radiation therapy

Reirradiation for Recurrent Head and Neck Cancer

Source: Medscape News

Date: November 29, 2012

Abstract

Recurrence of head and neck cancer in a previously irradiated volume presents a challenging problem and has poor prognosis. A minority of patients are eligible for the preferred therapy, surgical resection. Systemic therapy is offered to patients with unresectable disease but offers little, if any, chance of cure. Repeat irradiation with systemic therapy is a potentially curative option. One randomized trial and several cooperative group and institutional studies support its use. Long-term disease-free survival has been observed, albeit with the risk of significant, possibly life threatening, late complications. Intensity-modulated radiotherapy has been shown to reduce toxicity and improve disease control. Novel systemic therapies and radiotherapy techniques, including stereotactic body radiotherapy, are under active study.

Introduction

Radiation therapy plays a central role in the treatment of head and neck cancer (HNC) patients. Within a treatment paradigm of functional organ preservation, evidence-based guidelines recommend radiotherapy for three quarters of all patients with HNC. [1] Both organ-preserving definitive chemoradiotherapy (CRT) and selective postoperative CRT improve locoregional recurrence (LRR) and prolong overall survival (OS). [2,3] Nevertheless, despite improvements, LRR after CRT continues to be a vexing problem for 20–35% of patients. [4–8] Even patients with favorable prognosis human papillomavirus-related HNC [9] have a LRR rate of nearly 15%. [4] Locoregional recurrence is related to a number of different factors. Some tumors are inherently radioresistant. Additionally, as radiation is delivered more precisely with smaller margins, the potential for recurrences related to ‘marginal misses’ has increased. Ongoing exposure to carcinogens, such as cigarette smoke, leads to a 3–5% yearly risk of a second malignancy. [4,10]

Recurrent or second primary HNC in a previously irradiated field has a poor prognosis with a median survival of approximately 6 months with best supportive care. [11] Uncontrolled disease at the primary site or regional lymph nodes can cause complications including pain, disfigurement, significant difficulties with speech and swallowing, as well as the development of metastatic disease. [12] Treatment options are often limited. A small proportion of patients have resectable disease recurrence and are sufficiently fit to undergo salvage resection. However, adverse pathologic features, such as extra-capsular extension (ECE) or positive surgical margins are often seen, raising concern for postoperative disease recurrence. For unresectable disease, systemic therapy alone, the historical standard of care, results in 10–15% 1-year OS and virtually no long-term survivors. [11,13] Previously irradiated patients fare even worse. [14]

For patients with recurrent or second primary HNC within a previously irradiated area, the only potentially curative option is a second course of radiation, with or without chemotherapy, termed reirradiation (RRT). Early experiences with RRT in selected patients demonstrated OS rates (30–50%) that compared favorably to chemotherapy. [15] More recently, concomitant chemotherapy and RRT has been adopted by some as a treatment strategy of choice. Unfortunately, given the heterogeneous patient population, very limited level I evidence is available to inform decision making of physicians and patients. This manuscript will review the evidence base supporting RRT and concurrent chemotherapy with RRT (CRRT) for both resectable and unresectable, recurrent and previously irradiated HNC.

Workup & staging

The care of patients with recurrent HNC is challenging from beginning to end. Even establishing the diagnosis can be problematic given the possibility of false-positive [16] or -negative [17] biopsy results. As discussed herein, treatment options should be tailored for each patient. The significant potential for lasting and debilitating harm from treatment-induced injury to normal structures must be carefully considered. Without exception, the care of these patients should be coordinated by an interdisciplinary team, [18] consisting of representatives from radiology, pathology, otolaryngology, medical oncology, radiation oncology, dentistry, speech pathology and nutrition.

Following pathologically confirmed tumor recurrence, re-staging is of paramount importance as up to 25% of patients will have metastatic disease. [19,20] Currently, there is no standard imaging protocol, and therefore, this should be tailored for each patient. However, when recurrent HNC is suspected, the sensitivity and specificity of PET-computed tomography (CT) for detecting distant metastasis is reported to be 86–91 and 84–93%, respectively. [19,20] The use of whole-body MRI is not routinely recommended as it did not improve upon the accuracy of PET-CT for the diagnosis of primary, regional or distant recurrence in patients with nasopharyngeal carcinoma. [21] Dedicated head and neck MRI demonstrated a trend towards improved sensitivity (96.4 vs 82%) for detecting local recurrence of nasopharyngeal carcinoma when compared with PET-CT, [22] and therefore should be considered for patients with recurrent tumors in this region.

