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• In the curative intent setting:
  • Concurrent chemoradiation is associated with risk of severe acute and long-term toxicities
• The combined results of four prospective trials:
  • Indicate that the rate of acute treatment-related death for standard cisplatin based chemoradiation:
    • For locally advanced head and neck squamous cell carcinoma:
      • Is approximately 4%:
        • 22 treatment related deaths among 545 patients
• Acute mucositis in the radiation field:
  • Can compromise nutritional intake severely,  and placement of a percutaneous gastrostomy tube:
    • Often is an effective strategy to improve nutrition in this setting
• Dermatitis in the radiation field:
  • Varies in severity among patients:
    • This issue has received increasing attention since the 2006 Food and Drug Administration approval for the use of cetuximab concurrent with radiation therapy for persons with head and neck squamous cell carcinoma
• Long-term complications of chemoradiation can include:
  • Xerostomia
  • Hypothyroidism
  • Trismus
  • Pharyngeal stricture
  • Osteoradionecrosis
• Although xerostomia remains a common long-term symptom after treatment:
  • The incidence of xerostomia with intensity-modulated radiation therapy:
    • Appears to be lower than the incidence associated with three-dimensional conventional radiotherapy
• Regarding hypothyroidism, in a review of 118 patients who participated in phase I / II trials of sequential chemotherapy and radiation for stage III / IV head  and neck cancer:
  • Elevated levels of thyroid-stimulating hormone  were detected in 45% of patients:
    • At a median of 24 months after radiation therapy
• Stricture requiring pharyngoesophageal dilation:
  • May occur in up to 21% of patients who receive definitive radiotherapy
    • The primary tumor site in the hypopharynx or oropharynx:
      • Has been identified as a risk factor for pharyngeal stricture in retrospective studies
• Fibrosis of the muscles of mastication:
  • As a consequence of chemoradiation may result in trismus:
    • Although the retrospective nature of this data has limited the ability to clearly establish risk factors for trismus
• For patients receiving combined modality therapy, accurate and comprehensive measurement of treatment-associated adverse events is challenging:
  • In clinical trials, traditional methods of toxicity reporting describe the frequency and severity of cumulative adverse events during the treatment interval.
  • The National Cancer Institute Common Toxicity Criteria for Adverse Events is a widely used method for toxicity reporting of this nature:
    • However, it is recognized that traditional methods probably do not fully summarize the extent and magnitude of acute and long-term adverse events
    • To address these concerns, a new reporting system (“TAME”) designed to account for the multiplicity and time dimensions of adverse events has been developed
• In a retrospective analysis of five trials for patients with head and neck cancer that was performed by the RTOG, the newer method appeared better able to distinguish between the acute toxicity burdens among treatment groups compared with traditional methods for summarizing adverse events

• Non-invasive follicular thyroid neoplasm with papillary-like nuclear features:
  • NIFTP is the pathological definition of a type of noninvasive follicular cell-derived thyroid neoplas:
    • That was first described in 2016
  • This topic post-dated the 2015 ATA thyroid nodule and DTC guidelines:
    • But a subsequent ATA task force statement in 2017 supported adoption of the NIFTP nomenclature for this entity
  • In 2017, NIFTP were classified as a distinct category in the revised WHO Classification of Tumors of Endocrine Organs:
    • Corresponding to a neoplasm with very low malignant potential
  • NIFTP:
    • Comprise approximately 2.1% to 9.6% of follicular cell derived thyroid neoplasms;
      • With relatively lower incidence in Asia than in North America and Europe
  • NIFTP:
    • Are characterized by validated histological inclusion and exclusion features (Table):
      • The original NIFTP validation study excluded tumors:
        • Measuring ≤ 1 cm
        • Those with oncocytic features
    • However, as subsequent literature has shown that tumors measuring ≤ 1 cm (micro-NIFTPs) or with oncocytic features (oncocytic-NIFTPs):
      • Demonstrate similar clinical behavior to those of original NIFTP these features also are included in the tumor’s current pathological definition
  • The initial definition of NIFTP had required the presence of < 1% papillae:
    • But subsequent experience has shown this feature can be associated with:
      • Lymph node metastases:
        • Therefore, the diagnostic criteria have been revised to require that papillae are absent
  • It is recommended to carefully examine the entire tumor capsule interface and tumor:
    • To exclude the possibility of invasive features and presence of papillae
  • NIFTPs:
    • Often coexist with one or more NIFTPs or other thyroid malignancies in the ipsilateral or contralateral lobes.
