Principles of Radiation Oncology and Organ Preservation Strategies

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Principles of Radiation Oncology and Organ Preservation Strategies

Head and Neck Surgery
Author Credentials 

Brandon A. Dyer, MD 
Resident Physician
Department of Radiation Oncology
University of California, Davis

Shyam S.D. Rao, MD, PhD
Assistant Professor
Department of Radiation Oncology
University of California, Davis

Address correspondence to:
Shyam S.D. Rao, MD, PhD
Department of Radiation Oncology
University of California, Davis
4501 X Street
Sacramento, CA 95817
E-mail: sdrao@ucdavis.edu

Module Summary

Surgery and radiotherapy both provide effective local management of squamous cell cancer of the head and neck. Nonetheless, these approaches impact patient quality of life in distinct ways, and it is important for the otolaryngologist to recognize the capabilities and limitations of nonsurgical therapy. Advances in radiotherapy delivery, surgical techniques, chemotherapy agents, and biological approaches promise significant improvements in survival and functional outcomes for patients with advanced disease treated with organ-preservation therapy over the next decade.

Module Learning Objectives 
  1. Recognize the basic principles of head and neck squamous cell cancer biology.
  2. Review the mechanisms and toxicities of radiation therapy.
  3. Explain how radiation therapy is delivered clinically.
  4. Appreciate the role of organ preservation for locally advanced head and neck cancer.
  5. Delineate which patients are candidates for organ preservation therapy.
  6. Review promising developments in organ-preservation therapy.

Basic Science

Learning Objectives 
  1. As with all cancers, head and neck malignancy represents the progression of abnormalities at the genetic and cellular level. These abnormalities lead to inappropriate dedifferentiation, survival, proliferation, and migration of tumor cells.
  2. Specific genetic culprits have been associated with head and neck (H&N) cancer. The most important include:
    1. Total genome analysis led to proposed genetic grouping of tumors based on smoking status, HPV status and genetic features. Proposed groupings are: atypical, classic, mesenchymal and basal groups1. The interaction of transcription factors SOX2, TP63, NFE2L2 and NOTCH1 drive differences between expression subtypes1:
      • Atypical group (human papillomavirus positive, HPV+): Lack of chromosome 7 amplification, HPV(+) enrichment, and activation of PIK3CA.
      • Classic group (oxidative stress/smoking related): p53 mutation, CDKN2A (p16) loss of function, chromosome 3q amplification, alteration of oxidative stress genes (KEAP1, NFE2L2 or CUL3), heavy smoking history and larynx sub-site.
      • Mesenchymal group: Significant mutation of p53, CASP8, NSD1, CDKN2A. 92% of oral cavity malignancies have CASP8 mutation.
      • Basal group: Disrupted cell death is the defining feature. Inactivation of NOTCH1 with intact oxidative stress genes (3q, NFE2L2, KEAP1, CUL3) results in a notable relative decrease in SOX2 (transcription factor for maintenance of pluripotency) compared with all other H&N squamous cell tumors. HRAS–CASP8 co-mutation and co-amplified 11q13/q22 tumors.
    2. Clinical outcomes have been directly correlated with genetic changes1:
      • HPV+ oropharynx cancers have favorable outcomes (>) compared with HPV-
      • Wild type p53 > mutated p53
      • Non-amplified 3q > amplified 3q
      • Nonamplified 11q > amplified 11q
      • Non-amplified EGFR > amplified EGFR
      • HRAS-CASP8 co-activation indicative of more aggressive tumors, and CASP8 is nearly universally mutated in oral cavity cancers.
    3. Human papilloma virus (HPV) infection (HPV+) is seen in 60-80% of oropharyngeal tumors compared with 6% of non-oropharyngeal tumors1. HPV is usually sexually transmitted and major high risk HPV subtypes includes 16, but also 18, 31, 33, and 451. HPV-associated tumors are dominated by mutations of the PI3CA oncogene, loss of TRAF3, and amplification of the cell cycle gene E2F11. If the host fails to clear the HPV infection, persistent infection can lead to malignant transformation. Viral E6 and E7 oncoproteins integrate into host DNA and promote malignancy and tumor growth2. P16/INK4a is a tumor suppressor whose overexpression serves as a marker for HPV-related tumors in oropharynx cancer.  HPV+ oropharynx cancers have significantly better survival outcomes compared with non-HPV-related cases. In one study, 3-year overall survival was 82% in HPV+ versus 57% in HPV-negative tumors3.
    4. Whole exome sequencing showed that HPV- squamous cell carcinomas (mostly smoking/oxidative stress-related) have low copy number alterations, alternative pathways of tumorigenesis and a 3-gene alteration pathway with increased HRAS, lack of CASP8, and wild-type p53 expression1.
    5. p53, a tumor suppressor protein, is responsible for regulating cell cycle progression at the G1/S check point. p53 acts on downstream p16, and p21 which in turn interact with cyclin proteins and cyclin dependent kinases as part of a regulatory cascade, and HPV-related tumors infrequently have p53 mutation. However, the HPV-related E6 oncoprotein leads to p53 degradation and loss of cell cycle regulatory control of downstream signaling pathways (losing the stop signal). The E7 oncoprotein competes for retinoblastoma protein (Rb) binding, a tumor suppressor, thus freeing transcription factor E2F to transactivate targets and promote cell cycle progression (foot on the gas).
    6. The tumor suppressor p16/ INK4a is mutated and lost in 60-80% of HPV- tumors1. Other distinct H&N genetic subgroups contain loss-of-function alterations of the chromatin modifier NSD1, WNT pathway genes AJUBA and FAT1, and activation of oxidative stress factor NFE2L2, mainly in laryngeal tumors1.
  3. A unique aspect of head and neck carcinogenesis is its ability to involve a large area of normal appearing mucosa (termed “field cancerization”). This phenomenon typically represents the effect of environmental exposure (e.g., cigarette smoke, alcohol) and leads to a high rate of multiple primary cancers.
  4. Identifying genetic lesions specific to head and neck cancer may lead to:
    1. Sensitive and specific screening of high-risk populations.
    2. Improved imaging and localization of disease (e.g., molecular imaging with positron emission tomography [PET]).
    3. Individualized disease prognosis.
    4. Individualized treatment strategy.
    5. Targeted biological therapies (e.g., C225 antibody therapy against EGFR).
    6. Improved assessment of surgical margin status.
References 
  1. Cancer Genome Atlas N. Comprehensive genomic characterization of head and neck squamous cell carcinomas. Nature. 2015 Jan;517(7536):576-582.
  2. Parfenov M, Pedamallu CS, Gehlenborg N, et al. Characterization of HPV and host genome interactions in primary head and neck cancers. Proc Natl Acad Sci U S A. 2014 Oct;111(43):15544-15549.
  3. Ang KK, Harris J, Wheeler R, et al. Human papillomavirus and survival of patients with oropharyngeal cancer. The New England journal of medicine. 2010 Jul;363(1):24-35.

