Update in the management of head and neck cancer

Update in the management of head and neck cancer

u p d a t e o n c a n c e r t h e r a p e u t i c s 1 ( 2 0 0 6 ) 211–219 available at www.sciencedirect.com journal homepage: www.updateoncancer.co...

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u p d a t e o n c a n c e r t h e r a p e u t i c s 1 ( 2 0 0 6 ) 211–219

available at www.sciencedirect.com

journal homepage: www.updateoncancer.com

Update in the management of head and neck cancer Michael Fanucchi ∗ , Fadlo R. Khuri, Dong Shin, Peter A.S. Johnstone, Amy Chen Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA 30322, United States

a r t i c l e

i n f o

a b s t r a c t

Keywords:

Patients with head and neck cancer present numerous challenges to treating physicians. The

Head and neck cancer

optimum management requires a co-ordinated, multispeciality team, comprising experi-

Squamous cell carcinoma

enced head and neck surgeons, medical and radiation oncologists, pathologists, diagnostic

Chemotherapy

radiologists and nuclear medicine physicians. The improved survival observed with CRT

Radiation

using high-dose cisplatin over RT alone warrants its use as standard care for fit patients with

Otolaryngology

high risk SCCHN following surgery or as definitive therapy for patients with unresectable

Epidermal growth factor receptor

disease. Patients with unresectable disease also have better survival with induction CT and RT compared to RT alone. However, when the goal of therapy is preservation of the larynx, CRT is superior to both induction CT followed by RT, and RT alone. Drugs that inhibit the EGFR pathway, alone or in combination with radiation, appear promising in the treatment of patients with unresectable disease and with recurrent or metastatic disease. Local control rates may improve with wider utilization of altered fractionation schedules in CRT regimens. Intensity modulation and PET-CT fusion are improved means to target and accurately deliver radiation therapy to the head and neck. Endoscopic laser surgery and supracricoid partial laryngectomy can improve organ preservation in suitable patients. © 2006 Published by Elsevier Ltd.

1.

Introduction

Squamous cell carcinoma of the head and neck (SCCHN) is the sixth most common neoplasm in the world today, with 500,000 cases expected each year. In the United States, approximately 40,000 cases will be diagnosed [1], with only 1/3 of patients presenting with local (stage I or II) disease, amenable to cure with surgery or radiation in a high percentage of patients. Approximately 2/3 of patients present with locally advanced disease, and are best treated with multimodality approaches; recurrences in these patients account for the majority of the 11,500 deaths from SCCHN expected in 2005. What follows summarizes important advances made over the past few years in the post-operative adjuvant treatment of high-risk patients and in the definitive treatment of unresectable patients that have led to an improvement in survival

rates. Important advances in surgery and in chemoradiation have led to better organ preservation for patients with carcinoma of the larynx. Treatment for patients with recurrent or metastatic disease remains problematic, although newer drugs provide less toxicity compared to older regimens.

1.1.

Adjuvant treatment of surgical disease

The survival rate of patients with surgically treated stage III or IV SCCHN is approximately 40% at 5 years, despite the use of post-operative radiation (RT). Cancer related deaths in approximately 30% of patients are primarily a consequence of local and regional recurrences. Distant metastases occur in approximately 25% of patients. Several factors predict for an increased risk of recurrence and decrease 5-year survival to 30%: incomplete resections of the primary tumor, involve-

∗ Correspondence to: Winship Cancer Institute at Emory-Crawford Long Hospital, 550 Peachtree Street, Glenn Building, Atlanta, GA 30308, United States. E-mail address: Michael [email protected] (M. Fanucchi).

