Journal of Cancer Research and Practice

ORIGINAL ARTICLE
Year
: 2022  |  Volume : 9  |  Issue : 2  |  Page : 52--58

Bleeding complications and possible resistance patterns of anti-angiogenesis treatments in recurrent/metastatic head-and-neck squamous cell carcinoma – Reflections from a phase II study of pazopanib in recurrent/metastatic head-and-neck squamous cell carcinoma


Jo-Pai Chen1, Ruey-Long Hong2,  
1 Department of Oncology, National Taiwan University Hospital, Yunlin Branch, Yunlin, Taiwan
2 Department of Oncology, National Taiwan University Hospital, Taipei, Taiwan

Correspondence Address:
Dr. Ruey-Long Hong
Department of Oncology, National Taiwan University Hospital, No. 7, Chung-Shan S. Road, Taipei
Taiwan

Abstract

Background: Due to smoking, alcohol, and betel nut use, head-and-neck squamous cell carcinoma (HNSCC) is a serious public health problem in Taiwan. Materials and Methods: We performed a single-arm Phase II trial of pazopanib in patients with platinum-refractory recurrent or metastatic HNSCC in 2011. Results: We screened 43 patients in about 6 months. Thirty-three of the patients were excluded due to easy bleeding and vessel contact resulting from the advanced tumor status. The remaining ten patients were included in this study. An objective response was seen in one patient; six patients had clinical benefits, which was comparable with the outcomes of sorafenib or sunitinib in this patient group. Four patients experienced at least Grade 3 bleeding. The tumor response was usually seen in the central cavity; the rim of the cavity extended outside, reflecting peripheral invasion and future resistance. Conclusion: The early use of anti-angiogenesis treatments is necessary for better tumor control and to prevent bleeding and potential resistance. In future, vascular endothelial growth factor receptor and/or epidermal growth factor receptor tyrosine kinase inhibitors may be used in combination with immunotherapy to increase the clinical benefits and avoid the risk of hyperprogression.



How to cite this article:
Chen JP, Hong RL. Bleeding complications and possible resistance patterns of anti-angiogenesis treatments in recurrent/metastatic head-and-neck squamous cell carcinoma – Reflections from a phase II study of pazopanib in recurrent/metastatic head-and-neck squamous cell carcinoma.J Cancer Res Pract 2022;9:52-58


How to cite this URL:
Chen JP, Hong RL. Bleeding complications and possible resistance patterns of anti-angiogenesis treatments in recurrent/metastatic head-and-neck squamous cell carcinoma – Reflections from a phase II study of pazopanib in recurrent/metastatic head-and-neck squamous cell carcinoma. J Cancer Res Pract [serial online] 2022 [cited 2022 Dec 1 ];9:52-58
Available from: https://www.ejcrp.org/text.asp?2022/9/2/52/346411


Full Text



 Introduction



As smoking, alcohol, and betel nut use is quite common in Taiwan, head-and-neck squamous cell carcinoma (HNSCC) is a serious public health problem, with more than 6,000 new patients/year. Even with multiple treatment modalities, still half of all patients with HNSCC finally succumb to the diseases within 5 years. In recurrent or metastatic disease, conventional chemotherapy often only palliates symptoms but does not prolong overall survival. Adding cetuximab to cisplatin and 5-fluorouracil treatment has been shown to offer survival benefits (7–10 months in overall survival) compared with chemotherapy alone in frontline treatment.[1] EPF has been covered by the National Health Bureau for the first-line treatment since early 2017. Afatinib is used for the second-line treatment of recurrent or metastatic recurrent/metastatic (R/M) HNSCC, and it has been shown to provide a borderline significant benefit in progression-free survival. However, the absolute benefit has been reported to be only 0.7 months, and severe diarrhea is common.[2] Patients with p16-negative status, epidermal growth factor receptor (EGFR) amplification, low human epidermal growth factor receptor 3, and intact PTEN have been shown to have a greater clinical benefit. Excitingly, immune checkpoint inhibitors (anti-PD1 monoclonal antibody), such as nivolumab, have been shown to provide survival benefits over chemotherapy in the second-line treatment of R/M HNSCC; however, treatment is expensive.[3] Tumor and stromal PDL1 levels may be biomarkers, and investigations are warranted to identify more biomarkers. Immunotherapy has been shown to potentially be more beneficial in Asian patients and especially in Taiwan.[4],[5],[6] Tumor or stromal PDL1 status, PDL2, p16/human papillomavirus (HPV) status, smoking, mutational or neoantigen load, INDEL signatures or frameshift mutations, APOBEC signatures, MSI status, DNA damage response or copy number alterations, cell cycle control (MDM2/4 or CCND1 or CDK4/6), inflammation gene expression profiles, angiogenesis, vascular endothelial growth factor (VEGF)-C level, gene changes of extrinsic apoptosis, antigen presentation, innate immunity, stromal Treg/myeloid-derived suppressor cell (MDSC)/tumor-associated macrophages type 2, fecal microbiota, epigenetic modifications, dynamic changes of plasma Treg or PD1 + effector CD8 cells, and T-cell reinvigoration (Ki67 + PD1 + CD8 cells/tumor burden) may influence the effects of immunotherapy.[7],[8],[9],[10],[11]