Incidence

Learning Objectives 

There will be an estimated 51,000 new head and neck malignancies in the United States in 2018 and 10,000 patients are expected to die of their disease. Oral cavity and pharynx cancer is the 8th leading new cancer diagnosis in men in the United States. In developing countries worldwide in 2015, malignancies of the lip and oral cavity were the 8th leading new cancer diagnosis in men, and 9th most common cause of cancer death.

References 
  1. American Cancer Society. Cancer Facts & Figures 2018. Atlanta: American Cancer Society; 2018.  
  2. American Cancer Society. Global Cancer Facts & Figures 3rd Edition. Atlanta: American Cancer Society; 2015.  

Patient Evaluation

Learning Objectives 
  1. Indications/prerequisites for radiotherapy or organ-preservation therapy:
    1. High risk for poor post-surgical functional outcome. Examples include cases requiring total glossectomy or extensive skull base resection. This also includes patients with high operative risk.
    2. Patient preference and motivation – patients may prefer to maintain their native tissues, especially the larynx. Patient occupation can also play a significant role.
    3. Early disease – localized (T1-2, N0) primaries, especially those of the glottic larynx, tonsil, and base of tongue, can be effectively treated with radiotherapy alone.
    4. Institutional resources – availability of an experienced team of otolaryngologists, radiation oncologists, medical oncologists, radiologists, dentists, nurses, speech pathologists, dietitians, social workers, and other allied providers is essential to provide organ-preservation therapy.
  2. Contraindications to organ preservation therapy. Since organ-preservation therapy encompasses a range of treatments, there is a range of relative contraindications. Elderly or frail patients can generally be offered radiotherapy or palliative chemotherapy alone. Any patient may be a poor candidate for radiation therapy, chemotherapy, or both.
    1. Radiotherapy: strong contraindications include unprotected airway compromise, actively infected wounds/mandibular exposure, marginal nutritional status/failure to thrive, poor patient compliance and/or social support, continued alcohol/substance abuse. Relative contraindications include previous radiotherapy (patients can receive full-dose re-irradiation; however, there is drastically increased risk of severe late toxicities), non-infected malignant dermal erosion, extensive tumor fistulas into trachea, esophagus, or vascular structures, unaddressed dental caries, and significant medical comorbidities, including collagen vascular disease or carotid stenosis.
    2. Chemotherapy: similar absolute contraindications apply as above. Also, history of marrow insufficiency or active/chronic infections. Many agents cannot be given in the presence of specific comorbidities (e.g., cisplatinum can worsen chronic renal failure or hearing, 5-FU can exacerbate unstable angina, and taxanes can intensify preexisting peripheral neuropathy).
  3. Staging and workup.
    1. Accepted tests: history and physical examination (including fiberoptic exam), direct laryngoscopy contrast-enhanced computed tomography (CT) ormagnetic resonance imaging (MRI) of the head and neck, PET/CT, chest x-ray, routine blood and chemistry panels. Tissue diagnosis is preferably obtained through fine needle aspiration of nodal disease or direct biopsy of mucosal lesions.  P16 immunohistochemistry should be performed in oropharynx cancer to evalaute for HPV-related disease.  EBV studies should be performed for nasopharyngeal tumors.

