head and neck cancer – a review article

一篇来自NEJM的概略性的综述¹，不过发表日期在2020年。看完后用Chatgpt进行了一下总结。

Epidemiology

The epidemiology section of the review on head and neck cancer highlights the following key points:

1. Prevalence: Head and neck cancer was the seventh most common cancer globally in 2018, with 890,000 new cases and 450,000 deaths. In the United States, it accounted for 3% of all cancers (51,540 new cases) and just over 1.5% of all cancer deaths (10,030 deaths).

2. Risk Factors: The traditional risk factors for head and neck cancers include heavy use of tobacco and alcohol, which are associated with older age groups. Due to decreased tobacco use, these types of head and neck cancers are slowly declining worldwide.

3. HPV-Associated Cancers: Conversely, cases of HPV-associated oropharyngeal cancer are increasing, particularly among younger individuals in North America and northern Europe. This is primarily due to HPV type 16, with a latency of 10 to 30 years after exposure through oral sex.

4. Trends: The proportion of head and neck cancers diagnosed as HPV-positive oropharyngeal cancers in the United States rose significantly from 16.3% in the 1980s to more than 72.7% in the 2000s. This increase is due to greater awareness, the identification of HPV as a cause, and improved diagnostic techniques.

5. Prognosis: Patients with HPV-positive oropharyngeal cancer generally have a better prognosis, responding more favorably to chemotherapy and radiotherapy. These patients also tend to be younger and in better overall health compared to those with HPV-negative disease, who often have other health complications from chronic tobacco and alcohol use.

Staging

The staging section of the review on head and neck cancer includes the following key points:

1. TNM Staging System: The American Joint Committee on Cancer (AJCC) uses the TNM (Tumor, Node, Metastasis) staging system to classify head and neck squamous-cell carcinomas and determine the appropriate therapy. Staging varies depending on the anatomical site of the cancer.

2. Staging Categories:

   • Early Stages (I and II): These involve smaller tumors without significant lymph-node involvement.
   • Later Stages (III and IV): Characterized by larger, locally advanced tumors with more extensive lymph-node involvement or distant metastasis.

3. HPV-Associated Oropharyngeal Cancer:

   • HPV Status: Staging of oropharyngeal cancer requires assessment of HPV status using methods like in situ hybridization, polymerase chain reaction (PCR), or immunohistochemical testing for p16, a surrogate marker for HPV positivity.
   • Prognosis: Patients with HPV-positive oropharyngeal cancer generally have a better prognosis compared to those with HPV-negative disease.

4. Separate Staging System for HPV-Positive Oropharyngeal Cancer:

   • In 2017, a separate staging system was introduced for HPV-positive oropharyngeal cancer, recognizing the better prognosis of this subgroup. This new system, based on the 8th edition of the AJCC–UICC staging manual, involves a "downstaging" for HPV-positive cases compared to the previous system, which did not differentiate based on HPV status.

5. Validation of New Staging System:

   • The International Collaboration on Oropharyngeal Network for Staging (ICON-S) validated the differences in prognosis using the new staging criteria. It found that patients with HPV-positive oropharyngeal cancer generally have higher survival rates, particularly in early stages (I, II, III, and IVA), with significantly lower survival in stage IVB.

HPV-associated disease

The HPV-associated disease section of the review on head and neck cancer discusses the following key points:

1. Treatment Considerations:

   • Current data do not support changes in treatment or less-intensive treatment specifically for HPV-positive head and neck cancers based solely on HPV status.
   • Downstaging HPV-positive cancers may lead to undertreatment and worse outcomes. For instance, patients with stage I HPV-positive oropharyngeal cancer treated with radiotherapy alone had reduced survival compared to those who received more intensive treatments like chemoradiotherapy or surgery with adjuvant therapy.

2. Survival Rates:

   • Patients with locally advanced HPV-positive oropharyngeal cancer have high long-term survival rates, often exceeding 80%. As a result, reducing morbidity and maintaining quality of life are major concerns.

3. Ongoing Research:

   • Research is ongoing to identify lower-risk subgroups among HPV-positive patients, reassess risk factors, and explore ways to reduce treatment intensity while maintaining efficacy. This includes investigating modifications to systemic therapy and potential reductions in radiotherapy doses.