Betel nut chewing causes inflammation of the mucosa in head-and-neck areas. Chronic inflammation initiates DNA damage, angiogenesis, and several kinds of signal transduction favoring early carcinogenesis.[12] In addition, HNSCCs often become large tumors with central necrosis contributing to hypoxia. Hypoxia induces further signals, such as increased expressions of VEGF, platelet-derived growth factor (PDGF), placental growth factor, and stromal growth factor.[13] Blocking these signals may be able to control refractory HNSCC.

Although subgroup analysis of the EXTREME study showed a greater benefit with EPF for oral cavity cancers, we previously found that EPF did not have a good response in the induction or R/M setting of oral cavity cancer caused by betel nut exposure in Taiwan compared with Western countries.[14],[15] The lower incidence of EGFR-dependent oncogenesis in oral cavity cancers in Taiwan is quite particular. Instead, a high response rate has been reported for bevacizumab (targeting VEGF) combined with PF in induction[16] and salvage settings (unpublished data); however, attention should be paid to bleeding, necrosis, and fistula formation. Bevacizumab with erlotinib[17] or bevacizumab combined with pemetrexed[18] has been associated with clinical benefits in the second-line setting of R/M HNSCC. However, the E1305 study comparing bevacizumab combined with chemotherapy alone in the first-line setting of R/M HNSCC showed no 5-year survival benefit,[19] although significantly improved response and progression-free survival rates with survival benefits were noted in the initial 4 years.

Multi-targeted VEGF tyrosine kinase inhibitors, such as sorafenib and sunitinib, have shown a disappointing overall response (below 10%) in cisplatin-refractory R/M HNSCC but a disease control rate of 40%–50%.[20],[21],[22],[23] In one trial of sunitinib, 10% of the patients had Grade 5 bleeding and 40% had skin ulcers and fistulas,[23] very similar to our experience (unpublished data). If the distance of the tumor from the carotid artery is below 0.5 cm, sunitinib should not be used, possibly due to PDFGR inhibition causing pericyte maturation arrest and rupture of fragile vessels.

Pazopanib is an active multi-targeted tyrosine kinase inhibitor, which blocks VEGF-A, B, C, and fibroblast growth factor (FGF) pathways and may suppress tumor angiogenesis and growth in HNSCC. For the first-line use of pazopanib in metastatic renal cell carcinoma, pazopanib has been shown to have similar efficacy but better toxicity profiles compared with sunitinib.[24] Our group planned a Phase II trial of pazopanib for cisplatin-refractory R/M HNSCC[25] due to the lack of standard treatments before 2010. However, this trial had some obstacles which we believe may be common in other anti-angiogenesis treatments in this patient group. We found that (1) bleeding complications are very common in heavily treated advanced R/M HNSCC, and anti-angiogenesis treatments may be contraindicated; (2) possible resistance mechanisms of anti-angiogenesis treatments were shown in special imaging patterns; and (3) earlier use of anti-angiogenesis treatments with novel combinations, such as chemotherapies, drugs modifying epithelial-mesenchymal transition (EMT), and immunotherapies, was warranted.

 Materials and Methods



We performed a single-arm Phase II trial of pazopanib (800 mg/day) in patients with platinum-refractory R/M HNSCC at National Taiwan University Hospital in 2011. The trial was registered at “ClinicalTrials.gov: NCT01377298-Pazopanib in patients with recurrent or metastatic HNSCC.” The trial was approved by the IRB of National Taiwan University Hospital, registered on June 21, 2011.

