Current concepts for the management of head and neck cancer: Chemotherapy

doi:10.1016/j.oraloncology.2008.05.014

Oral Oncology

Volume 45, Issues 4–5, April–May 2009, Pages 409-415

https://doi.org/10.1016/j.oraloncology.2008.05.014 Get rights and content

Summary

Chemotherapy can be administered in patients with locoregionally advanced (LA) squamous cell carcinoma of the head and neck (SCCHN) either concurrently with irradiation or as induction chemotherapy prior to local treatment or as palliative therapy in patients with recurrent and/or metastatic disease. Cisplatin-based chemoradiation is still the standard for LA–SCCHN. TPF has emerged as the new standard regimen when induction chemotherapy is indicated. Areas of active investigation in LA–SCCHN are the sequential administration of induction chemotherapy followed by chemoradiation and the integration of targeted therapies. None of the combination chemotherapy regimens demonstrated an overall survival benefit when compared to single agent methotrexate, cisplatin or 5-fluorouracil in recurrent/metastatic disease. Combination chemotherapy in this setting is preferably used in younger patients with a good performance status and with symptomatic disease who require prompt symptom relief. However, a survival benefit was observed when cetuximab was combined with platinum-5-fluorouracil.

Introduction

The role of chemotherapy is slowly moving towards a more prominent position within the different treatment paradigms in patients with squamous cell carcinoma of the head and neck (SCCHN). This is particularly true for the locoregionally advanced (LA) disease condition in which chemotherapy may be given either concurrently with irradiation (as definitive treatment or postoperatively) or before (induction) or after (adjuvant) locoregional treatment as a single modality. However, also at last in the recurrent/metastatic setting results are changing with the introduction and integration of molecular targeting therapies.1, 2

Section snippets

Locoregionally advanced squamous cell carcinoma of the head and neck

Two-thirds of the SCCHN are in a LA stage at time of diagnosis. Treatment paradigms in that setting include various forms of curative combined modality therapies, including concurrent chemoradiation (or biochemoradiation), induction chemotherapy followed by irradiation and sequential therapy (induction chemotherapy followed by concurrent chemoradiation). The role of bio(chemo)radiation will be discussed in the separate chapter on targeted therapies in this issue.

Recurrent disease

While the vast majority of the patients presenting with stage I and II SCCHN will remain disease free after surgery and/or radiotherapy, the majority of patients presenting in a more advanced disease stage will eventually relapse either locoregionally and/or at distant sites. A few patients with a locoregional recurrence can be salvaged by surgery or reirradiation. However, most patients with recurrent or metastatic disease only qualify for palliative treatment. Treatment options in these

Combination of chemotherapy with targeted therapies

Targeted therapies are discussed in a separate chapter in this issue. The most promising data on targeted therapies in SCCHN have been observed with the anti-EGFR monoclonal antibodies. The combined use of chemotherapy and anti-EGFR antibodies is strongly supported by preclinical data,⁸² and recently, by randomized phase III studies in the recurrent/metastatic disease setting.83, 84, 85, 86 In the EXTREME study,84, 85, 86 442 patients were randomized to receive either chemotherapy alone

Conclusions

We conclude that cisplatin-based chemoradiation is still the standard approach for the treatment of LA–SCCHN. TPF has emerged as the new standard regimen when induction chemotherapy is appropriate. Areas of active investigation in LA–SCCHN are the sequential administration of induction chemotherapy followed by chemoradiation and the integration of targeted therapies. None of the combination chemotherapy regimens demonstrated an overall survival benefit when compared to single agent

Conflict of interest statement

None declared.