  • Studies assessing the molecular profile of NIFTPs:
    • Have shown them to be clonal neoplasms
  • Molecular alterations are present in approximately 78% of cases:
    • With approximately 30% to 54% of NIFTP tumors:
      • Harboring a RAS mutation:
        • NRAS mutations most common:
          • Followed by HRAS and rarely KRAS mutations
      • However, the NRAS mutations seen in NIFTPs may also be identified in FTCs and IEFVPTC:
        • Therefore, they are nonspecific
    • A small subset of NIFTP cases have been shown to harbor:
      • PAX8::PPARc fusions
      • THADA fusions
      • BRAF K601E mutations
    • Some studies also have explored miRNA expression in NIFTP cases:
      • Demonstrating that two mi-RNAs (miR-10a05p and miR-320e):
        • Can effectively discriminate between NIFTP and the infiltrative follicular variant of PTC:
          • Further studies are required to validate these findings
  • While NIFTPs are characterized by:
    • A follicular growth pattern and nuclear features of PTC:
      • They are associated with extremely low malignant potential
    • Several multiinstitutional series (largest sample, n = 363), including several that reclassified DTCs as NIFTP upon retrospective analyses:
      • Have mostly reported zero risk of disease persistence / recurrence:
        • Over a mean or median follow-up of up to 11.8 years
    • Lymph node metastases:
      • Have been seen in < 5% of the total cohort and in only a few series
    • Only one retrospective analysis of 102 cases showed the presence of distant metastases (to the lungs) in one case:
      • Although this study was limited by incomplete follow-up (80%) and a high proportion of patients who received more aggressive care (total thyroidectomy and radioiodine ablation)
  • At present, there are no available data comparing the clinical benefits and harms of various short- and long-term monitoring strategies in patients with NIFTP tumors

• Surgical Management of DCIS (2024 to 2025 Update):
  • Re-excision vs Mastectomy:
    • Re-excision is indicated for positive (ink-on-tumor) margins after lumpectomy;
      • Unless specific skin-only or fascia-only circumstances justify margin acceptance:
        • Always document clearly
    • Total mastectomy is appropriate when negative margins cannot be achieved, or if disease is diffuse or multifocal:
      • Most mastectomy patients do not require radiotherapy after DCIS resection
  • Reference:
    • American Cancer Society. Treatment of ductal carcinoma in situ (DCIS). accessed June 2025.
  • Reference:
    • American Society of Breast Surgeons. “Margins in Breast Conservation Surgery: Resource Guide.” 2024.
  • Axillary Management:
    • Avoid ALND (axillary lymph node dissection):
      • In pure DCIS without clinical / radiologic evidence of invasion or nodal disease
    • SLNB (sentinel lymph node biopsy):
      • Omit for pure DCIS treated with BCS when there’s no clinical / radiological suspicion of invasion:
        • Nodal involvement is very low
      • Perform or strongly consider if:
        • Mastectomy is planned (because SLNB is not feasible afterward if invasion is unexpectedly found)
        • There’s high suspicion of invasion (e.g., palpable mass, abnormal imaging / biopsy)
        • Excision location could compromise future SLN (upper-outer quadrant /axillary tail)
    • References:
      • American Society of Breast Surgeons, “Management of the Axilla: Position Statement.” 2024.
      • American Cancer Society. Treatment of ductal carcinoma in situ (DCIS). accessed June 2025.
      • NCCN-derived peer-reviewed statement, “Strong consideration for SLNB with mastectomy or mapping-compromising locations,” published in Annals of Surgical Oncology (exact citation not available; institutional statement)
    • Emerging data:
      • Older patients ≥ 50 with radiologically normal axilla undergoing mastectomy:
        • Suggest SLNB may be omitted, but this is not yet in guidelines and must be individualized
      • Reference:
        • Madak-Erdogan et al., Annals of Surgical Oncology, 2023
  • De-escalation and Active Surveillance:
    • Early results from COMET (Comparison of Operative versus Monitoring and Endocrine Therapy) randomized trial in low-risk DCIS:
      • At 2 years active surveillance ± endocrine therapy yielded non-inferior rates of invasive progression compared to surgery /RT:
        • Patient-reported outcomes are pending
      • Long-term outcomes:
        • Not yet available
      • Active surveillance:
        • Should only be considered within clinical trials or carefully selected settings
    • Reference:
      • Narod et al., Journal of Clinical Oncology, 2025; and associated JAMA Oncology report 2025.
• Margins in DCIS:
  • Standard Adequate Margin:
    • For pure DCIS (and DCIS with microinvasion) treated with BCS plus whole-breast radiotherapy:
      • A negative margin of ≥ 2 mm is recommended:
        • Wider margins do not further reduce ipsilateral breast tumor recurrence (IBTR)
    • Reference:
      • Morrow M, Van Zee KJ, Solin LJ, et al. “Society of Surgical Oncology–American Society for Radiation Oncology–American College of Surgeons consensus guideline on margins for breast-conserving surgery with whole-breast irradiation in ductal carcinoma in situ.” Journal of Clinical Oncology. 2016;34(33):4040–4046.
      • American Society of Breast Surgeons. “Margins in Breast Conservation Surgery: Resource Guide.” 2024.
  • Margin-Width Decision Chart:
    • Ink-positive margins:
      • Re-excision required
        • Reference: American Society of Breast Surgeons. 2024.
    • < 2 mm but still negative:
      • With WBRT planned, re-excision generally not required, unless there are complicating features:
        • Multifocality, specimen fragmentation, APBI plans
      • Reference: American Society of Breast Surgeons. 2024.
    • ≥ 2 mm:
      • Adequate:
        • No evidence to support further wider excision
      • Reference: American Society of Breast Surgeons. 2024.
