Carcinoma of unknown primary

Carcinoma of unknown primary may also be referred to as carcinoma of unknown primary site, cancer/carcinoma of unknown primary (CUP), occult primary, or unknown primary carcinoma.

15 regimens on this page 16 variants on this page

Guidelines

Given the rapid change in evidence in many areas of hematology/oncology, readers are encouraged to consider any guideline published 5+ years ago to be for historical purposes, only.

ASCO

• 2020: Maghami et al. Diagnosis and Management of Squamous Cell Carcinoma of Unknown Primary in the Head and Neck: ASCO Guideline PubMed

ESMO

• 2023: Krämer et al. Cancer of unknown primary: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up PubMed
  • 2015: Fizazi et al. Cancers of unknown primary site: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up PubMed
  • 2011: Fizazi et al. Cancers of unknown primary site: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up PubMed
  • 2010: Pavlidis et al. Cancers of unknown primary site: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up PubMed
  • 2009: Briasoulis et al. Cancers of unknown primary site: ESMO clinical recommendations for diagnosis, treatment and follow-up PubMed
  • 2008: Briasoulis et al. Cancers of unknown primary site: ESMO clinical recommendation for diagnosis, treatment and follow-up PubMed
  • 2007: Cancers of unknown primary site: ESMO clinical recommendations for diagnosis, treatment and follow-up PubMed
  • 2005: Briasoulis et al. ESMO Minimum Clinical Recommendations for diagnosis, treatment and follow-up of cancers of unknown primary site (CUP) PubMed
  • 2001: ESMO Minimum Clinical Recommendations for diagnosis, treatment and follow-up of cancers of unknown primary site (CUP) PubMed

NCCN

• NCCN Guidelines - Occult Primary (Cancer of Unknown Primary (CUP))

• 2014: Ettinger et al. Occult Primary, Version 3.2014 PubMed
• 2011: Ettinger et al. NCCN Clinical Practice Guidelines Occult primary. PubMed
• 2005: Ettinger et al. Occult primary cancer clinical practice guidelines. PubMed

All lines of therapy

BEP

BEP: Bleomycin, Etoposide, Platinol (Cisplatin)
PEB: Platinol (Cisplatin), Etoposide, Bleomycin

Regimen

Study	Evidence
Hainsworth et al 1992	Phase 2

Chemotherapy

• Bleomycin (Blenoxane) 30 units IV once per day on days 1, 8, 15
• Etoposide (Vepesid) 100 mg/m² IV once per day on days 1 to 5
• Cisplatin (Platinol) 20 mg/m² IV once per day on days 1 to 5

21-day cycles

References

1. Hainsworth JD, Johnson DH, Greco FA. Cisplatin-based combination chemotherapy in the treatment of poorly differentiated carcinoma and poorly differentiated adenocarcinoma of unknown primary site: results of a 12-year experience. J Clin Oncol. 1992 Jun;10(6):912-22. link to original article contains dosing details in manuscript PubMed

Carboplatin & Docetaxel

Regimen variant #1

Study	Evidence
Pentheroudakis et al. 2008	Phase 2

Chemotherapy

• Carboplatin (Paraplatin) AUC 5 IV over 30 minutes once on day 1, given second
• Docetaxel (Taxotere) 75 mg/m² IV over 30 minutes once on day 1, given first

Supportive therapy

• Dexamethasone (Decadron) 8 mg PO twice per day on day -1, then 16 mg IV once on day 1, prior to chemotherapy
• Ondansetron (Zofran) 8 mg IV once on day 1, prior to chemotherapy
• Ranitidine (Zantac) 100 mg IV once on day 1, prior to chemotherapy
• Dimetindene (Fenistil) 0.1 mg/kg (route unclear) prior to chemotherapy

21-day cycle for up to 8 cycles

Regimen variant #2

Study	Evidence
Greco et al. 2000	Phase 2

Chemotherapy

• Carboplatin (Paraplatin) AUC 6 IV over 20 minutes once on day 1, given second
• Docetaxel (Taxotere) 65 mg/m² IV over 60 minutes once on day 1, given first

Supportive therapy

• Dexamethasone (Decadron) 8 mg PO twice per day on days -1 to 2
• One of the following serotonin 5-HT3 antagonists:
  • Ondansetron (Zofran) 32 mg IV once on day 1; 15 minutes prior to chemotherapy
  • Granisetron 10 mcg/kg IV once on day 1; 15 minutes prior to chemotherapy