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Cetuximab versus methotrexate in first-line treatment of older, frail patients with inoperable recurrent or metastatic head and neck cancer (ELAN UNFIT): a randomised, open-label, phase 3 trial
2024, The Lancet Healthy Longevity
At present, there is no established standard treatment for frail older patients with recurrent or metastatic head and neck squamous cell carcinoma. We aimed to compare the efficacy and safety of cetuximab to those of methotrexate (the reference regimen) in this population.
This randomised, open-label, phase 3 trial was done at 20 hospitals in France. Patients aged 70 years or older, assessed as frail by the ELAN Geriatric Evaluation, with recurrent or metastatic head and neck squamous cell carcinoma in the first-line setting and with an Eastern Cooperative Oncology Group (ECOG) performance status of 0–2 were eligible for inclusion. Patients were randomly assigned (1:1) to receive cetuximab 500 mg/m² intravenously every 2 weeks or methotrexate 40 mg/m² intravenously every week, with minimisation by ECOG performance status, type of disease evolution, Charlson Comorbidity Index score, serum albumin concentration, and geriatrician consultation. To avoid deterministic minimisation and assure allocation concealment, patients were allocated with a probability of 0·80 to the treatment that most reduced the imbalance. Treatment was continued until disease progression or unacceptable toxicity, whichever occurred first. The primary endpoint was failure-free survival (defined as the time from randomisation to disease progression, death, discontinuation of treatment, or loss of 2 or more points on the Activities in Daily Living scale, whichever occurred first) and was analysed in the intention-to-treat population. 151 failures expected out of 164 patients were required to detect a hazard ratio (HR) of 0·625 with 0·05 alpha error, with 80% power. A futility interim analysis was planned when approximately 80 failures were observed, based on failure-free survival. Safety analyses included all patients who received at least one dose of the study drug. This study is registered on ClinicalTrials.gov (NCT01884623) and was stopped for futility after the interim analysis.
Between Nov 7, 2013, and April 23, 2018, 82 patients were enrolled (41 to the cetuximab group and 41 to the methotrexate group); 60 (73%) were male, 37 (45%) were aged 80 years or older, 35 (43%) had an ECOG performance status of 2, and 36 (44%) had metastatic disease. Enrolment was stopped for futility at the interim analysis. At the final analysis, median follow-up was 43·3 months (IQR 30·8–52·1). At data cutoff, all 82 patients had failure; failure-free survival did not differ significantly between the groups (median 1·4 months [95% CI 1·0–2·1] in the cetuximab group vs 1·9 months [1·1–2·6] in the methotrexate group; adjusted HR 1·03 [95% CI 0·66–1·61], p=0·89). The frequency of patients who had grade 3 or worse adverse events was 63% (26 of 41) in the cetuximab group and 73% (30 of 41) in the methotrexate group. The most common grade 3–4 adverse events in the cetuximab group were fatigue (four [10%] of 41 patients), lung infection (four [10%]), and rash acneiform (four [10%]), and those in the methotrexate group were fatigue (nine [22%] of 41), increased gamma-glutamyltransferase (seven [17%]), natraemia disorder (four [10%]), anaemia (four [10%]), leukopenia (four [10%]), and neutropenia (four [10%]). The frequency of patients who had serious adverse events was 44% (18 of 41) in the cetuximab group and 39% (16 of 41) in the methotrexate group. Four patients presented with a fatal adverse event in the cetuximab group (sepsis, decreased level of consciousness, pulmonary oedema, and death of unknown cause) as did two patients in the methotrexate group (dyspnoea and death of unknown cause).
The study showed no improvement in failure-free survival with cetuximab versus methotrexate. Patients with an ECOG performance status of 2 did not benefit from these systemic therapies. New treatment options including immunotherapy should be explored in frail older patients with recurrent or metastatic head and neck squamous cell carcinoma, after an initial geriatric evaluation, such as the ELAN Geriatric Evaluation.
French programme PAIR-VADS 2011 (sponsored by the National Cancer Institute, the Fondation ARC and the Ligue Contre le Cancer), GEMLUC, GEFLUC, and Merck Santé.
For the French translation of the abstract see Supplementary Materials section.
Therapeutic strategy for oncovirus-mediated oral cancer: A comprehensive review