The inclusion criteria were as follows: (1) histologically confirmed HNSCC; (2) recurrent or metastatic setting, refractory to previous cisplatin, or carboplatin-based chemotherapy; (3) at least one measurable lesion (according to the RECIST v 1.1 criteria); (4) Eastern Cooperative Oncology Group performance status 0–2; (5) age >18 y/o, ≤70 y/o; (6) adequate bone marrow, hepatic, and renal functions as evidenced by the following: (a) absolute neutrophil count ≥1,500 cells/μL, platelet count ≥100,000 cells/μL, and hemoglobin ≥9 g/dL; (b) total bilirubin ≤1.5 × ULN and AST/ALT ≤3.0 × ULN; and (c) creatinine ≤1.5 mg/dL; and (7) patients who could provide written informed consent.

The exclusion criteria were as follows: (1) second malignancy; (2) locoregional recurrence amenable to definite surgery or further radiation treatment; (3) brain/meningeal metastasis with IICP or bone metastasis with spinal cord compression; (4) pregnancy or nursing women; (5) having received more than two prior lines of intravenous chemotherapy in a palliative setting; (6) having received anti-angiogenesis agents in a palliative setting; (7) having received chemotherapy or radiation therapy or surgery within the past 3 weeks; (8) patients with major systemic diseases making them unsuitable for systemic chemotherapy according to the clinicians' professional judgment; (9) mental status not fit for a clinical trial; (10) clinically significant gastrointestinal abnormalities that may have increased the risk of gastrointestinal bleeding including, but not limited to: (a) active peptic ulcer disease; (b) known intraluminal metastatic lesions with a risk of bleeding; (c) inflammatory bowel disease (e.g. ulcerative colitis or Crohn's disease) or other gastrointestinal conditions with an increased risk of perforation; and (d) history of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within 28 days prior to beginning the study treatment; (11) corrected QT interval >480 ms using Bazett's formula; (12) poorly controlled hypertension defined as systolic blood pressure ≥140 mmHg or diastolic blood pressure ≥90 mmHg; (13) concomitant diseases that may be aggravated by the investigational drugs including: (a) active or noncontrolled infection; (b) severe upper gastrointestinal bleeding; and (c) history of any one or more of the following cardiovascular conditions within the past 12 months: cardiac angioplasty or stenting, myocardial infarction, unstable angina, symptomatic peripheral vascular disease, and Class III or IV congestive heart failure, as defined by the New York Heart Association; (14) hemoptysis within 6 weeks of the first dose of pazopanib, prior major surgery within 4 weeks of the first dose of pazopanib, and the presence of any nonhealing wounds/fractures; and (15) tumors located within 0.5 cm of large blood vessels (such as internal/external carotid arteries, internal/external jugular veins, superior vena cava, subclavian artery/vein, ascending/descending aorta, pulmonary artery/vein, and mediastinal vessels).

Toxicity was recorded according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE), Version 4.0 published by National Cancer Institute (located in 9609 Medical Center Drive, Rockville, Maryland 20850, United States) on May 28, 2009 Initially, 43 patients were expected to be enrolled. Follow-up images after pazopanib were also examined for patterns of failure.

 Results



We screened 43 patients in about 6 months, of whom 10 were enrolled in the study. All patients were male, all had a history of smoking and drinking, and nine had a history of betel nut chewing. Three criteria were commonly met in R/M HNSCC: (1) hemoptysis within 6 weeks of the first dose of pazopanib; (2) presence of any nonhealing wounds; and (3) tumors located within 0.5 cm from large blood vessels (such as internal/external carotid arteries, internal/external jugular veins, superior vena cava, subclavian artery/vein, ascending/descending aorta, pulmonary artery/vein, and mediastinal vessels). Thirty-three of the 43 patients (77%) were excluded due to easy bleeding and vessel contact resulting from an advanced tumor status. Betel nut chewing can induce severe inflammation, local tissue destruction, regional huge masses, and queer metastatic sites. Many patients developed metastatic lesions in the pleura, pericardium, and mediastinum, and also locoregional lesions around carotid vessels causing unhealed fistulas or ulcers. Therefore, there was a high exclusion rate in this patient group due to concerns about bleeding complications.