21-day cycle for 4 to 8 cycles

References

1. Greco FA, Erland JB, Morrissey LH, Burris HA 3rd, Hermann RC, Steis R, Thompson D, Gray J, Hainsworth JD. Carcinoma of unknown primary site: phase II trials with docetaxel plus cisplatin or carboplatin. Ann Oncol. 2000 Feb;11(2):211-5. link to original article contains dosing details in manuscript PubMed
2. Pentheroudakis G, Briasoulis E, Kalofonos HP, Fountzilas G, Economopoulos T, Samelis G, Koutras A, Karina M, Xiros N, Samantas E, Bamias A, Pavlidis N; Hellenic Cooperative Oncology Group. Docetaxel and carboplatin combination chemotherapy as outpatient palliative therapy in carcinoma of unknown primary: a multicentre Hellenic Cooperative Oncology Group phase II study. Acta Oncol. 2008;47(6):1148-55. link to original article contains dosing details in manuscript PubMed

Carboplatin & Gemcitabine (GCb) & Paclitaxel

GCP: Gemcitabine, Carboplatin, Paclitaxel

Regimen

Study	Evidence
Greco et al. 2002	Phase 2

Chemotherapy

• Gemcitabine (Gemzar) 1000 mg/m² IV once per day on days 1 & 8
• Carboplatin (Paraplatin) AUC 5 IV over 20 to 30 minutes once on day 1
• Paclitaxel (Taxol) 200 mg/m² IV over 60 minutes once on day 1

Supportive therapy

• Corticosteroids IV once on day 1; 30 minutes prior to paclitaxel
• Diphenhydramine (Benadryl) 50 mg IV once on day 1; 30 minutes prior to paclitaxel
• Cimetidine (Tagamet) 300 mg IV once on day 1; 30 minutes prior to paclitaxel

21-day cycles

References

1. Greco FA, Burris HA 3rd, Litchy S, Barton JH, Bradof JE, Richards P, Scullin DC Jr, Erland JB, Morrissey LH, Hainsworth JD. Gemcitabine, carboplatin, and paclitaxel for patients with carcinoma of unknown primary site: a Minnie Pearl Cancer Research Network study. J Clin Oncol. 2002 Mar 15;20(6):1651-6. link to original article contains dosing details in manuscript PubMed

Carboplatin & Paclitaxel (CP)

Regimen

Study	Dates of enrollment	Evidence
Briasoulis et al. 2000	1996-02 to 1999-02	Phase 2
Hayashi et al. 2019	2008-10 to 2015-02	Phase 2

Chemotherapy

• Carboplatin (Paraplatin) AUC 6 IV over 30 minutes once on day 1, given first
• Paclitaxel (Taxol) 200 mg/m² IV over 3 hours once on day 1, given second

Supportive therapy

per Briasoulis 2000 study

• Methylprednisolone (Solumedrol) 32 mg PO for three doses, 24 and 12 hours before paclitaxel, and 10 minutes before carboplatin
• Dexamethasone (Decadron) 16 mg IV once on day 1, at least 10 minutes prior to chemotherapy
• One of the following antihistamines:
  • Diphenhydramine (Benadryl) 50 mg IV once on day 1, at least 10 minutes prior to chemotherapy
  • Dimetindene (Fenistil) 0.1 mg/kg IV once on day 1, at least 10 minutes prior to chemotherapy
• Ranitidine (Zantac) 100 mg IV once on day 1, at least 10 minutes prior to chemotherapy
• Ondansetron (Zofran) 8 mg IV once on day 1, after the above premedications
• Suggested: Filgrastim (Neupogen) 300 mcg SC once per day on days 5 to 12

21-day cycle for 6 to 8 cycles

References

1. Briasoulis E, Kalofonos H, Bafaloukos D, Samantas E, Fountzilas G, Xiros N, Skarlos D, Christodoulou C, Kosmidis P, Pavlidis N; Hellenic Cooperative Oncology Group. Carboplatin plus paclitaxel in unknown primary carcinoma: a phase II Hellenic Cooperative Oncology Group Study. J Clin Oncol. 2000 Sep;18(17):3101-7. link to original article contains dosing details in manuscript PubMed
2. Hayashi H, Kurata T, Takiguchi Y, Arai M, Takeda K, Akiyoshi K, Matsumoto K, Onoe T, Mukai H, Matsubara N, Minami H, Toyoda M, Onozawa Y, Ono A, Fujita Y, Sakai K, Koh Y, Takeuchi A, Ohashi Y, Nishio K, Nakagawa K. Randomized Phase II Trial Comparing Site-Specific Treatment Based on Gene Expression Profiling With Carboplatin and Paclitaxel for Patients With Cancer of Unknown Primary Site. J Clin Oncol. 2019 Mar 1;37(7):570-579. Epub 2019 Jan 17. link to original article contains dosing details in manuscript PubMed

