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

ESMO

• 2015: Fizazi et al. Cancers of unknown primary site: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up

Older

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

NCCN

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

All lines of therapy

BEP

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

Regimen

Study	Evidence
Hainsworth et al 1992	Phase II

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 verified protocol PubMed

Carboplatin & Docetaxel

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Regimen variant #1

Study	Evidence
Pentheroudakis et al. 2008	Phase II

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 medications

• 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
• Dimethindene maleate (Fenestil) 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 II

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 medications

• 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 verified protocol 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 verified protocol PubMed

Carboplatin & Paclitaxel (CP)

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Regimen

Study	Evidence
Briasoulis et al. 2000	Phase II
Hayashi et al. 2019	Phase II

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 medications

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
  • Dimethindene maleate (Fenestil) 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 verified protocol 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. link to original article contains verified protocol PubMed

Cisplatin monotherapy

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Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Gross-Goupil et al. 2012 (GEFCAPI 02)	2003-2007	Randomized Phase II (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 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 verified protocol PubMed NCT00126269

Cisplatin & Docetaxel (DC)

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Regimen

Study	Evidence
Greco et al. 2000	Phase II

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 medications

• 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 (Platinol)
• 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 (Platinol)
  • Granisetron 10 mcg/kg IV once on day 1; 15 minutes prior to Cisplatin (Platinol)
• 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 verified protocol PubMed

Cisplatin & Gemcitabine (GC)

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GC: Gemcitabine & Cisplatin

Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Culine et al. 2003 (GEFCAPI 01)	1999-2000	Randomized Phase II (E-switch-ic)	Cisplatin & Irinotecan	Not reported
Gross-Goupil et al. 2012 (GEFCAPI 02)	2003-2007	Randomized Phase II (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 verified protocol 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 verified protocol PubMed NCT00126269

Cisplatin & Irinotecan (IC)

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IC: Irinotecan & Cisplatin

Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Culine et al. 2003 (GEFCAPI 01)	1999-2000	Randomized Phase II (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 verified protocol PubMed

DCF

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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 medications

• 1 liter normal saline before and after Cisplatin (Platinol) +/- 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

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Regimen

Study	Evidence
Pouessel et al. 2004	Phase II

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 medications

• Corticosteroids PO the day before, the day of, and day after Docetaxel (Taxotere)

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 verified protocol PubMed

Erlotinib & Bevacizumab

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Regimen

Study	Evidence
Hainsworth et al. 2007a	Phase II

Targeted therapy

• Erlotinib (Tarceva) 150 mg PO on days 1 to 28, 1 hour before or 2 hours after meals
• 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 verified protocol PubMed

GCP

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GCP: Gemcitabine, Carboplatin, Paclitaxel

Regimen

Study	Evidence
Greco et al. 2002	Phase II

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 medications

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

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 verified protocol PubMed

Gemcitabine & Irinotecan

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Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Hainsworth et al. 2010	2003-2008	Phase III (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. 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

PCE

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PCE: Paclitaxel, Carboplatin, Etoposide

Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Greco et al. 2000a	1995-1996	Phase II
Hainsworth et al. 2010	2003-2008	Phase III (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 medications

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

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 verified protocol PubMed
2. 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

PCF

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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