Paclitaxel-Ifosfamide-based Therapy as Salvage Treatment in Platinum-resistant Recurrent/Metastatic Head and Neck Cancer

Abstract

Background

Treatment options are limited, and the prognosis is poor for patients with platinum-resistant recurrent metastatic (R/M) head and neck squamous cell carcinoma (HNSCC). This study evaluated the efficacy and safety of a paclitaxel and ifosfamide (TI) regimen in patients with R/M HNSCC whose disease had progressed following platinum-based therapy.

Patients and Methods

In this retrospective study, we included 53 patients with R/M HNSCC who underwent at least one cycle of TI-based therapy, post platinum failure, between February 2020 and August 2023. Some patients received the TI regimen in combination with immunotherapy and/or cetuximab. Key metrics assessed included the objective response rate (ORR), disease control rate, and progression-free as well as overall survival.

Results

The study observed an ORR of 15.8% and a disease control rate of 36.8%. The median progression-free survival for the entire cohort was 3.3 months, and the median overall survival was 9.6 months. Notably, the combination of TI with immunotherapy yielded a higher ORR of 30.8%, compared to 14.3% with TI alone. The most prevalent grade 1-2 adverse events were anemia (81%), weight loss (68%) and hypernatremia (55%).

Conclusion

The TI-based regimen demonstrated favorable efficacy and safety profile in treating R/M HNSCC. Enhanced outcomes may be attainable when combining it with immunotherapy. This study suggests that TI-based therapy could serve as a potential salvage option for this specific patient group.

Head and neck squamous cell carcinoma (HNSCC) is a life-threatening form of cancer that originates in the mucosal epithelium of the oral cavity, pharynx, hypopharynx, and larynx (1,2). Ranking as the seventh most prevalent cancer worldwide (3), its prominence is further underscored in Taiwan, where it has ascended to being the third most common cancer among men (4). Despite aggressive treatments, including surgery and platinum-based concurrent chemoradiotherapy (CCRT), over 50% of patients with locally advanced stages of HNSCC experience a recurrence or develop metastases within 3 years (5,6).

For those facing recurrent and metastatic (R/M) HNSCC, the first-line treatment typically involves platinum-based regimens. These include the EXTREME regimen (consisting of platinum, 5-fluorouracil, and cetuximab) and a combination of pembrolizumab, platinum, and 5-fluorouracil (6,7). However, the options become limited once the disease progresses beyond the effectiveness of platinum-based treatments. Alternative standard therapies at this stage often comprise monotherapies, such as methotrexate, ifosfamide, paclitaxel, docetaxel, cetuximab, pembrolizumab, or nivolumab (8). Despite these treatments, the prognosis for patients with R/M HNSCC remains grim, with a median overall survival (OS) time ranging only from 3 to 8 months (2,9).

Taxanes play a pivotal role in the chemotherapy treatment of both locally advanced and R/M HNSCC. They can be co-administered with platinum in neoadjuvant chemotherapy prior to curative surgery or definitive CCRT in locally advanced HNSCC, and also serve as a second-line or subsequent treatment for R/M HNSCC (10-12). However, the emergence of platinum resistance necessitates the exploration of alternative drug combinations. In the late 1990s, Forastiere and Urba pioneered the combination of paclitaxel with ifosfamide (TI), each previously established as effective single agents in treating advanced HNSCC (13). In their study of 13 patients with R/M HNSCC, notable results included partial response (PR) in five patients and stable disease (SD) in another five (13). These encouraging results spurred further phase II trials to evaluate the efficacy of a paclitaxel, ifosfamide, and carboplatin regimen as a first-line treatment for R/M HNSCC. This regimen was well-tolerated and demonstrated considerable antitumor activity, achieving an objective response rate (ORR) of 59%, a complete response (CR) rate of 17%, and a median OS of 9.1 months (14).

Building on these findings, we opted to treat patients with R/M HNSCC with a TI combination regimen, excluding platinum due to its frequent resistance or refractory nature in such patients. We hypothesized that this TI-based regimen might be advantageous in the current era of targeted therapy and immunotherapy for R/M HNSCC. To this end, we conducted a retrospective cohort study to assess the efficacy of the TI-based regimen in patients with R/M HNSCC whose disease had progressed following platinum-containing multimodal therapy.