Cisplatin monotherapy

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Gross-Goupil et al. 2012 (GEFCAPI 02)	2003-2007	Randomized Phase 2 (C)	Cisplatin & Gemcitabine	Did not meet primary endpoint of OS

Note: to our knowledge, this regimen was not tested as an experimental arm in an RCT in this context, prior to becoming a standard comparator arm.

Chemotherapy

• Cisplatin (Platinol) 100 mg/m² IV once on day 1

21-day cycles

References

1. GEFCAPI 02: Gross-Goupil M, Fourcade A, Blot E, Penel N, Négrier S, Culine S, Chaigneau L, Lesimple T, Priou F, Lortholary A, Kaminsky MC, Provencal J, Voog E, Bouzy J, Laplanche A, Fizazi K. Cisplatin alone or combined with gemcitabine in carcinomas of unknown primary: results of the randomised GEFCAPI 02 trial. Eur J Cancer. 2012 Mar;48(5):721-7. Epub 2012 Feb 6. link to original article contains dosing details in manuscript PubMed NCT00126269

Cisplatin & Docetaxel (DC)

Regimen

Study	Evidence
Greco et al. 2000	Phase 2

Chemotherapy

• Cisplatin (Platinol) 75 mg/m² IV over 60 minutes once on day 1
• Docetaxel (Taxotere) 75 mg/m² IV over 60 minutes once on day 1

Supportive therapy

• Dexamethasone (Decadron) 8 mg PO twice per day on days -1 to 2
  • Suggested: 20 mg IV once on day 1; 15 minutes prior to cisplatin
• 2 liters of normal saline with chemotherapy
• One of the following serotonin 5-HT3 antagonists:
  • Ondansetron (Zofran) 32 mg IV once on day 1; 15 minutes prior to cisplatin
  • Granisetron 10 mcg/kg IV once on day 1; 15 minutes prior to cisplatin
• Ondansetron (Zofran) 8 mg PO three times per day on days 2 to 6

21-day cycle for up to 8 cycles

References

1. Greco FA, Erland JB, Morrissey LH, Burris HA 3rd, Hermann RC, Steis R, Thompson D, Gray J, Hainsworth JD. Carcinoma of unknown primary site: phase II trials with docetaxel plus cisplatin or carboplatin. Ann Oncol. 2000 Feb;11(2):211-5. link to original article contains dosing details in manuscript PubMed

Cisplatin & Gemcitabine (GC)

GC: Gemcitabine & Cisplatin

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Culine et al. 2003 (GEFCAPI 01)	1999-2000	Randomized Phase 2 (E-switch-ic)	Cisplatin & Irinotecan	Not reported
Gross-Goupil et al. 2012 (GEFCAPI 02)	2003-2007	Randomized Phase 2 (E-esc)	Cisplatin	Did not meet primary endpoint of OS

Chemotherapy

• Cisplatin (Platinol) 100 mg/m² IV once on day 1
• Gemcitabine (Gemzar) 1250 mg/m² IV once per day on days 1 & 8

21-day cycles

References

1. GEFCAPI 01: Culine S, Lortholary A, Voigt JJ, Bugat R, Théodore C, Priou F, Kaminsky MC, Lesimple T, Pivot X, Coudert B, Douillard JY, Merrouche Y, Allouache J, Goupil A, Négrier S, Viala J, Petrow P, Bouzy J, Laplanche A, Fizazi K; Trial for the French Study Group on Carcinomas of Unknown Primary (GEFCAPI 01). Cisplatin in combination with either gemcitabine or irinotecan in carcinomas of unknown primary site: results of a randomized phase II study--trial for the French Study Group on Carcinomas of Unknown Primary (GEFCAPI 01). J Clin Oncol. 2003 Sep 15;21(18):3479-82. link to original article contains dosing details in manuscript PubMed content property of HemOnc.org
2. GEFCAPI 02: Gross-Goupil M, Fourcade A, Blot E, Penel N, Négrier S, Culine S, Chaigneau L, Lesimple T, Priou F, Lortholary A, Kaminsky MC, Provencal J, Voog E, Bouzy J, Laplanche A, Fizazi K. Cisplatin alone or combined with gemcitabine in carcinomas of unknown primary: results of the randomised GEFCAPI 02 trial. Eur J Cancer. 2012 Mar;48(5):721-7. Epub 2012 Feb 6. link to original article contains dosing details in manuscript PubMed NCT00126269