1872-115X/$ – see front matter © 2006 Published by Elsevier Ltd. doi:10.1016/j.uct.2006.04.006

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Table 1 – Comparison of results for the EORTC and RTOG adjuvant trialsa EORTC 22931

Overall survival Disease-free survival Local or regional relapse rate Severe acute toxicityb Severe late toxicity a b

RTOG 9501 RT (%)

CRT (%)

p value

RT (%)

CRT (%)

p value

40 36 31 21 41

53 48 17 41 38

0.02 0.04 0.007 0.001 0.25

57 45 28 34 21

64 54 18 77 17

0.19 0.04 0.01 <0.001 0.29

Estimates at 5 years for EORTC, 2 years for RTOG. Functional acute mucosal toxicity for EORTC and all adverse effects for RTOG, including acute hematologic and gastrointestinal toxicities.

ment of two or more lymph nodes in the neck, and spread of cancer beyond the capsule of the lymph node. Two small studies initiated in the late 1980s suggested that adjuvant chemoradiotherapy (CRT) improved local control and survival compared to radiotherapy alone. Recently, two larger studies confirmed the benefits of post-surgical CRT in patients at high risk for recurrence. The European Organization for the Research and Treatment of Cancer study (EORTC 22931) [2] randomized 334 patients, predominantly stage III or IV but excluding T3N0 SCC of the larynx, to postoperative radiotherapy (66 Gy over a period of 6.5 weeks, using isocentric techniques) versus the same radiotherapy with 100 mg/m2 of cisplatin on days 1, 22, and 43 of the radiotherapy regimen. There was a significant difference in disease free survival (the primary objective of the study) and overall survival (53% for CRT versus 40% for RT at 5 years). Locoregional control rates and time to progression were also superior in the CRT arm (Table 1). The Radiation Therapy Oncology Group study (RTOG 9501) [3] randomized 459 patients with a high risk for recurrence (metastases to two or more lymph nodes, extracapsular spread or microscopically involved mucosal margins of resection) to the same treatment regimens. There was a significant difference in the rates of local and regional control (the primary objective of the study, Table 1) and disease free survival (54% for CRT versus 45% for RT at 2 years), but not overall survival (64% for CRT versus 57% for RT at 2 years). However, the authors point out that the survival curves are diverging in favor of CRT, and longer follow-up may show a survival advantage. Both studies found higher rates of severe acute hematologic and mucosal side effects in the CRT arms, but the rates of severe late toxicities were similar in the CRT and RT arms (Table 1). There are differences in patient characteristics between the two studies that may explain the lack of a significant survival benefit in the RTOG study (Table 2). The EORTC study used a broader definition of increased risk, enrolling patients with 0–1 involved lymph nodes with adverse biologic features in the primary tumor (perineural involvement and vascular embolisms) in addition to patients with extracapsular spread. More patients in the EORTC had involved mucosal margins in the resection specimens. However, with the improved survival and rates of local and regional tumor control, the data support the use of post-operative CRT in patients with high risk for recurrence, as defined in the two studies.

1.2.

Treatment of patients with unresectable SCCHN

Patients with stages III and IV SCCHN whose disease cannot be resected with the expectation of achieving tumor-free margins have in the past been treated with RT alone. Patients with locally advanced tumors of the oropharynx originating in the base of tongue or tonsils who were unwilling to accept the limitations in swallowing and speech necessitated by potentially curative surgery were also treated with radiation alone. Conventional radiotherapy fractionation is generally accepted as a single 2 Gy fraction per day, 5 days per week for 6–7 weeks. The altered fractionation schedules best studied in advanced SCCHN have been hyperfractionated radiotherapy (1.2 Gy per fraction twice daily to a total of 81.6 Gy over 7 weeks) and accelerated fractionation with concomitant boost (1.8 Gy fractions in 6 weeks with an additional 1.6 Gy fraction per day in the last 12 days of treatment, to a total of 72 Gy in 42 fractions over 6 weeks). In patients with stages III and IV disease, the latter two regimens produced significantly better locoregional control than conventional fractionation (54% versus 46%), but there were no differences in survival [4]. Four randomized studies reported in the late 1990s demonstrated the superiority of CRT over RT alone in improving local and regional control rates and survival [5]. In general, CRT approximately doubles 3–5-year local and regional control rates and survival compared with RT alone. The majority of the trials used high-dose cisplatin, but other regimens have been used. Data from an update of the French Head and Neck Oncology and Radiotherapy Group (GORTEC) trial [6], and the

