Managing recurrent/advanced oropharyngeal/oesophageal cancer with cetuximab-based regimens: A case series

Introduction

An overwhelming one out of every 10 Indians are likely to develop cancer through their lifetimes, and one out of 15 Indians could die of cancer.¹ Globally, head and neck cancer is the seventh leading cancer, and it ranks fifth in men.¹ Cancer of the oral cavity is significant as it is one of the three most common cancers in India.² According to the Indian National Cancer Registry Programme–2020, cancers of the lung, mouth, stomach, and oesophagus are frequent in men.³ The burden of oral/oesophageal cancer is high in the North-eastern and central regions of India.³ A high burden of head and neck cancer, particularly oral cancer, in men in India is related to tobacco use.¹

The location, size, and stage of the primary tumour determine the course of treatment.^2,4 In the early stages, the standard of care is surgery or radiation therapy combined with chemotherapy or cetuximab. Patients at high risk of locoregional recurrence need postoperative adjuvant treatment. The National Comprehensive Cancer Network recommends concurrent systemic and radiotherapy (RT).⁵ Concurrent chemotherapy is offered in patients with positive margins and extra-nodal extension.² Resectable or unresectable locoregional recurrence or second primary before RT can be treated with a trial of systemic therapy and RT. A clinical trial of cetuximab and concurrent RT is suggested for recurrent or persistent disease.

Cetuximab is an immunoglobulin G1 (IgG1) subclass monoclonal antibody, which acts by binding to the extracellular domain of the epidermal growth factor receptor (EGFR).⁶ It also induces antibody-dependent cellular cytotoxicity by enhancing the fragment crystallizable (Fc) region–Fc receptor (FcγR) contact between the effector cells (neutrophils, monocytes, dendritic cells, and eosinophils) and the cancer cells.^7,8 Compared to adjacent normal tissue, the expression of EGFR is higher in squamous cell carcinoma of the head and neck (HNSCC), including the oral cavity.^9,10 A high level of EGFR expression strongly correlates to tumor aggressiveness and poor survival. Hence treatment targeting EGFR is an ideal option as a molecular adjuvant therapy in head and neck cancer.^9,10 Several clinical trials in a setting of recurrent/metastatic HNSCC have reported using cetuximab with chemotherapy or RT. The addition of cetuximab to definitive RT improves survival. As cetuximab does not augment the acute toxicities of radiation, it can be considered in patients who cannot tolerate chemoradiation therapy. Evidence shows that cetuximab plus cisplatin monotherapy improves the prospect of objective response in the first-line therapy of recurrent or metastatic head and neck cancer.⁹ Hence cetuximab plus platinum-based chemotherapy is the standard of care in the first-line recurrent or metastatic HNSCC setting.¹¹ In this paper, we present a series of case reports on patients with recurrent/metastatic oropharyngeal/oesophageal cancer who received cetuximab along with other chemotherapies. We treated fourteen patients with docetaxel, cisplatin, cetuximab (TPEx) regimen; docetaxel, cisplatin, and 5-fluorouracil (DPF or TPF) plus cetuximab; or folinic acid, 5-fluorouracil and irinotecan (FOLFIRI) plus cetuximab.

Methods

Case reports

The profile of patients (10 men and four women) with oropharyngeal/oesophageal cancer treated in our clinic is depicted in Table 1. The youngest patient was 52 years, and the oldest was 71 years (mean age: 64.1±7.01 years). Four patients were diagnosed with tongue cancer (#1, #5, #9, and #10) and cancer of the oral cavity (patient #2, #3, #4, and #7). One patient each had cancer of the oesophagus and larynx, respectively. All the patients were alive when the data was extracted.

Patients #2 and #6 received only RT for primary cancer after surgical resection. Patients #1, #3, #4, #5 #7 and #8 received concurrent chemotherapy (cisplatin) and RT while patient #10 received RT and cetuximab (weekly). One patient (number 8) received TPEx as a second line of therapy after treatment failure with concomitant chemotherapy and RT for primary cancer.

