Radiation Oncology Synopsis

Laryngeal Cancer

Natural History

Most common malignancy of hte upper aerodigestive tract: 1% of all malignancies and 25% of all head and neck tumors. Primary glottic larynx cancers are 3 times more common than supraglottic larynx cancers. Subglottic larynx tumors are rare accounting for l1-2% of all larynx cancers. *0% are in men and larynx cancer is the most curable of the upper aerodigestive tract cancers. OS5 remains at approximately 65% over the past 3 decades. the major strides in laryngeal cancer is organ preservation with the majority of patients now treated initially with organ preservation protocols.

Genetics. There are a variety of genetic alterations seen in laryngeal cancer: p54, Ki-67, EGFR, h-TERT, cyclin D1, cathepsin D and TGF-B. p53 mutations are seen in 55% of smokers and driners. p53 changes are also seen in HPV infections.

Anatomy

There are three anotomic regions: supraglottic, glottic and subglottic regions. The SGL is composed of epiglottis, aryepiglottic folds, arytenoids and false vocal cords. The epiglottis is divided into a suprahyoid and infrahyoid component based on its relation to the yoid bone.

The SGL boundaries are: tip of the epiglottis to the superior surface of the TVC.

The glottic larynx consists of TVC and anterior and posterior commissures which include the mucosa between the arytenoids.The TVC average 2 cm long and are thinnest anteriorly and posteriorly. Most lesions arise on the free edge, upper surface of the anterior 2/3 of the cords and frequently extend to the anterior commissure. The lower boundary is a plane 1 cm below the apex of the venricls or 0.5 cm below the free edge of the TVC.

The subglottic larynx extends down to the inferior margin of the cricoid cartilage and the beginning of the trachea.

Clinical Presentation

Most present with sore throat and dysphagia in SGL cancers. The auricular nerve of Arnold, a branch of the vagus n. can lead to referred pain in the deep unilateral ear. This nerve also innervates the SGL. Hoarseness occurs with more advanced lesions that involve the TVC, but is not seen in early stage disease. Often a neck mass is the first manifestation of carcinoma of the supraglottis. Weight loss, dyspnea, halitosis and aspiration can occur with locally advanced disease.

Glottic larynx cancers are most commonly diagnosed at an early stage. Sore throat, otalgia, localized pain resulting from cartilage invasion and dyspnea are symptoms of advanced disease.

Diagnositc Evaluation. A careful H & P with careful neck palpation for neck metastases. If there is localized tenderness or a mass over the thyroid cartilage, there may be thyroid coartilage invasion. Loss of thyrovertebral crackle is a sign of postcricoid extension.

Endoscopic examination is the most valuable and essential step in the diagnosis and staing of laryngeal cancer. Endoscopic examination is critical ini assessing superficial spread of neoplasm and is better than imaging in detecting mucosal spread. Invovlemnt of the deep spaces of the larynx is greatly underestimated by clinical examination and will understage approximately 50% of all patients.

Imaging is essential. CT is predominantly used with high resolution CT scans. Correct T-stage classificaiton is 70-80% and N-staging around 80%. CT is limited in subtle evaluation of cartilage and bone invasions and superficial tumor detection. MRI is hamstrung my motion artifacts. NCCN recognizes either study modality.

PET/CT use is increasing. PET can distinguish between growing disease and post-treatment change.

In addition, metastatic workup is required including chest imaging.

Prior to treatment, (radiation) VFSS, full dental evaluation and triple endoscopy to rule out other tumors.

Patterns of Spread

Supraglottic Larynx

The SGLhas a rcih lymphatic network with bilateral lymphatic drainage. There is a high propensity for bilateral node involvement. The lymphatics of the SGL pass through the thyrhyoid membrane and drain into the jugular (Level II) chain. The subdigastric/Level II lymph nodes are most commonly involved. Next are level III nodes followed by level IV. Posterior cervical nodes (Level V) are not usually involved. Level IB/IA nodes are rarely involved. Clinical incidence of nodal involvement at diagnosis is 55% with 16% bilateral. Tumor size and grade is associated with extent of nodal involvement. For T1/T2 tumors 40% are node positive and T3/T4, 60%.

Subglottic Larynx

Subglottic larynx drainage is to an anterior and a posterolateral region. The anterior drainage is through the cricothyroid membrane and drain into the Level III/IV nodes to the Delphian node. From there they drain into the pretracheal and supraclavicular nodes. The posteriolateral channels drain through the cricotracheal membrane and terminate in the high paratracheal nodes. Mediastinal invovlemnt is rare even with subglottic primaries and is more likely a metastases.