Table 2 – Comparison of patient characteristics for the EORTC and RTOG adjuvant trials EORTC 22931 (%)

RTOG 9501 (%)

Primary tumor site Oral Cavity Oropharynx Hypopharynx Larynx

26 30 20 22

24 48 7 20

Resection margin involved N2-3 lymph nodes Extracapsular spread present Perineural involvement Vascular embolisms

29 56 57 13 20

18 93

a

Not provided.

a a a

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recently published Intergroup trial [7], further support CRT as standard care for patients with unresectable disease. The GORTEC randomized 226 patients with stages III and IV SCC of the oropharynx to RT or CRT (using carboplatin and 5FU). After a median follow-up of 5.5 years, specific disease free survival (26.6% versus 14.6%) and overall survival (22.4% versus 15.8%) significantly favored CRT, as did local and regional control rates (47.6% versus 24.7%). The rates of severe toxic effects at 5 years to mucosa, skin and salivary glands were numerically higher in the CRT patients (56% versus 30%) but not significantly different. The Intergroup randomized 295 patients to RT (70 Gy over 7 weeks), CRT using high-dose cisplatin administered during RT as previously described, and a split course of CRT with surgery after two cycles of chemotherapy with cisplatin/5-FU and 30 Gy of RT. Unresectability was carefully defined and 96% of all patients had stage IV disease and 85% had T4 or N3 tumors. At the completion of therapy, any patients with residual disease could be considered for surgical resection and neck dissection was recommended for patients with initial N2 or greater neck disease. There was again a significant improvement in 3-year disease specific survival for CRT (51%) versus RT (33%). The split course arm was intermediate between the CRT and RT arms in survival although there was a higher CR rate due to the planned midcourse surgical intervention. Toxicity from CRT was similar to previous descriptions. Approximately 20% of the patients in each arm underwent salvage surgery, primarily neck dissections, suggesting the importance of continued surgical follow-up in the management of these patients. The strategy of sequential (or induction) CT followed by RT also appears superior to RT alone in the management of patients with unresectable disease. For example, the Gruppo di Studio sui Tumori Testa e Collo (GSTTC) compared four cycles of cisplatin and infusional 5-FU followed by RT to RT alone in 237 patients with operable and inoperable stages III and IV SCC (56% oropharynx, 26% hypopharynx, and 16% oral cavity). Of the patients entered, 72% were inoperable and 64% had stage IV disease. After a minimum follow-up of 10 years, the survival for unresectable patients at 5 and 10 years were significantly better for induction CT followed by RT than for RT alone (23% and 19% versus 8% and 6%) [8]. EORTC 24971 [9] attempted to optimize induction CT by comparing cisplatin and infusional 5-FU to cisplatin, infusional 5-FU, and docetaxel in 384 patients with unresectable disease. Patients received four cycles of CT, followed by RT. A neck dissection before RT for patients with bulky disease or after RT for persistent disease was permitted. There were significant differences in overall survival, progression free survival and response rates (54% versus 68%) favoring the threedrug regimen. A similar trial (TAX324) comparing the same two induction regimens followed by CRT with low-dose weekly carboplatin has been completed, as has a trial comparing cisplatin and infusional 5-FU with cisplatin, infusional 5-FU and paclitaxel, with both arms followed by CRT using cisplatin [10]. There have been no comparisons between multiagent induction chemotherapy followed by RT (or CRT) to CRT using high-dose cisplatin. The opportunity to better treat metastatic disease with optimal multiagent chemotherapy remains an important potential advantage of induction CT, compared to