Except for patients #2 and #6, all other patients received a TPEx regimen as a part of their treatment plan for recurrent/metastatic cancer (Table 2). The TPEx regimen comprised of doceAqualip (docetaxel) 20-40 mg, carboplatin 150 mg/cisplatin 20-40 mg, and cetuximab 400-700 mg (all given intravenously). For each cycle, these three drugs were administered on days 1, 8, and 15, and on day 22, only cetuximab was given.

Discussion

In this case series, we present the various regimens (TPEx, variations in TPEx, DPF plus cetuximab, FOLFIRI plus cetuximab, immunotherapy, immunotherapy with platinum-5-FU or methotrexate plus cetuximab) offered to patients with recurrent/advanced oropharyngeal/oesophageal cancer. All patients were treated with cetuximab (dose ranging from 10-20 mg/kg body weight).

Currently, cetuximab is the only anti-EGFR monoclonal antibody approved for use in local/regional advanced and recurrent or metastatic HNSCC.^12,13 All patients who completed six cycles or currently undergoing TPEx treatment were alive. In our experience, cetuximab is suited for treating recurrent/metastatic oropharyngeal/oesophageal cancer as all our patients were stable and compliant to therapy. One patient completed 10 cycles of TPEx; two patients completed six cycles of TPEx; two patients completed four cycles; three patients completed or were amid three cycles, and one patient completed one cycle. Only one patient (#3) stopped TPEx after four cycles due to financial constraints. In our study, TPEx was given either first-line or second-line therapy for recurrent and/or metastatic oropharyngeal/oesophageal cancer. The loading and maintenance dose of cetuximab used in our patients was similar to that used in the clinical trials.

The first-line standard of care for patients with recurrent or metastatic HNSCC was a six-cycle EXTREME regimen of cetuximab plus platinum-based chemotherapy with 5-fluorouracil followed by weekly cetuximab maintenance therapy. After that, the TPEx regimen was introduced as an alternative to the EXTREME regimen.^11,14 The 5-fluorouracil dosage for the EXTREME regimen was 4000 mg/m² on days 1 through 4, 100 mg/m² of cisplatin on Day 1, and 400 mg/m² of cetuximab on days 1, 8, and 15 (400 mg/m² on day 1 of the first cycle and 250 mg/m² weekly thereafter). Every 21 days, six cycles were given, then weekly 250 mg/m² cetuximab was given as maintenance treatment to manage the illness. Docetaxel 75 mg/m², cisplatin 75 mg/m², and cetuximab on days 1, 8, and 15 (400 mg/m² on day 1 of the first cycle and 250 mg/m² every other week) were the components of the TPEx regimen. Every 21 days, four cycles were performed with each cycle having systematic granulocyte colony-stimulating factor (G-CSF) support. The EXTREME regimen was demonstrated in patients with recurrent or metastatic HNSCC in real-life evidence studies such as the DIRECT, SOCCER, and ENCORE investigations.^15–17