Imaging

Learning Objectives 
  1. CT: Primary imaging modality for radiotherapy treatment planning. CT sensitivity for detection of primary head and neck disease is 68%, 67% in the recurrent setting, while specificity is 69% in the primary setting and 80% in the recurrent setting6. Detection of nodal disease has a sensitivity of 84% and specificity of 96%6.
  2. MRI: Can be used in conjunction with CT to improve target delineation. MRI offers superior soft tissue resolution compared with CT. It is particularly useful in delineating soft tissue planes, and perineural extension of tumor. The sensitivity of MRI for primary tumors has been shown to be 80- 98%7,8, but only 62% in the recurrent setting, with a specificity of 80%. The sensitivity of MRI for detecting nodal metastases is 49-85%8,9, with a specificity of 99%9.
  3. PET/CT &,PET/MRI: PET imaging may significantly improve detection of malignancy and alter staging results. FDG-PET/CT has demonstrated sensitivity of 80-95% and specificity of 92-100% for detection of primary or recurrent tumors6,7.In the clinically node negative neck, PET/CT has demonstrated sensitivity of 71% and specificity of 97% for detection of occult nodal disease10. The sensitivity of PET/CT is limited by spatial resolution (8-10 mm); however, PET/MRI has shown sensitivities of 77-90% and specificity of 91-96% for primary tumor and nodal staging7,9,11. PET imaging is approved for initial staging of disease, and in the recurrent setting. Ongoing radiotracer development allows for detection and quantification of tumor biology and hypoxia. 
  4. Fused imaging: The use of combined imaging modalities. Images are co-registered, including PET/CT–CT, PET/MRI-CT, or MRI-CT. Fused images may help optimize radiotherapy target delineation, or in identifying nerve involvement. Images can be fused (overlaid) with the radiotherapy planning CT scan. Fusion can be accomplished manually, or using advanced deformable image registration techniques. New deformation algorithms allow for registration using rigid features (bone to bone), or take into account image similarity, grid regularization, controlling structure match, or anatomic regions of interest10,12,14.
References 
  1. Di Martino E, Nowak B, Hassan HA, et al. Diagnosis and staging of head and neck cancer: a comparison of modern imaging modalities (positron emission tomography, computed tomography, color-coded duplex sonography) with panendoscopic and histopathologic findings. Arch Otolaryngol Head Neck Surg. 2000;126(12):1457-1461.
  2. Huang H, Ceritoglu C, Li X, et al. Correction of B0 susceptibility induced distortion in diffusion-weighted images using large-deformation diffeomorphic metric mapping. Magn Reson imaging. 2008;26(9):1294-1302.
  3. Nakamoto Y, Tamai K, Saga T, et al. Clinical value of image fusion from MR and PET in patients with head and neck cancer. Mol Imaging Biol. 2009;11(1):46-53.
  4. Kanda T, Kitajima K, Suenaga Y, et al. Value of retrospective image fusion of (1)(8)F-FDG PET and MRI for preoperative staging of head and neck cancer: comparison with PET/CT and contrast-enhanced neck MRI. European journal of radiology. 2013;82(11):2005-2010.
  5. Chauhan A, Kulshrestha P, Kapoor S, et al. Comparison of PET/CT with conventional imaging modalities (USG, CECT) in evaluation of N0 neck in head and neck squamous cell carcinoma. Medical J Armed Forces India. 2012;68(4):322-327.
  6. Buchbender C, Heusner TA, Lauenstein TC, Bockisch A, Antoch G. Oncologic PET/MRI, part 1: tumors of the brain, head and neck, chest, abdomen, and pelvis. J Nucl Med. 2012;53(6):928-938.
  7. Weistrand O, Svensson S. The ANACONDA algorithm for deformable image registration in radiotherapy. Med Phys. 2015;42(1):40-53.
  8. Brock KK, Mutic S, McNutt TR, Li H, Kessler ML. Use of image registration and fusion algorithms and techniques in radiotherapy: Report of the AAPM Radiation Therapy Committee Task Group No. 132. Med Phys. 2017;44(7):e43-e76.
  9. Velec M, Moseley JL, Svensson S, Hardemark B, Jaffray DA, Brock KK. Validation of biomechanical deformable image registration in the abdomen, thorax, and pelvis in a commercial radiotherapy treatment planning system. Med Phys. 2017;44(7):3407-3417.

Pathology

Learning Objectives 

Recently, in January 2018, the American Joint Committee on Cancer (AJCC) released new staging guidelines which significantly altered prognostic grouping for head and neck malignancies to reflect the difference in treatment response and long term outcome of HPV(+) versus HPV(-) tumors vis-á-vis a difference in tumor biology. 
As discussed in the Basic Science section above, HPV related tumors have distinctly different tumor biology and distribution of disease from non-HPV related tumors. Whereas HPV+ tumors express E6/7 oncoproteins, and genetically lack of chromosome 7 amplification, have wild type p53, and have activation of PIK3CA, HPV negative tumors are largely driven by alteration of oxidative stress genes (KEAP1, NFE2L2 or CUL3), chromosome 3q amplification, p53 mutation, and altered apoptosis pathways. 
HPV+ tumors are predominantly seen in the oropharynx subsite (up to 80%), and represent only 6-10% of non-oropharyngeal tumors1. HPV+ tumors tend to have disproportionately large, cystic and/or matted lymph nodes which have bland histology, and which respond well to radiotherapy. HPV related tumors are associated with HPV 16 DNA by PCR, with higher Ki-67 (more cellular proliferation) and lower p53 staining score (wild type p53)15

References 
  1. Cancer Genome Atlas N. Comprehensive genomic characterization of head and neck squamous cell carcinomas. Nature. 2015;517(7536):576-582.
  2. El-Mofty SK, Lu DW. Prevalence of human papillomavirus type 16 DNA in squamous cell carcinoma of the palatine tonsil, and not the oral cavity, in young patients: a distinct clinicopathologic and molecular disease entity. Am J Surg Pathol. 2003;27(11):1463-1470.

Treatment

Learning Objectives 

Mechanisms of Radiation Treatment

  1. Understand that radiation kills cells in several ways.
    1. Direct damage to cellular DNA (responsible for 10-30%of cell kill).
    2. Indirect cellular and DNA damage resulting from free radical formation (60-75% of radiotherapy effect). This effect is dominated by water interactions and is enhanced by the presence of oxygen, explaining why hypoxic tumors are resistant to radiation.
    3. Bystander (abscopal) effect: irradiated cells can induce tumor regression in unirradiatied cells which may be in relatively close proximity, or distantly, through paracrine/ endocrine signaling, or mediated by an immune response. 
    4. Apoptosis (“cellular suicide”): responsible for a small minority of radiation killing in solid tumors. Many tumor cells are genetically resistant to this mechanism.
  2. Double-strand DNA breaks and multiple single-strand DNA breaks can kill cells. As cells progress through the cell cycle, their ability to repair radiation DNA damage changes.
    1. Linear-quadratic model: when cell survival is plotted versus delivered dose the cell survival curve is initially linear, representing lethal (unrepairable) double-strand DNA breakage. This lethal, unrepairable cell kill remains linear with increasing dose. However, as dose further increases, an exponential cell kill becomes dominant representing accumulated single-strand DNA breaks that were not repaired prior to entry into mitosis (cellular division). Note that that the cell-killing curve is steeper for tumor cells than for normal cells (normal cells have intact DNA repair mechanisms and fix more damage). Small repetitive treatments (“fractions”) take advantage of this differential killing (therapeutic index or window)—normal tissues typically recover better from each daily treatment than tumor cells.
    2. Cells are most susceptible to radiation right before mitosis (G2/M checkpoint) and most resistant during S phase, when high fidelity DNA repair proteins are most active. Note that radiation most effectively kills actively dividing cells since these cells have limited damage repair capability. Also, treatment using small, repetitive fractions allows more chancers for tumor cells in S phase (radioresistant) to redistribute through the cell cycle and receive radiation in a more radiosensitive phase of the cell cycle.
  3. Normal tissue effects.
    1. Normal cells repair radiation DNA damage better than malignant cells because they have intact DNA repair mechanisms.
    2. The proliferation rate (e.g., fast-dividing mucosa keratinocytes versus dormant cartilage or nerves) and architecture of each organ determine the kinetics and severity of radiation toxicity. For example, localized radiation damage to the spinal cord (which is structured as a serial “circuit”) can cause complete failure of this organ (transverse myelitis). Localized damage to the parotid gland (organized as a parallel structure) causes only partial loss of gland function.