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standard CRT with high-dose cisplatin alone. Trials comparing standard CRT using high-dose cisplatin to multiagent induction CT followed by CRT are underway. Several trials are also underway that target overexpression of the epidermal growth factor receptor (EGFR), which is detected in the majority of head and neck cancers. A recent trial randomized 424 patients with locoregionally advanced disease to RT versus RT plus weekly cetuximab, a monoclonal antibody which inhibits signal transduction by blocking EGFR [11]. Patients were stratified for RT with standard fractionation, hyperfractionation or accelerated fractionation with concomitant boost. Two- and three-year survival rates significantly favored RT plus cetuximab, 62% and 57% versus 55% and 44% for RT alone. There was an increase in severe skin reactions at 34% of patients for the combination versus 18% for RT, but there was no difference in the rate of severe mucositis. Studies integrating cetuximab and CRT are underway.

1.3.

Organ preservation in carcinoma of the larynx

Organ preservation has become an acceptable goal for patients with locally advanced SCC of the larynx, since the publication of the study conducted by the Department of Veterans Affairs Laryngeal Cancer Study Group. This study compared induction chemotherapy (CT) followed by RT (with total laryngectomy for patients with persistent or recurrent disease) to total laryngectomy followed by RT. The larynx was preserved in 64% of the patients who received CT followed by RT, and there were no differences in survival between the two groups. However, there was uncertainty regarding the benefits of induction CT followed by RT versus RT alone for preservation of the larynx, and the newer approach of CRT was untested. These treatments were compared in RTOG 91-11, which demonstrated the superiority of CRT as a strategy for preservation of the larynx [12]. RTOG 91-11 randomized 547 patients to one of three treatments: three induction courses of cisplatin plus 5-fluorouracil followed by RT (70 Gy over 7 weeks), CRT using high-dose cisplatin (100 mg/m2 on days 1, 22 and 43 of the same RT), and RT alone. The primary objective of the trial was to compare the rates of preservation of the larynx across the three treatments. Patients were eligible if they had stage III or IV cancers of the glottic or supraglottic larynx. Patients with tumors limited to one subsite of the supraglottis or limited to the vocal cords with normal vocal cord mobility were excluded, as were patients with tumors penetrating through the cartilage or extending more than 1 cm into the base of the tongue. Patients who had either a single lymph node 3 cm or greater in diameter or multiple lymph node metastases on initial clinical staging of the neck were required to undergo neck dissection 8 weeks after the completion of RT. Laryngectomy was performed in patients who had less than a partial response after two courses of induction cisplatin and 5-fluorouracil and in patients who had persistent cancer 8 weeks after RT and in patients with recurrent carcinoma. The rate of laryngeal preservation at 2 years was significantly higher for the group receiving CRT (88%) than for the groups receiving induction CT followed by RT (75%) or RT (70%). Survival rates (75% at 2 years) and rates of severe late toxicity were not different among the three treatment groups (Table 3).

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Table 3 – Summary of RTOG 91-11 RT (%)

CT/RT (%)

p value

CRT (%)

Stage III IV

64 36

64 36

67 33

Site of tumor Supraglottis Glottis

72 28

68 32

66 34

Larynx preservation rate at 2 years Laryngectomy-free survival at 2 yearsa Overall survival at 5 years Disease free survival at 5 years Local control rate at 2 years Distant metastasis rate at 5 years Moderate or severe speech impairment at 2 years Difficulty swallowing at 2 yearsb

70 53 54 27 56 22 8 14

75 59 55 38 61 15 3 16

a b

88 66 56 36 78 12 6 15

0.08 (vs. RT) 0.02 (vs. RT)

p value

0.005 (vs. CT/RT 0.01 (vs. RT) 0.006 (vs. RT) <0.001 (vs. RT) 0.03 (vs. RT)

Treatment failure defined as laryngectomy or death from any cause. Able to swallow only soft foods or liquids.