Patients and Methods

Study design and participants. From February 2020 to August 2023, a retrospective review was conducted on patients with R/M HNSCC who underwent at least one cycle of the TI-based regimen at Taipei Veterans General Hospital. This review included individuals over 18 years of age diagnosed with cancer of the oral cavity, oropharynx, larynx, hypopharynx, or nasopharynx. Eligible patients had shown disease progression within 6 months of previous multimodal therapy incorporating platinum for locally advanced disease or had experienced disease progression during or following platinum-based treatment for recurrent or metastatic disease.

The administered regimen comprised paclitaxel (135 mg/m²) on day 1, and ifosfamide (1000 mg/m²) from day 1 to day 2, repeated every three weeks. Concurrently, pembrolizumab was administered to patients with a programmed cell death ligand-1 (PD-L1) tumor proportion score ≥1% or a combined positive score ≥1, at a dose of 100 mg every 3 weeks. For those with a PD-L1-positive tumor cell percentage (TC) >1%, nivolumab (100 mg every 2 weeks) was given in combination with the TI regimen. Additionally, cetuximab was administered in conjunction with immune checkpoint inhibitors (ICIs) for patients requiring swift suppression of their disease. Separately, it was also prescribed to individuals either not meeting the criteria for immunotherapy or those who had experienced disease progression following immunotherapy treatment.

Patient characteristics, such as sex, age, history of tobacco, alcohol, or betel nut consumption, primary tumor site, initial stage as defined by the American Joint Committee on Cancer (8th edition) staging system, Eastern Cooperative Oncology Group performance status prior to initiating the TI-based regimen, and history of initial curative therapies and subsequent systemic treatments were collated through meticulous examination of electronic medical records at the institution.

This study was granted ethical clearance by the Institutional Review Board of Taipei Veterans General Hospital, under the protocol reference 2024-01-016BC, and was rigorously conducted in strict compliance with the ethical standards as delineated in the Declaration of Helsinki.

Outcome assessment. Treatment responses, encompassing CR, PR, SD, and progressive disease (PD), were periodically evaluated using computed tomography (CT) scans or magnetic resonance imaging every 2 to 3 months. Tumor responses were assessed in line with the Response Evaluation Criteria in Solid Tumors version 1.1 (16) by two independent investigators. The ORR was defined as the percentage of patients who achieved either a CR or PR. Likewise, the disease control rate (DCR) was determined as the percentage of patients who achieved an objective response or maintained a state of SD.

OS was measured from the commencement of TI-based regimen to the occurrence of death from any cause. Progression-free survival (PFS) was calculated from the initiation of treatment until the point of disease progression or death, whichever occurred first. Treatment-related adverse effects were systematically graded according to the Common Terminology Criteria for Adverse Events, version 5.0.

Statistical analysis. All statistical analyses were conducted utilizing IBM^® SPSS^®, version 21.0 (IBM Corp., Armonk, NY, USA). The ORR and DCR are reported as percentages accompanied by 95% confidence intervals (CIs). Survival analyses for OS and PFS were conducted using the Kaplan-Meier method. Additionally, the 95% CIs for both the median OS and median PFS are provided. The exploration of prognostic factors influencing OS was performed using a univariate Cox proportional hazards model. However, factors with an exceedingly low number of cases were deliberately excluded from the univariate analysis. In all statistical tests, a p-value of less than 0.05 was set as the threshold for statistical significance.

Results

Patient characteristics. We identified 53 patients with R/M HNSCC who underwent at least one cycle of TI-based therapy at Taipei Veterans General Hospital from February 1, 2020, through August 31, 2023. The cohort, with a median age of 53.5 years (spanning from 28 to 79 years), was predominantly male (90.6%), with a significant proportion having histories of cigarette smoking (73.9%), alcohol consumption (60.6%), and betel nut chewing (58.5%).

The primary tumor sites were largely in the oral cavity (34.0%), followed by the oropharynx (24.5%) and hypopharynx (22.6%). A majority of the patients were initially diagnosed at stages IVA (26.4%) and IVB (26.4%). Their initial curative treatments comprised induction chemotherapy (45.3%), curative surgery (47.2%), and CCRT (75.5%). At the point of recurrence, 37% had solely locally advanced disease, 39.6% exhibited metastases, and 22.6% suffered from both locally advanced and metastatic conditions. Approximately 56.6% of the patients had an Eastern Cooperative Oncology Group performance status of 1 or less at the commencement of the TI regimen, while 32.1% had previously received more than three lines of systemic treatment. Regarding prior systemic therapy, the most commonly received treatments were cetuximab (37.7%) and ICIs (30.2%). The detailed clinical characteristics of these patients are catalogued in Table I.

Table I. Clinicopathological characteristics of patients (n=53).

