What alternate radiotherapy fractionation schedules have been studied for locally advanced head and neck squamous cell carcinoma, and what are the key landmark randomized trials and their outcomes?

Alternate Fractionation Schedules in Head and Neck Cancer: Landmark Trials and Outcomes

Overview of Altered Fractionation Rationale

Altered fractionation schedules—specifically hyperfractionation and accelerated fractionation—have demonstrated superior locoregional control and survival compared to conventional fractionation in locally advanced head and neck squamous cell carcinoma, with the strongest evidence supporting hyperfractionation for patients under 60 years of age. 1

The biological basis for altered fractionation stems from the rapid growth potential of head and neck squamous cancers and their ability to compensate for radiation-induced cell loss through accelerated repopulation during treatment. 1 This phenomenon makes prolonged conventional schedules less effective, particularly when delivering less than 1000 cGy per week. 1

Landmark Trials: RTOG 90-03

Trial Design and Arms

The RTOG 90-03 trial represents the most definitive North American study comparing fractionation schedules in head and neck cancer. 1, 2 This four-armed phase III randomized trial compared:

• Standard fractionation (SF): 70 Gy at 2.0 Gy once daily over 7 weeks 1
• Hyperfractionation (HFX): 81.6 Gy at 1.2 Gy twice daily over 7 weeks 1
• Accelerated fractionation with concomitant boost (AFX-C): 72 Gy delivered with split-course technique over 6 weeks 1, 2
• Accelerated fractionation with split course: Another accelerated variant 1

Key Outcomes at 2 Years

Both hyperfractionation and accelerated fractionation with concomitant boost demonstrated statistically significant improvements in 2-year locoregional control and disease-free survival compared to standard fractionation. 1, 2 The AFX-C schedule showed particular promise for improving locoregional control (P=.02 for locoregional control benefit). 1, 2

Acute mucosal toxicity was significantly higher with AFX-C compared to standard fractionation, but critically, the incidence of grade 3 or worse late effects between 6 and 24 months did not differ significantly among treatment groups. 1, 2 This finding is essential because it demonstrates that the therapeutic gain from altered fractionation is not offset by increased long-term morbidity.

Long-Term Follow-Up Results

Long-term follow-up of RTOG 90-03 confirmed statistically significant improvements in both locoregional control and overall survival with hyperfractionation compared to standard fractionation. 1, 2 This represents level I evidence establishing hyperfractionation as a superior option for definitive radiotherapy alone in locally advanced disease. 2

Landmark Trials: EORTC Studies

EORTC 22791 (Hyperfractionation)

The EORTC 22791 trial compared hyperfractionation (1.15 Gy twice daily to 80.5 Gy over 7 weeks) versus conventional fractionation (2.0 Gy once daily to 70 Gy over 7 weeks) in T2-T3, N0-1 oropharyngeal carcinoma excluding base of tongue primaries. 1

At 5 years, hyperfractionation achieved statistically significant improvement in local control (56% vs 38%; P=0.01) with no increase in late complications. 1 Long-term follow-up analysis demonstrated a small but significant survival advantage for hyperfractionation (P=0.05). 1

EORTC 22851 (Accelerated Fractionation)

The EORTC 22851 protocol compared accelerated fractionation (1.6 Gy three times daily to 72 Gy over 5 weeks) with conventional fractionation (1.8-2.0 Gy once daily to 70 Gy over 7-8 weeks) in various intermediate to advanced head and neck cancers. 1

Patients receiving accelerated fractionation had significantly better locoregional control at 5 years (P=0.02), with disease-specific survival showing a favorable trend (P=0.06). 1 However, both acute and late toxicity were increased with acceleration, raising important questions about the net therapeutic advantage. 1

Meta-Analysis: Quantifying the Survival Benefit

A meta-analysis of updated individual patient data from 15 randomized trials demonstrated an absolute survival benefit for altered fractionation of 3.4% at 5 years (hazard ratio 0.92; 95% CI 0.86-0.97; P=0.003). 1

