Newer approaches to treatment of disseminated
disease
Matteo Landriscina, MD PhD
Assistant Professor of Clinical OncologyUniversity of Foggia
UNKNOWN PRIMARY TUMORS: NEWER CONCEPTS AND APPROACHES
Rome, March 5-6, 2010
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
FAVORABLE SUBSETS
1. Women with isolated axillary adenopathy2. Women with papillary serous adenocarcinoma of
the peritoneal cavity3. Squamous cell carcinoma involving cervical lymph
nodes4. Isolated inguinal adenopathy from squamous cell
carcinoma5. Men with bone metastases, elevated serum PSA,
or PSA positive on tumor staining6. Men with poorly differentiated carcinoma of
midline distribution7. Poorly differentiated neuroendocrine carcinoma8. Single, small and potentially resectable metastatic
site
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)
TREATMENTUNFAVORABLE 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
Chemotherapy for unfavorable subsetsOpen Questions
• Which chemotherapy regimen?
• Is the combination of Platinum and Taxane the standard of care?
• Is there any role for a third agent?
TREATMENTUNFAVORABLE SUBSETS
Platinum/Taxane chemotherapy regimensAuthor/year Chemotherapy Patients RR (%) MS (months)
Voog (2000) CpE 23 32 8
Briasoulis (2000) PCb 77 39 13
Greco (2000) DCb 47 22 8
Greco (2000) DCp 26 26 8
Park (2004) PCp 37 42 11
Berry (2007) PCb (weekly) 42 18 8.5
Pentheroudakis (2008)
DCb 47 32 (46) 16.2 (22.6)
Cb –Carboplatin; Cp – Cisplatin; D – Docetaxel, E – Etoposide, P – Paclitaxel
TREATMENTUNFAVORABLE SUBSETS
Triplet chemotherapy regimensAuthor/year Chemotherapy Patients RR (%) MS (months)
Greco (2000) PCbE 71 48 11
Greco (2002) PCbG 120 25 9
Greco (2004) PCbE 132 30 9
Schneider (2007) CbGCAP 33 39 7.6
Cb –Carboplatin; E – Etoposide, G – Gemcitabine; P – Paclitaxel
Pentheroudakis (2009)
Platinum conining regimens
918 32 9
TREATMENTUNFAVORABLE SUBSETS
Anthracycline and Gastrointestinal-type chemotherapy regimens
Author/year Chemotherapy Patients RR (%) MS (months)
Piga (2005) CbEA 102 26.5 9
Briasoulis (2008) IrOx 47 13 9.5
Sprenger (2008) CAPOx 51 12 7.3
Holtan (2008) GIr 31 12 7.3
Cb –Carboplatin; E – Etoposide, G – Gemcitabine; A – doxorubicin; Ir – irinotecan; CAP – capecitabine; Ox - oxaliplatin
Pentheroudakis (2009)
Anthracyclin- conining regimens
401 22 7
TREATMENTUNFAVORABLE SUBSETS
Gemcitabine or Irinotecan containig doubletsAuthor/year Chemotherapy Patients RR (%) MS (months)
Pouessel (2004) DG 35 40 10
Pittman (2006) CbG 51 30 8.5
Ando (2008) CbIr 43 40 11.4
Yonemari (2009) CbIr 45 42 12.2
Cb –Carboplatin; D – Docetaxel, G – Gemcitabine; Ir - irinotecan
Phase II randomized trialsAuthor/year Chemotherapy Patients RR (%) MS (months)
Dowell (2001) PFU
CbE
32 19
19
8.4
6.5
Coline (2003) CpGEM
CpIR
80 55
38
8
6
Assersohn (2003) FUPVI
FUMit
88 11.6
20
6.6
4.7
Palmieri (2006) Cp/CbP
Cp/CbVI
66 48
42
9.6
13.6
Huebner (2009) PCb
GEMVI
90 23.8
20
11
7
Hainsworth (2010) PCbE
GEMIr
198 18
18
7.4
8.5Cb –Carboplatin; Cp – Cisplatin; GEM – gemcitabine; FU – 5-fluorouracil; Mit – Mitomycin; Ir – irinotecan; VI – vinorelbine; E – Etoposide, P – Paclitaxel
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)
• 198 pts were randomized to paclitaxel, carboplatin, etoposide (PCE, 93 pts) or gemcitabine, irinotecan (GI, 105 pts). Responding/stable pts then received gefitinib until tumor progression.