Cisplatin & Irinotecan (IC)

IC: Irinotecan & Cisplatin

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Culine et al. 2003 (GEFCAPI 01)	1999-2000	Randomized Phase 2 (E-switch-ic)	Cisplatin & Gemcitabine	Not reported

Chemotherapy

• Cisplatin (Platinol) 80 mg/m² IV once on day 1
• Irinotecan (Camptosar) 150 mg/m² IV once on day 1

21-day cycles

References

1. GEFCAPI 01: Culine S, Lortholary A, Voigt JJ, Bugat R, Théodore C, Priou F, Kaminsky MC, Lesimple T, Pivot X, Coudert B, Douillard JY, Merrouche Y, Allouache J, Goupil A, Négrier S, Viala J, Petrow P, Bouzy J, Laplanche A, Fizazi K; Trial for the French Study Group on Carcinomas of Unknown Primary (GEFCAPI 01). Cisplatin in combination with either gemcitabine or irinotecan in carcinomas of unknown primary site: results of a randomized phase II study--trial for the French Study Group on Carcinomas of Unknown Primary (GEFCAPI 01). J Clin Oncol. 2003 Sep 15;21(18):3479-82. link to original article contains dosing details in manuscript PubMed

DCF

DCF: Docetaxel, Cisplatin, Fluorouracil

Regimen

Note: Various guidelines list this as a suitable regimen in this setting, but we are not aware of any specific protocols for this setting.

Chemotherapy

• Docetaxel (Taxotere) 75 mg/m² IV once on day 1
• Cisplatin (Platinol) 75 mg/m² IV once on day 1
• Fluorouracil (5-FU) 750 mg/m²/day IV continuous infusion over 120 hours, started on day 1 (total dose per cycle: 3750 mg/m²)

Supportive therapy

• 1 liter normal saline before and after cisplatin +/- mannitol, potassium chloride, magnesium sulfate
• Dexamethasone (Decadron) 8 mg PO once per day the day before, the day of, and day after chemotherapy
• Ciprofloxacin (Cipro) 1000 mg PO (reference did not specify, but assume 500 mg twice per day) on days 5 to 15

21-day cycle for 3 cycles

References

1. None that we are aware of

Docetaxel & Gemcitabine

Regimen

Study	Evidence
Pouessel et al. 2004	Phase 2

Chemotherapy

• Docetaxel (Taxotere) 75 mg/m² IV over 60 minutes once on day 8
• Gemcitabine (Gemzar) 1000 mg/m² IV over 30 minutes once per day on days 1 & 8

Supportive therapy

• Corticosteroids PO the day before, the day of, and day after docetaxel

21-day cycle for up to 6 cycles

References

1. Pouessel D, Culine S, Becht C, Ychou M, Romieu G, Fabbro M, Cupissol D, Pinguet F. Gemcitabine and docetaxel as front-line chemotherapy in patients with carcinoma of an unknown primary site. Cancer. 2004 Mar 15;100(6):1257-61. link to original article contains dosing details in manuscript PubMed

Erlotinib & Bevacizumab

Regimen

Study	Evidence
Hainsworth et al. 2007a	Phase 2

Targeted therapy

• Erlotinib (Tarceva) 150 mg PO once per day on days 1 to 28
• Bevacizumab (Avastin) 10 mg/kg IV once per day on days 1 & 15
  • Infusion time is 90 minutes for the first dose, then if tolerated, 60 minutes for the second dose, and 30 minutes for the third dose and later

28-day cycles

References

1. Hainsworth JD, Spigel DR, Farley C, Thompson DS, Shipley DL, Greco FA; Minnie Pearl Cancer Research Network. Phase II trial of bevacizumab and erlotinib in carcinomas of unknown primary site: the Minnie Pearl Cancer Research Network. J Clin Oncol. 2007 May 1;25(13):1747-52. link to original article contains dosing details in manuscript PubMed