Of interest, 144 out of 168 patients assigned to induction CT followed by RT had a complete or partial response to two cycles of cisplatin and 5-fluorouracil and only eight patients required an immediate laryngectomy. Chemotherapy reduced the rates of distant metastases. This trial established CRT using highdose cisplatin (followed by neck dissection in patients with high risk neck disease) as standard care for patients with stage III or IV SCC of the glottic or supraglottic larynx whose disease is within the categories studied in the trial. Laryngectomy should only be performed in patients with persistent or recurrent disease, or as initial therapy for patients with T4 tumors beyond the limits imposed by the study.

1.4.

Recurrent or metastatic SCCHN

Despite the improved treatments described above for patients with stages III and IV SCCHN, approximately 50% of patients will develop locally recurrent or metastatic disease. Many studies of CT for recurrent or metastatic SCCHN enrolled patients who recurred after surgery and/or radiation, without having been treated with high-dose cisplatin or multiagent chemotherapy. Two randomized trials documented a response rate of 32% for cisplatin and infusional 5-FU in good performance status patients who had not received prior therapy. The median survival was approximately 8 months and 35% of the patients survived 1 year [13,14].

Cisplatin and paclitaxel are commonly used in the treatment of patients with recurrent or metastatic SCCHN. The ECOG conducted two successive randomized studies (E1393 [15]: cisplatin/paclitaxel, high dose versus cisplatin/paclitaxel, low dose; and E1395 [16]: cisplatin/paclitaxel versus cisplatin/5-FU) in patients with recurrent or metastatic SCCHN. There were no significant differences in response rates or survival among the treatments. However, the cisplatin/paclitaxel arm in E1395 was better tolerated than cisplatin/5-FU, perhaps due to the lower dose of cisplatin (75 mg/m2 versus 100 mg/m2 ) and the avoidance of mucosal damage from the 5-FU (29% of patients had grade 3–5 stomatitis in the cisplatin/5-FU arm). E1395 also assessed pain using the Brief Pain Index and quality of life using the Functional Assessment of Cancer Therapy—Head and Neck. The patients treated with cisplatin/paclitaxel experienced a significant reduction in pain at week 7, compared to patients treated with cisplatin/5-FU, who experienced a slight increase. Overall quality of life was better for the patients treated with cisplatin/paclitaxel. Unfortunately, the pain scores in the cisplatin/paclitaxel arm returned to baseline by week 16, consistent with the short response duration [17]. A report of the long-term follow-up of these two studies found 7% of patients alive at 3 years and 3.6% alive at 5 years [18]. In a multivariate analysis, factors that predicted for reduced long-term survival were weight loss, performance

Table 4 – Representative platinum/taxane combinations,a in comparison to cisplatin/5-FU, for treatment of recurrent of metastatic SCCHN Treatment Cisplatin/5-FU [13,14] Cisplatin/paclitaxel [16] Carboplatin/paclitaxel [22] Cisplatin/docetaxel [19] Cisplatin/5-FU/docetaxel [26] Carboplatin/ifosfamide/paclitaxel [25]

Number of patients 168 96 49 36 19 56

Most patients studied had not received prior cisplatin.

Response rate (%)

Median survival (months)

1-year survival (%)

32 28 23 40 44 59

8.0 9.0 7.3 9.6 11.0 9.1

35 30 28 27 49 36

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Table 5 – Signal transduction inhibitors in comparison to cisplatin in recurrent or metastatic SCCHN Treatment

Number of patients

Cisplatin [33] Cisplatin/cetuximab [33] Cetuximab [32] Gefitinib [27] Erlotinib [28]

Response rate (%)

60 60 103 52 115

9 21 16.5 11 4.3

Median survival (months) 6 6 6 8 6

Most patients received prior chemotherapy.