Of the ten enrolled patients [Table 1], one had a partial response and five had stable disease; therefore, six patients had clinical benefits, which was comparable with the outcomes of sorafenib or sunitinib in this patient group. Two patients experienced severe fatal bleeding; one patient suffered from Grade 3 bleeding, and the other patient suffered from Grade 4 bleeding. The first of these patients had a partial response initially but then died from massive hemoptysis soon thereafter; therefore, this patient was not categorized as having a partial response. The other case of fatal bleeding also had massive hemoptysis (tumor progression and treatment effect were both likely). The third case of bleeding also occurred rapidly, with Grade 4 left lingual artery bleeding (tumor progression favored). This patient was stabilized by emergent transarterial embolization. One patient with stable disease initially and pulmonary cavity formation [Figure 1] finally had tumor progression and Grade 3 bleeding. Because of the high exclusion rate and severe bleeding complications, the trial was terminated early (from June 2011 to May 2013). {Table 1}{Figure 1}

Two oropharyngeal patients, with histories of smoking, alcohol, and betel nut exposure, were HPV negative. However, one had a partial response after pazopanib treatment, and the duration of response was 157 days; the other patient had a prolonged duration of stable disease for 450 days and survived for 2 years and 11 months after subsequent intra-arterial chemotherapy. Another gingival cancer patient had stable disease for 140 days under pazopanib, and his pazopanib dose was tapered to 400 mg/day due to repeated Grade 3 hand and foot syndrome. He then received bio-chemotherapy, afatinib, and erlotinib with everolimus and survived for 594 days.

The median duration of response in the evaluable patients was 112 days. The median progression-free survival was 82 days, and the median overall survival was 132 days. The image pattern of tumor response was usually central cavity or necrosis formation, typical of the effect of anti-angiogenesis treatments previously reported in the literature [Figure 1].[16],[17] However, the rim of the cavity after anti-angiogenesis treatments extended outside, possibly reflecting peripheral invasion, and finally led to future resistance [Figure 1].

 Discussion



Tumor bleeding is usually seen in the end-stage of R/M HNSCC, and it is always the cause of death. The risk of bleeding in our patient group (R/M HNSCC patients refractory to platinum) was very high (about 77%) in our screening process for enrollment into the anti-angiogenesis agent trial. The disease status at this stage was very advanced, which resulted in unpredictable bleeding events and death, and the risk for receiving anti-angiogenesis treatments was too high. The strict eligibility criteria in this advanced disease status were warranted. Therefore, the outcomes of these patients were even worse than usually expected, and further earlier interventions are urgently needed. Three of the four cases with at least Grade 3 bleeding had hemoptysis, and two died (one with an unconfirmed response); the other patient initially had stable disease with pulmonary cavity formation and finally had tumor progression with Grade 3 hemoptysis. Therefore, great vessel involvement in the head and neck is a risk factor for bleeding, and multiple lung lesions with cavity formation before or after pazopanib may be another important risk factor. In addition, peripheral invasion seen in our cases is a possible resistance pattern of anti-angiogenesis treatments, which may result from tumor invasion/migration signals and EMT. This phenomenon may further aggravate bleeding complications due to easy vessel rupture.

The treatment of HNSCC in Taiwan is still very challenging and may be related to betel nut use. Betel nut chewing has been reported to cause: (1) strong inflammation and angiogenesis; (2) strong invasion ad queer metastatic sites;[26] (3) easy recurrence or metastasis, usually accompanied with hypercalcemia; (4) poor response to chemotherapy and EGFR inhibitors;[14],[15] (5) relatively good response to VEGF inhibitors combined with chemotherapy;[16] and (6) difficult wound healing and repair. Novel mechanism-guided treatments in betel nut-related HNSCC in Taiwan are urgently needed. Molecular classification for betel nut-related HNSCC in Taiwan will also be needed for the development of further precision medicine.

In VGH studies in Taiwan, huge HNSCCs from betel nut chewing have frequently been reported to cause tumor central necrosis and hypoxia and to mediate the EMT through the upregulation of Twist, Snail, and Slug. Let7i would be suppressed, resulting in increased H-Ras/RAC activity and enhanced tumor migration. EMT signals and suppressed let7i would also induce body mass index-1 expression and cause tumor stemness. Acetylated Snail has been shown to confer cisplatin resistance and induce M2 polarization by upregulating exosomal miR-21. M2 polarization has been shown to lead to enhanced tumor angiogenesis and migration, while miR-21 has been shown to cause NLRP3 ubiquitination and poor inflammasome activity. Acetylated Snail and exosomal miR-21 may also increase tumor MDSC and Treg.[27],[28],[29],[30] Therefore, betel nut-related HNSCC in Taiwan may harbor possible resistance mechanisms to immunotherapy from strong angiogenesis and EMT. Targeting angiogenesis, EMT, and M2 polarization with immunotherapies may be important in this special phenotype.