Glottic Larynx

The true vocal cords have little lymphatic drainage. The incidence of lymphatic involvment for T1: 0%, T2: 2%, T3: 15-20% and T4: 20-40%. Lymphatic dissemination occurs mainly when there is supraglottic extension.

Treatment

Verrucous Carcinoma

Treatment of verrucous carcinoma of the TVC is controversial. VC does not metastasize and control is excellent. Princess Margaret Hospital, showed that radiation was not associated with anaplastic transformation and 1/3 of the patients recurred. Nearly all were salvaged with laryngectomy. The ultimate survival rate was 97% and larynx preservation was 80%. The study was limited to 62 cases. Radiation is indicated for large tumors requiring laryngectomy. Otherwise smaller tumors can be treated with excision or partial laryngectomy.

CIS

CIS can be treated with surgery or radiation therapy. For patients electing observation after biopsy 2/3 will develop invasive cancers and some will no longer be candidates for layrnx preservation. Repeated biopsies and laser excisions or strippings can lead to reduction of voice quality and should be avoided. Surgical approaches include cord stripping, cordectomy, laser excision, and open partial laryngectomy.

Radiation is effective treatment for CIS with a slightly higer rate of local control with RT than cord stripping or laser excision. Primary radiation local control is 70-100% (average is 87%). Local control rate for laser resections and stripping is 83% and 72%. Radiation doses of 51 Gy @ 2.55 Gy/fx in 20 fractions (Note: EQD2 dosing is EQD2= 51 Gy (2.55+10)/(2+10) = 51(12.55/12) = 53.33 Gy ). Radiation should be considered for patients who have recurrence after surgical methods. Also radiation is useful in more diffuse lesions or those not suited for limited surgical intervention. some centers prefer to use 60 Gy / 2 Gy/fx because of the risk of occult invasive disease in 1/3 of these patients.

T1 Glottic Larynx

The treatment goal for early invasive glottic laryngeal cancer is to cure while preserving optimal voice quality with minimal morbidity. All patients should be offered larynx preserving approach. Every effort should be made to avoid combining surgery and radiation due to the risk of compromising functional outcomes.

No one treatment modality has been demonstrated superior with respect to all treatment goals. There are no randomized studies directly comparing surgery and radiation therapy. Both surgery and radiation modalities are accepted as standard treatment options.

The rates of local control, larynx and voice preservation are comparable for Radiation,open partial laryngectomy and transoral laser excision. If the lesion is well defined, superficial, involving one cord, laser resection can be used. More extensive lesions and those involving the anterior commisure or both vocal cords have decreased local control after laser ablation and radiation is preferred. For most T1 glottic cancers, voice quality is usually better after radiotherapy. Local control after initial resection is lower compared with radiation but local control is similar after salvage therapy. For those who require a high-quality voice, RT may be the preferred initial treatment. If radiotherapy fails, salvage surgery is successful in 75% to 85% of all patients who undergo salvage surgery. 50% of recurrent patients undergoing salvage surgery can undergo larynx preservation.

Results of Radiation Therapy for T1 Glottic Larynx Cancer

Yamazaki reported a trial of 2 Gy v. 2.25 Gy/fraction in Stage I Glottic larynx cancers to a total dose of 56.25 Gy (2.25 Gy/fx) or 60 Gy (2.0 Gy/fx) in smaller tumors and 63 Gy or 66 Gy in larger tumors at the same fractionation schemes. They reported larger fraction size increased local control from 77% to 92%, consistent with retrospective studies. Stanford treats T1 glottic larynx tumors to 63 Gy at 2.25 Gy/fraction. The EQD2 dose is 64.32 (early/tumor) and 66.15 Gy (late -- α / β = 3)

T2 Glottic Larynx Cancers

T2 glottic larynx cancers (extension to the supraglottic larynx or with impaired vocal cord mobility) are treated with radiation therapy and open partial laryngectomy. Laser excision can be used for select tumors that are superficial and well localized. Deeply infiltrating lesions and those with impaired cord mobility are more likely to recur after laser resection. In Megative margins are more difficult to obtain, often making post-operative radiation therapy necessary, causing poorer voice quality. Open surgery results in permanent hoarseness.

For patients treated with RT initial local control rates are in the range of 67% -- 88%. Studies have demonstrated improved local control with hyperfractionaed and hypofractionated radiation therapy. The RTOG did a phase 3 trial comparing 79.2 Gy @ 1.2 Gy BID (66 fractions) to 70 Gy in 35 fractions @ 2 Gy QD. Early results of this study showed a non-significant improvement from 70% to 79% local control with hyperfractionation. Debate over the optimal fractionation scheme is ongoing. MSKCC treats T2N0 /Stage II Glottic larynx cancers to 65.25 Gy @ 2.25 Gy/fraction. (EQD2 = 66.6 Gy. Ultimate local control is in the range of 94% with surgical salvage.