ECOG PS: Eastern Cooperative Oncology Group performance status; EGFR: epidermal growth factor receptor; PD-1: programmed cell death 1; PD-L1: programmed cell death 1 ligand; VEGFR: vascular endothelial growth factor receptor. ^aEsophagus (2 patients) and maxilla (1 patient). ^bDiagnosis confirmed at another hospital. *American Joint Committee on Cancer 8^th edition.

TI-based regimen. TI was administered as a sole treatment to 32.1% of the cohort, while 34.0%, 24.5%, and 3.8% received it in combination with cetuximab, immunotherapy (pembrolizumab or nivolumab), or both cetuximab and ICI, respectively. Following the ineffectiveness of the TI-based regimen, 16 patients were transitioned to alternative salvage therapies. Of these, nine received exclusive chemotherapy, and the remainder were treated with a mixed regimen of cetuximab or other targeted therapies, immunotherapy, or drugs from clinical trials. Further details are provided in Table II.

Table II. Paclitaxel-ifosfamide based therapy and further salvage therapy.

^aOne patient received the regimen in combination with methotrexate, epirubicin, mitomycin-C, vincristine, cisplatin, leucovorin and 5-fluorouracil (MEMOCLUB); another received a combination of pembrolizumab and lenvatinib; the third patient received lenvatinib alone. ^bTrial therapy with toripalimab and GHF018.

Treatment responses. As of the data cut-off on 31 August 2023, 38 patients with post-treatment CT or magnetic resonance imaging were deemed evaluable for assessing the best tumor response, as detailed in Table III. Those considered unevaluable had either succumbed early or lacked sufficient measurable target lesions on their post-treatment CT scans. Among all evaluable patients, the investigator-assessed ORR was 15.8% (6/38; 95% CI=4.2-27.4%), and the DCR was 36.8% (14/38; 95% CI=21.5-52.1%). CR was observed in 1 patient (2.6%). Five patients (13.2%) achieved PR, and eight (21.1%) attained SD. A waterfall plot illustrating the best percentage change in target lesions are depicted in Figure 1. Tumor shrinkage was noted in 28.9% (11/38) of evaluable patients. Among the 38 evaluable patients, the ORR and DCR of those treated solely with TI (nine patients) were 14.3% and 28.6%, respectively. Conversely, in the group receiving TI in combination with ICIs (13 patients) or cetuximab (15 patients), the ORR and DCR stood at 30.8% and 40.2%, 6.7% and 33.3%, respectively.

Table III. Treatment responses of evaluable patients.

CI: Confidence interval; CR: complete response; ICI: immune checkpoint inhibitor; PD: progressive disease; PR: partial response; SD: stable disease; TI: paclitaxel-ifosfamide. ^aOne of the evaluable patients received paclitaxel-ifosfamide in combination with pembrolizumab and lenvatinib, and the best response was PD.

Figure 1. Best percentage change in target lesions among the evaluable patients.

The median duration of follow-up was 6.2 months, during which patients were treated with the TI-based regimen for a median of 2.5 months (interquartile range=1.7-4.6). The median OS across all patients was 9.6 (95% CI=3.5-15.7) months, while the median PFS was 3.3 (95% CI=2.9-3.7) months. Kaplan-Meier plots illustrating OS and PFS are presented in Figure 2 and Figure 3, respectively. In terms of OS and PFS, patients who received TI in conjunction with ICIs or cetuximab showed no significant differences compared to those who received TI alone (median OS: 12.9 vs. 8.2 vs. 9.6 months, p=0.441; median PFS: 3.5 vs. 3.3 vs. 3.1 months, p=0.824).

Figure 2. Overall survival of patients who underwent the paclitaxel-ifosfamide-based regimen.

Figure 3. Progression-free survival of patients who underwent the paclitaxel-ifosfamide-based regimen.

Prognostic factors. The prognostic factors linked to OS as identified in the univariate analysis are detailed in Table IV. Notably, oral cavity cancer emerged as a poor prognostic factor, with patients having primary tumors in this location exhibiting a markedly shorter OS compared to those with tumors situated elsewhere (hazard ratio=4.08, p=0.03). Other prognostic factors, however, did not demonstrate significant differences in the univariate analysis of OS.

Table IV. Univariate analysis of potential prognostic factors on overall survival.

CCRT: Concurrent chemoradiotherapy; CI: confidence interval; ECOG PS: Eastern Cooperative Oncology Group performance status; HR: hazard ratio; ICI: immune checkpoint inhibitor. *American Joint Committee on Cancer 8^th edition. Statistically significant p-values are shown in bold.