Critical findings from this meta-analysis include:

• The survival benefit was limited to patients younger than 60 years of age 1
• Hyperfractionation specifically was associated with an 8% survival benefit at 5 years 1
• Standard fractionation served as the control arm in all included trials 1

Important Caveat: GORTEC 99-02

The GORTEC 99-02 trial reported that altered fractionation did not improve outcomes compared to conventional fractionation, creating ongoing controversy. 1 This discordant result has prevented consensus among NCCN member institutions regarding the universal adoption of altered fractionation schedules for stage III-IV oral cavity, oropharynx, supraglottic larynx, and hypopharyngeal squamous cell cancers. 1

Altered Fractionation with Concurrent Chemotherapy

The Controversy

No consensus exists regarding the optimal radiation dose fractionation scheme when combined with concurrent chemotherapy. 1 Most published studies have used conventional fractionation (2.0 Gy per fraction to 70 Gy in 7 weeks) with single-agent high-dose cisplatin (100 mg/m² every 3 weeks). 1

RTOG 0129: Accelerated vs Conventional with Chemotherapy

RTOG 0129 directly compared accelerated fractionation with 2 cycles of concurrent cisplatin versus standard fractionation with 3 cycles of concurrent cisplatin in locally advanced disease. 1

No significant difference in overall survival was observed between the arms, suggesting that when chemotherapy is added, the fractionation schedule may be less critical. 1 This finding has important practical implications, as conventional fractionation with adequate chemotherapy cycles may be preferable due to lower acute toxicity burden.

Toxicity Considerations

Concurrent chemoradiation increases acute toxicity compared to radiation alone, though the increase in late toxicity beyond that caused by radiotherapy alone remains less clear. 1 Altered fractionation and/or multiagent chemotherapy may further increase the toxicity burden, requiring experienced teams and substantial supportive care. 1

Numerous trials have demonstrated that modified fractionation combined with concurrent chemotherapy is more efficacious than modified fractionation alone, but at the cost of significantly increased acute toxicity. 1

Practical Dosing Recommendations

Definitive Radiotherapy Doses

For conventional definitive fractionation:

• High-risk sites (primary tumor and involved lymph nodes): 66-70 Gy at 2.0-2.2 Gy per fraction 1
• Doses exceeding 72 Gy using conventional fractionation (2.0 Gy/fraction) may lead to unacceptable rates of normal tissue injury 1

For hyperfractionation:

• High-risk sites: Up to 81.6 Gy at 1.2 Gy per fraction twice daily 1
• This converts to approximately 70 Gy₂ (biologically equivalent dose) 3

For elective nodal irradiation:

• Low-risk and intermediate-risk sites: 44-63 Gy depending on tumor burden and technique 1
• For 3D conformal RT: 44-50 Gy at 2.0 Gy per fraction 1
• For IMRT: 54-63 Gy at 1.6-1.8 Gy per fraction 1

Postoperative Radiotherapy

Higher doses of postoperative radiotherapy alone (60-66 Gy) or with chemotherapy are recommended for high-risk features including extracapsular disease and/or positive margins. 1 The RTOG 9501 trial established that concurrent chemoradiotherapy (cisplatin 100 mg/m² on days 1,22,43) with 60 Gy in 30 fractions over 6 weeks (with optional 6 Gy boost) achieves better long-term outcomes in high-risk patients compared to radiotherapy alone. 2

The preferred interval between resection and commencement of postoperative radiotherapy is 6 weeks or less. 1

Clinical Decision Algorithm

For Radiotherapy Alone (No Chemotherapy)

T1 and favorable T2, N0-1 tumors:

• Conventional fractionation: 66-70 Gy at 2.0 Gy per fraction 4
• Ensure at least 1000 cGy per week delivery 1

Unfavorable T2 or exophytic T3, N0-1 disease:

• Altered fractionation alone is preferred 4
• Hyperfractionation: 81.6 Gy at 1.2 Gy twice daily (6-hour interfraction interval minimum) 1
• Accelerated fractionation with concomitant boost: 72 Gy over 6 weeks 1, 2