Adjuvant Therapy Following Salvage Surgical Resection

Surgical salvage is the preferred curative treatment for LRR following prior radiotherapy. Unfortunately, resection is attempted in a small proportion of patients due to tumor extension, medical comorbidity and patient preference. [23–26] More than a quarter of the patients experience major postoperative complications [27] and operative mortality is approximately 5%. [23,27] Even for the selected patients who undergo resection, rates of second recurrence remain suboptimal (50–65%). [11,27,28] A detailed discussion regarding the many factors that influence surgical outcomes is beyond the scope of this review. Readers who desire more detail are encouraged to review a meta-analysis on this topic. [27]

Following surgical salvage, multiple single-institution series [29–32] and one multicenter, randomized trial have shown improved disease-free survival (DFS) following postoperative CRRT. The specifics of these studies are summarized in and the following paragraphs concisely present the relevant information.

Single Institution Studies (Level II Evidence)

Several single institution series have evaluated CRRT following surgical resection of recurrent HNC. Summarized in , a total of 129 patients have been followed for a median of 32–67.4 months from four institutions. [29–32] The Institut Gustave–Roussy, [29] reported a series of 25 patients who underwent postoperative CRRT with the FHX regimen (5 day cycles of 2 Gy every day [q.d.] radiotherapy [RT] with concurrent hydroxyurea [1.5 g/day] and continuous infusion 5-fluorouracil [800 mg/m 2] were given every other week for a total of 6 cycles). [33,34] Conventional radiotherapy planning was used and cobalt-60 photons were given to a median dose of 60 Gy. CRRT was given a median of 40 days following surgery and no patients experienced acute wound breakdown. A vast majority of patients received all planned treatment. Encouraging locoregional control (64% at 6 months) and OS (43% at 4 years) led to the aforementioned randomized trial. Acute grade 3 and 4 mucositis was observed in 40 and 12% of patients, respectively. Of the six disease-free surviving patients, five had grade 2–3 cervical fibrosis, three had moderate dysphagia, two had trismus, two had moderate facial pain and one had osteoradionecrosis (ORN). As part of a series of University of Chicago (IL, USA) Phase I studies testing novel agents in combination with the FHX regimen, [32] postoperative CRRT was given to 49 patients using 4–6 MV linear accelerators and 3D conformal RT (3DCRT) planning to a median dose of 64.8 Gy. Three year locoregional control (LRC) and OS was 68 and 39%, respectively. Of the 22 patients suffering treatment failure, 13 had evidence of distant metastasis. On multivariate analysis, triple-agent chemotherapy (hazard ratio [HR]: 0.33; 95% CI: 0.15–0.83; p = 0.006) and radiation dose (HR: 0.73; 95% CI: 0.60–0.90; p = 0.003) were associated with improved OS. Likewise, when compared with patients with unresectable disease, salvage surgery was associated with superior survival (HR: 0.50; 95% CI: 0.32–0.77; p = 0.002).

Randomized Trials (Level I Evidence)

The Group d’Etude des Tumeurs de la Tete et du Cou (GETTEC) and Group d’Oncologie Radiotherapie Tete Et Cou (GORTEC) accrued 130 patients to a Phase III, multicenter, randomized trial comparing CRRT with observation following R0 or R1 surgical resection of previously irradiated, recurrent HNC. [35] Patients were required to have ‘rapid and complete’ wound healing by postoperative week 8 and no severe sequelae from prior RT. High-risk pathologic features of ECE and positive surgical margins were observed in 26 and 29% of patients, respectively, and well balanced between groups. Patients were randomized to either observation or CRRT with the FHX regimen. Adjuvant CRRT improved both LRR (HR: 2.73; 95% CI: 1.66–4.51; p < 0.0001) and DFS (HR: 1.68; 95% CI: 1.13–2.50; p = 0.01), but not OS (p = 0.50). Acute toxicity was increased following CRRT and was observed in 28% of patients in the CRRT arm, and three patients died during CRRT. At 1 and 2 years, the actuarial rates of grade 3 or 4 toxicity were 26 and 39%, respectively, in the CRRT arm compared with 9 and 10% in the observation arm. Death related to treatment (5 vs 0), distant metastasis (6 vs 3) and second primary malignancy (4 vs 1) were higher in the CRRT arm.