4. Surgical Advances:

   • Transoral robotic surgery and transoral laser microsurgery are highlighted as promising techniques for treating locally advanced oropharyngeal cancer, especially in HPV-positive cases. These approaches offer good visualization, functional outcomes, and survival rates.

5. De-escalation Trials:

   • Early-phase clinical trials are exploring de-escalation strategies, such as reducing radiation doses (e.g., the E1308 trial) or both dose and volume (e.g., the OPTIMA trial) for patients who respond well to induction chemotherapy. These trials aim to decrease treatment-related toxicities while preserving overall survival.

In summary, while HPV-positive oropharyngeal cancers have a better prognosis and high survival rates, treatment approaches are being carefully studied to avoid undertreatment while aiming to reduce long-term side effects and improve quality of life.

Early-Stage Disease

The early-stage disease section discusses the management of head and neck cancers in patients who present with stage I or II disease. Key points include:

1. Curability:

   • Approximately 30-40% of patients are diagnosed with stage I or II disease, which is often curable with surgery alone or definitive radiotherapy alone.
   • Both surgery and radiotherapy can achieve similar oncologic control, with long-term survival rates ranging from 70% to 90% in patients with early-stage disease.

2. Treatment Selection:

   • The choice between surgery and radiotherapy depends on the tumor’s anatomical accessibility, with efforts to minimize morbidity and preserve function.
   • Advances in robotic surgery for oropharyngeal cancers and minimally invasive laser microsurgery for laryngeal and hypopharyngeal cancers have increased the likelihood of preserving function.

3. Specific Cancer Sites:

   • Surgery is the preferred treatment for easily accessible oral cavity cancers, offering high cure rates with reduced morbidity.
   • Oropharyngeal cancers may be managed with either primary surgery or radiotherapy.
   • Radiotherapy plays an established role in laryngeal preservation for patients with laryngeal cancer, and surgery is often preferred for paranasal sinus cancers.

4. Lymphatic Drainage and Recurrence:

   • Treatment decisions are influenced by the risk of occult metastatic spread, guiding the use of selective neck dissection, elective neck dissection, or prophylactic neck radiotherapy to decrease recurrence risks.

Locally Advanced Disease

The locally advanced disease section covers the treatment approaches for patients with stage III or IV head and neck cancer. Key points include:

1. Prevalence and Prognosis:

   • Over 60% of patients present with stage III or IV disease, characterized by large tumors with marked local invasion and/or metastasis to regional nodes.
   • Locally advanced disease carries a high risk of local recurrence (15-40%) and distant metastasis, with a poor prognosis (5-year overall survival of less than 50%).

2. Multimodal Approaches:

   • Multimodal treatment approaches have improved cure rates over the past two decades, focusing on preserving function and quality of life.
   • The choice of initial therapy is individualized based on factors such as the size and location of the tumor, the patient’s age, performance status, coexisting conditions, and patient preferences.

3. Surgical Treatment:

   • Surgical resection is preferred for oral cavity cancers, often followed by elective neck dissection and adjuvant radiotherapy or chemoradiotherapy for high-risk features.
   • Surgery is typically reserved for smaller, accessible primary tumors at other sites or for patients with poor responses after induction chemotherapy.

4. Chemoradiotherapy:

   • Chemoradiotherapy is the curative standard for patients with unresectable tumors or when surgical resection would result in poor long-term functional outcomes.
   • The Meta-analysis of Chemotherapy in Head and Neck Cancer (MACH-NC) study confirmed the benefits of adding concurrent chemotherapy to radiotherapy, showing a significant reduction in 5-year mortality and locoregional failure rates.

5. Site-Specific Considerations:

   • For advanced laryngeal or hypopharyngeal cancers, chemoradiotherapy is preferred, with salvage laryngectomy reserved for recurrent or persistent disease.
   • Oropharyngeal cancer treatment requires close multidisciplinary evaluation, with decisions guided by advanced surgical techniques, prophylactic selective neck dissection, or chemoradiotherapy, depending on the tumor’s extent.

In summary, early-stage head and neck cancers are often curable with single-modality treatment, while locally advanced cancers require a complex, individualized, multimodal approach to optimize outcomes while preserving function and quality of life.