Toxicities. The frequencies of adverse events arising from the TI-based regimen are reported in Table V. The most frequently encountered adverse event was grade 1-2 anemia, affecting 81% of the patients, followed by grade 1-2 weight loss in 68%, and both grade 1-2 hypernatremia and hyponatremia, each occurring in 55% of the cases. Severe adverse events classified as grade 3 or higher were mainly due to hematological and metabolic toxicity. Of these, anemia was the most common, comprising 19.0% of such events, with grade 3 hypokalemia accounting for 13%.

Table V. Treatment-related adverse events.

ALT: Alanine aminotransferase; AST: aspartate aminotransferase.

Example case report. A 71-year-old male patient attended our outpatient clinics, initially complaining of a sore throat and odynophagia persisting for six months. He was subsequently diagnosed with right supraglottic squamous cell carcinoma accompanied by lung metastasis, staged as cT4aN3bM1, IVC. Pathological examination of the biopsy tumor sample revealed a TC percentage of 19%. Owing to the metastatic nature of his condition, he underwent induction chemotherapy comprising docetaxel, cisplatin, and 5-fluorouracil every 3 weeks for 3 cycles. This was followed by definitive CCRT with a high palliative intent, which included radiotherapy targeting the supraglottic gross tumor and lymphadenopathy (6,600 cGy in 45 fractions) and extending to the larynx, oropharynx, and bilateral neck levels II, III, and IV (5,940 cGy in 33 fractions), combined with two cycles of chemotherapy using cisplatin, 5-fluorouracil, and hydroxyurea.

However, a restaging CT scan 4 months later revealed not only new and enlarged lung lesions, but also identified multiple metastatic lymphadenopathies in bilateral paratracheal, subcarinal, paraesophageal, and celiac trunk regions. This occurred despite the reduction in size of the previously identified neck lymph nodes and the primary tumor. Given the disease’s progression within 6 months post-definitive treatment and the high TC percentage, he was prescribed a regimen of nivolumab, paclitaxel and ifosfamide, administered every 3 weeks. After 10 cycles of this treatment, the patient’s condition regressed to near-CR, and biweekly maintenance with nivolumab followed. The treatment course and response of the patient are vividly depicted on a timeline display in Figure 4.

Figure 4. Swimmer plot of the treatment course and response of the representative patient. Within the computed tomography images, the red arrows highlight the metastatic lung lesions. The green dotted arrows pinpoint the largest metastatic neck lymph node, as identified at the time of diagnosis, offering a visual narrative of the patient’s medical journey. CCRT: Concurrent chemoradiotherapy; NTI: nivolumab, paclitaxel and ifosfamide; PD: progressive disease; PR: partial response.

Discussion

In this retrospective study, we present an evaluation of the efficacy of combining paclitaxel and ifosfamide in the treatment of platinum-resistant R/M HNSCC. Our study observed a median of two treatment lines for the TI-based regimen, recording an ORR of 15.8%, a DCR of 36.8%, a median OS of 9.6 months, and a median PFS of 3.3 months across the total TI population.

For patients with R/M HNSCC whose disease progressed during or after platinum-based therapy, treatment options are scarce. Despite chemotherapy, recent key phase III trials, such as CHECKMATE-141 (9) and KEYNOTE-040 (12) have focused on this patient group. CHECKMATE-141 disclosed an ORR of 13.3% for nivolumab monotherapy, compared to 5.8% for standard therapy. In a similar context, KEYNOTE-040 demonstrated an ORR of 14.6% for pembrolizumab alone in comparison to 10.1% for standard care, specifically in the context of second-line or subsequent systemic treatment. Although ICI monotherapy seemed advantageous in both trials, their outcomes lacked statistical significance or the desired efficacy. Therefore, the exploration of combining ICIs with other regimen is critical for improved outcomes. In our study, a subgroup analysis revealed a high ORR of 30.8% among patients treated with the combination of ICI and TI. Conversely, TI alone showed a non-inferior ORR of 14.3%, but its combination with cetuximab did not show a benefit, with an ORR of only 6.7%.

The observed increase in ORR from combining ICI with the TI regimen may partly stem from their synergistic effects. ICIs enhance chemotherapy sensitivity, while chemotherapy itself has immunostimulatory properties beyond its cytotoxic effect on cancer cells (15,16). Paclitaxel, for instance, is known to reduce immunosuppressive cells while preserving CD4⁺ and CD8⁺ lymphocytes, and also stimulates the expression of tumor-infiltrating lymphocytes within the tumor microenvironment (8,17). However, despite KEYNOTE-048 showing OS benefits with ICI–chemotherapy combinations compared to chemotherapy alone in first-line treatment, this did not translate into an increased ORR, leaving the precise explanation open to further investigation (18).