Level III Evidence

The American College of Radiology (ACR) Expert Panel on HNC authored Appropriateness Criteria for the treatment of recurrent, previously irradiated HNC. [36] In the setting of positive margins following salvage resection of recurrent HNC, the panel favored CRRT over RRT alone. Chemotherapy alone was not recommended for fit candidates who were thought to be RRT candidates. External beam RT, brachytherapy, alone or in combination was deemed appropriate. Following resection of an isolated nodal recurrence with ECE, the panel again favored CRRT over RRT. Chemotherapy alone was not recommended. In addition to the RT techniques listed above, intraoperative RT was also considered appropriate in this setting.

RRT for Unresectable Disease

Nonsurgical salvage therapies are generally offered to patients with a greater burden of disease and to those unfit for surgery. Two randomized trials were prematurely closed due to poor accrual. Several single institution and two multi-institutional trials have evaluated a variety of CRRT regimens. [32,33,37–43] Significant caveats notwithstanding, modern trials have shown incremental improvements in clinical outcomes when compared with historical controls. They are summarized in and selected studies are detailed below.

Randomized Trials (Level I Evidence)

No randomized controlled trials examining curative intent CRRT have completed planned accrual to date. In the USA, RTOG 04-21, a multicenter, Phase III, randomized trial was opened to compare salvage CRRT (RTOG 99-11 regimen, below) with doublet chemotherapy alone. Unfortunately, this trial was closed due to poor accrual.

Palliative intent CRRT (FHX regimen) and indefinite single agent methotrexate (40 mg/m 2) were compared in a randomized, Phase III trial (GORTEC 98-03) that accrued 57 out of a planned 160 patients. [44] Patients ineligible for salvage surgery or ‘curative intent’ CRRT were enrolled. Patients in the CRRT arm had more extensive disease (83% T3–4 and 80% with tumor extension to multiple sites) and only 43% of patients completed protocol-directed CRRT. More late toxicity was observed in the CRRT arm with 11 out of 23 patients developing RTOG/EORTC grade 3+ toxicity compared with five out of 20 in the methotrexate arm. With limited statistical power, no difference was detected in 1-year OS, the primary end point, between groups (23 and 22%; p = 0.6). No patients survived beyond 5 years and 77% died due to locoregional disease progression. Four patients died of toxicity – three received CRRT and one methotrexate.

Multi-institutional Trials (Level II Evidence)

RTOG 96-10 was a multi-institutional, Phase II trial that evaluated the FHX regimen for unresectable, recurrent, previously irradiated HNC in 79 patients. [42,43] Radiotherapy was delivered 1.5 Gy twice per day (b.i.d.), with hydroxurea (1.5 g/day) and 5-fluorouracil (300 mg/m 2 bolus) for 5 consecutive days followed by 9 days rest for four cycles. 3DCRT and CT simulations were encouraged but not mandated; no patients received intensity-modulated RT (IMRT). The median RT dose delivered was 60 Gy and 73% of patients completed all planned therapy. The 2-year OS was 15.2% (95% CI: 7.3–23.1) and three patients survived beyond 5 years. Patients with a disease-free interval of greater than 1 year showed improved median survival (5.8 vs 9.8 months; p = 0.036). Six patients (7.6%) died during treatment – two from bleeding in an area of compromised vasculature and four due to neutropenia. Grade 3 and 4 late toxicity was observed in 19.4 and 3.0% of patients, respectively. No new late effects were noted beyond 2 years.