Prognostic factors include impaired vocal cord mobility and anterior commisure involvement which may be associated with lower local control and survival. Adverse prognostic factors include (reported in some series but not others):

Supraglottic Larynx

Although the prognosis for supraglottic larynx is slightly worse, all early stage tumors should be treated initially with larynx preservation intent. Optimal treatment modality for these tumors is still debated. For early stage, favorable lesions, endoscopic laser resection, open partial supraglottic laryngectomy and radiation are all considered standard treatment options. Not all patients are candidates for larynx preserving surgery because of tumor site or extent or medical comorbidities.

Only half of the patients will not be candidates for open partial laryngectomy due to comorbidities or location and extent of disease. Local control may be slightly higher with surgery than radiation. Many patients receive post-op radiation therapy. Surgical candidates tend to be younger and healthier.

Contraindications to surgery include:

There may be slightly better initial local control with partial laryngectomy but radiation with salvage surgery both resulted in ultimate local control of 90% for T1/T2 N0 supraglottic larynx tumors.

The 5 year actuarial local control probability for radiation therapy for T1/2 supraglottic tumors was 100% and 86%. A large fraction of these patients were not eligible for partial laryngectomy. Prognostic factors include: grade, size and sex and tumor size. Tumors more than 6 -8 cm3 on ct have much higher rates of recurrence after radiation. Lymphadenopathy, especially nodes > 3 cm have an adverese effect on local control and survival. An UK retrospective study demonstrated equivalence between surgery and radiation as primary treatment modes.

Locally Advanced Laryngeal Cancers (Stage III/IVA-B)

Locally advanced disease outcomes are much worse than early stage disease. Long term survivaal rates range from 30% - 60%. Prior to the VA Laryngyl Study laryngectomy was the preferred treatment for surgically resectable locally advanced laryngeal cancers, followed by radiation therapy. Laryngectomy is a feared procedure with 25% of individuals wowilling to trade a 20% absolute survival benefit for the opportunity to save their voice.

Laryngectomy should be reserved for patients with T4 lesions with extensive cartilage involvement or for salvage after chemo/radiation failures or non-responders. For select T3/T4 lesions amenable to surgery but post-op radiation is often needed and voice quality can be low. Unresectable laryngeal cancer should receive concurrent chemo-radiation due to sub-optimal results with radiation alone.

Select patients with more favorable Stage III/IV disease or those not candidates for chemotherapy are treated with definitive radiation alone. These patients should receive altered (usu. hyperfractionated) fractionation schemes. A phase III RTOG 9111 study showed hyperfractionation and accelerated fractionation with concomitant boost are more effective than standard fractionation for locally advanced head and neck cancer for local control and disease free survival.

RTOG 9111 was a three arm trial that compared sequential chemotherapy » radiation ; concurrent chemo-radiation and radiation alone. A 5 year follow up in 2006 noted that both sequential radiation and and concurrent chemoradiation improved laryngectomy free survival (44%) compared iwth radiation alone (34%). There was no difference between the two chemotherapy/radiotherapy arms in laryngectomy free survival. Local-regional control, larynx preservation adn disease free survival were better with concurrent chemoradiation than with the other two arms. Overall survival was equivalent between arms at yeasr 2 and 5.

Neck Management

Post RT neck dissection is controversial. With a pathologically complete response to chemo-radiation, selective use of neck dissection may be more appropriate. A study of 121 patients with node positive suprglottic cancer who had definitive RT and achieved a complete response at 4-6 weeks resulted few isolated neck recurrences. Post-RT neck dissection is not routinely recommended. A complete response on PET/CT at 8 weeks can be used to determine if neck dissection is required. A Canadian study suggests that neck dissection is not required for N1/N2 disease with a complete response on CT. University of Iowa demonstrated in a small study 100% negative predictive value for a complete response on PET. Generally N1 disease is observed, and N2/N3 disease undergo neck dissections.

Surgical Managment for bulky T4 disease/Cartilage Invasion

There is a high local failure rate for bulky T4 disease with extensive thyroid cartilage invasion. The standard for these remains laryngectomy. Extensive cartialge invasion causes poor functional outcome even if radiation is successful. Indications for post operative radiation are:

Post operative RT gives significantly better local/regional control, but overall survival differences was not significantly altered. Altered fractionation and dose escalation studies have been negative.

