Unknown Primary Updated May 2017 by Di Maria Jiang (PGY-5 Medical Oncology Resident, University of Toronto)

Reviewed by Dr. Chistine Elser (Staff Medical Oncologist, University of Toronto) and Dr. Scot Dowden (Staff Medical Oncologist, University of Calgary)

DISCLAIMER: The following are study notes compiled by the above PGY-5 medical oncology residents and reviewed by a staff medical oncologist. They reflect what we feel is relevant knowledge for graduating medical oncology residents preparing for their final examination. The information has not been surveyed or ratified by the Royal College.

A) DEFINITION

- A heterogeneous group of metastatic cancers for which a standardized work-up has failed to

identify the site of origin at the time of diagnosis B) PUBLIC HEALTH

EPIDEMIOLOGY - Incidence: 7th-8th most common malignancy in developed world; 3-5% of all malignancies (2% in

US) o Incidence and prevalence is decreasing over time (prevalence decreased by 51%

between 1973 and 2008 and the incidence decreased by 30%) - Mortality: 4th most common cause of cancer-related death - Lymph node confined metastases median survival 6-9 months - Extranodal metastases median survival 2-4 months - Primary tumor found in <30% of patients - In 20-50% of patients, primary not found in postmortem examination

• Fourcategorieswhichguidefurtherevaluation

o Adenocarcinoma70%

o SCC5%

o Neuroendocrinecarcinoma1%

o Poorlydifferentiatedtumors20-25%

RISK FACTORS - Genetic: 2.8% familial and associated with lung, kidney and colorectal cancers in families

C) PRESENTATION & DIAGNOSIS

SYMPTOMS & SIGNS - General complaints - Symptoms related to site of metastatic disease - Multiple sites of involvement >50% of patients - Common sites:

o Liver o Lungs o Bones o Lymph nodes

- Pattern of metastatic sites unreliable to determine primary site

Favorable Prognostic Subgroups - poorly differentiated carcinoma with midline distribution - women with papillary adenocarcinoma of peritoneal cavity

- women with adenocarcinoma involving only axillary lymph nodes - SCC of cervical lymph nodes - Isolated inguinal adenopathy - Poorly differentiated neuroendocrine carcinomas - Single, small and potentially resectable tumor

Unfavorable Prognostic Features - male - poor PPS - high LDH - low albumin - adenocarcinoma with metastases involving multiple organs - non-papillary malignant ascites - peritoneal metastases - multiple cerebral metastases - adenocarcinoma with multiple lung/pleural or bone lesions

INVESTIGATIONS

For all patients: - Physical Exam

o Head and neck, GU, rectal, pelvic, breast - Baseline bloodwork (CBC, electrolytes, LFT, Cr, calcium) - CT Chest/ Abdomen/ Pelvis - Mammogram - Urine cytology/ urinalysis - Core biopsy

For women with isolated axillary lymph node(s)

- Breast MRI Squamous cell carcinoma of the neck

- PET CT Other investigations if indicated:

- Pelvis ultrasound - Tumor markers: PSA, AFP, HCG

o In certain situations CEA, Ca125, Ca19-9 Invasive procedures:

- Not recommended for initial workup - guided by clinical presentation and initial work-up

o gastroscopy o colonoscopy for liver metastases o cystoscopy for retroperitoneal lymph nodes and suspicious urine cytology o triple endoscopy for isolated neck lymph node (laryngoscopy, bronchoscopy, upper

endoscopy) Note: PET CT can be helpful to rule out other sites of metastases if there is a known single metastatic site and aggressive local treatment is being considered

Avoid unnecessary tests and delays

Complete H/P, including

breast, GU, pelvic, rectal exam

Review of past biopsies or malignancies, removed lesions, spontaneously regressing lesions and existing imaging studies

CBC, lytes, LFTs, Cr, Ca

CT c/a/p

Hemoccult

Symptom-directed endoscopy and focused imaging

Biopsy Core needed biopsy and/or FNA of most acceptable site Detailed pathology review Gene signature profiling for tissue of origin not recommended for standard management at this time (however, appropriate tumour specific mutations acceptable e.g. EGFR/ALK for lung)