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Oral cancer is a neoplastic disorder of the oral cavities, including the lips, tongue, buccal mucosa, and lower and upper gums. Oral cancer assessment entails a multistep process that requires deep knowledge of the molecular networks involved in its progression and development. Preventive measures including public awareness of risk factors and improving public behaviors are necessary, and screening techniques should be encouraged to enable early detection of malignant lesions. Herpes simplex virus (HSV), human papillomavirus (HPV), Epstein-Barr virus (EBV), and Kaposi sarcoma-associated herpesvirus (KSHV) are associated with other premalignant and carcinogenic conditions leading to oral cancer. Oncogenic viruses induce chromosomal rearrangements; activate signal transduction pathways via growth factor receptors, cytoplasmic protein kinases, and DNA binding transcription factors; modulate cell cycle proteins, and inhibit apoptotic pathways. In this review, we present an up-to-date overview on the use of nanomaterials for regulating viral proteins and oral cancer as well as the role of phytocompounds on oral cancer. The targets linking oncoviral proteins and oral carcinogenesis were also discussed.
Discovery of fluorinated 2‑Styryl 4(3H)-quinazolinone as potential therapeutic hit for oral cancer
2023, Bioorganic and Medicinal Chemistry
Oral squamous cell carcinoma (OSCC) is the most common malignant epithelial neoplasm, affects the mouth and throat, and accounts for 90 % of oral cancers. Considering the associated morbidity with neck dissections and the limitation of existing therapeutic agents, the discovery and development of new anticancer drugs/drug candidates for oral cancer treatment are of the utmost need. In this context, reported here is the identification of fluorinated 2‑styryl 4(3H)-quinazolinone as a promising hit for oral cancer. Preliminary studies indicate that the compound blocks the transition of G1 to S phase, thereby leading to arrest in the G1/S phase. Subsequent RNA-seq analysis revealed that the compound induces the activation of molecular pathways involved in apoptosis (such as TNF signalling through NF-κB, p53 pathways) and cell differentiation and suppresses the pathways of cellular growth and development (such as KRAS signaling) in CAL-27 cancer cells. It is noted that identified hit complies with a favorable range of ADME properties as per the computational analysis.
Effect of cisplatin on oral ulcer-induced nociception in rats
2022, Archives of Oral Biology
Citation Excerpt :
In some cases, the pain leads to delays or interruptions in cancer therapy (Carlotto et al., 2013; Donnelly et al., 2003). Cisplatin-based systemic chemotherapy was initially recommended as a basic treatment for head and neck cancer patients (Chen et al., 2013; Specenier & Vermorken, 2009; Winquist et al., 2014). Oral ulceration in patients is most likely triggered by direct mucosal injury from the combination of exposure to radiation, biting while eating or exposure to gastric acid while vomiting.
The aim of this study is to investigate effects of cisplatin preadministration on oral ulcerative mucositis-induced nociception by using an experimental model of rats.
After two rounds of cisplatin administration, oral ulcers developed with topical acetic acid treatment in rats. Spontaneous mouth rubbing behavior was observed as spontaneous nociceptive behavior in a plastic cage. Head-withdrawal behavior was observed as mechanical allodynia by using von Frey test in the oral mucosa of conscious rats. Bacterial invasion and inflammatory cell infiltration into oral ulcerative region and systemic leukocyte phagocytic activity were assessed.
Following cisplatin preadministration, oral ulcerative mucositis-induced spontaneous nociceptive behavior was not observed in the model. The preadministration enhanced leukocyte phagocytic activity, leading to reduce bacterial invasion and inflammatory cell infiltration in the oral ulcerative region. In contrast, oral ulcerative mucositis-induced mechanical allodynia was induced. The exaggerated mechanical allodynia in the oral ulcerative region was largely inhibited by topical treatment with the antioxidative drug, ɑ-lipoic acid, or the blocker of N-formyl peptide receptor 1, N-t-butoxycarbonyl-methionyl-leucyl-phenylalanine.
These results suggest that cisplatin preadministration suppresses spontaneous nociception in oral ulcerative region, due to antiinflammatory effects by enhancement of leukocyte phagocytic activity, but exaggerates mechanical allodynia due to oxidative stress with N-formyl peptide receptor 1 activation. The suppression of spontaneous nociception is one of the advantages of cisplatin treatment for head and neck cancer patients although the exaggerated allodynia is a serious symptom.
Cisplatin induces TRPA1-mediated mechanical allodynia in the oral mucosa
2022, Archives of Oral Biology
Citation Excerpt :
