Răspuns terapeutic promiţător la imunoterapie într-un carcinom nazofaringian metastazat asociat cu hepatită virală C – caz clinic

Introduction

Nasopharyngeal carcinoma is originating in the epi­the­lial cells of the nasopharynx.

In 1921, the German pathologist Alexander Schminke along with the French radiologist Claude Regaud pu­b­lished the first paper on this hystology, described as a distinct entity from other types of throat cancers⁽¹⁾.

In 2020, the International Agency for Research on Can­cer announced approximately 133,354 new cases of nasopharyngeal carcinoma, with higher incidence in males, and a ratio of about 2.6 in worldwide statistics. In the overall population, the peak incidence occurs be­t­ween 50 and 60 years old.

There is an unbalanced glo­bal distribution, and South-Eastern Asia is an en­de­mic re­gion, with 85.2% of the to­tal new cases⁽²⁾.

The World Health Organization (WHO) classified in 2005 nasopharyngeal carcinoma into three main patho­lo­gical subtypes: keratinising squamous cell carcinoma, non­ke­ra­tinising carcinoma, and basaloid squamous cell carci­noma⁽³⁾.

The most important risk factors associated with nasopharyngeal carcinoma include host genetics, en­viron­mental factors, and Epstein-Barr virus infection.

Epstein-Barr virus is almost always present in na­so­pha­ryngeal cancers, being correlated with a poor prog­no­sis and highly associated with nonkeratinizing car­ci­no­ma.

Several epidemiological studies suggested a positive association between nasopharyngeal carcinoma and the consumption of preserved food and salted fish, poor oral health, and active or passive tobacco smo­king. Moreover, people with a family history of naso­pha­ryn­geal carcinoma present a significantly higher risk of de­ve­lo­ping nasopharyngeal cancer^(4-6).

This present report describes the treatment and evolution of a 25-year-old patient with metastatic nasopharyngeal carcinoma

Case report

A 25-year-old male, former smoker, with chronic hepatitis C virus infection and no oncological family history, was admitted to the “Elias” University Emer­gen­cy Hospital, Bucharest, at the end of 2017.

His medical background presented a nasopharyngeal carcinoma diagnosed by endoscopic biopsy in July 2017. The histology report confirmed poorly differentiated nonkeratinizing squamous cell nasopharyngeal carcinoma, clinically staged T4N2M0, stage IV according to the fifth edition of the American Joint Committee on Cancer. The CT scan showed a left-sided mass in the nasopharynx, with skull base invasion and extension into the left carotid space, left ethmoid and sinus, and supracentimetric left and right laterocervical lymph node metastasis.

The patient received three courses of concurrent chemotherapy with cisplatin and external radiotherapy, with a total dose of 48.6 Gy, between September and October 2017. After definitive chemoradiotherapy, he underwent flexible fiberoptic pharyngoscopy which revealed no tumor mass, but diagnosed grade III radiation induced mucositis. A hole-body CT scan and bone scintigraphy showed no metastasis.

The definitive chemoradiotherapy was followed by adjuvant systemic therapy with cisplatin and 5-fluorouracil, with a total of six cycles.

At the end of adjuvant chemotherapy, cerebral and cervical MRI showed nasopharyngeal asymmetry with focal thickening of the right-side wall with Rosenmüller fossa obstruction and enhanced contrast at this level. Chest CT scan was also conducted and did not reveal any metastasis. Given the nasopharyngeal location of the tumor and its frequent association with metastatic spread, it was agreed that PET-CT should be performed. This was done at the end of April 2018 and showed residual metabolic activity in the cavum, along with metabolically active bone lesions in the L2-L4 vertebrae.

Unfortunately, after the PET-CT, the patient neglected his disease until August, when it was decided to perform a biopsy of a bone lesion that confirmed the imaging suspicion.

In August 2018, a total spine MRI showed rapidly di­sease progression with multiple bone metastases (T7, T8, L2, L3, L4, L5), a circumferential paravertebral tu­mor in the L2-L4 area with intracanalar invasion and sig­ni­fi­cant compression of the filum terminale roots and a left iliac bone metastasis. Bone metastasis had a profound negative impact on the patients’ quality of life, determining important pain and spinal cord com­pres­sion.
 

To complete the assessment, it was performed a CT scan of the chest, abdomen and pelvis, that showed mul­tiple lung, liver, lymph nodes, retroperitoneal and bone metastases, resulting in further oncological pro­gression.

A neurosurgeon’s opinion was also requested, stating that there is no indication for surgery. The tumor board de­ci­ded to initiate palliative therapy with gemcitabine, cis­platin and zoledronic acid. Moreover, external radio­the­rapy was performed in the areas of L3-L4 vertebrae, with a total dose of 16 Gy.

