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Newer approaches to treatment of disseminated disease

DEFINITION. Carcinoma of unknown primary (CUP) is a biopsy-proven metastatic malignant tumor whose primary site can not be identified during pretreatment evaluation including:Thorough history and physical examLaboratory and radiographic studiesDetailed histological evaluation. EPIDEMIOLOGY. CUP

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Newer approaches to treatment of disseminated disease

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    1. Newer approaches to treatment of disseminated disease

    2. DEFINITION Carcinoma of unknown primary (CUP) is a biopsy-proven metastatic malignant tumor whose primary site can not be identified during pretreatment evaluation including: Thorough history and physical exam Laboratory and radiographic studies Detailed histological evaluation

    3. EPIDEMIOLOGY CUP constitutes 2-4% of all malignacies Annual age-adjusted incidence in US is 7-12 cases per 100,000 population Median age at presentation is 60 years Slightly more prevalent in males 5-10% of case are characterized by a relatively favourable prognosis

    4. FAVORABLE SUBSETS Women with isolated axillary adenopathy Women with papillary serous adenocarcinoma of the peritoneal cavity Squamous cell carcinoma involving cervical lymph nodes Isolated inguinal adenopathy from squamous cell carcinoma Men with bone metastases, elevated serum PSA, or PSA positive on tumor staining Men with poorly differentiated carcinoma of midline distribution Poorly differentiated neuroendocrine carcinoma Single, small and potentially resectable metastatic site

    5. UNFAVOURABLE SUB-SETS Adenocarcinoma metastatic to the liver or other organs Non-papillary malignant ascites (adenocarcinoma) Multiple cerebral metastases (adeno or squamous carcinoma) Multiple lung/pleural metastases (adenocarcinoma) Multiple metastatic bone disease (adenocarcinoma)

    6. TREATMENT UNFAVORABLE SUBSETS With the exception of the favorable subsets, most patients with CUP have a tumor that is resistant to chemotherapy The prognosis is very poor, with median survival of 2 to 3 months in unselected patients and 6 to 10 months in those enrolled into clinical trials Patients with good performance status may benefit from systemic chemotherapy

    7. Chemotherapy for unfavorable subsets Open Questions Which chemotherapy regimen? Is the combination of Platinum and Taxane the standard of care? Is there any role for a third agent?

    8. TREATMENT UNFAVORABLE SUBSETS

    9. TREATMENT UNFAVORABLE SUBSETS

    10. TREATMENT UNFAVORABLE SUBSETS

    11. TREATMENT UNFAVORABLE SUBSETS

    13. Randomized phase III comparison of paclitaxel/carboplatin/etoposide versus gemcitabine/irinotecan, both followed by gefitinib, in patients (pts) with carcinoma of unknown primary site (ASCO 2009, Abs 4931)

    14. CONCLUSIONS Clinical trials evaluated a group of heterogeneous tumors sharing the unique characteristic of metastatic disease without identifiable origin at the time of initial therapy Only phase II trials, few randomized No randomized phase III trials designed to establish the efficacy of combination chemotherapy over BSC or Platinum single agent Among unfavourable subsets, patients with good performance status may benefit from systemic chemotherapy There is no chemotherapy of choice although the most commonly used regimens use the combination of a platinum and a taxane The role for a third agent such as gemcitabine, irinotecan or etoposide remains unclear

    15. Comparative survival with diverse chemotherapy regimens for cancer of unknown primary site: Multiple-treatments meta-analysis Golfinopoulos et al, 2009

    16. Comparative survival with diverse chemotherapy regimens for cancer of unknown primary site: Multiple-treatments meta-analysis Golfinopoulos et al, 2009

    17. Multiple-treatment meta-analysis for death Golfinopoulos et al, 2009

    18. Comparative survival with diverse chemotherapy regimens for cancer of unknown primary site: Multiple-treatments meta-analysis Golfinopoulos et al, 2009

    19. Open Issues Molecular assignment of tissue of origin and response to chemotherapy Molecular-targeted agents in unknown primary carcinomas Liver metastases of unknown origin