Radiation Treatment

Recognize that radiation therapy can be administered in various ways.

  1. Radiation can be given externally or internally.
    1. External beam radiation (teletherapy): radiation is typically delivered with a linear accelerator unit. The patient can be treated from nearly any direction by rotating the position of the machine or the patient. There are four major “types” of external radiation:
      • Photons – X-rays are the most commonly used radiation. Can deposit dose deeply, minimizing treatment to superficial tissues or skin.
      • Electrons – Deposit dose superficially. Good for skin treatment, and relatively simple superficial targets. 
      • Neutron/ Carbon ions – Impart increased damage (Relative Biological Effect) given their increased mass. May be more be effective against relatively radioresistant tumors such as salivary gland tumors and head and neck sarcomas. Impractical for routine use due to limited number of facilities in the world.
      • Protons – can be delivered with high precision to deep structures, such as the skull base with reduced exit dose (Bragg peak).  Available only at specialized centers.
    2. Implanted or internal radiation (brachytherapy): traditionally used for oral cavity/oropharyngeal lesions, or for recurrent nasopharyngeal lesions. Allows for focal, high-dose treatment with steep dose drop off to adjacent structures at risk (normal tissue). Treatment is given either with temporary catheters or with permanent radioactive iodine seeds placed intraoperatively. Implants have become less popular because of improvements in external radiation techniques.
  2. External radiation planning and delivery is evolving.
    1. Traditional 2-dimensional techniques: the patient is treated with clinically defined fields from the sides or front/back. The field was traditionally shaped by the use of shielded blocks (bismuth/lead/tin/cadmium = cerrobend). This has largely been replaced by IMRT
    2. Three-dimensional conformal therapy: Patient anatomy is acquired from CT scans for computer-assisted treatment design. Radiation beams can be oriented in any direction. Computer-controlled tungsten plates are robotically moved into position in front of the field to statically shape the beam (“multileaf collimation”).
    3. Intensity modulated radiotherapy (IMRT): The current standard technique for head and neck radiation therapy. Complex computer based treatment planning is used to sculpt the radiation dose distribution into specific 3 dimensional shapes that conform precisely to tumor anatomy. Beams are actively shaped by computer control of multileaf collimators during the delivery of treatment (intensity modulation).
  3. Fractionation: radiation is given in divided fractions over multiple weeks to take advantage of differential repair (normal tissue recovers more quickly from small doses than do tumor cells), as well as changes cell cycle phases, hypoxia and growth kinetics of individual tumor cells. Recognize that treatment can be delivered using different dose and fractionation strategies.
    1. Standard fractionation: Once daily treatment, 5 days/week, 1.8-2 Gray (Gy) per fraction (Gray is the SI unit of absorbed radiation). Treatment is delivered to 50-70 Gy over 6 to 7 weeks as the standard of care in the United States.
    2. Altered fractionation: Anything that isn’t once daily treatment, 5 days/week, 1.8-2 Gy/fraction.
      • Hyperfractionation: Fractions sizes < 1.8 Gy to allow for decreased late tissue toxicity. Overall treatment course remains 6-8 weeks. Total dose often increased to more than 70 Gy given sparing of late tissue toxicity.
      • Hypofractionation: Fractions sizes > 2.2-2.5 Gy.
      • Accelerated fractionation: radiation is given over a shorter period of time, typically 5-6 weeks. Total dose remains 70 Gy. Can be accomplished by “concomitant boost” which adds a second daily dose starting the 4th week of treatment.  Alternatively, can be achieved by giving 6 fractions per week when using simultaneously integrated boost plans with IMRT.  This is designed to counteract tumor cell repopulation during treatment.
      • Accelerated hyperfractionation. Using fractions sizes <1.8 Gy while decreasing the overall treatment course time by delivering treatment twice daily.
      • Radiosurgery/ Stereotactic body radiation Therapy – Using very large fractional doses (~5 to 20Gy) delivered with 1-5 fractions.  Requires highly focused radiation delivery to minimize toxicity to adjacent normal tissues.  Used in limited settings for small volume tumors in which elective coverage not required.
    3. RTOG 90-03: A phase III trial for patients with locally advanced (stage II base of tongue, or stage III/IV AJCC 7th Edition) squamous cell cancers of the oral cavity, oropharynx, larynx, and hypopharynx. Patients were treated with radiation alone and randomized to one of four different fractionation schemes (standard fractionation (SFX), hyperfractionated (HFX), accelerated fractionation (AFX), or accelerated fractionation with concomitant boost (AFX-C))16. After 5 years of follow up, only the HFX was significantly different from SFX, and favored HFX for locoregional control (hazard ratio 0.79) and overall survival (hazard ratio 0.81). There was no difference between the arms in terms of severe (> Grade 3) toxicity at 5 years; however, comparing accelerated fractionation arms to combined SFX and HFX arms there was a trend toward increase in severe toxicity (p = 0.06) with dose acceleration. This trial provides useful information about definitive radiotherapy alone and is useful for patients who may not be medical candidates for concurrent chemoradiation, which is the standard of care for locally advanced disease.  