Subsequently, RTOG 99-11, a similar multi-institutional, Phase II trial, tested the combination of paclitaxel (20 mg/m 2/day) and cisplatin (15 mg/m 2/day) in place of FHX. [40] Radiotherapy treatment planning with CT or conventional simulation was mandated. In addition, both 3DCRT and IMRT were allowed. Ninety nine patients were enrolled and 82% completed protocol-directed therapy with minor deviations. The 2-year OS rate of 25.9% (95% CI not given) compared favorably to RTOG 96-10. Disease-free interval did not correlate with clinical outcomes. Eight patients (8%) died as a result of treatment – two from neutropenic sepsis, one from pneumonitis, one from dehydration, one from cerebrovascular accident, two from carotid hemorrhage and one from oral-cutaneous fistula. In the first 2 years, RTOG/EORTC grade 3–5 toxicity was reported in 85% of patients; 48% had grade 3–4 gastrointestinal toxicity.

Single Institution Studies (Level II Evidence)

One of the largest experiences comes from the Institut Gustave–Roussy. [33] Three institutional regimens were used throughout the study period: 65 Gy RT alone (2 Gy q.d.), 60 Gy RT (2 Gy daily every other week) with FHX, 60 Gy split course RT (1.5 Gy b.i.d.) with mitomycin (5 mg/m 2 day 1), 5-fluorouracil (150–450 mg/m 2/day) and cisplatin (60 mg/m 2/week, continuous infusion). A total of 139 patients (27, 106 and 36, respectively) were treated with cobalt photons between 1980 and 1996. Unbalanced clinical factors and small numbers made comparisons between groups infeasible. Overall, DFS and OS at 2 years was 11% (95% CI: 7–17) and 21% (95% CI: 15–29), respectively. Multivariate analysis identified RT target volume as the only significant factor associated with survival (relative risk: 1.8; 95% CI: 1.13–5.7; p = 0.01). As expected, grade 3 and 4 mucositis were worse when chemotherapy was given. The crude rates of late toxicity were significant but acceptable with 11 patients developing ORN (three requiring hemimandibulectomy) and five dying of carotid hemorrhage. Thirteen long-term survivors were disease free a median of 42 months after CRRT.

Investigators at the University of Chicago reported on 85 patients undergoing CRRT for unresectable, recurrent HNC following prior RT from 1986 to 2006. [37] A vast majority of patients were treated with the FHX regimen (described above) with a variety of third chemotherapy agents on several institutional protocols. The median RT dose was 64.8 Gy and median cumulative dose was 131 Gy. The 5-year rate of DFS and OS was 13.4% (95% CI: 8.4–19.8) and 14.3% (95% CI: 9.1–20.7), respectively. Increasing radiation dose was associated with improved progression-free survival (HR: 0.82; 95% CI: 0.71–0.95; p = 0.008). [32] Multivariate analysis identified radiation dose greater than 60 Gy (HR: 0.35; 95% CI: 0.23–0.53; p < 0.0001) and disease free interval greater than 36 months (HR: 0.64; 95% CI: 0.42–0.95; p = 0.026) as significant predictors of improved OS. Prior CRT, on the other hand, was associated with worse OS (HR: 1.83; 95% CI: 1.21–2.70; p = 0.0043). Triple-agent chemotherapy was not associated with OS. Eighteen patients died during CRRT and an additional 15 died of treatment-related complications. Carotid hemorrhage occurred in 15 patients. Eighteen patients required surgery for ORN of the mandible.

Between 1996 and 2005, 105 patients with recurrent, previously irradiated HNC underwent CRRT at the Memorial Sloan–Kettering Cancer Center (NY, USA). [41] Chemotherapy was not standardized, and 68% of patients were treated with CRRT with or without induction and/or adjuvant chemotherapy. All patients underwent CT-based RT planning and 70% were treated with IMRT. The median RT dose was 59.4 Gy with cumulative dose 121.4 Gy. At 2 years, LRC and OS were 42 and 37%, respectively. On multivariate analysis, IMRT was associated with improved LRC (HR: 0.37; 95% CI: 0.19–0.76; p = 0.006) and RT dose ≥50 Gy with improved OS (HR: 0.44; 95% CI: 0.20–0.98; p = 0.043). There were no treatment-related deaths. Grade 3–4 late toxicity occurred in 11% of patients with no cases of carotid hemorrhage and one case of grade 2 osteitis.

