Introduction It is not too rare 3-5% year of newly diagnosed malignant tumours 4° most common cause...

IntroductionIt is not too rare 3-5% year of newly

diagnosed malignant tumours

4° most common cause of cancer-related death in both sex.

BackgroundThe most important breakthrough in the management

of CUP is the identification of clinicopathologic subgroups to choose specific treatment protocols

20% of patients, the similarity of clinical presentation to those of known primary cancer at a similar stage as resulted in the identification of patients with favourable clinical and pathological future

Background80% of pts have an ufavourable outcome

future

Identification of reliable prognostic factors are currently investigated in many trials

Background Favourable risk (20%)

Unfavourable risk (80%)

Favourable groups

•Poorly differentiated carcinoma with midline nodal distribution

•Women with papillary adenocarcinoma of peritoneal cavity

•Poorly differentiated neuroendocrine carcinomas

•Women with adenocarcinoma involving only axillary lymph nodes

Favourable groups

•Squamous cell carcinoma involving cervical lymph nodes

•Men with blastic bone metastatic lesions from an adenocarcinoma with elevated serum prostate-specific antigen

•Isolated inguinal lymphadenopathy from squamous carcinoma

•Patients with a single small metastasis

Favourable highlights

Tailored treatment as applied in metastatic tumours of known primary

Similar prognosis and clinical course

High response rates to treatments

Observations of the metachronous appearance of the primary tumor

FavourableTreatable Subset of Patients with Cancer of Unknown Primary Site

Subset Histology Special diagnostic Tests Treatment

Women, isolated axillary adenopathy

Adenocarcinoma, PDC

ER/PR/HER2 stains, MR breast

Treat as stage II breast cancer

Women, peritoneal carcinomatosis

Adenocarcinoma, PDC

Serum CA 125 Treat as stage III ovarian cancer

Man, blastic bone metastasis Adenocarcinoma Serum, tumor PSA Treat as metastatic prostate cancer

Single metastasis Adenocarcinoma, PDC

PET scan Definitive local therapy+-chemotherapy

Young man, extragonadal GCT features

PDC Serum HCG, AFP Treat as poor prognosis germ cell tumor

Isolated cervical nodes Squamous ENT exam, PET scan Treat as locally advanced head/neck cancer

Isolated inguinal nodes Squamous Definitive local therapy +-chemotherapy

Neuroendocrine Tumors Well and Poor differentiated

Ocrteoscan,Chromogranine

Octreotide Analogs, Chemotherapy

PENTHEROUDAKIS et Al: Acta Oncologica, 2005

Favourable Chemotherapy for patients with two favourable subsets of unknown primary carcinoma: Active, but how effective?

Pts with predominantly nodal disease Burden

Female patients had predominantly peritoneal malignant deposits of papillary serous adenocarcinomatous or undifferentiated carcinomatous histology


Favourable

Chemotherapy for patients with two favourable subsets of CUP: Active, but how effective?

Pts characteristics

SUBSET

PENTHEROUDAKIS et Al:

Acta Oncologica, 2005


Univariate analysis



Multivariate analysis



OSCR

Non CR



OS and TTP in months



Response to chemotherapy




ConclusionHighly predictive positive factors:

• N° of metastatic sites (1-3 Vs 4 or more)

• High serum CA125

• Normal serum CA 19-9

Complete response status was not included in the prognostic factor analysis, although its achievement predicted superior outcome




Conclusion

• No prognostic significance In patient management with platinum-based regimens, sex, performance status,histological grade, and peritoneal or nodal disease group

• Trend for statistical significance for female sex and peritoneal disease

G. R. Varadhachary, et Al:

Lancet Oncol 2008

Favourable Carcinoma of unknown primary with a colon-cancer profile changing paradigm and emerging definitions

• CUP in association with a colon-cancer profile (CCP-CUP) is an example of an emerging, specific CUP subset that seems to benefit from a tailored approach

• CCP-CUP is identified by CK20 and CDX2- positive and CK7-negative immunohistochemistry

• CCP-CUP derive substantial benefit from the use of specific treatments developed for colon cancer

• Larger clinical trials are warranted to more definitely test this finding


Lancet Oncol 2008

Favourable Carcinoma of unknown primary with a colon-cancer profile changing paradigm and emerging definitions


JCO 2008

Favourable Molecular Profiling of CUPCorrelation With Clinical Evaluation

Unfavourable groups

•Adenocarcinoma metastatic to the liver or other organs

•Malignant ascites from a nonpapillary adenocarcinoma

•Multiple cerebral metastases from an adenocarcinoma or squamous carcinoma

•Multiple lung/pleural metastases from an adenocarcinoma

•Multiple metastatic bone disease from an adenocarcinoma

Unfavourable highlights

• Regression or dormancy of the primary

• Development of early

•Aggressive biology

•Systemic metastases

• Resistance to the therapy

Unfavourable highlights

•Despite of biomolecular knowledge, this remain an eterogeneous group of pathology