• Median progression-free survival for PCE versus GI was 3.2 months versus 5.3 months, p=0.19
• Median overall survivals were 7.4 months (PCE) versus 8.6 months (GI), p=0.34
• 2-year survivals were 16% (PCE) and 19% (GI)• Response rates were similar (PCE 19%, GI 20%)• GI was less toxic, with lower rates of grade 3/4
neutropenia (11% vs. 35%; p< 0.01), febrile neutropenia (0% vs. 9%; p<0.01), thrombocytopenia (3% vs. 8%; p=.05), anemia (3% vs. 9%; p=0.05), and RBC transfusions (10% vs. 24%; p<0.01).
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
Comparative survival with diverse chemotherapy regimens for cancer of unknown primary site:
Multiple-treatments meta-analysisGolfinopoulos et al, 2009
• Meta-analysis of 10 randomized controlled trials comparing at least two different systemic regimens or a systemic regimen to no treatment
• Data on favorable subset CUP were excluded
• Overall 683 subjects were randomly assigned
• No trials compared systemic treatment to BSC
Comparative survival with diverse chemotherapy regimens for cancer of unknown primary site:
Multiple-treatments meta-analysisGolfinopoulos et al, 2009
Comparative survival with diverse chemotherapy regimens for cancer of unknown primary site:
Multiple-treatments meta-analysisGolfinopoulos et al, 2009
• Multiple-treatments meta-analysis showed no significant benefit for any treatment group over others
• No type of chemotherapy has been solidly proven to prolong survival in patients with CUP
• Regimens using either platinum or taxanes or both show some trends for prolongation of survival, but the data a limited. Taxane regimens seem to have the best results
• Median OS is 8-12 months for the trial published after the year 2000, but this gain may not necessary depend on systemic chemotherapy
• A taxane/platimun combination may prolong survival by 1.5 months
• BSC may be considered for old or unfit unfavorable CUP
Open Issues
• Molecular assignment of tissue of origin and response to chemotherapy
• Molecular-targeted agents in unknown primary carcinomas
• Liver metastases of unknown origin
Autopsy-found primaries, N = 644 (%)
Lung 27 Pancreas 24Liver/bile duct 8Kidney/adrenals 8Bowel 7Genital system 7Stomach 6Bladder/ureter 0.01Breast 0.007Other 10
DNA-assigned primaries, N > 500 (%)
Lung 11.5Pancreas 12.5Liver/bile duct 8Kidney/adrenals 6Bowel 12Genital system 9Stomach 3Bladder/ureter 5Breast 15Other 18
N RR (%)MS (months)
CUP-Platinum Advanced NSCLC
N RR (%)MS (months)
589530-458-11
918329
Adv Pancreas
446510-25
5-9
CUP-Anthra or GI
401227
Adv breast
395340-7018-24
Adv colon
1387535-5515-20
Chemotherapy activity and patients outcome in CUP and metastatic
tumors of known primary
Molecule
Ras HER2EGFRC-KIT PDGFR BCL2 P53 VEGFVEGFR
Therapeutic modulation
Farnesyl-transferase inhibitors Antibodies, tyrosine kinase inhibitors Antibodies, tyrosine kinase inhibitorsTyrosine kinase inhibitorsTyrosine kinase inhibitors Antisense oligonucleotidesGene therapy, degradation inhibitors AntibodiesTyrosine kinase inhibitors
Developed agents
Tipifarnib, lonafarnibTrastuzumab, lapatinibCetuximab, gefitinib, erlotinibImatinib, sunitinibImatinib, sunitinibOblimersen G3139ONYX015, INGN201, MI63BevacizumabZD6474, sorafenib, sunitinib
Promising molecular targets and targeting compounds in CUP
Pentheroudakis and Pavlidis, Cancer Treat Rev, 2006
Author N Clinicopathologic parameters and outcome
Pavlidis, 1995 26
Results
Method: IHC
HER2 expression 65%,overexpression 27%
None
Hainsworth, 2000 100 HER2 overexpression 11% None
Fizazi, 2003 56 HER2 overexpression 4% None
Rashid, 2005 76 HER2 expression 68%, Overexpression 24%
Co-expression of EGFR, HER2 and VEGF or Cox-2 in 54%. Superior survival on co-expession of EGFR, HER2 and Cox-2.