    • If RT is omitted (e.g., in select older or low-risk patients):
      • Retrospective data suggest wider margins correlate with lower local events:
        • But no definitive guideline threshold exists
        • Document discussions clearly
      • Reference: American Society of Breast Surgeons. 2024.
    • Mixed Invasive + DCIS:
      • Treat according to invasive cancer standards:
        • “No ink on tumor” is adequate, even if DCIS is near the edge
      • Reference: American Society of Breast Surgeons. 2024.
    • DCIS with Microinvasion (≤ 1 mm):
      • Manage margins like pure DCIS:
        • Aim for ≥ 2 mm margin with whole-breast RT
      • Reference: American Society of Breast Surgeons. 2024.
    • Margin Exceptions:
      • Skin-only or fascia-only positive margins after full-thickness excision may be acceptable without re-excision if no residual breast parenchyma remains:
        • Document rationale
      • Reference: American Society of Breast Surgeons. 2024.
    • Atypical ductal hyperplasia (ADH), ALH, or classic LCIS at / near the margin:
      • Should not prompt re-excision:
        • Re-excise based solely on DCIS or invasive cancer margins
      • Reference: American Society of Breast Surgeons. 2024.
    • New Evidence (PRECISION Cohort):
      • PRECISION pooled international cohort (≈ 47,000 DCIS cases) demonstrated that:
        • Margins < 2 mm are associated with higher 10-year ipsilateral events compared to ≥ 2 mm, although absolute differences are modest, supporting the 2 mm standard with RT
      • Reference:
        • PRECISION Collaboration. “Margin width and local recurrence in DCIS: pooled analysis of international cohorts.” BMJ. 2023;383:e076022.
        • PRECISION Collaboration. PubMed; PMID 37903527.
• References:
  • Morrow M, Van Zee KJ, Solin LJ, et al. Society of Surgical Oncology–American Society for Radiation Oncology–American College of Surgeons consensus guideline on margins for breast-conserving surgery with whole-breast irradiation in ductal carcinoma in situ. Journal of Clinical Oncology. 2016;34(33):4040–4046.
  • American Society of Breast Surgeons. Margins in Breast Conservation Surgery: Resource Guide. 2024. Available from: https://www.breastsurgeons.org/docs/statements/asbrs-rg-margins.pdf
  • American Society of Breast Surgeons. Management of the Axilla: Position Statement. 2024. Available from: https://www.breastsurgeons.org/docs/statements/management-of-the-axilla.pdf
  • American Cancer Society. Treatment of ductal carcinoma in situ (DCIS). Accessible via: https://www.cancer.org/cancer/types/breast-cancer/treatment/…dcis.html (Accessed June 2025).
  • Narod SA, et al. COMET trial early outcomes — active surveillance versus surgery/radiation in low-risk DCIS. Journal of Clinical Oncology. 2025.
  • PRECISION Collaboration. Margin width and local recurrence in DCIS: pooled analysis of international cohorts. BMJ. 2023;383:e076022.
  • PRECISION Collaboration. PMID: 37903527.
    Madak-Erdogan Z, et al. Considerations regarding omission of SLNB in selected DCIS mastectomy patients. Annals of Surgical Oncology. 2023.

• One in eight women in the United States (US):
  • Will be diagnosed with breast cancer in her lifetime:
    • 20% to 25% of these newly diagnosed cases;
      • Will be DCIS
• In 2025:
  • An estimated 59, 080 cases of DCIS:
    • Will be diagnosed in US
• Widespread use of screening mammography:
  • Has resulted in a 10-fold increase in the reported incidence of DCIS since the mid-1980s:
    • However, since 2003:
      • The incidence of DCIS has declined in women aged 50 years and older:
        • Possibly due to decreased use of hormone replacement therapy
      • The incidence of DCIS in women aged under 50 years:
        • Continues to increase
  • Approximately 1 in every 1,300 mammography examinations performed in US:
    • Will lead to a diagnosis of DCIS:
      • Representing 17% to 34% of all mammographically detected breast cancers
  • Before the introduction of screening mammography,:
    • Most cases of DCIS were not detected:
      • Until a palpable mass formed:
        • But today 80% to 85% of DCIS cases are detected on screening mammography
• The incidence of DCIS in autopsy studies is higher than in the general population:
  • Suggesting that not all DCIS lesions are clinically significant:
    • Supporting concerns that most of the increase in DCIS incidence is due to the detection of nonaggressive subtypes:
      • That are unlikely to progress to invasive cancer
• The median age reported for patients with DCIS:
  • Ranges from 47 to 63 years:
    • Similar to that reported for patients with invasive carcinoma
  • However, the age of peak incidence for DCIS:
    • 96.7 per 100,000 women:
      • Occurs between the ages of 65 and 69 years:
        • Which is younger than for invasive breast cancer:
          • For which peak incidence:
            • 453.1 per 100,000 womem:
              • Occurs between the ages of 75 and 79 years
• The frequency of first-degree relatives having breast cancer (10% to 35%) as well as rates of deleterious mutations in the breast cancer–associated (BRCA) genes are:
  • Similar for patients with DCIS as for women with invasive breast cancer
• Other risk factors for DCIS:
  • Including older age, proliferative breast disease, increased breast density, nulliparity, older age at primiparity, history of breast biopsy, early menarche, late menopause, long-term use of postmenopausal hormone replacement therapy, and elevated body mass index in postmenopausal women:
    • Are the same as those for invasive breast cancer

• Throughout the American Thyroid Association (ATA) 2025 Thyroid Cancer Guidelines:
  • The 5th edition of the WHO Classification of Thyroid Tumors has been utilized for descriptions of the types of non-anaplastic follicular cell-derived thyroid carcinomas and NIFTP
• Approximately 90% of thyroid cancer cases are well differentiated and are classified based on the predominant histomorphology:
  • However, they now also can be categorized based on their molecular profiles
• Four main types of DTC include:
  • Follicular thyroid carcinoma (FTC)
  • Invasive encapsulated follicular variant of papillary thyroid carcinoma (IEFVPTC)
  • Papillary thyroid carcinoma (PTC)
  • Oncocytic thyroid carcinoma (OTC)
• PTC is the most common type of DTC:
  • PTC is typically indolent and associated with excellent long-term survival:
    • 96% at 5 years
    • 93% at 10 years
    • Greater than 90% at 20 years
  • Overall, mortality rates for PTC are:
    • 1% to 6.5%
  • Overall recurrence rate of 15% to 35%:
    • Tumor recurrence typically occurs in the:
      • Tumor bed
      • Cervical lymph nodes
      • Distant sites (rarely)
  • PTCs have characteristic nuclear features:
    • Core elements fall into three buckets (per WHO 5th ed. framework and modern scoring systems):
      • Size / shape/ crowding:
        • Nuclear enlargement
        • Elongation / ovality
        • Overlapping / crowding
        • Pseudostratification at the papillary edges
          • These are low-power cues to look closer
      • Membrane irregularities:
        • Nuclear grooves (longitudinal folds)
        • Intranuclear cytoplasmic pseudoinclusions (INCIs):
          • Round, sharply circumscribed, eosinophilic inclusions:
            • Caused by cytoplasmic invagination
        • Irregular nuclear contours / notches
        • Notes for practice:
          • Grooves are sensitive but not specific
          • INCIs are more specific for PTC when true (focus and multiple planes help)
      • Chromatin changes:
        • Chromatin clearing with peripheral margination:
          • The classic “Orphan Annie-eye” look
        • Fine (“powdery”) chromatin with micronucleoli
        • Apparent thickened nuclear membrane on H&E
        • Clearing can be mimicked by Hashimoto thyroiditis or fixation artifact:
          • So it needs to be interpreted with the full nuclear constellation
    • How pathologists operationalize this:
      • In follicular-patterned lesions (e.g., NIFTP vs infiltrative FV-PTC), a 3-category nuclear score is applied:
        • Size / shape
        • Membrane irregularities
        • Chromatin features
      • A score ≥ 2 supports PTC-type nuclear features
      • NIFTP requires papillary-type nuclei (score ≥ 2) and strict architectura l/ invasion criteria
    • WHO 2022 emphasizes first deciding whether PTC-type nuclei are present before subtyping;
      • This step drives nomenclature:
        • Low-risk neoplasm vs malignancy
    • Molecular correlations you’ll see in reports:
      • BRAF V600E–driven tumors (classic / tall-cell subtypes):
        • Tend to show florid nuclear features:
          • Grooves (longitudinal folds)
          • INCIs
          • Glassy nuclei
      • RAS-mutated follicular-patterned tumors:
        • Often have subtler nuclei
    • Papillary thyroid carcinomas (PTC) can present as:
      • Infiltrative and encapsulated tumors
    • Molecular studies have shown that most PTCs (90%) develop by:
      • The activation of a Mitogen-Activated Protein Kinase (MAPK) pathway-event:
        • This activation occurs via mutually exclusive mutations in:
          •  BRAF or RAS oncogenes
      • A subset of PTCs is acquired by gene fusions involving:
        • Rearranged during transfection (RET) or (less commonly) other receptor tyrosine kinases
      • Oncogenic mutations at BRAF^V600E:
        • Are the most common in PTC
      • A minority can show non-V600E mutations:
        • Such as BRAF^K601E or BRAF fusions
      • The IEFVPTC is an encapsulated and invasive follicular-patterned tumor:
        • Based on its tendency for vascular invasion, distant metastasis, and molecular profile:
          • It can behave similarly to FTC
• Histologically, FTCs are encapsulated follicular patterned tumors:
  • Without the nuclear features of PTC
  • They are characterized by the presence of:
    • Vascular:
      • Limited or extensive
    • Capsular invasion:
      • Vascular invasion involving vessels within the tumor capsule
    • Widely invasive:
      • Extensive invasion of the thyroid parenchyma beyond the tumor capsule
  • These tumors are mostly driven by activating mutations in:
    • RAS oncogenes (NRAS > HRAS > KRAS), PAX8::PPARγ fusions, EIF1AX mutations, PIK3CA mutations, or loss of PTEN expression:
      • BRAF^V600E and RET fusions typically are not seen in FTC
    • Expression of PAX8::PPARγ fusions oncoprotein:
      • Occur in 25% of FTC:
        • In which the thyroid transcription factor PAX8 drives the expression of PPARγ:
          • A receptor involved in adipocyte biology
    • Mutations in DICER1:
      • Which encodes a ribonuclease in the processing of microRNA precursors:
        • Occur in RAS-like thyroid neoplasms and are prevalent in FTC
      • DICER1 mutations can also be seen in subsets of PTC, differentiated high-grade thyroid carcinoma (DHGTC), poorly differentiated thyroid carcinoma (PDTC), and anaplastic thyroid carcinoma (ATC)
• With greater recognition of the unique genomic features of OTC (previously known as Hürthle cell carcinoma) and different clinical behavior from classical forms of FTC:
  • These tumors are now considered a third form of DTC:
    • Rather than a subtype of FTC in the current WHO classification:
      • They account for ∼ 3% of all DTC
  • An “oncocyte” is an enlarged polygonal cell with an abundant granular eosinophilic cytoplasm, round nuclei with even chromatin pattern, and prominent nucleoli:
    • As defined by WHO:
      • Oncocytic neoplasms are usually encapsulated and composed of ≥ 75% oncocytic cells
    • Oncocytic features can be identified in some PTC or FTC cells at lower frequencies
  • Most of these tumors are larger in size; however, smaller tumors can be identified
  • Like FTC, the presence of invasive characteristics:
    • Tumor capsule and / or vascular invasion:
      • In an encapsulated oncocytic neoplasm:
        • Is diagnostic of OTC
    • OTCs can be classified as:
      • Minimally invasive
      • Encapsulated angio-invasive
      • Widely invasive
  • Genomically, OTCs are characterized typically by:
    • A near-haploid genome
    • Mitochondrial DNA mutations:
      • Commonly involving genes encoding Complex 1 of the mitochondrial respiratory chain
    • Mutations in DAXX and ATRX:
      • Involved in telomere length
    • OTCs can also have mutations that activate:
      • Mammalian target of rapamycin (mTOR) and MAPK signaling
    • Like PTC and FTC:
      • More aggressive OTCs can have mutations in the:
        • TERTpromoter or TP53
    • Clinically, some studies have shown that OTCs have a greater tendency toward lymph node metastases while retaining a predilection for distant metastases, and unlike FTC:
      • OTCs often are not radioiodine-avid despite retaining other differentiated features:
        • Such as Tg secretion and TSH receptor expression
• The 5th edition of the WHO Classification of Thyroid Tumors:
  • Also introduces a new category of high-grade follicular cell derived, non-anaplastic carcinoma that includes:
    • PDTC and DHGTC.
  • By molecular analysis, poorly differentiated thyroid cancer and DHGTC:
    • Harbor driver mutations in BRAF (BRAF^V600E) and RAS genes:
      • In some cases may show gene fusions:
        • Often RET and NTRK3
    • Additional mutations in the:
      • TERT promoter, PIK3CA, and TP53 are commonly identified
  • DHGTC has been defined by certain authors as a:
    • “Thyroid malignancy” that is recognized as DTC but in which certain histological and cytopathologic features are present that justify the lesion being classified as “high-grade”
    • The DHGTCs are invasive, high-grade carcinomas:
      • That show one of the following two histological features:
        • Mitotic count ≥ 5 per 2 mm²
        • Tumor necrosis
  • By contrast, thyroid carcinomas classified as PDTC are follicular cell-derived tumors that show a minor component of DTC (papillary, follicular, oncocytic):
    • Show solid and / or insular growth pattern with presence of either:
      • Necrosis or ≥ mitotic count of 3 per 2 mm², and lack the usual histological characteristics and aggressiveness of ATC
  • In both cases, clinical behavior is considered:
    • Intermediate between DTC and ATC

• Citation: Ghi MG et al. Induction TPF followed by concomitant treatment versus concomitant treatment alone in locally advanced head and neck cancer: a phase II–III trial. Annals of Oncology, 1 September 2017; 28(9): 2206–2212. DOI: 10.1093/annonc/mdx299
• Key Findings:
  • Design:
    • A randomized phase II–III study comparing:
      Induction TPF (docetaxel, cisplatin, 5‑FU) followed by concomitant treatment (either chemoradiation [CCRT] or cetuximab/RT),
      versus concomitant treatment alone (CCRT or cetuximab/RT without induction)
  • Participants:
    • 414 patients analyzed (206 in the induction arm, 208 in the no‑induction arm)
  • Outcomes (median follow-up ~ 44.8 months):
    • Overall Survival (OS):
      • Significantly improved with induction:
        • Hazard Ratio (HR) 0.74; 95% CI, 0.56–0.97; P = 0.031
    • Progression-Free Survival (PFS):
      • Significantly better in the induction (IC) arm (P = 0.013)
    • Complete Response Rates:
      • Higher in the induction arm (P = 0.0028)
    • Locoregional Control:
      • Also significantly improved (P = 0.036)
    • Treatment Compliance:
      • Not adversely affected by induction therapy 
• Summary for Head and Neck Surgeons
  • Publication:
    • This is an official, peer-reviewed publication, no longer merely an abstract
  • Significance:
    • It remains the only phase II–III trial reporting a statistically significant survival benefit (OS, PFS), better response rates, and improved locoregional control when adding TPF induction before chemoradiation, without harming treatment compliance
  • Clinical Interpretation:
    • These results strengthen the hypothesis that carefully administered TPF induction can offer meaningful benefit:
      • But they differ from the negative phase III findings of PARADIGM and DeCIDE
    • This raises important questions about variations in trial populations, concurrent treatments (cisplatin vs. cetuximab), and trial settings
  • Regulatory and Guideline Context:
    • While promising, broader adoption must weigh this one positive study against other evidence
    • Induction TPF remains non-standard but can be considered within multidisciplinary discussions:
      • Especially for patients with high-risk features or when organ preservation is a priority
        
        
        
        

• Background:
  • While major phase III trials in North America (PARADIGM, DeCIDE):
    • Failed to demonstrate a survival benefit for induction chemotherapy (IC) with docetaxel, cisplatin, 5-FU (TPF) before chemoradiation:
      • Italian investigators from the Gruppo di Studio Tumori della Testa e del Collo (GSTTC):
        • Reported the only positive phase III trial in this setting
• GSTTC Trial Findings (abstract form):
  • Design:
    • Randomized phase III trial comparing TPF induction chemotherapy:
      • Follow by CRT vs CRT alone in patients with locally advanced HNSCC
  • Results (as reported in abstract form):
    • Improved progression-free survival (PFS) in the induction arm
    • Superior overall survival (OS) compared with CRT alone
    • Benefit appeared most pronounced in patients with:
      • High-risk, bulky, or unresectable disease
    • Publication status:
      • Results have only been presented in abstract form, not yet fully peer-reviewed or published, limiting their integration into international guidelines
• Interpretation and Clinical Implications:
  • Consistency issue:
    • Unlike GSTTC, large U.S. trials (PARADIGM, DeCIDE) were negative:
      • Raising questions about patient selection, trial design, and population differences
  • Potential value:
    • The GSTTC data suggest that selected patients:
      • Those with high tumor burden or unfavorable disease biology may benefit from TPF induction before CRT
  • Guideline stance:
    • Induction chemotherapy with TPF is not standard of care but can be considered in high-risk or organ-preservation cases within multidisciplinary discussion
  • Take-home point:
    • GSTTC provides the only phase III evidence suggesting a survival advantage with induction:
      • But the lack of full peer-reviewed publication and discordant international trial results prevent broad adoption
• Summary sentence for surgeons:
  • The GSTTC phase III trial remains the only study to report superior outcomes with TPF induction followed by CRT versus CRT alone, though its abstract-only publication and contrast with negative U.S. trials mean that CRT alone continues as the standard, with induction reserved for carefully selected high-risk patients

• Background:
  • Both PARADIGM and DeCIDE were phase III randomized trials that evaluated the role of induction chemotherapy (IC) followed by chemoradiation versus chemoradiation alone:
    • In patients with locally advanced head and neck squamous cell carcinoma (HNSCC)
• Trial Findings:
  • PARADIGM Trial (Haddad et al., 2013):
    • Compared IC (docetaxel, cisplatin, 5-FU) followed by CRT vs. CRT alone
    • No overall survival (OS) benefit was seen for the IC arm
    • The control arm (CRT alone) performed better than expected:
      • Narrowing potential differences
    • Trial closed early due to poor accrual (145 patients instead of 300+ planned)
  • DeCIDE Trial (Cohen et al., 2014):
    • Also tested induction chemotherapy followed by CRT vs. CRT alone in advanced HNSCC with high-risk features
    • It failed to show significant improvement in OS or progression-free survival (PFS)
    • Similar to PARADIGM, poor accrual and favorable outcomes in the control arm limited conclusions
• Key Takeaways for Surgeons:
  • Negative Results:
    • Neither trial demonstrated a survival advantage for adding induction chemotherapy before CRT
  • Reasons for Negativity:
    • Poor accrual:
      • Underpowered to detect meaningful differences
    • Unexpectedly favorable outcomes in control arms:
      • CRT alone did better than historical benchmarks
  • Clinical Implication:
    • CRT alone remains the standard of care for most patients with locally advanced HNSCC:
      • IC is not routinely recommended outside of select cases:
        • Organ preservation
        • Laryngeal /hypopharyngeal cancers
        • Where rapid tumor shrinkage is needed
  • Ongoing Relevance:
    • These trials highlight the challenges of large cooperative studies in HNSCC and the importance of accrual in detecting real benefits
• Summary Sentence:
  • The PARADIGM and DeCIDE trials did not demonstrate a survival benefit for induction chemotherapy in head and neck cancer:
    • Largely due to poor accrual and unexpectedly strong results in the control arms:
      • Confirming that CRT alone remains the standard of care for most patients

• With the advent of taxanes in the 1990’s:
  • A series of phase I / II trials used paclitaxel or docetaxel for induction chemotherapy (IC) for head and neck cancer came out
• While taxane and platinum doublets:
  • Have not shown outstanding results (Singh et al., 2022):