Organ-Preservation Therapy

  1. Understand that this term pertains to locally advanced (stage III-IV) disease. Early stage, low-volume disease can be treated with limited functional morbidity by using surgery alone, radiotherapy alone, or a combination of the two modalities. Good examples of early-stage disease well controlled by radiation alone are T1-2 glottic larynx (80%-95% disease-free survival) and base of tongue/tonsil (up to 86%-100% disease-specific survival).
  2. When this term was coined decades ago, cancer surgery for advanced disease remained limited to highly morbid procedures (e.g., total laryngectomy). It was presumed that nonsurgical therapy could preserve quality of life by preempting disfiguring and functionally morbid surgery, without sacrificing disease control. Organ-preservation therapy centers on combined radiotherapy and chemotherapy. Unfortunately, besides the Veterans Administration (VA) and European Organization for Research and Treatment of Cancer (EORTC) studies described below, definitive surgery has not been directly compared with nonsurgical therapy in a phase III setting. Although this remains an important question, provider and patient biases may well prevent large-scale randomized comparisons in the future.
    1. Patient selection: the term “unresectable disease” is difficult to define, given advances in surgical technique and varying practices across institutions. Accordingly, “non-surgical disease” is more practical. Bulky disease that cannot be resected with clear margins or without sacrificing a functional larynx or tongue falls into this category and is eligible for organ-preservation therapy. Typically, this includes advanced oropharyngeal, laryngeal, nasopharyngeal or hypopharyngeal disease. Any tumor originating from a radiosensitive subsite (glottic larynx, tonsil, base of tongue) is a candidate for nonsurgical therapy. Oral cavity disease may also be considered if surgical options are morbid.
      • An important caveat: modern, aggressive organ-preservation therapy is toxic and logistically complex. It should be offered only to functional, compliant patients by experienced multidisciplinary centers. Otherwise, radiation alone remains a reasonable option.
    2. Induction chemotherapy: the seminal approach dating from the 1980s designed to improve upon the results of radiation treatment alone. Initial trials centered on laryngeal or hypopharyngeal disease in which disease is challenged with several cycles of induction therapy and patients who respond proceed to radiotherapy (sequential chemoradiation). Classic phase III trials include:
      • VA Laryngeal Cancer Study Group17: 332 patients with stage III/IV glottic disease were randomly assigned to laryngectomy or to induction chemotherapy (cisplatin and fluorouracil) followed by radiation alone. Larynx preservation was achieved in 64% of patients in the nonsurgical arm, without a survival decrement. However, 56% of patients with T4 disease failed (80% within 1 year of chemoradiation) thus requiring salvage laryngectomy versus only 29% of patient with T3 disease. This provides rationale for organ preservation for T3 patients (confirmed in the RTOG 91-11 study18) and laryngectomy with adjuvant chemoradiation for T4 patients.
      • EORTC 24891 Hypopharyngeal Trial19: a similar trial that randomly assigned 194 patients with stage III/IV hypopharyngeal disease.  Larynx preservation was achieved in 42% of patients, with equivalent survival noted in the nonsurgical arm.
      • RTOG 91-1118: Phase III trial of 518 patients randomized to 1.) induction chemotherapy followed by RT, or if less than partial response (similar to VA trial), laryngectomy, 2.) concurrent chemoradiation, 3.) radiation alone. The primary endpoint was larynx preservation. At 10 years follow-up concurrent chemoradiation demonstrated the highest locoregional control and larynx preservation, but overall survival and laryngectomy free survival were similar to that of sequential chemoradiation.  
      • TAX 32420,21: Phase III trial in patients with stage III/IV H&N disease randomized to two induction chemotherapy regimens followed by concurrent chemoradiation (with carboplatin).  The addition of docetaxel to cisplatin and fluoruracil showed better overall survival then cisplatin and fluorouracil alone for induction chemotherapy
      • PARADIGM trial22: Phase III trial comparing concurrent chemoradiation (with cisplatin) to induction chemotherapy (docetaxel, cisplatin, fluorouracil) followed by concurrent chemoradiation ( with carboplatin or docetaxel) in patient with Stage III-IV head and neck cancers. The addition of induction chemotherapy to concurrent chemoradiation did not show an improvement in survival compared to concurrent chemoradiation alone. Note, several other studies have not shown any benefit to the addition of induction chemotherapy prior to concurrent chemoradiation.
    3. Concurrent chemoradiation: synchronous combined therapy is superior to radiation alone or sequential chemotherapy and radiation. Essentially all new head and neck clinical trials use concurrent chemoradiation in the setting of advanced disease, with newer trials looking at the addition of immunotherapeutic agents. Important trials:
      • MACH H&N meta-analysis23: meta-analysis of 87 trials with 16192 patients investigating chemoradiotherapy for head and neck cancer. Trials included investigated induction or concurrent chemotherapy. This showed an absolute improvement in overall survival of 6.5% for the addition of concurrent chemotherapy, with most of the benefit coming from platinum-containing regimens.
      • Bonner24: Phase III randomized trial in patients with Stage III/IV H&N squamous carcinoma (56-63% with oropharynx cancer) randomized to 1.) RT or 2.) RT + cetuximab (a monoclonal antibody for EGFR inhibition). Primary outcome was locoregional control (LRC). At 3 years of follow up, LRC was superior in the RT + cetuximab arm. At 5 years of follow up, LRC was not reported, but median and OS also favored the cetuximab arm.
      • GORTEC 940125: French multicenter phase III trial randomly assigned 226 patients with stage III/IV oropharyngeal disease to 70 Gy daily radiation with or without three cycles of 5-FU/carboplatin. Local control and overall survival were improved in the chemoradiotherapy arm.
      • Brizel, et al.26: institutional trial analyzed 116 patients with advanced disease randomly assigned to hyperfractionated radiation with or without platinum-based chemotherapy. Response rate and local control were improved by the addition of chemotherapy. A borderline improvement (p = 0.07) in overall survival with chemotherapy was also demonstrated.
      • GORTEC 99-0227: French multicenter trial comparing concurrent chemoradiation (with carboplatin & fluorouracil) with standard fractionation, concurrent chemoradiation with accelerated fractionation, or very accelerated fractionation radiotherapy alone in 279 patient with stage III/IV head and neck cancer. Chemoradiation demonstrated improved progression free survival compared to accelerated fractionation radiation therapy alone. Furthermore, concurrent chemoradiation with accelerated fractionation was not superior to concurrent chemoradiation with standard fractionation. Note that concurrent chemoradiation with standard fractionation is now considered the standard of care.
    4. Role of surgery in organ-preservation therapy.
      • Consolidation neck dissection: Recommended for patients who present with clinical N3 or greater adenopathy, or who have an incomplete disease response in the neck.
      • Organ-preservation surgery: Surgery may indeed provide better quality of life than radiation-based therapy to the oral cavity because of the reduction in osteonecrosis.  Innovative techniques, such Transoral robotic surgery, promise improved functional outcomes.
      • Salvage surgery: Surgical resection after organ-preservation protocols is possible, but tends to be wrought with increased complications and poor prognosis.