Suspected metastatic

malignancy

Workup for Possible Breast Primary - suspect when:

o adenocarcinoma with positive axillary and mediastinal nodes o adenocarcinoma in supraclavicular nodes, chest, peritoneum, retroperitoneum, liver,

bone or brain - Mammogram - MRI and/or U/S of breast for non-diagnostic mammogram if histopathologic evidence of breast

cancer - MRI if mammogram not adequate to assess extent of disease

o Dense breast tissue o Positive axillary nodes o Evaluate chest wall

- Consider NSCLC if mediastinal involvement but workup negative for breast primary Workup for Possible Germ Cell Primary

- suspect when: o adenocarcinoma of mediastinal nodes o retroperitoneal mass in male <65 years of age

- Beta-hCG and AFP - Testicular U/S if elevated beta-hCG and AFP in male with mediastinal or retroperitoneal mass - Consider NSCLC or ovarian germ cell if mediastinal involvement but workup negative for primary

germ cell tumor Workup for Possible Ovarian Primary

- suspect non-germ cell ovarian when: o mediastinal, inguinal, chest, peritoneal or retroperitoneal involvement

- CA 125 Workup for Possible Prostate Primary

- PSA when: o Male >40 years of age with adenocarcinoma or carcinoma NOS

▪ Except if metastases limited to liver or brain o Male with bone metastases or multiple sites of involvement regardless of age

Additional Workup for Adenocarcinoma or Carcinoma Not Otherwise Specified

- CA 19-9 o Peritoneal disease or liver involvement for suspected pancreatic or biliary primary

- AFP o Liver involvement

- Urinary cytology followed by cystoscopy o Retroperitoneal mass

- Proctoscopy for rectal or anal cancer o Male and females with Inguinal lymph node involvement

- Endoscopy o Liver involvement o Not routinely for malignant ascites

Workup for SCC

- anal endoscopy for inguinal node involvement PATHOLOGY & MOLECULAR BIOLOGY

- 5 major subtypes (from light microscopy)

o well to moderately differentiated adenocarcinoma (60%) o poorly differentiated adenocarcinoma or undifferentiated carcinoma (29%) o SCC (5%) o Poorly differentiated malignant neoplasm (5%)

▪ Unable to be further classified by light microscopy o Neuroendocrine tumors (1%)

- Immunohistochemistry

o predicts primary in 35-40% of patients o impact on treatment choice and outcome not clear o often valuable to direct further workup

Credit: NCCN Clinical Practice Guideline Occult Primary V1.2015

- Molecular markers o Cytogenetics relevant for unknown primary carcinomas/ neoplasms:

▪ i12p – germ cell tumors ▪ (Ig) gene rearrangement – lymphomas ▪ HPV/ p16 – cervical cancer ▪ EBV genome – nasopharyngeal cancer ▪ t(15:19) – midline carcinoma ▪ (t[11;22] [q24;q12]) – peripheral neuroepithelial carcinoma

o Oncogene overexpression (testing for mutations/ overexpression not recommended

routinely) ▪ C-myc ▪ Ras ▪ Her2 ▪ EGFR ▪ C-kit ▪ BCL-2 ▪ p53

Experimental options:

- Gene Expression Profiling o Rationale: pattern of gene expression may reflect genetic make-up of primary

o Outcome data not currently available to recommend routine use for workup (NCCN)

- Next Generation Sequencing o Potential to identify actionable biomarkers outside of tissue specific markers o Remains experimental

D) TREATMENT

- no specific regimen of chemotherapy is considered standard of care - choice of regimen based on histologic type of cancer - in general chemotherapy has limited efficacy and considerable toxicity in occult primaries

Adenocarcinoma

First- Line Regimens

- Carboplatin + Paclitaxel - Gemcitabine + Carboplatin - Gemcitabine + Irinotecan response rates 25-45%

• GolfinopoulosCancerTreatRev2009:meta-analysisof10randomizedtrials,683patients,excludingfavorablesubsetCUP.Comparedplatinumvstaxanevsbothvsneither

o nosurvivalbenefitwitheitherplatinumvstaxanevsboth

o notrialsthatcomparedsystemictreatmenttobestsupportivecare

Paclitaxel/carboplatin/etoposide versus gemcitabine/irinotecan in the first-line treatment of patients with carcinoma of unknown primary site: a randomized, phase III Sarah Cannon Oncology Research Consortium Trial

Hainsworth JD et al. Cancer J. 2010;16(1):70.

