CONCLUSION: pT4 and lymphatic, venous or perineural invasion are confirmed as significant prognostic factors in Stage II colon cancer and should be taken into account in the clinical validation process of new molecular prognostic factors.

SEOM clinical guidelines for diagnosis and treatment of testicular seminoma (2010)

Testicular cancer represents the most common malignancy in males aged 15-34 years. Nearly 40% of cases correspond to seminomas and three quarters of them are diagnosed with stage I disease. After orchiectomy, clinical staging should include serial tumour marker assays (alphafetoprotein must be negative), abdominal CT scan and chest X-ray films. Patients with stage I disease can be followedup (active surveillance) or receive adjuvant carboplatin chemotherapy (those with rete testis invasion or non-compliant with follow-up). More advanced disease (stage II and III) and patients with extragonadal seminomas should receive chemotherapy (3-4 courses of BEP) according to IGCCCG risk classification. Residual lesions must be managed by surveillance if they are smaller than 3 cm, while those larger than 3 cm should be evaluated by means of PET. Surgery is only recommended in PET-positive lesión (AU)

Advanced ovarian cancer: phase III randomized study of sequential cisplatin-topotecan and carboplatin-paclitaxel vs carboplatin-paclitaxel.

BACKGROUND: Topotecan has single-agent activity in recurrent ovarian cancer. It was evaluated in a novel combination compared with standard frontline therapy. METHODS: Women aged 75 years or younger with newly diagnosed stage IIB or greater ovarian cancer, Eastern Cooperative Oncology Group Performance Status of 1 or less, were stratified by type of primary surgery and residual disease, treatment center, and age; then randomly assigned to one of the two 21-day intravenous regimens. Patients in arm 1 (n = 409) were administered four cycles of cisplatin 50 mg/m(2) on day 1 and topotecan 0.75 mg/m(2) on days 1-5, then four cycles of paclitaxel 175 mg/m(2) over 3 hours on day 1 followed by carboplatin (area under the curve = 5) on day 1. Patients in arm 2 (n = 410) were given paclitaxel plus carboplatin as in arm 1 for eight cycles. We compared progression-free survival (PFS), overall survival, and cancer antigen-125 normalization rates in the two treatment arms. A stratified log-rank test was used to assess the primary endpoint, PFS. All statistical tests were two-sided. RESULTS: A total of 819 patients were randomly assigned. At baseline, the median age of the patients was 57 years (range = 28-78); 81% had received debulking surgery, and of these, 55% had less than 1 cm residual disease; 66% of patients were stage III and 388 (47.4%) patients had measurable disease. After a median follow-up of 43 months, 650 patients had disease progression or died without documented progression and 406 had died. Patients in arm 1 had more hematological toxicity and hospitalizations than patients in arm 2; PFS was 14.6 months in arm 1 vs 16.2 months in arm 2 (hazard ratio = 1.10, 95% confidence interval = 0.94 to 1.28, P = .25). Among patients with elevated baseline cancer antigen-125, fewer in arm 1 than in arm 2 had levels return to normal by 3 months after random assignment (51.6% vs 63.3%, P = .007) CONCLUSIONS: Topotecan and cisplatin, followed by carboplatin and paclitaxel, were more toxic than carboplatin and paclitaxel alone, but without improved efficacy. Carboplatin plus paclitaxel remains the standard of care for advanced epithelial ovarian cancer.

The oncology acute toxicity unit (OATU): an outpatient facility for improving the management of chemotherapy toxicity.

OBJECTIVE: To provide an outpatient facility to improve the management of chemotherapy toxicity in cancer patients. PATIENTS AND METHODS: We set up an oncology acute toxicity unit (OATU) to improve toxicity management. A telephone helpline was the initial contact which filters out inappropriate non-toxicity-related events. Patients were provided an information booklet describing the possible side effects of the chemotherapy and the helpline telephone number. A specialist nurse received the calls and consulted the doctor if necessary. Depending on requirements, the patient's problem was resolved by telephone, or a consultation visit at the OATU was arranged. RESULTS: Between February 1999 and August 2001, 1126 patients made 2007 contacts with the OATU. The most common tumours were breast (26%), colorectal (20%) and lung (20%). The telephone helpline was used in 87% of contacts and 37% were considered inappropriate. Of the 1263 appropriate contacts, the most frequent chemotherapy schedules that had been administered were 5FU-leucovorin (11.2%) and CMF (10.4%). The most frequent side effects were fever (35.5%), diarrhoea (18.5%), mucositis (16.2%) and emesis (13%). The problem was resolved by telephone in 48% of cases and 52% required attendance in the OATU, of which 40% required hospital admission, i.e., 21.1% of the initial appropriate helpline contacts. The most frequent reason was Grade 3-4 neutropenic fever (56.5%). CONCLUSIONS: The OATU enables prompt and efficient access of patients to medical oncology facilities in the event of toxicity due to chemotherapy. Unnecessary emergency room use is avoided while oncology outpatient and hospitalisation facilities are optimised.