The imaging after 12 courses of chemotherapy showed, in June 2019, a clear numeric and dimensional re­gres­sion of the pulmonary, hepatic and lymphatic me­ta­sta­ses, but the osteolytic lesions seen on the last CT scan were now described as blastic metastases.

The patient had no history of viral infection, but when elevated transaminases were discovered, a he­pa­­ti­­tis serology was performed, with the detection of he­pa­titis C virus antibodies. Hepatitis cytolysis re­quired the suspension from the oncologic treatment for ap­pro­xi­ma­tively five months.

After this delay, the tumor board decided to re­chal­lenge with gemcitabine and cisplatin, because the patient did not progress while receiving chemotherapy.

After seven courses of rechallenge therapy, the ima­gis­tic assessment demonstrated progressive lymphatic, he­pa­tic and pulmonary metastases, whithout visceral cri­sis.
 

Thus, the tumor board decided the initiation of nivolumab flat dose (240 mg) q2w, until disease pro­gres­sion or unacceptable toxicity. After three admi­nis­tra­tions, the patient developed progressive fatigue. A screening evaluation for immunotherapy-induced en­do­cri­nopathies was made, and a diagnosis of clinical pri­mary hypothyroidism was established, managed by an endocrinology specialist who recommended sub­sti­tu­tion therapy with levothyroxine 125 mcg daily. Im­mu­no­therapy was not interrupted in the meanwhile.

The next imagistic assessment demonstrated par­tial response to immunotherapy, with dimensional regres­sion of the pulmonary and lymphatic metastases.

The therapy was continued until the patient developed grade II transaminitis (acording to CTCAE criteria) caused by hepatitis C virus reactivation, with enhanced HCV-RNA viral load.

Thus, the treatment was interruped until liver en­zymes normalized. 

At present, the patient receives nivolumab, which he tolerates well, with good performance status (ECOG 1), 39 months after starting the initial treatment.

Discussion

Nasopharyngeal carcinoma has a distinct profile com­pared to other head and neck cancers, in terms of geo­gra­phical distribution, histopathological subtypes and na­tural history.

Though rare among Europeans, nasopharyngeal car­ci­noma is particularly frequent in young adults, and the nonkeratinizing and undifferentiated subtypes are the most common.

This type of cancer is strongly associated with Ep­stein-Barr virus, but both environmental conditions and genetic predisposition play essential pathological roles^(7,8).

A review of young patients (25 years old or younger) with nasopharyngeal carcinoma showed that 93% of the patients had advanced disease at the time of diagnosis.

But, despite the advanced presentation, in young pa­tients the overall prognosis is surprisingly good after the aggressive treatment with concurrent che­­mo­­ra­dio­therapy⁽⁹⁾.

Moreover, a study using recent data from the Sur­veil­lance, Epidemiology, and End Results (SEER) database, assessed the prognosis of patients youger than 30 years of age with nasopharyngeal cancer. Reaserchers showed that younger patients presented with more advanced tumor stages (74.5% stage III/IV versus 63.1% in older patients) and a worse pathological differentiation, but had a better prognosis (p<0.0001)⁽¹⁰⁾.

In nasopharyngeal carcinoma, the bone is the most com­mon site of metastatic disease⁽¹¹⁾.

Data have shown that the median overall survival in patients diagnosed with metastatic stages is between 10 months to 20 months. But metastasis confined to the bones were associated with longer survival compared to hepatic involvement^(12-14).

There are also studies indicating that the incidence of metastases and disease progression may be attributed to the differences in the histopathological patterns. Indeed, patients with nonkeratinizing or undifferentiated carcinomas present a higher risk of early metastases and local advanced tumors at diagnosis, compared to kera­tinizing cancers^(15,16).

As a former smoker, our patient associated an in­creased risk of cancer, but he had no history of alcohol con­sump­tion, human papillomavirus or Epstein-Barr virus infections.

He survived for 39 months from the time the meta­sta­tic disease was first diagnosed.

Curative chemoradiotherapy followed by adjuvant sistemic therapy offered a good control of the primary lesion, but bone metastases rapidly occured. Therefore, palliative chemotherapy was needed.

After multiple relapses on platinum-based regimens, the next available category of drugs were the immune checkpoint inhibitors (nivolumab).

In 2016, FDA approved nivolumab for the treatment of recurrent or metastatic squamous cell carcinoma of the head and neck that is refractory to platinum-based therapy, based on the CheckMate-141 phase III trial. In this study, nivolumab conferred clinical benefit, with higher overall survival (7.5 months versus 5.1 months) and fewer severe side effects (13.1% versus 35.1%), compared with patients treated with cetuximab, docetaxel or metrotrexate⁽¹⁷⁾.