Level III Evidence

The ACR Expert Panel on HNC offered appropriateness criteria for unresectable, recurrent, previously irradiated HNC. [36] For patients with unresectable recurrence who are fit for a second course of CRT, the panel recommends CRRT. A limited RT target volume encompassing known disease with a safety margin was favored over elective nodal RRT. RRT with less than 50 Gy was considered inappropriate, and 60 Gy or higher was recommended. Continuous course once (2 Gy per fraction) or twice daily RT (1.2 Gy per fraction) was considered appropriate. Twice daily RT using 1.5 Gy fractions with planned split course was considered appropriate but split course once daily RT was not recommended.

Treatment-related Toxicity

CRRT with or without salvage surgery offers a small, but real, chance of long-term survival, which may come at the price of significant treatment-related morbidity and mortality. However, the grave prognosis of these patients left untreated may indeed sanction high risk, high reward therapy. That said, the exact toxicity associated with RRT and CRRT is very difficult to elucidate, as toxicity may be ascribed to one of multiple therapies (initial RT, chemotherapy, surgery and CRRT). It is likely that the reported rates of adverse effects may be underestimates. [45] Moreover, heterogeneity in toxicity scoring obfuscates meaningful comparisons between studies.

Acute Toxicity

Acute toxicity, occurring during and within 60–90 days after CRRT, is comparable with that seen with primary CRT. Early Phase I/II trials that established the FHX regimen showed no difference in acute mucositis between patients irradiated de novo or for a second time. [46] In fact, when paclitaxel was added to the FHX platform, the rate of grade 3–4 mucositis was lower for previously irradiated patients. [47] More contemporary trials have demonstrated similar results. Primary CRT is associated with higher rates of grade 3–4 mucositis (71–77%) [48,49] when compared with CRRT (14–26%). This is probably due to the smaller RT target volumes that are commonly used for a course of salvage RRT. Hematologic toxicity appears to correlate with the intensity of the systemic therapy regimen and is also not influenced by prior therapy. Rates of grade 3 or worse febrile neutropenia, anemia and thrombocytopenia were 15, 21 and 6%, respectively, in RTOG 99-11 versus 11, 14, 3%,respectively, in a Phase II trial evaluated concomitant docetaxel and cisplatin given every 3 weeks with standard daily RT. [50] Unfortunately, rates of treatment-related death are higher during CRRT (5–19.9%). This may be related to the fact that functional reserve is compromised in heavily pretreated patients and similar rates of acute toxicity have more dire consequences, as well as the cumulative impact of high radiation doses on normal tissues.

Late Toxicity

Second courses of radiation to the same treatment area, particularly the head and neck, have long aroused fear of significant late toxicity. While CRRT is associated with significant late toxicity, grade 4–5 late toxic events are relatively rare. In the GETTEC–GORTEC randomized trial, the actuarial rate of grade 3–4 toxicity at 2 years was 39%. [35] The crude rates of grade 4 or higher toxicity in RTOG 96-10 and RTOG 99-11 were 3 and 31.8%, respectively. [40,43]

One of the most feared consequences of repeat irradiation is delayed neurologic toxicity. Reports of central or peripheral CNS toxicity associated with CRRT are rare. This may be due in part to mandated cumulative dose limits of 50 Gy to the spinal cord in many studies. Following delivery of a median cumulative RT dose of 130.9 Gy, investigators at the University of Chicago identified only one patient with myelopathy and none with either brachial plexopathy or brain necrosis. [32] Out of 139 patients undergoing CRRT at the Institut Gustave–Roussy to a median cumulative dose of 115 Gy, one patient developed brachial plexopathy after receiving 130 Gy. [33] For patients with base of skull recurrences, temporal lobe necrosis is a small but real possibility even following treatment with IMRT. [41]

Carotid artery rupture (CAR) is a devastating complication for patients treated with salvage therapies for recurrent, previously irradiated HNC. Risk factors for CAR include tumor recurrence, chronic infection, surgery (pharyngocutaneous fistula and neck dissection), poor nutrition and chronic inflammation (long-term tracheostomy and nasogastric tubes). [51] A meta-analysis of CRRT trials reporting CAR showed a crude incidence rate of 2.6% at a median of 7.5 months following CRRT. [52] Surgical salvage or concurrent chemotherapy did not significantly affect incidence. CAR was often fatal (76%). Optimal treatment is therefore prophylactic when there is high risk of CAR. [53] Reconstructive [54] or deconstructive endovascular management [53,55] of the carotid artery is often employed in lieu of open surgery. [51] However, rates of rebleeding, restenosis, cerebral ischemia and thromboembolism remain suboptimal.