•Majority (80%) of pts with CUP had unfavourable outcome features

•Identification of reliable prognostic indicators remain a challenge

•Many studies with multivariate analysis have try to discover prognostic factors, but without an international consensus

Prognostic Factors in CUP Adverse Prognostic Variables

Autor N° pts Univariate Multivariate Results Kambhu 62 Poor performance status Visceral metastases below the

diaphragm 30% of Response Rate

Visceral metastases below the diaphragm

Hainsworth 220 Tumor location outside retroperitoneal and peripheral

Tumor location outside retroperitoneal and peripheral

138 pts-63% Response Rate, 58 pts-26% had complete

response, 10-year survival 16%

lymph nodes lymph nodes No. of metastatic sites No. of metastatic sites Abnormal serum CEA levels Positive smoking history Abnormal serum LDH levels

Older age

Positive smoking history Abbruzzese 657 Male sex Male sex

Adenocarcinoma histologic type


No. of metastatic sites No. of metastatic sites Lung, Liver, Bone, Pleura,Brain metastases

Liver metastases

Van der Gaast

79 Poor performance status Poor performance status Good-prognosis WHO- 0 and alkaline phosphatase < 1.25 times the (N).

median survival >4 years. Intermediate-prognosis WHO 0<=1 or an alkaline

phosphatase level > or = 1.25 N. median survival 10 months

Poor-prognosis WHO>=1 and an alkaline phosphatase level > or = 1.25 N.

median survival 4 months


Serum alkaline phosphatase

Bone, Liver metastases Serum alkaline phosphatase

Serum AST

Prognostic Factors in CUPPrognostic Variables

Autor N° pts Prognostic Variables Results Lortholary 311 Male sex

PS 1Adenocarcinoma

No. of metastatic sites 1

adenocarcinoma: 164 cases; squamous cell carcinoma: 90 cases; neuro-endocrine tumor: 10 cases; and others: 20 cases primary carcinoma was found in only 6% of the cases

Median survival 9 monthsCuline 150 PS 1

Elevated LDH levels3 subgroups of patients with median survivals of 10.8, 6.0, and 2.4 months; Good-risk and poor-risk patients were identified, with median survivals of 11.7 months and 3.9 months, 1-year survival rates were 53% and 23%, respectively

Seve 317 PS 1Liver metastases

High comorbidity scoreLymphopenia

Elevated LDH serum levelsLow serum albumin levels

good-risk patients median survivals of 371 days poor-risk patients median survivals 103 days

Lenzi 337 Male sexAge 64 years

No. of metastatic sites 2

977 pts with CUP; PDC patients enjoyed better survival than PDA; The long median survival and chemotherapy

responsiveness of UPC patients with PDC and PDA could not be confirmed

Hess 1000 1 or 2 metastatic organ sites, nonadenocarcinoma , histology,

NO liver, bone, adrenal, or pleural metastases

Mediansurvival of the 10 subgroups ranged from 40 months

(95% confidence interval, 22–66 months), High risk group median survival 5 months

Kenneth R. Hess et Al: Clinical Cancer Research 1999

Classification and Regression Tree Analysis of 1000 Consecutive Patients with Unknown Primary Carcinoma

1000 pts

segregated into 10 groups with similar clinical features and survival

Unfavourable



OS

S Culine et Al: JCO, 2002

Unfavourable Development and Validation of a Prognostic Model to Predict the Length of Survival in Patients With Carcinomas of an Unknown Primary Site

• Identification of subsets of patients with clinical and pathologic features requiring specific guidelines that may translate into prolonged survival

•Unfortunately, the majority of CUP (85%) do not fall into one of these favorable subsets

•The benefit of chemotherapy over best supportive care is still unknown

• The optimal chemotherapy remains to be determined


Development and Validation of a Prognostic Model to Predict the Length of Survival in Patients With CUP

• 150 pts

•CUP excluding favourable subset

•Results were validated in an independent

set of pts

Unfavourable



Unfavourable

Pts characteristics


Unfavourable


Univariate analysis for survival


Unfavourable Development and Validation of a Prognostic Model to Predict the Length of Survival in Patients With CUP



Univariate analysis for survival



Prognostic Model



OS in Reference Population



OS in Validation Population

P. Seve et Al: Cancer, march 2006

The Influence of Comorbidities, Age, and Performance Status on the Prognosis and Treatment of Patients with Metastatic Carcinomas of Unknown Primary Site

