Patterns of Recurrence in Patients with Non-Metastatic Head and Neck Squamous Cell Cancer. Can Radiotherapy Interruptions Influence The Patients’ Prognosis?

Aims: To determine the impact of interruptions/suspensions of radiotherapy in relation to the stage and histopathological features in patients with Non-Metastatic Head and Neck Squamous Cell Cancer (NMHNSCC), undergoing chemotherapy and Intensity-Modulated Radiation Therapy (IMRT).

Materials and methods: We retrospectively analyzed patients with T3-T4 N+ NMHNSCC treated with IMRT in our department from January 2014 to December 2023, matching the following inclusion criteria: age > 18 years, availability of 18F-FDG CT/PET before and after the treatment, T3-4 N+ disease, adjuvant or exclusive Concurrent Chemoradiation Therapy (cCTRT) +/- Induction Chemotherapy (ICT). The patients were divided into two groups according to the nodal disease stage: Group A with limited (N1-N2b) and group B (N2c-N3) with extensive nodal involvement. Prescribed doses and Treatment volumes extension were determined according to international guidelines. Data concerning time of treatment, interruptions, dose prescriptions, sites of progression, and histopathological features were collected.

Results: A total of 107 eligible patients were collected. Median age was 68.6 years (range 53-78 years). Median time of follow-up 36.7 months (range 12-60 months).

Group A included 79 patients; of these, 62.02% (49) achieved a complete response, 12.66% (10) showed no response to treatment; 25.32% (20) showed loco-regional progression. Median End of Treatment Delay (EoTD) for patients experiencing recurrences was 9.05 days, being > 5 days in 85% (17) of them.

Group B included 28 patients. Of these, only 14.29% (4) achieved a complete metabolic response. 21.43% (6) showed no response to treatments. 60.71% (17) showed loco-regional progression.

Median EoTD for these patients experiencing pathologic relapses was 7.4 days, being > 5 days in 71.43% (20) of them. LC for all patients was 49.53% (53). Cumulative 1 year-PFS was 71.1%. Cumulative 3 years-PFS was 55.4%.

The PFS analysis was also performed in relation to patients’ HPV status confirming worse clinical outcomes in those with HPV-unrelated tumors.

Conclusion: This study shows the role of a correctly timed radiotherapy. It was also confirmed that patients, not achieving complete remission, experience disease progression in sites located outside the areas where higher radiation doses were delivered, but still included in the treatment field. Thus, patients with tumor progression after chemoradiation should be included in clinical trials testing immunotherapy, alone or combined with chemotherapy.

Head and Neck squamous cell carcinoma is the seventh most common tumor worldwide, being responsible of roughly 4.5% of cancer diagnoses and death [1]; it may involve different sites such as oral cavity, oropharynx hypopharynx, nasal cavity, nasopharynx and salivary glands.

Risk factors include alcohol and tabagism, Epstain Barr Virus (EBV), notoriously a negative prognostic factor for nasopharyngeal carcinoma [2] and Human Papilloma Virus (HPV), with HPV related tumors being more common in developed nations, confirming the importance of vaccinations on both genders [3] from an age of 11-12 and educational campaigns in favor of secure sexual practices.

Tumor staging generally implies the patient’s clinical examination, ORL assessment, radiological staging through MRI with gadolinium, Head-Neck-Thorax CT scan with iodine contrast enhancement [4] and 18F-FDG CT-PET scan. Treatment includes surgery for resectable, not-locally advanced tumors, Radiotherapy, as an exclusive approach for non-resectable tumors or as an adjuvant treatment within 4-6 weeks from surgery [5] for all the other cases, and chemotherapy, which may be employed in patients with locally advanced disease as a neoadjuvant approach for patients not directly eligible for surgery, in order to reduce the tumor burden or as an adjuvant approach consisting of Induction Chemotherapy (ICT) and/or Concurrent Chemoradiation (cCTRT).

Tumor recurrences and the importance of patients’ stratification

Despite the many different approaches at our disposal, local and nodal recurrences represent a critical aspect in the management of these patients, given the extreme biological and histopathological variability of these tumors.

Haring CT, et al. [6], by collecting the data of 447 patients that were treated in their department between 2008 and 2019, confirmed that most of recurrences occur within 2 years after the end of treatment. Besides that, they also underlined that current surveillance guidelines do not consider patient- and tumor-specific risk factors (tumor subsites, stage, and HPV status), which greatly affect treatment response and patterns of failure.

HPV proved a great importance as a positive prognostic factor in patients with HPV related-tumors resulting in better clinical outcomes (especially for oropharyngeal ones), if compared with unrelated tumors [7,8], to the point that some even proposed treatments de-intensification strategies for HPV positive patients [9]. The RTOG 1016 trial [10] compared the outcome of patients with HPV-related oropharyngeal cancer at stage III–IV (T1-2 N2-3 or T3-4 N0-3, according to the AJCC, 7th edition) treated with cisplatin or cetuximab; as expected, patients treated with cetuximab experienced lower grade toxicities. Unluckily, the study also showed that patients treated with cisplatin were associated with fewer failures in the radiation field than those treated with cetuximab.