Many clinical trials have suggested significant efficacies of antioxidative drugs, such as glutathione, vitamin E and amifostine, for the treatment of cisplatin-induced CIPN (Avan et al., 2015). The regimen of single-agent cisplatin or multiagent cisplatin plus 5-fluorouracil combined with radiation is the standard care for head and neck cancer patients (Specenier & Vermorken, 2009; Winquist, Al-Rasheedy, Nichols, Palma, & Stitt, 2014). The major side effect, severe oral ulcerative mucositis, is thought to be triggered by radiation, bites and gastric acid while vomiting.
Cisplatin, a platinum-based anticancer drug, produces reactive oxygen species (ROS) in many cell types and induces mechanical allodynia in the hands and/or feet (chemotherapy-induced painful neuropathy: CIPN). In this study, we examined the possibility of inducing neuropathy in the oral region using oral keratinocytes and rats.
Human oral keratinocytes (HOKs) were used to evaluate ROS generation after cisplatin application by a ROS-reactive fluorescent assay. In rats, after cisplatin administrations (two times), the trigeminal ganglion (TG) was investigated by electron microscopy and quantitative RT-PCR. Using our proprietary assay system, oral pain-related behaviors were observed in cisplatin-treated rats.
In rats, cisplatin administration reduced food intake and body weight. In electron microscopic analysis, glycogen granules in the TG were depleted following administration, although organelles were intact. In HOK cells, cisplatin significantly increased ROS generation with cell death, similar to glycolysis inhibitors. Cisplatin administration did not show any effects on Trpa1 mRNA levels in the TG. However, the same procedure induced hypersensitivity to mechanical stimulation and the TRPA1 agonist allyl isothiocyanate in the oral mucosa. Mechanical hypersensitivity was inhibited by the antioxidative drug α-lipoic acid and the TRPA1 antagonist HC-030031, similar to that of the hind paw.
The present findings suggest that cisplatin induces TRPA1-mediated CIPN due to ROS generation in the oral region. This study will provide a better understanding of persistent oral pain in cancer patients.
Identification of Novel Cdc7 Kinase Inhibitors as Anti-Cancer Agents that Target the Interaction with Dbf4 by the Fragment Complementation and Drug Repositioning Approach
2018, EBioMedicine
Citation Excerpt :
Since Cdc7-Dbf4 interacts with and phosphorylates HSP90-MRN complex to enhance ATR/ATM checkpoint signaling and DNA damage tolerance for the survival of cancer cells [41], the kinase inhibitor becomes an excellent anti-cancer agent that not only blocks DNA synthesis at the beginning but also sensitizes cancer cells to DNA damage agents. Although the resistance development of chemo- and radio-therapy, cis-diamminedichloroplatinum (II) (CDDP, cisplatin) and radiation are still widely used for the treatment of various solid tumors, including oral cancers [42]. Thus we tried to address whether Cdc7-Dbf4 inhibitors, Dequalinium chloride and Clofoctol, are promising therapeutic strategies to enhance the therapeutic effect of chemotherapy and radiation.
Cdc7-Dbf4 is a conserved serine/threonine kinase that plays an important role in initiation of DNA replication and DNA damage tolerance in eukaryotic cells. Cdc7 has been found overexpressed in human cancer cell lines and tumor tissues, and the knockdown of Cdc7 expression causes an p53-independent apoptosis, suggesting that Cdc7 is a target for cancer therapy. Only a handful Cdc7 kinase inhibitors have been reported. All Cdc7 kinase inhibitors, including PHA-767491, were identified and characterized as ATP-competitive inhibitors. Unfortunately, these ATP-competitive Cdc7 inhibitors have no good effect on clinical trial.
Here, we have developed a novel drug-screening platform to interrupt the interaction between Cdc7 and Dbf4 based on Renilla reniformis luciferase (Rluc)-linked protein-fragment complementation assay (Rluc-PCA). Using drug repositioning approach, we found several promising Cdc7 inhibitors for cancer therapy from a FDA-approved drug library.
Our data showed that dequalinium chloride and clofoctol we screened inhibit S phase progression, accumulation in G2/M phase, and Cdc7 kinase activity. In addition, in vivo mice animal study suggests that dequalinium chloride has a promising anti-tumor activity in oral cancer. Interestingly, we also found that dequalinium chloride and clofoctol sensitize the effect of platinum compounds and radiation due to synergistic effect. In conclusion, we identified non-ATP-competitive Cdc7 kinase inhibitors that not only blocks DNA synthesis at the beginning but also sensitizes cancer cells to DNA damage agents.
The inhibitors will be a promising anti-cancer agent and enhance the therapeutic effect of chemotherapy and radiation for current cancer therapy.
This work was supported by grants from the Ministry of Science and Technology, Ministry of Health and Welfare, and National Health Research Institutes, Taiwan.