Regimen ● paclitaxel/carboplatin/etoposide (PCE) versus gemcitabine/irinotecan

● 4-6 cycles of each ● both arms followed by single-agent gefitinib (median duration 3 months)

Primary Endpoint ● 2 year survival Inclusion/Exclusion Criteria

● Inclusion: ● Untreated unknown primary histologically documented

adenocarcinoma, poorly differentiated andeocarcinoma, poorly differentiated carcinoma, or poorly differentiated squamous carcinoma

● Exclusion: ● Neuroendocrine tumors ● Women w/ adenocarcinoma isolated to axillary LN ● Women w/ adenocarcinoma isolated to peritoneal

involvement ● Patients w/ resectable single metastasis ● Patients w/ squamous carcinoma limited to cervical,

supraclavicular or inguinal nodes ● Young men with features of extragondal germ cell tumor ● Brain metastases unless controlled by previous surgical

resection or radiation and not requiring ongoing steroids ● Treatment for another cancer type within last 4 years

Size (N) ● 198 patients in total but with slow accrual ● Target accrual was 320

Results ● 2 year survival o PCE 15% o Gemcitabine/Irinotecan 18%

● Median Survival o PCE 7.4 months o Gemcitabine/Irinotecan 8.5 months

● Median PFS o PCE 3.3 months o Gemcitabine/Irinotecan 5.3 months

● Response Rate o PCE 18% = Gemcitabine/Irinotecan 18%

● Quality of Life: Toxicity ● PCE Grade 3/4

o Neutropenia, thrombocytopenia, anemia, febrile neutropenia ● Gemcitabine/Irinotecan Grade 3/4

o Diarrhea Conclusion ● PCE and gemcitabine/irinotecan comparable efficacy in the first-line

● Gemcitabine/irinotecan preferable regimen due to favorable toxicity profile. ● However, the moderate efficacy of both regimens underscores the need for

novel treatment approaches in this patient population. Other Comments ● Short duration of Gefitinib maintenance suggests little single-agent activity

in this setting

Carbo/Taxol

• 3phaseIItrials

Second Line:

• Nostandardofcare

• clinicaltrialsthebest,treatasmostlikelyprimary

• Hainsworth2001:39patientstreatedwithgemcitabine

o RR8%,SD25%

• HainsworthCancer2005phaseII:n=40CUPatleast1previouschemoregimen,treatedwithgemcitabine(1000mg/m2)andirinotecan(100mg/m2D1D8)q3w

o 10%ORR,43%SD

o Mediansurvival4.5months

o Treatmentwelltolerated

• HainsworthCancer2010phaseII:n=48CUPatleast1previouschemoregimen,treatedwithoxaliplatin(130mg/m2D1)andcapecitabine(1000mg/m2BIDD1-14)q3w

o ORR19%,46%SD

o MedianPFS3.7mo,OS9.7mo

o Reasonablywelltolerated

Targeted Therapy

• HainsworthJCO2007:n=51CUPpreviouschemooruntreated,poorprognosticclinicalfeaturesreceivedBevacizumab(10mg/kg)anderoltinib(150mgOD)q2w

o 10%partialresponse,61%SD

o MedianOS7.4months

o Welltolerated

• Hainsworth2009:n=60CUP,receivedcarbo/taxol+bev/erlotib

o RR53%,SD28%

o OS12.6mo

o PFS8mo

• Goetz2013:n=46CUPtreatedwithcarbo/taxol/everlimus

o RR34%

o OS10.0mo

o PFS4.1mo

• Hainsworth2015:n=89CUPtreatedwithcarbo/taxol+/-belinostat

o RR45%vs21%

o OS12.4vs9.1months

o PFS5.4vs5.3months