Prolonged survival in adenocarcinoma of unknown primary treated with chemoradiotherapy

Discussion

CUP is divided into favorable and unfavorable subsets.¹ The favorable subset includes women with adenocarcinoma involving axillary lymph nodes, women with papillary adenocarcinoma of peritoneal cavity, and adenocarcinoma with a colon profile. The unfavorable subset includes moderate to poorly differentiated adenocarcinomas (64%) and undifferentiated tumors (36%). It involves the liver in 40% to 50% of the cases, followed by lymph nodes (35%), lungs (31%), bones (28%), and the brain (15%).^1,2,6 Although data suggest that CUP with lymph-node–only metastases generally fall into an unfavorable prognosis group, our patient’s survival and progression-free survival have been especially prolonged. Remarkably, our patient is still alive 44 months after the diagnosis.

The combined platinum–paclitaxel-based regimens are the treatment of choice in this unfavorable subset of CUP,^7,8 with patients showing 16% to 38% response rates and median overall survival times of 6.5 to 13 months.⁷ Platinum–gemcitabine combinations can also be used as an alternative first-line regimen, with an overall response rate of 55% and a median survival of 8 months.⁹ The addition of the targeted agents bevacizumab and erlotinib to the carboplatin–paclitaxel combination, followed by bevacizumab and erlotinib maintenance, has been shown to yield a median survival of 12.6 months but was not meaningfully superior to historical studies with chemotherapy alone.¹⁰

We chose the FOLFIRINOX regimen for our patient. Conroy and colleagues reported a notably improved survival of 11.1 months with that combination chemotherapy in patients with metastatic pancreatic cancer compared with 6.8 months with gemcitabine alone.⁵ Given the possible pancreatobiliary site of tumor origin on IHC, the lymph node pattern of spread, and the patient’s young age and robust performance status, we felt that this multiagent systemic therapy would offer the best chance of prolonged survival. FOLFIRINOX includes a platinum agent, oxaliplatin, and platinum agents are recommended to be included in chemotherapy combinations for CUP.^9,10 Although there is no data to suggest the superiority of a triplet regimen over a doublet regimen in a CUP, a triplet chemotherapy regimen may be considered in select cases.

There have been only a few reports showing the effectiveness of radiotherapy in the treatment of adenocarcinomas of unknown primary outside of the head and neck. Kubisch and colleagues have reported a case of a woman with hepatic adenocarcinoma of unknown primary that was treated with chemotherapy and surgery. Upon recurrence, the patient was then treated with selective internal radiation therapy (SIRT). She was still alive 3 years after diagnosis, and there had been no tumor relapse 21 months after SIRT.¹¹ Shiota and colleagues have reported a case of a mediastinal lymph node CUP that was treated with docetaxel and cisplatin with concurrent thoracic radiation therapy.¹² The patient remained free of symptoms without regrowth of the primary site 22 months after disease onset, and exploration of the body with enhanced and PET-CT scan showed no further abnormalities.

Other reports suggest that locoregional therapy such as surgery and radiation may be of benefit to select patients with CUP. A retrospective study by Löffler and colleagues reported that patients with a limited local involvement who received radical surgery had a median overall survival of 52.7 months compared with those who received radiation (median overall survival, 19.4 months) and those who received chemotherapy alone (median overall survival, 16 months).¹³ A case of a metastatic undifferentiated CUP also reported a long-term (>5 years), disease-free survivor after pancreaticoduodenectomy and systemic adjuvant chemotherapy.¹⁴

Our case further demonstrates that a multidisciplinary approach to CUP may lead to excellent clinical outcomes. Chemotherapy followed by chemoradiation in our patient increased local tumor control and survival. Our patient’s 44-month survival was superior to the historic 6.5- to 13-month median survival in CUP patients treated with chemotherapy alone. Consolidation chemoradiation treatment may therefore be a viable and more effective therapy in the treatment of adenocarcinoma of unknown primary, in which anatomical disease concentration is amenable to radiotherapy following control with systemic chemotherapy. Nevertheless, it is difficult to draw conclusions from select cases. Another case of mediastinal adenocarcinoma, favoring a colorectal primary but with no evidence of a primary lesion on endoscopy, had a poorer outcome than did our patient, with the cancer recurring 6 months after completion of chemotherapy, surgical excision, and adjuvant radiotherapy.¹⁵

Adenocarcinomas of unknown primary cases should involve management by a multidisciplinary team. Clinical trials incorporating locoregional therapies for CUP in addition to systemic therapy are warranted.