Gemcitabine & Irinotecan

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Hainsworth et al. 2010 (SCRI UNKPRI 12)	2003-2008	Phase 3 (E-switch-ic)	PCE	Did not meet primary endpoint of OS24

Chemotherapy

• Gemcitabine (Gemzar) 1000 mg/m² IV once per day on days 1 & 8
• Irinotecan (Camptosar) 100 mg/m² IV once per day on days 1 & 8

21-day cycle for up to 6 cycles

References

1. SCRI UNKPRI 12: Hainsworth JD, Spigel DR, Clark BL, Shipley D, Thompson DS, Farley C, West-Osterfield K, Lane CM, Cescon T, Bury MJ, Greco FA. 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. Cancer J. 2010 Jan-Feb;16(1):70-5. link to original article PubMed NCT00193596

Nivolumab monotherapy

Regimen

Study	Dates of enrollment	Evidence
Tanizaki et al. 2021	2018-02-19 to 2019-08-09	Phase 2 (RT)

Note: This was the trial supporting PMDA approval for this indication.

Immunotherapy

• Nivolumab (Opdivo) 240 mg IV once on day 1

14-day cycle for up to 52 cycles (2 years)

References

1. Tanizaki J, Yonemori K, Akiyoshi K, Minami H, Ueda H, Takiguchi Y, Miura Y, Segawa Y, Takahashi S, Iwamoto Y, Kidera Y, Fukuoka K, Ito A, Chiba Y, Sakai K, Nishio K, Nakagawa K, Hayashi H. Open-label phase II study of the efficacy of nivolumab for cancer of unknown primary. Ann Oncol. 2022 Feb;33(2):216-226. Epub 2021 Nov 26. link to original article PubMed UMIN000030649

PCE

PCE: Paclitaxel, Carboplatin, Etoposide

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Greco et al. 2000a	1995-1996	Phase 2
Hainsworth et al. 2010 (SCRI UNKPRI 12)	2003-2008	Phase 3 (E-switch-ic)	Gemcitabine & Irinotecan	Did not meet primary endpoint of OS24

Chemotherapy

• Paclitaxel (Taxol) 200 mg/m² IV over 60 minutes once on day 1
• Carboplatin (Paraplatin) AUC 6 IV over 20 to 30 minutes once on day 1
• Etoposide (Vepesid) as follows:
  • Days 1, 3, 5, 7, 9: 50 mg PO once per day
  • Days 2, 4, 6, 8, 10: 100 mg PO once per day

Supportive therapy

• Dexamethasone (Decadron) 20 mg PO for two doses, 12 hours and 4 hours prior to paclitaxel
• Dexamethasone (Decadron) 20 mg IV once on day 1; 30 minutes prior to paclitaxel
• Diphenhydramine (Benadryl) 50 mg IV once on day 1; 30 minutes prior to paclitaxel
• Cimetidine (Tagamet) 300 mg IV once on day 1; 30 minutes prior to paclitaxel

21-day cycle for 4 to 8 cycles

References

1. Greco FA, Burris HA 3rd, Erland JB, Gray JR, Kalman LA, Schreeder MT, Hainsworth JD. Carcinoma of unknown primary site. Cancer. 2000 Dec 15;89(12):2655-60. link to original article contains dosing details in manuscript PubMed
2. SCRI UNKPRI 12: Hainsworth JD, Spigel DR, Clark BL, Shipley D, Thompson DS, Farley C, West-Osterfield K, Lane CM, Cescon T, Bury MJ, Greco FA. 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. Cancer J. 2010 Jan-Feb;16(1):70-5. link to original article PubMed NCT00193596

PCF

PCF: Paclitaxel, Cisplatin, Fluorouracil

Regimen

Note: Various guidelines list this as a suitable regimen in this setting, but we are not aware of any specific protocols for this setting.

Chemotherapy

• Paclitaxel (Taxol) 175 mg/m² IV over 3 hours once on day 1
• Cisplatin (Platinol) 100 mg/m² IV once on day 2
• Fluorouracil (5-FU) 500 mg/m²/day IV continuous infusion over 120 hours, started on day 2 (total dose per cycle: 2500 mg/m²)

21-day cycle for 3 cycles

References

1. None that we are aware of