HER2 signalling in CUP
Pentheroudakis and Pavlidis, Cancer Treat Rev, 2006
Author N Clinicopathologic parameters and outcome
Fizazi, 2003 56
Results
Method: IHC, PCR, qPCR
EGFR overexpession 4%
None
Rashid, 2005 76 EGFR expression 75%, overexpression 61%
Co-expression of EGFR, HER2 and VEGF or Cox-2in 54%. Superior survival on coexpession of EGFR, HER2 and Cox-2
Dova, 2005 50 EGFR expression 74%, overexpression 12%Wild-type exons 18,19,21 EGFR gene in 96%. No exons 18, 19, 21 EGFR gene amplification
None
EGFR signalling in CUP
Pentheroudakis and Pavlidis, Cancer Treat Rev, 2006
Author N Clinicopathologic parameters and outcome
Fizazi, 2003 56
Results
Method: IHC, PCR, qPCR
C-KIT overexpression 11%
None
Rashid, 2005 76 C-KIT expression 12%, overexpression 4%
None
Dova, 2005 50 C-KIT expression 81%, overexpression 13%No exon 11 C-KIT gene mutations
None
cKIT signalling in CUP
Pentheroudakis and Pavlidis, Cancer Treat Rev, 2006
Author N Clinicopathologic parameters and outcome
Van de Wouw, 2004
48
Results
Method: IHC
CD34 microvessel density median 56/mm3. VEGF expression 39%,overexpression 26%
None
Hillen, 1997
69 No difference in CD34 microvessel density between39 CUP liver metastases and 30 known primaryliver metastases
CD34 microvessel density with adverse prognostic significance for survival
Karavasilis, 2005
80 CD34 microvessel density median 59 microvessels/mm2
Positive correlation of VEGF with microvessel density.
Angiogenesis in CUP (1)
Pentheroudakis and Pavlidis, Cancer Treat Rev, 2006
VEGF expression 100%,overexpression 83%
Increased microvessel density in unfavourable group CUP
Author N Clinicopathologic parameters and outcome
Karavasilis, 2005
75
Results
Method: IHC
MMP2 expession 69%, overexpression 49%MMP9 expession 49%, overexpression 36%TIMP1 expession 79%, overexpression 44%
Correlation of MMP2 and MMP9 expression.Adverse prognostic significance ofTIMP1 expression
Rashid, 2005
75 VEGF expression 49%, Overexpression 29%
Co-expression of EGFR, HER2 and VEGF or Cox-2 in 54%
Angiogenesis in CUP (2)
Pentheroudakis and Pavlidis, Cancer Treat Rev, 2006
• Phase II trial which evaluated the combined inhibition of VEGF and EGFR with bevacizumab and erlotinib.
• Patients who either had received previous chemotherapy or were previously untreated with poor-prognosis clinical features.
• All patients received bevacizumab 10 mg/kg every 2 weeks, along with erlotinib 150 mg orally daily.
• 47/51 patients received at least 8 weeks of treatment. • 10% PR, 61% SD • Median survival for the entire group was 7.4 months,
with 33% of patients alive at 1 year. • This regimen was well tolerated by most patients.
The Community Oncologist
Paclitaxel/Carboplatin plus Bevacizumab/Erlotinib in the First-Line Treatment of Patients with Carcinoma of Unknown Primary Site
John D. Hainswortha, David R. Spigela, Dana S. Thompson, Patrick B. Murphy, Cassie M. Lane, David M. Waterhouse, Yuval Naot, F. Anthony Greco
• Phase II trial with the combination of paclitaxel, carboplatin, bevacizumab, and erlotinib in the first-line treatment of patients with CUP
• 49/60 patients completed 4 cycles of therapy, and 44 received maintenance bevacizumab and erlotinib.
• 53% with major responses to treatment; 18 patients with SD.
• Median PFS was 8 months, with 38% of patients progression-free at 1 year.
• Median survival 12.6 months; 2-year overall survival rate 27%.
• Treatment was generally well tolerated.
• CUPL is an unfavourable subset of cancer of unknown primary site
• Male/female ratio 2:1. • Median age at diagnosis: 61–65. • Lung, pancreatic and colorectal primary tumors are most
commonly identified in the setting of CUP patients presenting with liver metastases
• The most commonly involved metastatic sites in addition to hepatic involvement are lymph nodes, bone and lung.
• Adenocarcinoma is the prevalent histology (64%), followed by undifferentiated carcinoma (20%), neurondocrine (8.4%) and squamous (3%).
Liver Metastasis subgroup
• Histology (neuroendocrine differentiation)
• Liver Metastasis only/Number of metastatic sites
• Age
• Performance Status
Liver Metastasis subgroupPrognostic Factors
CONCLUSIONS
• Potential roles for DNA microarray technology 1. Identify the primary site2. Identify clinically relevant subsets of tumors with similar gene
expression profiles3. 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