Metronomic chemotherapy: an antiangiogenic scheduling.

Conventional cytotoxic anticancer chemotherapeutic drugs were developed with the intent of treating cancer by direct killing or inhibition of growth of cycling tumour cells. Recently, however, there has been considerable interest in the notion of exploiting such drugs as angiogenesis inhibitors. The rationale is based on the fact that virtually all classes of cancer chemotherapeutic drugs are designed to damage DNA or disrupt microtubules of dividing cells, and endothelial cell division takes place during new blood vessel formation, including tumour angiogenesis. The results of recent experimental studies have suggested that frequent administration of certain cytotoxic agents at low doses, known as "metronomic chemotherapy", increases the putative antiangiogenic activity of certain drugs. Metronomic chemotherapy refers to the chronic administration of comparatively low doses of cytotoxic drugs at close, regular intervals, with no prolonged drug-free interruptions. The advantage of this strategy is lower toxicity and risk of emergence of drug-resistant tumour cells than conventional administration. This review describes the possible antiangiogenesis basis of this therapeutic strategy, the experimental studies published and the recent clinical studies that explore this less toxic schedule.

Metronomic chemotherapy: an antiangiogenic scheduling

Conventional cytotoxic anticancer chemotherapeutic drugs were developed with the intent of treating cancer by direct killing or inhibition of growth of cycling tumour cells. Recently, however, there has been considerable interest in the notion of exploiting such drugs as angiogenesis inhibitors. The rationale is based on the fact that virtually all classes of cancer chemotherapeutic drugs are designed to damage DNA or disrupt microtubules of dividing cells, and endothelial cell division takes place during new blood vessel formation, including tumour angiogenesis. The results of recent experimental studies have suggested that frequent administration of certain cytotoxic agents at low doses, known as "metronomic chemotherapy", increases the putative antiangiogenic activity of certain drugs. Metronomic chemotherapy refers to the chronic administration of comparatively low doses of cytotoxic drugs at close, regular intervals, with no prolonged drug-free interruptions. The advantage of this strategy is lower toxicity and risk of emergence of drug-resistant tumour cells than conventional administration. This review describes the possible antiangiogenesis basis of this therapeutic strategy, the experimental studies published and the recent clinical studies that explore this less toxic schedule (AU)

Treatment of stage I testicular germ-cell tumors.

More than a half of patients with testicular cancer are diagnosed with clinical stage I disease. In this setting, definitive cure is the rule. However, there is no consensus on the optimal treatment choice. A literature review (1990-2005) was performed in order to identify the pros and the cons associated with each therapy, as well as their long-term outcomes. Several treatment alternatives yield similar efficacy results. Thus, therapy-related morbidity, economic costs, quality-of-life issues, and patient preferences should be considered. Refinement in the knowledge of predictive factors for relapse and amounting experience with both surveillance and adjuvant chemotherapy have led to consideration of risk-adapted treatment policies as an alternative to more traditional approaches (i.e., prophylactic irradiation for seminomas and retroperitoneal lymph node dissection for non-seminomas). In conclusion, with cure rates approaching 100%, close surveillance for low-risk patients and adjuvant chemotherapy for those at high risk of relapse seems the preferred option for clinical stage I testicular cancer, in both seminoma and non-seminoma cases.

Control of E1A under an E2F-1 promoter insulated with the myotonic dystrophy locus insulator reduces the toxicity of oncolytic adenovirus Ad-Delta24RGD.