status 1 (versus 0), well/moderate tumor differentiation, oral cavity or hypopharyngeal primary and a history of RT. Three phase II studies of cisplatin and docetaxel have been published [19–21], and suggest comparable activity to cisplatin and paclitaxel. Two phase II studies of carboplatin and paclitaxel [22,23] suggest comparable efficacy and better tolerance compared to cisplatin regimens. Several phase II studies adding a third drug to a platinum/taxane combination have shown generally higher response rates, including complete responses in 15% of patients, but have enrolled primarily patients without previous chemotherapy and have shown no clear improvement in survival [24–26] (Table 4). Signal transduction inhibitors are likely to become important in the management of patients with recurrent or metastatic SCCHN. Early studies with gefitinib, erlotinib and cetuximab show survivals comparable to what is achieved with chemotherapy with much less toxicity, and these agents warrant further evaluation (Table 5). Several other EGFRtargeting agents are under development. Gefitinib, an oral small molecule inhibitor of the EGFR tyrosine kinase activity, was the first to be tested [27]. In a study of 52 patients with recurrent or metastatic SCCHN, the response rate to 500 mg/day of gefitinib was 10.6%, the median survival was 8.1 months, and 30% of the patients survived 1 year. The study population had been heavily treated with chemotherapy: two-thirds had received CRT and nearly half had received a prior regimen for metastatic disease. Erlotinib, another oral small molecule inhibitor of the EGFR tyrosine kinase activity, was evaluated at a dose of 150 mg/day in 115 patients with recurrent or metastatic SCCHN [28]. Prior therapies consisted of RT in 97% and chemotherapy, either as induction or palliation, in 72%. The response rate was 4.3% and 38.3% of patients had stable disease for a median duration of 16 weeks. The median overall survival was 6.0 months and 20% of patients survived 1 year. The drug was well tolerated, with 11% of patients developing severe skin rash and 3% severe diarrhea. Cetuximab has also had limited evaluation in patients with recurrent or metastatic SCCHN. In a phase Ib study of cetuximab in combination with cisplatin [29], six of nine evaluable patients had a major response, including three patients who had received cisplatin previously. Pharmacodynamic studies in these patients documented saturation of EGFR and reduction of EGFR tyrosine kinase activity. In two phase II trials in platinum-refractory patients, the response rate to the combination of cetuximab and cisplatin was 15%, and median survival was 6 months [30,31]. A phase II study of cetuximab alone in 105 patients with progressive disease on or within 30 days of two to six cycles of platinum-based chemother-

apy found a response rate of 16.5% and median survival of 6 months [32]. The ECOG conducted a randomized, double-blinded study of cetuximab versus placebo in combination with cisplatin in 121 patients with recurrent or metastatic SCCHN who had not received prior chemotherapy for metastatic disease [33]. The response rate was 21% for the combination versus 9% for cisplatin. There was a trend towards improved 1and 2-year survival in the cetuximab plus cisplatin arm, but the median survival for the entire study population was 6 months.

2.

Innovations in radiation therapy

Xerostomia is the most frequent and bothersome chronic toxicity with current radiotherapy protocols. Pharmacologic interventions [34,35] to reduce xerostomia have had variable results. A relatively recent technological innovation, intensity modulation RT (IMRT), has emerged as a means for improving the therapeutic index of radiotherapy in several tumor sites [36]. IMRT is a beam delivery technology, made possible by better computer control of hardware within the linear accelerator and by more sophisticated modeling of dose distribution in tissue. Conventional RT fields for head and neck treatment traditionally use opposed right and left lateral photon fields to encompass the lesion and at-risk lymph nodes. These fields abut a single anterior inferior field that covers the bilateral low neck. The results of such therapy in the head and neck have been limited by the fact that the opposed lateral fields treat all tissue within their borders – normal and malignant – equally. For most tonsil lesions, the location medial to the parotid glands puts them at risk, usually bilaterally. Treatment of a head and neck lesion with IMRT requires the following: (a) Immobilization of the patient: This is performed using a custom thermoplastic mask. This reduces patient motion to a minimum, thus maximizing potential accuracy. (b) Imaging of the immobilized patient: This provides CT-based anatomic data, referable to a known point in threedimensional space within the treatment volume, the isocenter. (c) Contouring of the necessary volumes: The process of contouring volumes involves the radiation oncologist outlining necessary structures on the CT simulation, to describe three-dimensional volumes with reference to the isocenter. Both malignant and normal tissues are contoured.