Earlier combinations of anti-angiogenesis treatments with chemotherapy and immunotherapy, even in neoadjuvant settings, may result in greater benefits and enhance cure rates of definite surgery or CCRT in HNSCC, especially betel nut-related phenotype in Taiwan. This kind of earlier intervention could possibly avoid the EMT, bleeding, and treatment refractoriness in advanced settings. Anti-angiogenesis treatments in betel nut-related HNSCC in Taiwan in future may be introduced early in three situations. First, with neoadjuvant chemotherapy (even with immunotherapy in future) in huge borderline resectable T4bN3 oral cavity cancer, such as the APF regimen in our institute.[16] Second, with immunotherapy in relatively frontline recurrent or metastatic settings (such as multi-targeted lenvatinib, targeting VEGF receptor (VEGFR1/2/3), PDGFR, FGF receptor, c-kit, RET, and some other invasion signals, combined with pembrolizumab which have been shown to result in 41% response rate and over 90% disease control[31]) to increase clinical benefits and avoid fatal bleeding, fistulas, and necrosis if later-line use. A first-line randomized placebo-controlled study of lenvatinib combined with pembrolizumab has been initiated (LEAP-10).[32] Third, with the use of EGFR monoclonal antibodies, such as cetuximab, in R/M settings. A Phase 1b study of pazopanib plus cetuximab in R/M HNSCC reported a complete response of 6%, an objective response rate of 35%, and a disease control rate of 81%. In cetuximab- and cisplatin-naïve patients, an objective response rate of 55% was reported, compared to 25% in patients who failed cetuximab and 28% in patients who failed cisplatin.[33]

Besides the VEGFR pathway, EGFR inhibition may cause immune modulation and overcome tumor immune escape. In our retrospective analysis, afatinib (EGFR tyrosine kinase inhibitor) 40 mg/day with pembrolizumab 200 mg/3 weeks was given to 51 refractory recurrent or metastatic Taiwanese patients with HNSCC (afatinib 30 mg/day and pembrolizumab 100 mg/3 weeks in patients with poor KPS or who could not tolerate the original dosage).[34] The objective response rate was 55.8% and the disease control rate was 79%. The median duration of response was 7.5 months, the median PFS was 8.3 months, and the 1-year survival was 59.2%. Most patients only received four cycles of pembrolizumab, but a durable response was observed in the responders. The toxicity profiles were tolerable and manageable. The high therapeutic index of the combination of afatinib and pembrolizumab in betel nut-related HNSCC in Taiwan has already led to the opportunity to initiate a Phase II study to further investigate this regimen, and the ALPHA study has already begun.[35] The preliminary results of the ALPHA study in ASCO2021 showed an objective response rate of 41.4%, median progression-free survival of 4.1 months, and median overall survival of 8.4 months. High tumor PDL1 and EGFR amplification predicted a good response; MTAP loss or mutation predicted a poor response.[36] Besides, a study conducted by a Harvard group using a colon cancer model showed that EGFR TKIs (such as erlotinib and afatinib) could enhance CD8 cytolytic activity by increasing MHC/HLA/beta2-microglobulin expression, STAT1 activation, PDL1 suppression, STAT3 inhibition, and NKG2D/KIR modulation in a mouse model. The authors mentioned our clinical experiences of afatinib and pembrolizumab in HNSCC in their article.[37] Furthermore, EGFR was shown through M2 polarization to promote carcinogenesis in a hepatocellular carcinoma mouse model.[38] EGFR has also been shown to increase CTLA4 + Treg and MDSC and suppress dendritic cell maturation, natural killer cell tumor killing, and TIL infiltration in the tumor microenvironment.[39]

In this study, two oropharyngeal patients were HPV negative but had relatively good outcomes with a prolonged duration of response. Some patients had a long survival due to a relatively prolonged duration of response under pazopanib and subsequent treatments, such as intra-arterial bio-chemotherapy, afatinib, and erlotinib with everolimus. Immunotherapy was still not readily available during the study enrollment period. From 2011 to 2013, afatinib[40] and erlotinib with everolimus[41] were shown to have salvage efficacy under a cisplatin-refractory setting in early abstracts. Aggressive subsequent therapy for R/M HNSCC in Asia could also prolong survival in a recent immunotherapy trial.[5],[42]

 Conclusion



The early use of anti-angiogenesis treatments is necessary for better tumor control and to prevent bleeding and potential resistance. It may be combined with current immunotherapy regimens to enhance immune-mediated tumor killing. Furthermore, this combination may overcome potential resistance to immunotherapy by blocking profound angiogenesis and the EMT in betel nut-related HNSCC in Taiwan [Figure 2].{Figure 2}

In future, VEGFR and/or EGFR tyrosine kinase inhibitors may be used in combination with immunotherapy to increase clinical benefits and avoid the risk of hyperprogression.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

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