We previously described Ad-Delta24RGD as an enhanced-infectivity oncolytic adenovirus that targets tumors with an impaired RB pathway. The common alteration of this pathway in cancer eliminates the interaction of pRB with E2F and releases free E2F to activate E2F-responsive promoters, including the E2F-1 promoter. To improve the selectivity towards RB pathway-defective tumors and reduce the toxicity of Ad-Delta24RGD we aimed to control E1A-Delta24 expression under the E2F-1 promoter. A polyA signal was inserted upstream of the E2F-1 promoter to stop transcription initiated at the adenovirus ITR and packaging signal. The human myotonic dystropy locus insulator (DM-1) was also located between the E1a enhancers and the E2F-1 promoter to further insulate the promoter. The Ad-Delta24RGD derivative containing these insulation sequences expressed less E1a-Delta24 in normal cells and resulted less toxic while maintaining the potent oncolytic activity of the parental virus. These results demonstrate that the human DM-1 inslulator can function in an adenovirus context to maintain heterologous promoter selectivity. The new oncolytic adenovirus presented here may represent a valuable therapeutic option for a broad range of tumors with a deregulated E2F/pRB pathway.

Treatment of malignant superior vena cava syndrome by endovascular stent insertion. Experience on 52 patients with lung cancer.

BACKGROUND: Superior vena cava syndrome (SVCS) is a frequent presentation of malignancies involving the mediastinum and can seriously compromise treatment options and prognosis. Stenting of superior vena cava is a well-known but not so commonly used technique to alleviate this syndrome. PATIENTS AND METHODS: Between August 1993 and December 2000 we performed 52 stenting procedures in patients affected by non-small cell lung cancer (NSCLC). RESULTS: Phlebographic resolution of the obstruction was achieved in 100% of cases with symptomatic and subjective improvement in more than 80%. One major complication was observed due to bleeding during anticoagulation. Re-obstruction of the stent occurred in only 17% of the cases, the majority due to disease progression. Improvement of the syndrome allowed hydration necessary for full dose platinum treatment when indicated in patients affected by lung cancer. CONCLUSIONS: Stenting of the superior vena cava syndrome is a safe and effective procedure achieving a rapid alleviation of symptoms in almost all patients, and allowing for full dose treatment in lung cancer patients. This procedure could change the traditional poorer prognosis attributed to non-small cell lung cancer patients presenting with this syndrome.

Multicenter study evaluating a dual policy of postorchiectomy surveillance and selective adjuvant single-agent carboplatin for patients with clinical stage I seminoma.

BACKGROUND: After decades of irradiation as standard therapy for clinical stage I testicular seminoma, alternative treatment approaches have emerged including postorchiectomy surveillance and adjuvant chemotherapy. This study was performed to assess a dual policy of surveillance and selective single-agent carboplatin (for high-risk cases) in a multicenter setting. PATIENTS AND METHODS: From 1994 to 1999, 203 patients with stage I seminoma were included. Sixty (29.6%) were considered poor-risk cases (i.e. with vascular invasion and/or pathological tumor stage pT2 or greater) and received two courses of adjuvant carboplatin, whereas 143 (70.4%) without risk criteria underwent close surveillance. RESULTS: Median follow-up was 52 months (range 14-92). Relapses were observed in two (3.3%) patients treated with carboplatin and in 23 patients (16.1%) on surveillance, with a median time to recurrence of 11 months (range 3.9-39.6). All relapsing patients were rendered disease-free, mainly with cisplatin-based chemotherapy. Four patients died from tumor-unrelated causes. Actuarial 5-year overall survival was 96.7% and cause-specific survival was 100%. Five-year disease-free survival was 83.5% for patients on surveillance, and 96.6% for those receiving carboplatin. CONCLUSIONS: This dual treatment policy is feasible in a multicenter setting and preserves 70% of patients from adjuvant chemotherapy. Single-agent carboplatin is effective in reducing the relapse rate in patients with high-risk stage I seminoma. A better definition of local risk features would probably improve patient selection, thus minimizing the incidence of recurrences on surveillance.

[Metastatic cáncer presentation. Validation of a diagnostic algorithm with 221 consecutive patients]. / Cáncer de presentación metastásica. Validación de un algoritmo diagnóstico en 221 pacientes consecutivos.