ORN of the mandible is a concerning late toxicity following radiotherapy. The rate of mandibular ORN is likely associated with the cumulative radiation dose delivered to a specific volume of tissue. Conventional radiotherapy technique with opposed lateral treatment portals leads to a 10–15% overdose approximately 0.5–1.5 cm below the skin surface precisely over the mandible. Increasing photon energies, 3DCRT and IMRT ameliorate this phenomenon. However, ORN is relatively uncommon (8 and 11% of patients, respectively) in large single institution series. [32,33] In one of these series, cases of ORN only occurred in patients receiving a cumulative RT dose of greater than 120 Gy. It is possible that the rates of ORN are less in patients treated with more modern radiotherapy techniques for CRRT. In a cohort of 105 patients treated between 1996 and 2005, 70% of whom received IMRT, only one case of grade 2 osteitis was reported. [41] In another cohort of 74 patients all treated with IMRT between 1999 and 2004, only 5% developed ORN. [56]

Radiotherapy Considerations

Treatment Planning & Delivery

Accurate and precise delivery of RT is vital in previously irradiated HNC. As newer technologies, such as IMRT, allow more conformal targeting and avoidance, reproducible patient positioning takes on greater importance. Thoughtful selection of immobilization devices reduce patient discomfort, which is especially important in this patient population who often have significant difficulties with swallowing and breathing, and simultaneously optimize exposure of the target. Commonly used devices include body molds, thermoplastic face masks and bite blocks (to minimize irradiation of the oral cavity).

Contrast-enhanced computed tomography (CT) images of the target volume are acquired with generous superior and inferior margins for treatment planning. Additional diagnostic studies including preoperative imaging (when surgery is performed), PET and MRI may be fused with the planning CT when indicated. Using all available information (e.g., surgical reports, physical exam findings, diagnostic imaging and so on), at-risk target volumes and critical organs at risk (OARs) should be delineated. When possible, the prior RT treatment plan should be recreated in the treatment planning software to estimate doses to OARs. When unavailable, it should be assumed that all OARs received the smaller of the full prescription dose or specific organ tolerance.

Conventional and 3DCRT forward planning requires manual selection of RT field shapes and angles assuming static photon fluence through the aperture. Using a computer algorithm, IMRT allows dynamically modulated photon fluence at each gantry angle to optimally attain physician-entered dosimetric priorities. Overall, compared with 3DCRT, IMRT treatment plans generally offer more conformal coverage of targets and avoidance of critical OARs. The downsides of IMRT include increased daily treatment time and greater low-dose irradiation of non-target structures.

IMRT is a potentially useful tool for a second course of radiation as a means of reducing the volume of high radiotherapy doses as well as minimizing doses to critical normal structures, primarily the spinal cord, brain and brainstem. A randomized trial comparing conventional RT and IMRT for primary HNC showed improved avoidance of the parotid, resulting in less chronic xerostomia without compromised disease control. [57] Several institutional reports of IMRT for RRT have demonstrated favorable disease control and toxicity when compared with historical standards (). [41,56,58–61] Sixty seven patients underwent RRT with IMRT with curative intent for recurrent, previously irradiated HNC at the MD Anderson Cancer Center (TX, USA). [56] The median IMRT dose was 63 Gy and median cumulative dose was 116 Gy. LRC and OS at 4 years was 52 and 46%, respectively. Five patients developed ORN, four developed dysphagia requiring hospitalization, and one developed temporal lobe necrosis. A comparison of 3DCRT and IMRT in 38 patients undergoing CRRT with weekly carboplatin (area under the curve 2) and paclitaxel (50 mg/m 2) showed significantly greater late toxicity with 3DCRT compared with IMRT (44 vs 7%; p < 0.05). [61]      

Treatment volumes for RRT are in general more limited than for initial courses of radiotherapy. This is due to the fact that the primary pattern of progression is within known disease as well as to minimize the risk of toxicity. In general, margins of 0.5–2.5 cm are often added to the detectable gross tumor volume to envelop microscopic disease and to account for patient setup uncertainty and organ motion. [39,41,56,60,62–64] To minimize toxicity to nearby critical OARs, the smallest possible target volume is used. Elective nodal irradiation is generally not recommended, as the risk of failure in these sites is low (0–6%). [30,60,63] However, patients who were treated to small target volumes in their initial course of radiotherapy, such as those used for early-stage laryngeal cancer, may benefit from and better tolerate more comprehensive elective nodal irradiation.

