newer approaches to treatment of disseminated disease matteo landriscina, md phd assistant professor...

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?


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


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


Platinum conining regimens

918 32 9


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


Anthracyclin- conining regimens

401 22 7


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

Multiple-treatment meta-analysis for deathGolfinopoulos 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



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


EGFR expression and response to chemotherapy

Massard, Br J Cancer, 2007


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



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)


VEGF expression 100%,overexpression 83%

Increased microvessel density in unfavourable group CUP


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)


• 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.

Hainsworth, J. D. et al. J Clin Oncol; 25:1747-1752 2007

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

Liver Metastasis subgroupResponse to chemotherapy

Lazaridis et al, Cancer Tret Rev, 2008

Liver Metastasis subgroup


Liver Metastasis subgroupPrognostic factors for OS


• 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

Current Clinical Practice

Diagnosis of metastatic carcinoma

Search for primary site

Rule out non-carcinoma histology Lymphoma, melanoma, sarcoma

Identify favorable subgroups

Unfavorable subgroup Poor PS BSCGood PS

●Clinical trial● Platinum-taxane chemotherapy

AND

newer approaches to treatment of disseminated disease matteo landriscina, md phd assistant professor...

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