BACKGROUND: The use of a diagnostic algorithm for metastatic cancer presentation (MCP) might enhance the diagnosis of primary tumors amenable to treatment with considerable savings both in time and diagnostic examinations. MATERIALS AND METHODS: From January 1992 to April 1997, all patients admitted with the diagnosis of MCP were prospectively studied. From each patient, a basic study consisting in a clinical interview, complete physical examination, standard blood testing with tumoral markers and chest X-ray were obtained. Patients with a negative basic study were classified as having a metastatic cancer of unknown origin (MUO); in these patients, a protocolized study (abdominal CT scan and mammography among women) were performed. Patients who after the application of the basic and protocolized studies had no primary tumor detected underwent an exhaustive investigation in order to validate the efficiency of the diagnostic algorithm. RESULTS: Two hundred twenty-one patients were included in the study. The mean age of patients was 63 years (range: 23-82). The main symptom was of bone (30%), neurological (24%), thoracic (16%) and abdominal (16%) origin. The basic study was positive for 138 patients (62.4%), with chest X-ray and physical examination yielding the highest number of diagnoses among these patients. The histology of metastases contributed to the definite diagnosis in 31 patients. Only PSA had a high sensitivity and specificity. Eighty-three patients were classified as MUO. The protocolized study diagnosed the primary tumor in 24 patients (30%), 20 by abdominal CT scan and four by mammography; eight of these patients were deemed to be amenable to treatment. The remaining 59 patients underwent an exhaustive study, and a diagnosis was made in 13; nevertheless, none of them was considered candidate for a specific treatment. Finally, 47 patients (21%) remained undiagnosed. The predominant primary tumors included sites at the lung (42%), prostate (6%) and breast (6%). The most common metastatic locations included bone (42%), central nervous system and liver (24%), and the most common histological types were adenocarcinoma (61%) and undifferentiated carcinoma (15%). CONCLUSIONS: Lung cancer and MUO represented 62% of MCP. The basic study oriented in two thirds of cases, and the physical examination and chest X-ray showed the highest diagnostic yield. The histology of metastases and PSA had a key, diagnostic relevance. A protocolized study based on abdominal CT scan and mammography (females) can identify the remaining treatable tumors.

Cáncer de presentación metastásica. Validación de un algoritmo diagnóstico en 221 pacientes consecutivos / Metastatic cáncer presentation. Validation of a diagnostic algorithm with 221 consecutive patients

Introducción. La aplicación de un algoritmo diagnóstico en el cáncer de presentación metastásica (CPM) podría facilitar, con un considerable ahorro de tiempo y exploraciones, llegar al diagnóstico de aquellos tumores primarios tratables. Material y métodos. Entre enero de 1992 y abril de 1997 se estudiaron de forma prospectiva todos los pacientes (pts) ingresados con el diagnóstico de CPM. Se les aplicó un estudio básico consistente en una historia clínica, un examen físico completo, una analítica estándar con marcadores tumorales y una radiografía de tórax. Se etiquetaron de cáncer metastásico de origen desconocido (CMOD) los pts con un estudio básico negativo, y en éstos se realizó un estudio protocolizado tomografía axial computarizada (TAC) (abdominopélvico y mamografía en mujeres). Aquellos pts en los que, tras la aplicación del estudio básico y el protocolizado no se detectó el tumor primario, fueron sometidos a un estudio exhaustivo a fin de validar la eficacia del algoritmo diagnóstico. Resultados. Se incluyeron 221 pts. La edad media era de 63 años (23-82). El síntoma principal fue óseo (30 por ciento), neurológico (24 por ciento), torácico (16 por ciento) y abdominal (16 por ciento). El estudio básico resultó positivo en 138 pts (62,4 por ciento); de éstos, la radiografía de tórax y la exploración física aportaron el mayor número de diagnósticos. La histología de las metástasis contribuyó al diagnóstico definitivo en 31 pts. Sólo el antígeno prostático específico (PSA) presentó una alta sensibilidad y especificidad. Fueron etiquetados de CMOD 83 pts. El estudio protocolizado diagnosticó el tumor primario en 24 pts (30 por ciento), 20 por TAC abdominal y 4 por mamografía; de éstos, 8 pts se consideraron tratables. En los 59 pts restantes se aplicó un estudio exhaustivo, hallándose el diagnóstico en 13; sin embargo, ninguno se consideró claramente merecedor de un tratamiento específico. Finalmente 47 pts (21 por ciento) quedaron sin diagnóstico. Los tumores primarios predominantes fueron pulmón (42 por ciento), próstata (6 por ciento) y mama (6 por ciento). Las localizaciones metastásicas más frecuentes fueron hueso (42 por ciento), sistema nervioso central e hígado (24 por ciento), y la histología, adenocarcinoma (61 por ciento) y carcinoma indiferenciado (15 por ciento). Conclusiones. El cáncer de pulmón y el CMOD representaron el 62 por ciento de los CPM. El estudio básico puede orientar dos tercios de los casos, siendo la exploración física y la radiografía de tórax las que tienen mayor rentabilidad diagnóstica. La histología de las metástasis y el PSA son de capital importancia. Un estudio protocolizado basado en la TAC abdominopélvica y la mamografía en mujeres puede identificar el resto de tumores tratables (AU)