Even though the de-intensification of the treatments showed contrasting results, it’s undeniable that a more accurate stratification of the patients according to the tumor biological features could help us establish the probability of eventual recurrences.

With the same intention, we tried to analyze the potential prognostic impact of factors more related to the therapy than to the pathology itself, as the time needed to carry out the RT course, which be different even for patients with the same kind of pathology, being it influenced by logistic factors, radio- and/or chemotherapy-related toxicities, and patients’ adherence, which other studies [11] proved to be also influenced by not tumor-related factors (i.e. socioeconomic ones). Specifically, we tried to determine if longer times of treatment could be associated with a worsening of patients’ outcome, in relation to the features of the disease (stage, involved sites, molecular expression and regimen of chemotherapy), by evaluating patients’ Progression Free Survival.

Inclusion criteria

We retrospectively analyzed NMHNSCC patients treated in our department from January 2014 to December 2023. The patients that were included in the study met the following criteria: age >18 years, availability of 18F-FDG CT/PET before and after the treatment [12], locally advanced (T3-4 N+) disease, treatment with adjuvant or exclusive cCTRT +/- iCT. They were divided into two groups according to the nodal disease stage: Group A with limited (N1-N2b) and Group B with extensive nodal disease (N2c-N3) (Table 1).

Table 1: Features and management of the eligible patients.

Radiotherapy Protocol: set-up, planning and treatment schedule

Radiotherapy was carried out, after proper set-up with CT scan and 5-point head, neck and shoulder thermoplastic mask for the immobilization of patients during the treatment [13]. Deformable Image Registration (DIR) of the centering CT images with those of 18F-FDG CT-PET (and MRI scans, when available) was also performed [14].

Intensity Modulated Radiation Therapy (IMRT) was carried out using an Elekta Synergy® Platform LINAC (linear accellerator), 6MV photons, daily Cone Beam CT (CBCT) to verify the patients’ setup [15] and the following prescription doses to the clinical target volumes, corresponding to those areas associated with variable risk of tumor relapse [16]: Low risk Clinical Target Volume (CTV1) receiving 54 Gy (1.8 Gy/fraction), intermediate risk Clinical Target Volume (CTV2) 60-62 Gy (2-2.07 Gy/fraction), gross nodal volume (GNV) corresponding to pathologically involved nodes receiving 63-66 Gy (2.1-2.2 Gy/fraction), Gross Tumor Volume (GTV) 66-69 Gy (2.2-2.3 Gy/ fraction).

Treatment volumes extension was decided according to DAHANCA guidelines [17].

Chemoradiation regimens

All the patients underwent cCTRT with one of the following schedules, in relation to age, comorbidities and tumor burden [18]: weekly Cisplatin (40 mg/mq for 6 cycles) or 3-weekly Cisplatin (100 mg/mq for 3 cycles).

ICT with TPF (docetaxel/cisplatin/5-FU) regimen was administered before cCTRT for those patients with HPV-unrelated Oropharyngeal Cancer (OPC) or EBV-related Nasopharyngeal Cancer (NPC), CT-PET detected high tumor burden and/or bilateral nodal involvement [19,20]. Weekly biochemical controls (for eventual CT-related toxicities) were performed.

Endpoints

For each patient, we collected the data regarding the time of treatment, eventual treatment interruptions and/or suspensions, prescribed doses to the target volumes, the sites of disease progression and tumor’s histopathological features.

Starting from an initial number of 336 patients, 107 eligible patients were selected. Median Male/ female patients ratio was 3:1. Patients’median age was 68.6 years (range 53-78 years). Median time of follow-up was 36.7 months (range 12-60 months).

Group A included 79 patients with N1-N2b nodal disease; End of Treatment Delay (EoTD), which is expressed by supplementary days required to carry out the treatment beyond an Overall Treatment Time (OTT) of 41 days (corresponding to a 6-weeks treatment schedule), ranged between 0 and 28 days; of these, 62,02% (49) achieved a complete metabolic response as showed by post-RT FDGPET scan, 12,66% (10) showed no response to treatment with 4 of them with oropharyngeal HPV unrelated tumors; 25,32% (20) experienced loco-regional progression showing pathology relapse inside the radiotherapy field, including 8 with HPV-unrelated oral cavity/oropharyngeal cancers and 1 with nasopharyngeal EBV-related cancer. Median dose delivered to the areas of recurrences was 56.71 Gy (range 54-63 Gy). Median EoTD for Group A patients experiencing recurrences was 9.05 days, being > 5 days in 85% (17) of them.