    • Adding docetaxel to cisplatin and 5-FU or cisplatin, 5-FU, and leucovorin:
      • Produced response rates exceeding 80% (Monnerat et al., 2002)
• Later, several phase 3 trials:
  • Caused the three-drug combination TPF:
    • Docetaxel 75 mg/m2 IV on day 1, cisplatin 75 to 100 mg/m2 IV on day 1, and 5-fluorouracil 750 to 1000 mg/m2 IV on days 1 to 4 or 5:
      • To become the standard regimen for IC:
        • This included the cardinal TAX 323 / EORTC 24971 (Vermorken et al., 2007) and TAX 324 (Posner et al., 2007) trials:
          • Which demonstrated the superiority of TPF over PF in terms of:
            • Progression free survival (PFS)
            • Overall survival (OS)
            • Local control
            • Organ preservation
            • Quality of life
              • In resectable and unresectable head and neck cancers
• The addition of taxanes to PF induction chemotherapy for patients with stage III or IV disease with no distant metastases:
  • Yields superior outcomes compared with PF alone
• The TAX 323 and TAX 324 studies randomly assigned patients to:
  • Three cycles of PF versus three cycles of TPF
  • In both studies, the total dose per cycle of 5-FU was reduced in the TPF regimens compared with the PF regimens
  • TAX 323 / EORTC 24971:
    • Was restricted to patients with unresectable disease
    • Subtle differences in the dose and schedule of cisplatin and 5-FU existed in the TPF regimens in these two studies
    • After induction chemotherapy:
      • Patients received definitive radiation therapy alone in TAX 323 or with concurrent weekly carboplatin (area under the curve of 1.5) in TAX 324
• Both studies demonstrated superior outcomes with TPF compared with PF
• In TAX 323:
  • Overall response rates after induction chemotherapy:
    • 37% versus 26%:
      • Were significantly higher for patients treated with TPF versus PF
• In TAX 324:
  • The overall response rates after induction chemotherapy:
    • 72% versus 64%, p = .07
  • 3-year overall survival were superior for the TPF group:
    • 62% versus 48%
• These results are consistent with those of a randomized trial reported by Hitt and colleagues:
  • That evaluated the addition of paclitaxel to cisplatin and 5-FU in patients with stage III or IV disease without distant metastasis:
    • The addition of paclitaxel yielded a significant improvement in response rate to induction chemotherapy and a trend toward improvement in overall survival
• These trials, however, were not designed to compare the strategy of induction chemotherapy followed by chemoradiation versus primary chemoradiation
• Several phase III randomized clinical trials that followed failed to demonstrate a significant efficacy advantage with this sequential approach
  • (Cohen et al., 2014; Haddad et al., 2013; Hitt et al., 2014)
• The negative results in the PARADIGM and DeCIDE trials:
  • Have been attributed to poor accrual and unexpected favorable outcomes in the control arms (Cohen et al., 2014; Haddad et al., 2013), and the Spanish Head and Neck Cancer Cooperative Group (TTCC) study has only been reported with relatively short follow-up (Hitt et al., 2014)
• The only positive phase III clinical trial demonstrating superior outcomes with TPF induction followed by chemoradiation over chemoradiation alone:
  • Was reported in abstract form by Italian investigators from Gruppo di Studio Tumori della Testa e del Collo (GSTTC)
• Taken together, these results suggest that more investigation is required to better elucidate the benefit of induction chemotherapy, and perhaps more importantly better defining the patient population who benefits from the sequential approach
• In Tax 323 TPF was used with a reduced dose form:

• Nevertheless, the details of TAX trials showed that toxicities were high in both regimens:
  • For instance, at least 70% of subjects on TPF and about half of PF patients experienced grade 3 and 4 neutropenia in both trials
• While subjects in TAX 323 received a sequential schedule, that was IC followed by RT rather than CCRT:
  • In Tax 324 patients proceeded with carboplatin with RT
• A critical commentary:
  • Emphasized on the percentage of patients who were ultimately treated off-protocol in the TPF, and PF arms:
    • Which were 21%, and 24% respectively:
      • It is assumed that this observation likely reflects greater response rates of taxane-based regimens, rather than the more favorable tolerance of the TPF treatment (Haddad and Posner, 2009)
      • Supposedly, some of these subjects of both trials who were not treated with concurrent chemotherapy may have been disadvantaged in receiving alternative treatments
      • Also, almost half of the patients in these trials were diagnosed with oropharyngeal cancer which is believed to have a more favorable prognosis, so the results of these trials might not be generalizable (Tural and Kilickap, 2013)
• The update of MACH-NC with the inclusion of taxane trials:
  • Showed that the addition of taxane to PF caused:
    • A 7.4% rise of OS in favor of TPF
  • This showed great promise, however, remarkably, only half of the patients on TPF went through concomitant chemotherapy as planned and about a third did not start RT in the TPF arm
  • Additionally, TPF induction was not compared to CCRT in this study (Blanchard et al., 2013)