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Fig. 1 – Axial CT slice of a patient with node-positive tonsil cancer after right tonsillectomy. The blue shaded areas are the retropharyngeal and posterior nodal areas at risk, the outlined green, blue and brown volumes are the right and left parotids, respectively, and spinal cord. The red shaded volume is the merging of the post-operative tonsillar fossa from CT and the corresponding pre-operative PET volume, with 0.5 cm margin. The green shaded volume is the merging of a CT-evident enlarged lymph node and the corresponding PET volume, without margin. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of the article.)

Accurate target volume delineation is thus crucial to accurate IMRT dose delivery. Recently, advances in PET-CT fusion have facilitated much more accurate targeting. This technique [37] allows the fusion of a PET volume onto the CT simulation image, and thus provides metabolic targeting data in addition to anatomic data. Sample contours are shown in Fig. 1. (d) Calculation of the IMRT plan: IMRT requires specific, proprietary algorithms to “inverse plan” the dose distribution. While conventional RT describes a dose to the target volume, IMRT also allows the prescribing physician to prescribe dose constraints to normal organs at risk, even if they are adjacent to the tumor. This inverse planning software then determines beam fluences to solve the dosimetry problem. Fluences are generated by computer-controlled metal leaves within the linear accelerator head which are precisely inserted into the beam for specified times, thereby modulating the ultimate dose reaching the various volumes. This multileaf collimation (MLC) is crucial to intensity modulation. Several different IMRT techniques exist. These are the dynamic MLC technique, which is also called “sliding window,”

Fig. 2 – Axial CT slice from the patient in Fig. 1 with isodose lines overlaid. Note that green shaded gross disease (the lymph node) receives 70 Gy, while the post-operative red shaded tonsillar fossa receives 63 Gy, and the blue shaded nodal areas at risk receive at least 57.8 Gy. The spinal cord is well spared, receiving a dose of about 40 Gy. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of the article.)

“step and shoot” technique and tomotherapy technique. The unifying theme of target coverage with normal tissue avoidance is consistent across techniques. Since photon RT is by its nature linear, the dose distribution plans generated by IMRT software must be carefully reviewed by the radiation oncologist. If the dose is not going to the organs at risk, it must be deposited somewhere else. A sample IMRT plan of the previous axial image is at Fig. 2. Note that high doses surround the target volume while the spinal cord is spared. Since serial stepwise review of axial images is clearly not optimal to properly interpret the overall plan, dose-volume histograms (DVHs) are used. A DVH (Fig. 3) allows the radiation oncologist to interpret the relationship between any volume of interest and the dose it receives. Clearly, a homogenous dose to the target volume is crucial. With respect to normal tissue, the dose received by 50% of a volume is most frequently noted, but in some circumstances the maximum dose may be important (spinal cord), or the volume receiving a specific dose (for instance, V20 , the volume receiving 20 Gy, for lung tolerance). Note that uniformly high doses above 70 Gy are delivered to the target volume for gross disease (PET NODES), while lesser doses are delivered to anatomic volumes such as the tonsillar fossa post-operatively (PTV), and the at-risk bilateral necks. Median doses to parotid glands are 28 Gy to the ipsilateral (right) and 24 Gy to the contralateral (left). The spinal cord is kept below 42 Gy. Note that because of their close proximity

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Fig. 3 – Dose-volume histogram corresponding to the patient in Figs. 1 and 2.