Future Directions for Organ-Preservation Therapy
Improved/more aggressive treatment options: 

  1. Heavy and charged particle radiotherapy: Charged particles (protons, α particles)  and heavy ions (carbon, silicon, neon) transfer more of their kinetic energy to the tissue over the same distance compared with photon therapy, and have very defined dose deposition curves. This increases the chance of a directly ionizing event, meaning that the particle, rather than the hydroxyl radical (indirectly ionizing), causes DNA damage. Additionally, because of the high energy transfer per path length traveled the likelihood of causing a lethal DNA aberration (unrepairable, double strand DNA break) is much higher than with traditional photon radiation and there is potentially more cell kill (Increased relative biological effect). Because these particles are directly ionizing they also demonstrate less of an oxygen-dependent effect on cell kill compared with photon radiation.
  2. Immunotherapy in head and neck cancer: The FDA has approved pembrolizumab and nivolumab (monoclonal, anti-programmed death receptor 1 (PD-1) antibody) for patients with recurrent or metastatic squamous cell carcinoma of the head and neck who have few treatment options.
    1. KEYNOTE-01228: In this phase Ib trial, patients with recurrent of metastatic squamous carcinoma of the H&N were eligible if they had at least 1% of tumor cells or stroma that were PD-L1-positive by immunohistochemistry. Primary outcomes were safety and overall response. 60 of 104 patients (58%) had PD-L1 expression and were enrolled. 38% were HPV+. 17% of patients had Grade 3/4 toxicity – predominantly hepatitis or hyponatremia, but 45% (27/60) had a serious adverse event. The overall response rate was 18% -- 25% in the HPV+ patients, and 14% in the HPV- patients.
    2. CheckMate 14129: In this phase III trial, 361 patients with recurrent squamous carcinoma of the H&N who had progressive disease within 6 months after the completion of platinum-based chemotherapy were enrolled to receive nivolumab q2w, or single agent therapy. The primary endpoint was overall survival (OS), and secondary endpoints were progression free survival (PFS), objective response rate (ORR), safety, and patient-reported quality of life (QoL). After a median follow up of 5 months, median OS significantly favored the nivolumab group, 7.5 versus 5.1 months, respectively. 1-year OS estimates were 36% versus 17%, respectively. Median PFS, ORR, and QoL all favored the nivolumab group. Among patients with platinum-refractory, recurrent squamous carcinoma of the head and neck, PD-1 inhibition is the new standard.
    3. REACH trial30: This is a phase III trial that is currently accruing. The study design seeks to determine if avelumab (monoclonal, anti-programmed death ligand 1 antibody) in combination with RT-cetuximab is superior to standard of care (SOC) cisplatin-RT and/or to SOC RT-cetuximab for progression-free survival (PFS) in front-line patients with locally advanced H&N squamous carcinoma. 
    4. Adoptive T-cell therapy in advanced nasopharynx cancer (NPC)31: This is a phase III trial that is currently accruing, and builds upon the prior phase II study which showed the best published 2-year (62.9%), and median overall survival (OS) data (29.9 months) in patients with advanced NPC who received autologous Epstein-Barr Virus (EBV)-specific cytotoxic T lymphocyte treatment (CTL)32. This study seeks to determine if combined gemcitabine-carboplatin (GC) followed by adoptive T-cell therapy would improve clinical outcome for patients with advanced nasopharyngeal carcinoma (NPC).
    5. In 2017 the American Society of Clinical Oncology (ASCO) named immunotherapy the “Advance of the Year” for the second year in a row, and immunotherapy had been called “the fourth modality.” Now, in 2018, there are 41 currently accruing phase II/III studies evaluating various combinations of immunotherapy, chemotherapy, radiation, and surgery. This is a burgeoning trend which is likely to continue to grow in the future.
References 