T1-2, N2-3 tumors:

• Radiation with planned neck dissection 4
• Consider altered fractionation for improved locoregional control 4

For Combined Modality Therapy

More advanced head and neck squamous cell carcinomas (T3-4 or N2-3):

• Concurrent chemoradiation is the standard of care 4
• Conventional fractionation (70 Gy at 2.0 Gy per fraction) with cisplatin 100 mg/m² every 3 weeks is most commonly used 1
• Altered fractionation with chemotherapy may be considered but increases toxicity without proven survival benefit over conventional fractionation with adequate chemotherapy 1

Age consideration:

• Patients under 60 years derive greater benefit from altered fractionation 1
• Consider patient performance status and ability to tolerate increased acute toxicity 1

Postoperative Setting

Standard risk factors (advanced T stage, depth of invasion, multiple positive nodes without extracapsular spread, perineural/lymphatic/vascular invasion):

• Postoperative radiotherapy: 60 Gy at 2.0 Gy per fraction 1

High-risk features (extracapsular disease or positive margins):

• Postoperative concurrent chemoradiotherapy: 60-66 Gy with cisplatin 100 mg/m² on days 1,22,43 1, 2
• Begin within 6 weeks of surgery 1

Common Pitfalls and How to Avoid Them

Inadequate Weekly Dose Delivery

Delivering less than 1000 cGy per week in radiotherapy-alone settings leads to higher recurrence rates, particularly in early-stage glottic laryngeal cancer. 1 Trials have shown higher recurrence with daily fraction sizes less than 200 cGy when cumulative weekly dose falls below 1000 cGy. 1

Excessive Total Dose with Conventional Fractionation

External beam radiation doses exceeding 72-75 Gy using conventional fractionation (2.0 Gy/fraction) lead to unacceptable rates of normal tissue injury. 1 If higher doses are needed, modify fractionation to less than 2.0 Gy per fraction for at least some of the treatment. 1

Inadequate Interfraction Interval

When delivering twice-daily fractionation (hyperfractionation or accelerated fractionation), maintain at least a 6-hour interval between fractions to allow for normal tissue repair. 5 Shorter intervals increase late toxicity risk without improving tumor control.

Combining Altered Fractionation with Chemotherapy Without Adequate Support

Altered fractionation combined with concurrent chemotherapy significantly increases acute toxicity and should only be performed by experienced teams with substantial supportive care infrastructure. 1 Consider conventional fractionation with chemotherapy as a safer alternative with equivalent survival outcomes. 1

Ignoring Age in Treatment Selection

The survival benefit from altered fractionation is limited to patients younger than 60 years. 1 For older patients, the increased acute toxicity burden may not be justified by the marginal benefit, making conventional fractionation more appropriate.

Delayed Postoperative Radiotherapy

Initiating postoperative radiotherapy beyond 6 weeks after surgery compromises outcomes. 1 Prioritize timely initiation even if it means simplifying the treatment plan or using conventional fractionation instead of altered schedules.

Supporting Evidence from Additional Studies

A prospective randomized study comparing conventional 5 fractions per week (66-70 Gy in 33-35 fractions) versus hyperfractionation 10 fractions per week (70.4 Gy in 64 fractions) following induction chemotherapy demonstrated superior outcomes with hyperfractionation. 6 The overall response at completion was 95.7% with hyperfractionation versus 89.5% with conventional fractionation, with complete response rates of 76.6% versus 64.6% respectively. 6 Hyperfractionation significantly increased progression-free survival and locoregional control. 6

An accelerated fractionation schedule using two fractions given 6 hours apart (1.7 Gy to comprehensive volume in morning, 1.1 Gy to gross disease in afternoon) achieved 100% response rate with 83% complete response in 13 patients who completed therapy. 5 At median follow-up of 24 months, corrected survival was 70%, demonstrating that accelerated schedules can be delivered without planned treatment breaks while maintaining excellent outcomes. 5