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ReviewCurrent concepts for the management of head and neck cancer: Chemotherapy

Summary

Introduction

Section snippets

Locoregionally advanced squamous cell carcinoma of the head and neck

Recurrent disease

Combination of chemotherapy with targeted therapies

Conclusions

Conflict of interest statement

Lancet

Int J Radiat Oncol Biol Phys

Lancet

Int J Radiat Oncol Biol Phys

Int J Radiat Oncol Biol Phys

Ann Oncol

Int J Radiat Oncol Biol Phys

Eur J Cancer

Oral Oncol

Eur J Cancer

Int J Radiat Oncol Biol Phys

Cancer Lett

Eur J Cancer

Ann Oncol.

Ann Oncol

Oral Oncol

Medical treatment in head and neck cancer

Ann Oncol

Targeted therapies in head and neck cancer

Target Oncol

A meta-analysis of hyperfractionated and accelerated radiotherapy and combined chemotherapy and radiotherapy regimens in unresected locally advanced squamous cell carcinoma of the head and neck

BMC Cancer

Mature results of a phase III randomized trial comparing concurrent chemoradiotherapy with radiation therapy alone in patients with stage III and IV squamous cell carcinoma of the head and neck

Cancer

An intergroup phase III comparison of standard radiation therapy and two schedules of concurrent chemoradiotherapy in patients with unresectable squamous cell head and neck cancer

J Clin Oncol

Hyperfractionated radiation therapy with or without concurrent low-dose daily cisplatin in locally advanced squamous cell carcinoma of the head and neck: a prospective randomized trial

J Clin Oncol

Concomitant cisplatin significantly improves locoregional control in advanced head and neck cancers treated with hyperfractionated radiotherapy

J Clin Oncol

Simultaneous radiochemotherapy versus radiotherapy alone in advanced head and neck cancer: a randomized multicenter study

J Clin Oncol

Hyperfractionated irradiation with or without concurrent chemotherapy for locally advanced head and neck cancer

New Engl J Med

Randomized trial of radiation therapy versus concomitant chemotherapy and radiation therapy for advanced-stage oropharynx carcinoma

J Natl Cancer Inst

Final results of the 94-01 French Head and Neck Oncology and Radiotherapy Group randomized trial comparing radiotherapy alone with concomitant radiochemotherapy in advanced-stage oropharynx carcinoma

J Clin Oncol

J Clin Oncol

Concomitant radiochemotherapy vs radiotherapy alone in patients with head and neck cancer: a Hellenic cooperative oncology group phase III study

Med Oncol

Postoperative irradiation with or without concomitant chemotherapy for locally advanced head and neck cancer

New Engl J Med

Postoperative concurrent radiotherapy and chemotherapy for high-risk squamous-cell carcinoma of the head and neck

New Engl J Med

Phase II trial of chemoradiation for organ preservation in resectable stage III or IV squamous cell carcinomas of the larynx or oropharynx: results of Eastern Cooperative Oncology Group Study E2399

J Clin Oncol

Concomitant radiotherapy and daily low-dose carboplatin in locally advanced, unresectable head and neck cancer. Definitive results of a phase I–II study

Acta Oncol

Randomized phase II trial of concomitant chemoradiotherapy using weekly carboplatin or daily low-dose cisplatin for squamous cell carcinoma of the head and neck

Cancer J

Induction chemotherapy followed by concomitant TFHX chemoradiotherapy with reduced dose radiation in advanced head and neck cancer

Clin Cancer Res

Weekly carboplatin and paclitaxel followed by concomitant paclitaxel, fluorouracil, and hydroxyurea chemoradiotherapy: curative and organ-preserving therapy for advanced head and neck cancer

J Clin Oncol

Single-cycle induction chemotherapy selects patients with advanced laryngeal cancer for combined chemoradiation: a new treatment paradigm

J Clin Oncol

Larynx preservation in pyriform sinus cancer: preliminary results of a European Organization for Research and Treatment of Cancer phase III trial. EORTC Head and Neck Cancer Cooperative Group

J Natl Cancer Inst

Concurrent chemotherapy and radiotherapy for organ preservation in advanced laryngeal cancer

N Engl J Med

Long-term results of Intergroup RTOG 91-11: a phase III trial to preserve the larynx – Induction cisplatin/5-FU and radiation therapy versus concurrent cisplatin and radiation therapy versus radiation therapy

J Clin Oncol

Phase III study comparing cisplatin plus fluorouracil to paclitaxel, cisplatin, and fluorouracil induction chemotherapy followed by chemoradiotherapy in locally advanced head and neck cancer

J Clin Oncol

Review
Current concepts for the management of head and neck cancer: Chemotherapy