    21. Chemotherapy activity and patients outcome in CUP and metastatic tumors of known primary

    25. EGFR expression and response to chemotherapy

    35. Liver Metastasis subgroup Response to chemotherapy

    36. Liver Metastasis subgroup

    37. Liver Metastasis subgroup Prognostic factors for OS

    39. TREATMENT FAVORABLE SUBSETS 1. Women with isolated axillary adenopathy Lymph nodes should be tested for ER, PR, and HER-2/neu In cases of negative mammogram, the primary may be seen on MRI or after mastectomy Prognosis is similar to lymph node positive breast cancer Mobile lymph nodes (N1) - Treat as stage IIA breast cancer Fixed lymph nodes (N2) - Treated as stage IIIA breast cancer MRM + AND ? chemotherapy ± hormonal therapy/RT Neoadjuvant chemotheray for N2 disease

    40. TREATMENT FAVORABLE SUBSETS 2. Women with papillary serous adenocarcinoma of the peritoneal cavity The germinal epithelium of the ovary and peritoneal mesothelium share the same embryological origin More common in women with BRCA-1 mutation and may also be seen after prophylactic oophorectomy Outcomes are similar to ovarian cancer at equivalent stage Patients should be treated as stage III ovarian carcinoma Surgical debulking followed by chemotherapy

    41. TREATMENT FAVORABLE SUBSETS 3. Squamous cell carcinoma of the cervical lymph nodes Despite aggressive diagnostic approach, the primary site is not found in the majority of patients Ipsilateral tonsilectomy is often performed since the primary can be found in 10 to 25% of cases - Small tumors may originate in the deep crypts and not be detected by superficial biopsy Treat as locally advanced head and neck cancer Low stage (N1) – Surgery ? RT or RT alone High stage (N2-N3) - Chemoradiotherapy

    42. TREATMENT FAVORABLE SUBSETS 4. Isolated inguinal squamous cell carcinoma Tumor is usually located in the genital or anorectal area Patients without an identifiable primary tumor may benefit from inguinal lymphadenectomy, with or without adjuvant radiation therapy The role for chemotherapy in the adjuvant setting is not well defined Surgery ± RT, ? chemotherapy

    43. TREATMENT FAVORABLE SUBSETS 5. Men with bone metastases, elevated serum PSA, or PSA positive on tumor staining Prostate cancer is the most likely diagnosis 1. Elderly men with adenocarcinoma of unknown primary and predominantly blastic bone metastases 2. Patients with increased PSA or positive PSA staining on the biopsy specimen despite atypical presentation Hormonal therapy

    44. TREATMENT FAVORABLE SUBSETS 6. Men with poorly differentiated carcinoma of midline distribution Young males with tumors of predominant midline distribution (mediastinum and retroperitoneum) should be treated as extragonadal germ cell tumors Cisplatin-based chemotherapy (BEP)

    45. TREATMENT FAVORABLE SUBSETS 7. Poorly differentiated neuroendocrine carcinoma IHC usually stains positive for chromogranin or NSE Patients frequently present with diffuse metastases to the liver or bones Platinum-based chemotherapy (platinum + etoposide)

    46. TREATMENT FAVORABLE SUBSETS 8. Single metastatic site Although other metastatic sites may become evident within a short period, some patients may achieve a prolonged disease-free interval with local therapies such as surgery or radiotherapy Adjuvant chemotherapy may also be considered Surgery or RT

    47. CONCLUSIONS Potential roles for DNA microarray technology Identify the primary site Identify clinically relevant subsets of tumors with similar gene expression profiles Identify specific and novel targets for treatment Targeted therapies such as EGFR inhibitors and anti-angiogenesis agents may have a role in the treatment of CUP, particularly in patients with unfavorable subsets PR 10%, SD 61% , Median survival 7.4 months in 2nd line RR 53%, PFS 8 months, median survival 12.6 months in 1st line

    48. Current Clinical Practice

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