<p>Department of Veterans Affairs Laryngeal Cancer Study G, Wolf GT, Fisher SG, et al. Induction chemotherapy plus radiation compared with surgery plus radiation in patients with advanced laryngeal cancer. The New England journal of medicine. Jun 13 1991;324(24):1685-1690.<br />
Forastiere AA, Zhang Q, Weber RS, et al. Long-term results of RTOG 91-11: a comparison of three nonsurgical treatment strategies to preserve the larynx in patients with locally advanced larynx cancer. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. Mar 1 2013;31(7):845-852.<br />
Lefebvre JL, Andry G, Chevalier D, et al. Laryngeal preservation with induction chemotherapy for hypopharyngeal squamous cell carcinoma: 10-year results of EORTC trial 24891. Annals of oncology : official journal of the European Society for Medical Oncology / ESMO. Oct 2012;23(10):2708-2714.<br />
Vermorken JB, Remenar E, van Herpen C, et al. Cisplatin, fluorouracil, and docetaxel in unresectable head and neck cancer. The New England journal of medicine. Oct 25 2007;357(17):1695-1704.<br />
Posner MR, Hershock DM, Blajman CR, et al. Cisplatin and fluorouracil alone or with docetaxel in head and neck cancer. The New England journal of medicine. Oct 25 2007;357(17):1705-1715.<br />
Haddad R, O'Neill A, Rabinowits G, et al. Induction chemotherapy followed by concurrent chemoradiotherapy (sequential chemoradiotherapy) versus concurrent chemoradiotherapy alone in locally advanced head and neck cancer (PARADIGM): a randomised phase 3 trial. The lancet oncology. Mar 2013;14(3):257-264.<br />
Blanchard P, Baujat B, Holostenco V, et al. Meta-analysis of chemotherapy in head and neck cancer (MACH-NC): a comprehensive analysis by tumour site. Radiother Oncol. Jul 2011;100(1):33-40.<br />
Bonner JA, Harari PM, Giralt J, et al. Radiotherapy plus cetuximab for locoregionally advanced head and neck cancer: 5-year survival data from a phase 3 randomised trial, and relation between cetuximab-induced rash and survival. The lancet oncology. Jan 2010;11(1):21-28.<br />
Calais G, Alfonsi M, Bardet E, et al. Randomized trial of radiation therapy versus concomitant chemotherapy and radiation therapy for advanced-stage oropharynx carcinoma. Journal of the National Cancer Institute. Dec 15 1999;91(24):2081-2086.<br />
Brizel DM, Albers ME, Fisher SR, et al. Hyperfractionated irradiation with or without concurrent chemotherapy for locally advanced head and neck cancer. The New England journal of medicine. Jun 18 1998;338(25):1798-1804.<br />
Bourhis J, Sire C, Graff P, et al. Concomitant chemoradiotherapy versus acceleration of radiotherapy with or without concomitant chemotherapy in locally advanced head and neck carcinoma (GORTEC 99-02): an open-label phase 3 randomised trial. The lancet oncology. Feb 2012;13(2):145-153.<br />

Complications

Learning Objectives 

Radiation therapy side effects are typically categorized as acute effects which occurring during or immediately after treatment and often transient, or late effects which can manifest after many months or years and be permanent.

  1. Normal structures commonly affected by radiation treatment include:
    1. Parotid glands – xerostomia, dysgeusia. Xerostomia is the number one cause for decreased long-term quality of life in radiotherapy patients.
    2. Pharyngeal mucosa and constrictor muscles – mucositis, dysphagia, odynophagia.
    3. Larynx – hoarseness, aspiration
    4. Skin and soft tissues – dermatitis, fibrosis.
    5. Inner and external ear canal – otitis, hearing loss.
    6. Nasal cavity – rhinorrhea, congestion, epistaxis.
    7. Muslces of mastication – trismus.
  2. Potential severe toxicities are listed below. Note: these complications are now very uncommon with modern techniques and standardized radiation doses. Chronic radiation toxicity will become less severe as new technologies allow us to miss normal tissues.
    1. Mandible and dentition – osteoradionecrosis, caries, tooth loss. Preventable with rigorous dental hygiene.
    2. Lacrimal gland – dry eye.
    3. Eye – keratoconjunctivitis, cataract.
    4. Cartilage – necrosis.
    5. Esophagus/trachea – fistula formation.
    6. Carotid artery – atherosclerosis, rupture.
    7. Spinal cord, optic nerves, brainstem, and temporal lobes – paralysis, blindness, cranial neuropathy, cerebral necrosis.