OS

evaluated at cancer center

NOT evaluated at cancer center

P. Seve et Al: Cancer, march 2006

The Influence of Comorbidities, Age, and Performance Status on the Prognosis and Treatment of Patients with Metastatic Carcinomas of Unknown Primary Site

P. Seve et Al: Cancer, September 2006

Unfavourable

Low Serum Albumin Levels and Liver Metastasis Are Powerful Prognostic Markers for Survival in Patients With Carcinomas of Unknown Primary Site


Unfavourable Low Serum Albumin Levels and Liver Metastasis Are Powerful Prognostic Markers for Survival in Patients With Carcinomas of Unknown Primary Site

P. Seve et Al: Cancer,

September 2006


Multivariate AnalisysOf OS



Prognostic Model

Good No liver Metastases

Poor Liver Metastases

and Low albumin

or Low albumin

61 39 371

122 12 108

Prognostic Group

Prognosticvariable

Survival,% Survival (months)

N° pts 1yr Median


Favourable Low Serum Albumin Levels and Liver Metastasis Are Powerful Prognostic Markers for Survival in Patients With Carcinomas of Unknown Primary Site

OSIn Reference pts

Good risk

Poor risk


Favourable Low Serum Albumin Levels and Liver Metastasis Are Powerful Prognostic Markers for Survival in Patients With Carcinomas of Unknown Primary Site

Good risk

Poor risk

OSIn Independent pts

M. Kodaira, et Al:

Annals of Oncology 2009

Bone metastasis and poor performance status are prognostic factors for survival of CUP in patients treated with systematic chemotherapy

Pts characteristics

M. Kodaira, et Al:


Treatments Results


M. Kodaira, et Al:



Univariate e

Multivariate analisys

M. Kodaira, et Al:



Prognostic Model

But the chemotherapy regimens influences the

outcome of CUP?

D. E. Saad, et Al:

Oncology/Hematology 2000

Prognostic stratification in UPC: a role for assessing the value of conventional-dose and high-dose chemotherapy for CUP

D. E. Saad, et Al:

Oncology/Hematology 2000

Prognostic stratification in UPC: a role for assessing the value of conventional-dose and high-dose chemotherapy for CUP

• No chemotherapy regimen can be considered standard in the treatment of CUP without features of the extragonadal germ cell syndrome or of the other favorable subgroups

• Trials performed to date had only active treatments in their arms, and therefore no definitive conclusions can be drawn regarding the superiority of active therapy versus best supportive care

V. Golfinopoulos, et Al:

Cancer Treatment Reviews 2009

Comparative survival with diverse chemotherapy regimens for cancer of unknown primary site: Multiple-treatments meta-analysis

• Data sources: PubMed and the Cochrane Library Central Registry of Controlled Trials

• Randomized controlled trials comparing

• No favourable subset

• Regimens are divided in : platinum, taxane, both, or neither; non-platinum/non-taxane.

• No type of chemotherapy has been solidly proven to prolong survival in patients with CUP




CONCLUSION• No trials compared systemic treatment to best supportive

care

• All arms referred to chemotherapy

• Multiple-treatments meta-analysis showed no significant benefit

• Point estimates of hazard ratios favored platinum, taxane,or both (hazard ratios 0.69, 0.66, and 0.81, respectively, as

compared with monotherapy with an agent other than platinum or taxane)

Molecular assignment of tissue of origin in cancer of unknown primary may not predict response to therapy or outcome: A systematic literature review

Pentheroudakis, et Al:


Molecular assignment of tissue of origin in cancer of unknown primary may not predict response to therapy or outcome: A systematic literature review

Pentheroudakis, et Al:


Chemotherapy activity and pts Outcome in CUP and Metastatic tumors

of KNOWN primary

CONCLUSION• Despite advances in molecular

immunohistochemistry and imaging technology, the diagnosis and therapy of CUP remains a challenge

• Major advance in the field over the last decade was made by identifying the clinicopathological subsets of CUP patients with a more favourable prognosis.

CONCLUSION• This allowed for tailoring of the therapeutic strategy

towards more intensive modalities for good risk groups

• Patients with midline nodal metastases as well as women with non-mucinous peritoneal carcinomatosis are thought to have entities equivalent to extragonadal germ cell cancer and ovarian cancer may respond to systemic platinum-based chemotherapy and occasionally enjoy long-term survival

CONCLUSION• Most patients received platinum based

chemotherapy, commonly coupled with a taxane. Response rate 50%, among the highest reported to date, reproduced by a few authors using platinum-taxane regimens

• No prospective studies or meta-analysis of prognostic factors for CUP have been published

Introduction It is not too rare 3-5% year of newly diagnosed malignant tumours 4° most common cause...

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Transcript of Introduction It is not too rare 3-5% year of newly diagnosed malignant tumours 4° most common cause...