When compared to the EXTREME regimen, the TPEx regimen reduced the amount of time patients were on chemotherapy while also dramatically reducing toxicity.¹⁸ Patients with locally progressed HNSCC (oropharynx, hypopharynx, or larynx without distant metastases; n=54) were treated in the phase II CSPOR HN01: ECRIPS study with cisplatin (75 mg/m²) and docetaxel (75 mg/m²) on day 1, repeated every three weeks for up to three sessions. Until the completion of RT, cetuximab was given in weekly dosages of 250 mg/m² starting on day 1 at a dose of 400 mg/m². Following the last docetaxel dose, radiotherapy (70 Gy/35 fr/7 w) was started. 72.2% of respondents responded altogether, and 90.7% of those survived three years. The success rate of the treatment was 76%; of the 50 patients (93%) who got weekly cetuximab and two sessions of TPEx (until radiation was finished), 41 (76%) finished radiotherapy. Therefore, other than the high frequency of febrile neutropenia, treatment compliance with TPEx followed by cetuximab and concurrent RT was satisfactory.¹⁹ In histologically-confirmed HNSCC with metastasis or recurrence inappropriate for locoregional curative therapy, the phase II GORTEC research assessed the effectiveness and safety of four cycles of TPEx, followed by maintenance with cetuximab every two weeks. The median overall survival and progression-free survival were 14 months and 6.2 months, respectively, and the objective response rate was 44.4%. Therefore, the TPEx regimen is a viable alternative for individuals with recurrent/metastatic HNSCC as a first-line therapy.²⁰ Patients whose recurrent or metastatic HNSCC was histologically verified and who were not candidates for curative therapy were randomised to the TPEx or EXTREME regimen in the GORTEC 2014-01 TPExtreme phase II research. The overall survival was comparable across the two groups at a median follow-up of 34.4 months (TPEx vs. EXTREME: median 14.5 months versus 13.4 months), however the TPEx regimen was linked to a positive safety profile. Despite the fact that the trial’s primary aim was not achieved (overall survival was 11% higher with TPEx versus EXTREME [non-significant]), TPEx had a good safety record.²¹

According to a published case report, a patient with the first recurrence of human papillomavirus positive stage IVA (T3N2bM0) adenocarcinoma of the glossotonsillar sulcus is unsuitable for locoregional curative treatment, and was treated with TPEx regimen followed by bimonthly cetuximab maintenance (500 mg/m²). After five months of maintenance therapy, the patient showed a complete clinical response, and progress-free survival was 25 months. Stereotactic irradiation, radiofrequency ablation, cetuximab, and paclitaxel were used to treat recurrences. The patient was alive for 11 years after the initial diagnosis of cancer.²² One of our patients showed proliferative growth over the larynx after one month of chemotherapy (cisplatin) and RT. We initiated treatment with TPEx. The patient was stable and completed the first cycle of treatment and underwent the second cycle of treatment.

One of our patients was treated with DPF and cetuximab. In the GORTEC 2000–2001 study, patients with larynx and hypopharynx cancer performed better on DPF than on cisplatin and 5-fluorouracil (PF) combinations. At a median follow-up of three years, the three-year actuarial larynx preservation rate was higher with DPF than PF (70.3% vs 57.5%). The absolute overall response was 20.8 higher with DPF than PF (80.0% versus 59.2%).²³ Although the study by Specenier et al. showed that DPF plus cetuximab led to unacceptable complications in patients with stage III/IV unresectable HNSCC,²⁴ we intended to explore this option in our patient with rare retromolar trigone cancer who metastasized after two years and seven months following wide local incision and RT. The patient completed only one dose of the first cycle. In the TREMPLIN study, Lefebvre et al. showed that sequential therapy with DPF followed by concurrent RT and cetuximab was better tolerated than concurrent RT and cisplatin with a similar larynx preservation rate three months after treatment in untreated patients with larynx or hypopharynx squamous cell carcinoma.²⁵ In this study, a higher proportion of patients treated with cetuximab were able to complete three cycles than those treated with cisplatin (71% versus 43%).²⁵ Fayette et al. confirmed the efficacy and tolerability of DPF induction therapy in locally advanced head and neck cancer and suggested a follow-up treatment with chemoradiation with either cisplatin or cetuximab. Further, Fayette et al. considered a combination of cisplatin, 5-fluorouracil, and cetuximab as a standard of care in metastatic head and neck cancer.²⁶