Review

References 
  1. Name three biologic markers associated with head and neck squamous cell cancer.
  2. Does radiation kill most cells through direct damage to DNA, or through indirect mechanisms that lead to DNA damage?
  3. Why is radiation given in small repeated doses?
  4. Would a patient you refer for radiation probably receive photons or protons?
  5. Explain the difference between the sequential chemoradiotherapy regimen used for the VA larynx trial and the concurrent chemoradiotherapy approaches now used.
  6. Does organ-preservation therapy indicate that a patient will not receive surgery?
  7. Should induction chemotherapy be routinely used prior to concurrent chemoradiation.
References
  1. Cancer Genome Atlas N. Comprehensive genomic characterization of head and neck squamous cell carcinomas. Nature. 2015;517(7536):576-582.
  2. Parfenov M, Pedamallu CS, Gehlenborg N, et al. Characterization of HPV and host genome interactions in primary head and neck cancers. Proc Natl Acad Sci U S A. 2014;111(43):15544-15549.
  3. Ang KK, Harris J, Wheeler R, et al. Human papillomavirus and survival of patients with oropharyngeal cancer. N Engl J Med.1 2010;363(1):24-35.
  4. American Cancer Society. Cancer Facts & Figures 2018. Atlanta: American Cancer Society; 2018. 
  5. American Cancer Society. Global Cancer Facts & Figures 3rd Edition. Atlanta: American Cancer Society; 2015. 
  6. Di Martino E, Nowak B, Hassan HA, et al. Diagnosis and staging of head and neck cancer: a comparison of modern imaging modalities (positron emission tomography, computed tomography, color-coded duplex sonography) with panendoscopic and histopathologic findings. Arch Otolaryngol Head Neck Surg. 2000;126(12):1457-1461.
  7. Huang H, Ceritoglu C, Li X, et al. Correction of B0 susceptibility induced distortion in diffusion-weighted images using large-deformation diffeomorphic metric mapping. Magn Reson Imaging. 2008;26(9):1294-1302.
  8. Nakamoto Y, Tamai K, Saga T, et al. Clinical value of image fusion from MR and PET in patients with head and neck cancer. Mol Imaging Biol. 2009;11(1):46-53.
  9. Kanda T, Kitajima K, Suenaga Y, et al. Value of retrospective image fusion of (1)(8)F-FDG PET and MRI for preoperative staging of head and neck cancer: comparison with PET/CT and contrast-enhanced neck MRI. Eur J Radiol. 2013;82(11):2005-2010.
  10. Chauhan A, Kulshrestha P, Kapoor S, et al. Comparison of PET/CT with conventional imaging modalities (USG, CECT) in evaluation of N0 neck in head and neck squamous cell carcinoma. Med J Armed Forces India. 2012;68(4):322-327.
  11. Buchbender C, Heusner TA, Lauenstein TC, Bockisch A, Antoch G. Oncologic PET/MRI, part 1: tumors of the brain, head and neck, chest, abdomen, and pelvis. J Nucl Med. 2012;53(6):928-938.
  12. Weistrand O, Svensson S. The ANACONDA algorithm for deformable image registration in radiotherapy. Med Phys. 2015;42(1):40-53.
  13. Brock KK, Mutic S, McNutt TR, Li H, Kessler ML. Use of image registration and fusion algorithms and techniques in radiotherapy: Report of the AAPM Radiation Therapy Committee Task Group No. 132. Med Phys. 2017;44(7):e43-e76.
  14. Velec M, Moseley JL, Svensson S, Hardemark B, Jaffray DA, Brock KK. Validation of biomechanical deformable image registration in the abdomen, thorax, and pelvis in a commercial radiotherapy treatment planning system. Med Phys. 2017;44(7):3407-3417.
  15. El-Mofty SK, Lu DW. Prevalence of human papillomavirus type 16 DNA in squamous cell carcinoma of the palatine tonsil, and not the oral cavity, in young patients: a distinct clinicopathologic and molecular disease entity. Am J Surg Pathol. 2003;27(11):1463-1470.
  16. Beitler JJ, Zhang Q, Fu KK, et al. Final results of local-regional control and late toxicity of RTOG 9003: a randomized trial of altered fractionation radiation for locally advanced head and neck cancer. Int J Radiat Oncol Biol Phys. 2014;89(1):13-20.
  17. Department of Veterans Affairs Laryngeal Cancer Study G, Wolf GT, Fisher SG, et al. Induction chemotherapy plus radiation compared with surgery plus radiation in patients with advanced laryngeal cancer. N Engl J Med.1991;324(24):1685-1690.
  18. Forastiere AA, Zhang Q, Weber RS, et al. Long-term results of RTOG 91-11: a comparison of three nonsurgical treatment strategies to preserve the larynx in patients with locally advanced larynx cancer. J Clin Oncol. 2013;31(7):845-852.
  19. Lefebvre JL, Andry G, Chevalier D, et al. Laryngeal preservation with induction chemotherapy for hypopharyngeal squamous cell carcinoma: 10-year results of EORTC trial 24891. Ann Oncol. 2012;23(10):2708-2714.
  20. Vermorken JB, Remenar E, van Herpen C, et al. Cisplatin, fluorouracil, and docetaxel in unresectable head and neck cancer. N Engl J Med. 2007;357(17):1695-1704.
  21. Posner MR, Hershock DM, Blajman CR, et al. Cisplatin and fluorouracil alone or with docetaxel in head and neck cancer. N Engl J Med. 2007;357(17):1705-1715.
  22. Haddad R, O'Neill A, Rabinowits G, et al. Induction chemotherapy followed by concurrent chemoradiotherapy (sequential chemoradiotherapy) versus concurrent chemoradiotherapy alone in locally advanced head and neck cancer (PARADIGM): a randomised phase 3 trial. Lancet Oncol. 2013;14(3):257-264.
  23. Blanchard P, Baujat B, Holostenco V, et al. Meta-analysis of chemotherapy in head and neck cancer (MACH-NC): a comprehensive analysis by tumour site. Radiother Oncol. 2011;100(1):33-40.
  24. Bonner JA, Harari PM, Giralt J, et al. Radiotherapy plus cetuximab for locoregionally advanced head and neck cancer: 5-year survival data from a phase 3 randomised trial, and relation between cetuximab-induced rash and survival. Lancet Oncol. 2010;11(1):21-28.
  25. Calais G, Alfonsi M, Bardet E, et al. Randomized trial of radiation therapy versus concomitant chemotherapy and radiation therapy for advanced-stage oropharynx carcinoma. J Natl Cancer Inst.1999;91(24):2081-2086.
  26. Brizel DM, Albers ME, Fisher SR, et al. Hyperfractionated irradiation with or without concurrent chemotherapy for locally advanced head and neck cancer. N Engl J Med.1998;338(25):1798-1804.
  27. Bourhis J, Sire C, Graff P, et al. Concomitant chemoradiotherapy versus acceleration of radiotherapy with or without concomitant chemotherapy in locally advanced head and neck carcinoma (GORTEC 99-02): an open-label phase 3 randomised trial. Lancet Oncol. 2012;13(2):145-153.
  28. Seiwert TY, Burtness B, Mehra R, et al. Safety and clinical activity of pembrolizumab for treatment of recurrent or metastatic squamous cell carcinoma of the head and neck (KEYNOTE-012): an open-label, multicentre, phase 1b trial. Lancet Oncol. 2016;17(7):956-965.
  29. Ferris RL, Blumenschein G, Jr., Fayette J, et al. Nivolumab for Recurrent Squamous-Cell Carcinoma of the Head and Neck. N Engl J Med. 2016;375(19):1856-1867.
  30. Groupe Oncologie Radiotherapie Tete et Cou. Randomized Trial of Avelumab-cetuximab-radiotherapy Versus SOCs in LA SCCHN (REACH).ClinicalTrials.gov Identifier: NCT02999087.  
  31. Tessa Therapeutics. A Phase III Trial Evaluating Chemotherapy and Immunotherapy for Advanced Nasopharyngeal Carcinoma (NPC) Patients. ClinicalTrials.gov Identifier: NCT02578641.  
  32. Chia WK, Teo M, Wang WW, et al. Adoptive T-cell transfer and chemotherapy in the first-line treatment of metastatic and/or locally recurrent nasopharyngeal carcinoma. Mol Ther. Jan 2014;22(1):132-139.
Resources 

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eCourse: Functional Consequences of Chemo Radiation Therapy