to at-risk nodal areas, the bilateral submandibular glands are not well spared using this plan. Another advantage of IMRT arises from this ability to provide differential radiation doses to different volumes, and is especially valuable in the head and neck. Not infrequently, different anatomic areas require different radiation doses because of different risk of tumor involvement. For instance, if a patient with a small tongue base lesion had undergone a left neck dissection for a positive lymph node, the tumor would require about 70 Gy for control, the undissected neck would require about 50 Gy to treat potential microscopic disease, and the dissected neck about 60 Gy (to account for postoperative hypoxia). Using IMRT, this simultaneous differential dose delivery is performed practically. If a standard head and neck field is treated with 32 fractions, the gross disease could be dosed with 2.19 Gy/fraction (the total dose [TD] would be 32 × 2.19 = 70.08 Gy), the post-operative neck could be dosed at 2 Gy/fraction (TD = 64 Gy), and the at-risk contralateral neck at 1.78 Gy/fraction (TD = 56.96 Gy). A further benefit of this technique arises from the increased biologic effectiveness of the larger dose per fraction delivered to gross disease. Thus, IMRT, especially based on PET-CT fusion, has potential for personalized “sculpting” of radiotherapy fields and doses. Continued improvements in technology will combine the increased accuracy in targeting provided by functional image fusion with daily onboard imaging or time-dependent delivery such as respiratory gating.

3.

Innovations in head and neck surgery

Advances in surgical techniques have been geared towards conservation surgery, both at the primary and in the neck. Significant progress has been made in conservation of the larynx with endoscopic laser surgery and with supracricoid partial laryngectomy, with results comparable to radiation therapy. A limitation to the broader use of these techniques is the lack of trained and experienced head and neck surgeons. Dr. Steiner and Dr. Ambrosch in Germany have the largest experience with laser surgery for laryngeal lesions and report >90% cure rate for early stage lesions. They also advocate endoscopic laser resection for higher staged cancers as well. Steiner and colleagues reported that the 5-year disease free survival rates for pyriform cancers after organ preserving laser resection were 95% for stages I and II and 69% for stages III and IV [38]. These surgeons also advocate endoscopic laser resection for early stage supraglottic carcinoma but advocate caution in higher staged lesions [39]. Advantages of endoscopic laser resection are avoidance of radiation, good voice and adequate swallowing preservation. Supracricoid laryngectomy represents another surgical advance. Laccourreye reports that supracricoid partial laryngectomy allows for local control rates of 85–90% for T3 lesions, and an improvement in overall survival when compared to other reported conservative surgical options [40]. Laccourreye

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update on cancer therapeutics

also reports excellent laryngeal preservation rates (91%) and very low rates of long-term dependence on gastrostomy tube feedings (0.7%) and tracheotomy (1%) [41]. Surgical management of the neck has progressed from radical neck dissections to modified radical neck dissections to selective neck dissections. The newest form of “minimal” neck surgery is sentinel lymph node sampling for head and neck cancers. This technique is currently being studied in a cooperative group setting and is still under investigation. However, recent reports suggest that sentinel lymph node sampling can detect disease with good sensitivity (93%) [42].

4.

Conclusion

The improved survival observed with CRT using high-dose cisplatin over RT alone warrants its use as standard care for fit patients with high risk SCCHN following surgery or as definitive therapy for patients with unresectable disease. Patients with unresectable disease also have better survival with induction CT and RT compared to RT alone. However, when the goal of therapy is preservation of the larynx, CRT is superior to both induction CT followed by RT, and RT alone. Drugs that inhibit the EGFR pathway appear promising in the treatment of patients with unresectable disease and with recurrent or metastatic disease. Local control rates may improve with wider utilization of altered fractionation schedules in CRT regimens. Intensity modulation and PET-CT fusion are improved means to target and accurately deliver radiation therapy to the head and neck. Endoscopic laser surgery and supracricoid partial laryngectomy can improve organ preservation in suitable patients. Patients with head and neck cancer present numerous challenges to treating physicians. The optimum management requires a co-ordinated, multispeciality team, comprising experienced head and neck surgeons, medical and radiation oncologists, pathologists, diagnostic radiologists and nuclear medicine physicians.

references

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