Postoperative Chemotherapy

Surgery with post-op radiation therapy still results in 25-30% recurrence within 2 years of surgery and higher recurrence rates with multiple adverse features. Two trials in 2004 established a role for concurrent chemo/RT. RTOG and EORTC included ≥ 2 nodes, postivie margins or extranodal extension were the most important prognostic factors in Stage III/IV (except T3N0 larynx) . Both the EORTC and RTOG trials found significantly better local/regional control with the addition of chemotherapy. In addition, the EORTC trial showed improved survival with the addition of CDDP, but the RTOG trial did not.

RTOG 0129 is investigation accelerated fractionation with concurrent chemotherapy (concomitant boost) with high dose concurrent CDDP and RTOG 05-22 is accruing patients for the addtion of cetuximab to standard chemo/RT regimens.

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Subglottic Larynx

Subglottic larynx primary cancers are rare. Most are locally advanced at diagnosis and are treated with surgery followed by post-op radiation therapy. Overall survival at 5 years is 25% due to advanced and metastatic disease at diagnosis.

IMRT Treatment Planning

GTV

The GTV consists of any visible tumor on imaging studies or physical examination. The PTV will include the GTV plus 5 mm expansion to account for organ motion and setup errors. The dose used is 70 Gy at 2 - 2.12 Gy/fraction (MSKCC).

CTV-High Risk

The high risk CTV encompasses the GTV/PTV and ipsilateral level II - IV neck nodes. The high risk PTV includes a 3-5 mm expansion. Dose is 59 - 63 Gy (1.8 Gy/fraction)

CTV-Low Risk

The low risk CTV is the clinically uninvolved neck and base of skull. The low risk PTV consists of a 3-5 mm expansion.

Toxicity

Acute Toxicity

Acute reactions include

These reactions are managed conservatively with topical anesthetics (Mylanta-Lidocaine-benedryl), oral rinse solutions, anti-inflammatory drugs and opiate analgesics. Thhey generally completely resolve withn 6 weeks of treatment. Voice generally returns to normal within a few months of treatment.

Acute toxicity is more severe for radiation of the supraglottic larynx due to the increased volume of tissue treated. Loss of taste, xerostomia and weight loss can be anticipated with increasing severity with increased treatment volume.

Acute toxity is worse in hyperfractionated or accelerated fractionation radiotherapy. Concurrent chemotherapy significantly increases the risk of acute toxicity, especially mucositis. The rate of acute grade 3/4 mucosal/pharyngeal toxicity doubles in patients receiving concurrent chemotherapy. Cetuximab does not appear to increase mucosal toxicity but is assocated with acneiform rash.

Late Toxicity

Laryngeal edema after RT can persist and is a complex managment problem in 15%. In about half of the patients with persistent laryngeal edema, persistend or recurrent disease is found. Initial treatment measures include

If laryngeal edema is mild and stable and no visible recurrence is seen, resist biopsy to avoide the risk of inducing laryngeal necrosis. If edema is progressive and unresponsive to consiervative measures, suspect persistence of disease or recurrence. Salvage surgery is performed if biopsies are positive.

Risk of late effects depends on fraction sized. T1/T2 TVC was studied with 44% occurence of laryngeal edema in with 50 Gy at 3.33 Gy/fraction in 3 weeks. This was reduced to 18% who received 60Gy at 2.5 Gy/fx and 17.2% @ 60.75 Gy / 2.25 Gy/fx. Other studies (Mendenhall and coworkers) report the incidedne of moderately severe and severe complications was significantly higher in patients who received > 2.25 Gy/fx.

Laryngeal necrosis was rare at 0% to 3% for glottic cancer and 1 - 2.5% for supraglottic cancer. At doses up to 66 Gy/2 Gy/fx or 63 Gy @ 2.25 Gy/fx Yamazaki reported no severe late complications.

Post op RT causes higher rates of serious toxicity after larynx preserving surgery. Major complications including post-op deaths and total aryngectomy for intractable aspiration in 5% of one study. An RTOG post op radiaiton trial for advanced laryngeal cancer found 17 of 270 patients had moderate to severe late complications and there were no treatment related deaths.

Aspiration is a major late effect of radiation with or without chemotherapy. pharyngoesophageal dysfunction resulting in dysphagia and PEG dependence has a profound effect on quality of life after treatment. This is greater than xerostomia. The rate of aspiration on barium swallow studies was > 80%. 50%

Voice quality after radiation is typically very good and superior to larynx preservation surgery, however 60% have some decline in voice quality. There is an increased risk of poor voice quality in those who continue to smoke after completion of radiation or those who had stripping of the cords.

There is emerging evidence that carotid artery disease increases after radiotherapy but not with surgery at 10 years. 1/3 of the patients treated with RT will develolp a cerebrovascular event at 10 years if they have not died of other causes.