Group B included 28 patients with N2c-N3 nodal disease. Of these, only 14.29% (4) achieved a complete metabolic response, all of them without histological risk factors related to HPV/EBV status. 21.43% (6) showed no response to treatments including 3 patients with HPV-unrelated oropharyngeal cancers and 1 with EBV-related nasopharyngeal ones. 60.71% (17) showed locoregional progression in sites with median delivered. Radiation doses of 61.16 Gy (range 52-65.3 Gy). No updated data on the disease status are available for one patient (3.57%) of this group. Median EoTD for Group B patients experiencing recurrences was 7.4 days, being > 5 days in 71.43% (20) of them.

We then evaluated PFS in relation to EoTD in Group A and B; for both groups, EoTDs > 10 days are associated with Expected PoS reduction of 50% (Figure 1).

Figure 1: Estimated PoS in the two groups of patients, according to the observed EoTD.

No meaningful differences were observed in terms of radio-/chemo-induced toxicities between the two groups.

LC for all patients was 49.53% (53), including those who obtained a complete response or disease chronicity after chemoradiation (specifically, one for each group).

Cumulative 1 and 3 year-PFS were respectively 71.1% and 55.4% (Figure 2). 1 and 3 year-PFS respectively were 85.5% and 67.6% for Group A and 23.8% and 14.3% for Group B (Figure 3). Expected Probability of Survival (PoS) was 30% at 10 months in high risk patients vs., 90% in low risk patients.

Figure 2: Expected PoS in relation to cumulative progression free survival.

Figure 3: Comparative analysis of expected PoS in relation to progression free survival observed in the two groups.

Furtherly, we analyzed PFS in patients with oral cavity/oropharyngeal cancer in relation to HPV Status: 1-year PFS was 81.8% for HPV+ and 45.4% for HPV- patients (Figure 4). Expected 1-year PoS was 50% for HPV- patients (vs., 82% for HPV+ patients).

Figure 4: Comparative analysis of expected PoS in relation to progression free survival observed in patients with HPV-related and HPV-unrelated tumors.

Expected PoS with EoTD = 2 days was 77% in HPV- patients (vs., 100% in HPV+ patients) and EoTD = 6 days was 50% in HPV- patients (vs., 75% in HPV+ patients) (Figure 5).

Figure 5: Comparative analysis of expected PoS in relation the EoTD observed in patients with HPV-related and HPV-unrelated tumors.

The results we obtained confirmed the importance of a stratification of the patients in relation to tumor staging and biological features.

As showed in literature [21], approximately 50% of the patients with locally advanced NMHNSCC is bound to experience recurrences. Our analysis confirmed this result (LC 49.5%), leading us to a critical point: the need of making a correct stratification of patients with head neck cancers, right from diagnosis with the possibility of developing predictive algorithms for the prognostic outcomes of these patients.

Ang KK, et al. [22], in the RTOG 0129 study retrospectively analyzed 721 patients with IIIIV stage head and neck cancer and found a 3-year PFS of 73.7% and 43.4% in patients with HPV related and unrelated tumors, respectively (vs., 81.8% and 27.3% we actually obtained). The difference in the PFS values of the two studies could be related to the important numeric gap between the two populations (743 vs., 107) and the non-homogeneous management of the patients (different radiotherapy fractionations and chemotherapy regimens), still representing the only extensive study with these aims available in literature, for this specific class of patients.

Still, in both cases, HPV-unrelated cancers were associated with lower values in terms of PFS if compared with HPV-related ones.

This study, in concordance with prior analyses [23,24], also showed that a correctly delivered radiotherapy with no or few delays was associated with better outcomes in patients with locally advanced disease, being the first one to determine, a time cut-off beyond which an increase of recurrences can be observed in patients undergoing homogenous treatment courses in terms of administered doses and length of treatment schedule. It was also the first study to evaluate the administered dose to the sites of recurrences in this class of patients, with HPV-unrelated tumors being associated with worse results in terms of PFS, with EoTD ≥ 2 days.

The high incidence of recurrences proves that these tumors are not to be underestimated. Therefore, further therapeutic strategies should be considered.

The patients experiencing tumor progression, not having other therapeutic options, could benefit from the inclusion in clinical trials [25] concerning the employment of chemotherapy and/or immunotherapy, with the latter requiring the analysis of the tumor’s molecular profile, that should be preventively performed right after diagnosis, in order to reduce the time required for the start of the therapy (given the high growth rate of these tumors).

This study shows the role of a correctly timed radiotherapy without long delays, which could compromise the patients’ clinical outcome, being worse in patients with HPV-unrelated disease and high tumor burden. It was also confirmed that patients, not achieving complete remission, experience disease progression in sites located outside the GTV/GNV, but still included in the low/ intermediate risk CTVs (CTV1/2). Given the lack of further treatment options, patients undergoing tumor progression after chemoradiation should be included in clinical trials implying the use of immunotherapy, alone or combined with chemotherapy.

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