One patient with oesophageal cancer who metastasized after one year ten months following esophagectomy and RT was treated with a cycle of DPF, FOLFIRI, and weekly cetuximab for three weeks. The phase II FOLCETUX study evaluated the safety and efficacy of cetuximab in combination with FOLFIRI in patients with untreated advanced gastric or gastroesophageal junction adenocarcinoma. Patients were treated with cetuximab at an initial dose of 400 mg/m² followed by weekly doses of 250 mg/m², irinotecan 180 mg/m² on day 1, levo-folinic acid 100 mg/m² followed by 5-fluorouracil 400 mg/m² bolus and 600 mg/m² 22 h continuous infusion on days 1 and 2 (FOLFIRI regimen) every two weeks, for a maximum of 24 weeks. Cetuximab was given as maintenance therapy in those who showed complete response, partial response, and stable disease. The objective response rate was 44.1%, with an eight-month median time to progression. The median expected survival time was16 months as 55.3% of patients were alive at a median follow-up of 11 months.²⁷

One patient (#5) with tongue cancer who progressed on nivolumab was initiated with TPEx. Fusimi et al. showed that salvage therapy after nivolumab treatment improved the clinical outcomes in patients with recurrent/metastatic HNSCC.²⁸ Patients received cetuximab and paclitaxel (n=16), EXTREME regimen (n=4), or paclitaxel as salvage therapy. The median overall survival, median progression-free survival, and objective response rate in patients who received salvage therapy were 7.3 months, 2.3 months, and 36%, respectively. Compared to best supportive care, salvage therapy prolonged the overall survival and was associated with better clinical outcomes. Hence, we considered the TPEx regimen for patient #5. Patient #13 with tongue cancer, who had also progressed after DPF, nivolumab, and afatinib therapy, was treated with methotrexate and cetuximab. A phase Ib-randomized phase II study reported improvement in PFS without any increase in toxicity following treatment with methotrexate and cetuximab combination in R/M HNSCC-patients. The median PFS with methotrexate and cetuximab was 4.5 months versus 2 months with methotrexate (hazard ratio: 0.37; p=0.002). There was no difference in OS, toxicity, and quality of life between methotrexate and cetuximab combination and methotrexate monotherapy.²⁹ According to a retrospective study in non-resectable R/M HNSCC patients, cetuximab and methotrexate combination was considered as an option for palliative treatment for R/M HNSCC patients.³⁰

Patient #14 with buccal cavity cancer was initially treated with pembrolizumab + carboplatin + 5-FU; however, after two cycles, the patient was shifted to TPEx. Pembrolizumab is indicated in patients with recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) with disease progression on or after platinum-containing chemotherapy. As a single agent, pembrolizumab is approved for patients whose tumors express PD-L1 (combined positive score [CPS] ≥1). Pembrolizumab in combination with platinum and 5-FU was approved as first-line for use in all patients with metastatic or unresectable recurrent HNSCC.³¹

Patient #11 and #14 had received a few cycles of paclitaxel, carboplatin, and cetuximab. The CETMET Trial reported that the efficacy of cetuximab and paclitaxel/carboplatin was comparable to that of cetuximab and 5-FU/cisplatin or carboplatin. The PFS showed a strong trend towards superiority in cetuximab and paclitaxel/carboplatin compared to cetuximab and 5-FU/cisplatin or carboplatin. The former combination was reportedly less toxic than the latter combination, and hence cetuximab and paclitaxel/carboplatin was regarded as a promising treatment option for the first-line treatment of RM-HNSCC.³²

Conclusions

The EGFR pathway plays a crucial role in the tumorigenesis and progression of head and neck cancer. Cetuximab, a chimeric monoclonal IgG1 subclass monoclonal antibody, is the only drug approved for local/regional advanced and recurrent or metastatic HNSCC. Cetuximab has been studied in combination with several other chemotherapy agents and targeted therapies. The TPEx regimen has emerged as an alternate to the EXTREME regimen in recurrent/metastatic HNSCC. The treatment compliance of cetuximab in combination with DPF regimen is evident from the TREMPLIN study. The FOLCETUX study further provides evidence on the activity of cetuximab and FOLFIRI regimens in the oesophageal cancer setting.