Definitive Concurrent Chemoradiotherapy

This section covers the standard treatment approach for patients with head and neck cancer who are undergoing chemoradiotherapy as part of their curative treatment. Key points include:

1. Standard of Care:

   • High-dose cisplatin (100 mg/m² every 21 days for three cycles) administered concurrently with radiotherapy is the standard of care for definitive chemoradiotherapy in patients with good performance status.
   • This regimen has established survival benefits but is associated with substantial short- and long-term toxic effects.

2. Patient Selection:

   • High-dose cisplatin is primarily reserved for younger, non-elderly patients without major coexisting conditions due to its toxicity.
   • For less fit patients or those who cannot tolerate high-dose cisplatin, alternative systemic therapies are being investigated, though none have yet proven as effective.

3. Alternative Therapies:

   • Low-dose weekly cisplatin has shown fewer adverse effects in some studies, but a phase 3 randomized trial found it resulted in worse local control compared to high-dose cisplatin.
   • Carboplatin is sometimes substituted for cisplatin in patients with renal impairment, but it is less effective than high-dose cisplatin.

4. Cetuximab:

   • The epidermal growth factor receptor (EGFR) antibody cetuximab was approved in 2006 for use with radiotherapy, showing improvements in locoregional control and overall survival compared to radiotherapy alone.
   • However, recent randomized trials have shown worse outcomes, including decreased survival, with cetuximab combined with radiotherapy compared to cisplatin combined with radiotherapy, especially in HPV-positive oropharyngeal cancer.

5. Radiotherapy Advances:

   • Intensifying radiation doses or accelerating fractionation schedules have not shown improvement over conventional fractionated, intensity-modulated, and imaging-guided radiotherapy combined with chemotherapy.
   • Newer radiotherapy techniques, such as proton therapy and intensity-modulated proton therapy, may improve outcomes by better targeting tumors and reducing radiation-related toxic effects, particularly in HPV-positive patients who are often successfully cured but suffer long-term consequences from treatment.

In summary, high-dose cisplatin with radiotherapy remains the standard of care for definitive chemoradiotherapy in head and neck cancer, though its toxicity necessitates careful patient selection. Alternative treatments and advancements in radiotherapy are being explored to improve outcomes and reduce side effects.

Induction Chemotherapy before Chemoradiotherapy

The section on induction chemotherapy before chemoradiotherapy discusses the role of induction (or neoadjuvant) chemotherapy in the treatment of head and neck cancers:

1. Controversy and Conflicting Data:

   • The use of induction chemotherapy followed by chemoradiotherapy remains controversial, with conflicting data from various studies.
   • While some trials, like TAX 324 and EORTC 24971/TAX 323, showed improved survival with taxane-based induction chemotherapy compared to non-taxane regimens, these benefits came with higher toxicity and treatment delays.
   • Other studies, such as PARADIGM and DECIDE, did not show improved survival with induction chemotherapy compared to chemoradiotherapy alone, but these studies were underpowered.

2. Meta-Analyses:

   • Meta-analyses support the use of taxane-based induction regimens, showing a significant decrease in locoregional relapse and death rates compared to non-taxane-based regimens. However, variability in trial design and patient populations limits the conclusions that can be drawn.

3. Toxicity Concerns:

   • A significant proportion of patients (20-30%) who undergo induction chemotherapy experience toxic effects that prevent them from completing subsequent chemoradiotherapy, which is crucial for maximizing locoregional control and overall survival.

4. Patient Selection:

   • Induction chemotherapy may be best reserved for patients at high risk for locoregional relapse and distant metastases, or for those whose symptomatic, locally advanced disease would prevent adequate delivery of up-front curative chemoradiotherapy.

Adjuvant Therapy

The adjuvant therapy section focuses on the role of postoperative treatment in head and neck cancers, particularly in high-risk patients:

1. Standard of Care:

   • Adjuvant chemoradiotherapy with high-dose cisplatin and conventional fractionation radiotherapy (60 to 66 Gy) is the standard of care for high-risk patients with squamous-cell carcinoma of the head and neck.