• In the most recent 2021 update on MACH-NC with a follow-up of 9.2 years:
  • The superiority of CCRT alone over the addition of IC was once again confirmed:
    • The OS benefit of 0.83 [0.79;0.86] with an absolute benefit of 6.5% and 3.6% at 5 and 10 years, respectively:
      • However, it failed to prove any survival benefit for TPF induction compared to CCRT alone:
        • These data are inconsistent with those reported for PF, which had shown superior survival when compared to CCRT (Lacas et al., 2021)
• A secondary finding of the MACH-NC report was rates of locoregional and distant failures per treatment type (Pignon et al., 2009):
  • The hazard ratio for death was 0.81 [0.78;0.86] by CCRT and 0.96 for the addition of IC but with an insignificant confidence interval ranging from 0.9 to 1.02
  • Their indirect comparison revealed an improvement in both local (HR, 0.74; 95% CI, 0.70–0.79; P = 0.001), and distant failure, (HR, 0.88; 95% CI, 0.77–1.00; P = 0.04):
    • In the CRT group, whereas, IC did not affect locoregional control but particularly reduced metastases (HR, 0.73; 95% CI, 0.61–0.88; P = 0.001):
      • The impact on reduced tumor dissemination did not cause survival benefit by IC regimens but instead, a higher local control seems to be causative for the significant survival benefit with CCRT alone compared to the addition of IC

TAX 324 Trial

• A randomized phase three trial of the treatment of squamous-cell carcinoma of the head and neck:
  • Compared induction chemotherapy with docetaxel plus cisplatin and fluorouracil (TPF) with cisplatin and fluorouracil (PF):
    • Followed by chemoradiotherapy
• Squamous-cell carcinoma of the head and neck:
  • Accounts for 5% of newly diagnosed cancers in adults in the United States and 8% of cancers worldwide
  • The disease is potentially curable at an early stage, but most patients present with locally advanced disease
• After standard therapy (surgery and radiation):
  • Only 30% to 50% of patients with locally advanced disease:
    • Live for three years
  • Locoregional recurrences or distant metastases develop in 40% to 60% of them
• Various strategies to improve outcomes by coordinating chemotherapy with surgery and radiotherapy have been tried:
  • But the optimal schedule for integrating chemotherapy into the management of this disease has yet to be defined
• Although chemoradiotherapy (radiotherapy plus concurrent chemotherapy) has become the standard of care for patients with unresectable squamous-cell carcinoma of the head and neck and for organ preservation:
  • Induction chemotherapy with cisplatin and fluorouracil (PF) also has benefits in this disease
• A comprehensive meta-analysis showed that induction chemotherapy (i.e., chemotherapy as the initial treatment) with PF:
  • Significantly improved the rate of survival at 5 years:
    • As compared with standard radiotherapy plus surgery in patients with locally advanced disease
• Docetaxel (Taxotere, Sanofi-Aventis) has substantial activity when administered alone in patients with recurrent or incurable disease
• In phase 1 and phase 2 studies of docetaxel plus cisplatin and fluorouracil (TPF) in the treatment of locally advanced squamous-cell carcinoma of the head and neck, including phase 2 studies of treatment with curative intent:
  • Clinical and pathological response rates have been high and survival has been prolonged
• Two phase 3 trials in which induction chemotherapy with TPF or PF was followed by radiotherapy (the European Organization for Research and Treatment of Cancer [EORTC] 24971 / TAX 323 study by Vermorken et al.) or chemoradiotherapy (TAX 324) in locally advanced disease have now been completed
• Results of the TAX 324 study here
• METHODS:
  • They randomly assigned 501 patients (all of whom had stage III or IV disease with no distant metastases and tumors considered to be unresectable or were candidates for organ preservation):
    • To receive either TPF or PF induction chemotherapy:
      • Followed by chemoradiotherapy with weekly carboplatin therapy and radiotherapy for 5 days per week
  • The primary end point was overall survival
• RESULTS:
  • With a minimum of 2 years of follow-up (≥ 3 years for 69% of patients):
    • Significantly more patients survived in the TPF group than in the PF group:
      • Hazard ratio for death, 0.70; P=0.006)
    • Estimates of overall survival at 3 years were 62% in the TPF group and 48% in the PF group:
      • The median overall survival was 71 months and 30 months, respectively (P=0.006)
    • There was better locoregional control in the TPF group than in the PF group (P=0.04):
      • But the incidence of distant metastases in the two groups did not differ significantly (P=0.14)
    • Rates of neutropenia and febrile neutropenia were higher in the TPF group
    • Chemotherapy was more frequently delayed because of hematologic adverse events in the PF group
• CONCLUSIONS:
  • Patients with squamous-cell carcinoma of the head and neck who received docetaxel plus cisplatin and fluorouracil induction chemotherapy plus chemoradiotherapy had a significantly longer survival than did patients who received cisplatin and fluorouracil induction chemotherapy plus chemoradiotherapy
  • ClinicalTrials.gov number, NCT00273546. opens in new tab