In our survival analysis, the median OS of 9.6 months and median PFS of 3.3 months, with a median of two treatment lines, indicates its non-inferiority compared to other studies. Notably, 48% of our patients received TI as third-line treatment or beyond. These circumstances might have diminished the assessed benefits. A meta-analysis of 20 studies investigating second-line treatments for patients with platinum-resistant R/M HNSCC showed median OS and PFS ranges of 3.1-10.4 months and 0.7-8.3 months, respectively. It revealed that, compared to standard care, only anti-PD-1 and afatinib, an epidermal growth factor inhibitor, improved OS and PFS, while the addition of other drugs, including PX-866, EMD1201081, gefitinib, 5-fluorouracil, vandetanib, sorafenib, tivantinib, and palbociclib, failed to significantly enhance outcomes (19).

It is of significant interest that numerous studies have posited that previous exposure to ICIs may augment the effectiveness of salvage chemotherapy. This enhancement is believed to stem from the restoration of chemosensitivity, a result of alterations in the tumor microenvironment engendered by immunotherapy (6,20,21). For example, an updated analysis from KEYNOTE-048 indicated that patients initially treated with pembrolizumab benefitted from subsequent taxane therapies. In a similar vein, our study, while not statistically significant, intimates a potential improvement in OS for patients treated with either ICI or cetuximab. On the contrary, having a primary tumor in the oral cavity emerged as an independent prognosticator of less favorable survival outcomes, a finding that stands in contrast to observations from other real-world studies (22).

The TI-based regimen was characterized by a notably well-tolerated safety profile. Predominantly, the treatment-related adverse events reported were of grade 1-2 severity, consistent with the established tolerability of paclitaxel and ifosfamide. Grade 4 adverse events occurred in fewer than 5% of all cases across various categories, with none leading to the discontinuation of treatment nor fatalities.

Our representative patient’s history is particularly instructive, demonstrating that an ICI combination with the TI regimen can be highly effective in platinum-refractory contexts, even in those with metastatic conditions, while also being safely administered to elderly patients, Additionally, it intimates the potential viability of ICI maintenance therapy once the disease shows signs of stabilization after regression.

The retrospective nature of our study introduces certain limitations to the interpretation of our findings and the analysis of subgroups. These constraints encompass the employment of varied drug regimens in combination, shaped by patients’ previous treatments and physicians’ preferences, as well as discrepancies in treatment lines and drug dose intensity, and the absence of any prior selection. While this mirrors typical scenarios in real-world medical practice, its relevance for peer review and reference is undeniable. Additionally, the modest size of the sample and the single-center basis for data collection might have led to practice bias and restrict the robustness of the statistical analysis. Moreover, the lack of a control group to rigorously evaluate the efficacy of the TI-based regimen poses a significant challenge, and the quest to identify a more fitting control group remains an unresolved issue.

Conclusion

To the best of our knowledge, this study is the first ever evaluation of the efficacy of a TI-based regimen in treating patients with R/M HNSCC whose disease had progressed following platinum-containing multimodal therapy. The TI-based regimen demonstrated an ORR, OS and PFS comparable to those of other studies. Notably, when combined with ICIs, the prognosis showed further improvement. Given the efficacy and safety profile observed, the TI-based regimen emerges as a suitable salvage treatment for patients with R/M HNSCC experiencing progression after platinum-containing multimodal therapy. Moreover, our data contribute valuable evidence from a real-world setting in the treatment of platinum-resistant R/M HNSCC. Further research into the TI combination treatment in R/M HNSCC is emphatically recommended.

Funding

This work received financial support from grants provided by the National Science and Technology Council (NSTC 111-2314-B-A49-030-MY3) and Taipei Veterans General Hospital (V113C-145).

Conflicts of Interest

The Authors declare no conflicts of interest.

Authors’ Contributions

Conceptualization - MHY; Data curation – MYC; Formal analysis – MYC and WCW; Investigation – MYC and WCW; Methodology – MYC and WCW; Project administration – MYC and WCW; Resources – MHY, PYC, SKT, MHC, TLL, THC, and WCW; Supervision – MHY and WCW; Visualization – MYC and WCW; Writing – original draft – MYC and WCW; Writing – review & editing – MHY and WCW. All Authors actively participated in the multidisciplinary conference and granted their final approval for the version of the article to be published.