2. Defining High-Risk Patients:

   • The EORTC 22931 trial defined high-risk patients as those with T3 or T4 disease, positive surgical margins, extranodal spread, perineural or lymphovascular invasion, or vascular tumor embolism. It showed that chemoradiotherapy improved progression-free survival, locoregional control, and overall survival compared to radiotherapy alone.
   • The RTOG 9501 trial defined high-risk patients as those with positive surgical margins, two or more involved regional nodes, or extranodal extension. The study found that chemoradiotherapy improved locoregional control and disease-free survival but not overall survival compared to radiotherapy alone.

3. Long-Term Outcomes:

   • Despite early improvements, the benefits of adjuvant chemoradiotherapy were not sustained in long-term follow-ups. For example, the RTOG 9501 trial showed that improvements in locoregional control and disease-free survival were no longer evident after a median follow-up of 9.4 years.

4. Extranodal Extension and Surgical Margins:

   • A comparative analysis of pooled data from the EORTC 22931 and RTOG 9501 trials suggests that adjuvant chemoradiotherapy benefits patients primarily with extranodal extension or positive surgical margins.

5. Ongoing Research:

   • Research continues to better define and improve adjuvant therapy approaches, aiming to enhance outcomes for high-risk patients.

In summary, induction chemotherapy before chemoradiotherapy is still debated due to conflicting evidence and concerns about toxicity, while adjuvant chemoradiotherapy is established as the standard for high-risk patients, particularly those with extranodal extension or positive surgical margins, though its long-term benefits require further exploration.

Recurrent or metastatic disease

The recurrent or metastatic disease section of the review discusses the treatment options and prognosis for patients with head and neck squamous-cell carcinoma who experience disease recurrence or metastasis. Key points include:

1. Poor Prognosis:

   • Recurrent or metastatic head and neck cancer has a poor prognosis, with survival typically ranging from 6 to 9 months without treatment.

2. Systemic Therapy as Mainstay:

   • For patients with recurrent or metastatic disease that cannot be treated with salvage surgery or radiotherapy, systemic therapy becomes the primary treatment option.
   • Common systemic therapies include platinum-based drugs, taxanes, antifolates, and the EGFR antibody cetuximab.

3. Choice of Treatment:

   • The choice of systemic therapy depends on several factors, including the patient’s performance status, coexisting conditions, prior treatments, and the toxic effects profile of the available drugs.
   • Combination therapies, such as cetuximab with chemotherapy (e.g., fluorouracil plus platinum), have been shown to improve overall survival compared to chemotherapy alone.

4. Immunotherapy Advances:

   • The development of PD-1 immune-checkpoint inhibitors, such as pembrolizumab and nivolumab, has significantly impacted the treatment of recurrent or metastatic head and neck cancer.
   • Both pembrolizumab and nivolumab have shown durable responses and survival benefits in patients previously treated with platinum-based chemotherapy, leading to their approval by the FDA in 2016.

5. Clinical Trials and Biomarkers:

   • The phase 3 KEYNOTE-040 trial with pembrolizumab and the CheckMate 141 trial with nivolumab demonstrated survival improvements compared to standard therapies, particularly in patients with PD-L1 expression on tumor cells.
   • PD-L1 expression is considered a predictive biomarker, although its reliability varies due to differences in assays and cutoff values.

6. First-Line Therapy:

   • Pembrolizumab, alone or combined with chemotherapy, has become a standard first-line treatment for recurrent or metastatic squamous-cell carcinoma of the head and neck, particularly in patients with PD-L1-expressing tumors.
   • The KEYNOTE-048 study showed that pembrolizumab with chemotherapy improved overall survival compared to the EXTREME regimen (cetuximab plus chemotherapy) in the total population.

7. Challenges and Future Directions:

   • Despite the advances with immunotherapy, a significant majority of patients (85-95%) do not respond to PD-1 inhibitors or experience disease progression after an initial response.
   • Ongoing research is focused on combining immunotherapy with other innovative approaches, such as HPV vaccines, T-cell therapies, and other immune modulators, to improve outcomes for patients with advanced disease.

In summary, the treatment of recurrent or metastatic head and neck cancer has evolved with the introduction of systemic therapies and immunotherapies, particularly PD-1 inhibitors. Despite these advances, challenges remain, and research is ongoing to improve survival and treatment outcomes for these patients.

1. Chow LQM. Head and Neck Cancer. Reply. N Engl J Med. 2020 May 14;382(20):e57. doi: 10.1056/NEJMc2001370. PMID: 32402180. ↩