Unfortunately, patients with nasopharingeal car­ci­no­mas were excluded from this trial.

Reconsidering the management of patients with na­so­pha­ringeal carcinoma, a recent subanalysis of the CheckMate-141 study evaluated the efficacy of nivo­lumab in cancer subtypes that were not included in the trial. Compared to histological subtypes assessed in CheckMate-141, in nasopharynx, nivolumab pro­vi­ded similar overall survival and progression-free sur­vival⁽¹⁸⁾.

Another important aspect of our case is represented by the chronic hepatitis C virus infection.

Unfortunately, our patient experienced a significant in­crease in ALT and AST levels, that required the dis­con­ti­nuation of chemotherapy. The hepatitis C virus re­ac­tivation negatively impacted the patients’ oncologic out­comes, with a delay in treatment and disease pro­gres­sion.

The oncological patients with viral hepatitis were frequen­tly excluded from immune checkpoint inhibitors trials, due to the immune-related toxicities and the risk of viral re­ac­ti­vation⁽¹⁹⁾.

In support, some recent studies showed the efficacy of immunotherapy in cancers associated with chronic hepatitis.

Studies evaluating HCV infected patients treated with PD-1 blockade established that nivolumab may po­ten­tially increase the production of specific CD8+ T cells and suppress the virus replication⁽²⁰⁾.

Cancer cells, such as chronic infections too, develop a mechanism to induce the exhaustion of the CD8+ T cells, in order to escape the immune destruction.

Specific CD8+ T cells are expressing high levels of PD1 (programmed death-1) and CTLA4 (cytotoxic T lym­pho­cyte antigen-4) molecules. Therefore, blocking these molecules can enhance the antiviral reaction and the immune responses⁽²¹⁾.

Interestingly, in the CheckMate 040 trial, immune check­point inhibitors demonstrated low antiviral ac­ti­v­i­ty in some hepatitis C infected patients, with transitory re­duc­tion in HCV RNA⁽²²⁾.

In 2020, Pei-Chang Lee and collegues suggested that immune checkpoint inhibitors (nivolumab or pem­bro­li­zumab) were safe and not a contraindication in the treat­ment of advanced hepatocarcinoma and VHB infection. From 62 patients enrolled in this study, there were no HBV reactivations during this therapy⁽²³⁾.

Another recent review, from 2020, supports the use of immune checkpoint inhibitors in hepatitis virus C or B infected patients with advanced cancer. The re­sults showed that viral infection did not particularly im­pact the effect of immune checkpoint inhibitors, and it should not be an obstacle for patients to receive im­mu­no­therapy⁽²⁴⁾.

Moreover, the CheckMate 459 phase III trial, pre­sen­ted at the Virtual ESMO World Congress on Gas­tro­in­tes­tinal Cancer 2020, supported the use of nivolumab, compared with sorafenib, in the first-line therapy of advanced hepatocarcinoma among patients with he­pa­ti­tis C virus or B virus etiology (the overall survival was sig­ni­ficantly higher in the nivolumab arm compared to sora­fenib arm: 17.5 versus 12.7 months, HR 0.72, 95% CI, 0.51-1.02 for HCV; and 16.1 versus 10.4 months, HR 0.79, 95% CI, 0.59-1.07, for HBV)⁽²⁵⁾. In conclusion, HCV infec­tion is not a contraindication for immunotherapy, being an efficient regimen in hepatitis C virus induced hepa­to­carcinoma.

Furthermore, a retrospective study demonstrated the safety and efficacy of nivolumab in hepatitis C infected patients with metastatic renal cell carcinoma, compared to noninfected subjects. Nivolumab was well tolerated, with no unexpected toxicity, and the increased levels of transaminases were more likely associated with autoimmune adverse events, because these patients had a stable viral load. Due to similarities of immune al­te­rations in cancer and chronic hepatitis C infection, ni­volumab can be a mutually beneficial therapeutic stra­t­­egy to treat HCV infected cancer patients⁽²⁶⁾.

Conclusions

This case report highlights the eficacy of using nivo­lumab in nasopharyngeal carcinoma associated with chronic hepatitis C infection.

Even though there is a low level of evidence regarding  im­mune checkpoint inhibitors in patients with viral he­pa­titis, our patient presented a sustained therapeutic out­come and partial response after four months of immu­notherapy.

This potential antiviral benefit derived from check­point inhibitors needs to be further observed in our case.