The effect of RRT fraction size is difficult to estimate. Rapidly evolving RT delivery systems, from 3DCRT to IMRT to stereotactic body radiotherapy (SBRT), have called into question the previously undisputed radiobiological advantages of fractionation. 2D and 3D treatment planning was utilized in every study listed in & . Many of these reports, including the two RTOG Phase II trials for unresectable disease, utilized hyperfractionated RT schedules to offset the toxicity expected with large irradiation targets. With more conformal treatment planning, studies utilizing IMRT () all used standard fractionation with no obvious exacerbation of late toxicity. The ongoing study of SBRT in this patient population detailed below and in , utilizes further hypofractionated treatment schedules. It remains unclear, however, if sophisticated nontarget avoidance can compensate for less sublethal and potentially lethal damage repair, as RT schedules become less fractionated. Regardless, hyperfractionated RT will continue to play a role in RRT and CRRT, particularly in patients with disease recurrence in close proximity to critical normal tissues or those with significant chronic sequelae from prior irradiation.

Future Directions

Patients undergoing RRT for HNC are commonly afflicted with chronic toxicities from prior therapy that may make supine positioning uncomfortable. IMRT may be disadvantageous in this setting due to increased treatment delivery times. Ongoing study of volumetric modulated arc radiotherapy reportedly offers up to 35% reductions in treatment time without compromising conformality when compared with IMRT. [65]

SBRT consists of the image-guided delivery of a few (three to ten) relatively large, highly conformal RT doses, which are thought to exploit fundamentally different biologic mechanisms for tumor control. [66,67] Following the development and application of radiotherapy planning and delivery advances, including improved image-guidance and respiratory motion management, a substantial body of literature supporting the use of SBRT for medically inoperable lung cancer [68] and isolated sites of extra-cranial metastasis [69] has emerged. The utility of SBRT to control tumors resistant to conventionally fractionated radiotherapy has led investigators to explore the utility of SBRT for RRT of HNC. Several reports of SBRT for RRT of recurrent HNC have recently been published (). [70–79] Researchers at the University of Pittsburgh (PA, USA) published a series of 96 patients with recurrent HNC treated with salvage SBRT. [75] From 2003 to 2008, patients were treated with one to five fractions in four SBRT dose groups, 15–28 Gy, 30–36 Gy, 40 Gy and 44–50 Gy. Thirty nine patients (41%) received concurrent cetuximab. Higher SBRT dose (40–50 Gy) was associated with improved LRC (HR: 0.7; 95% CI: 0.3–0.9; p = 0.02). At 2 years, OS was 28.4% and LRC for patients treated with 40–50 Gy was 57.8%. No late grade 4–5 toxicities were observed. Three late grade 3 toxicities (two for dysphagia, one for fibrosis) were reported. The same group compared 35 patients treated with salvage SBRT and concurrent cetuximab (400 mg/m 2 loading dose, then 250 mg/m 2 weekly) versus 63 patients treated with SBRT alone. [72] Patients treated with cetuximab showed improved LRC (HR: 0.37; 95% CI: 0.14–0.79; p = 0.009) and OS on multivariate analysis (HR: 0.48; 95% CI: 0.11–0.89; p = 0.008). Reporting of late toxicity such as soft tissue necrosis following SBRT has been variable but at least one group identified an unacceptable rate of CAR (17%) following SBRT to a median dose of 30 Gy. [70] Further study is required before SBRT is recommended for routine use in this clinical setting. While SBRT may have clinical utility for RRT or CRRT for HNC patients, studies performed to date have been careful to select patients who have the potential to benefit from the therapy. Certainly, patients with large tumors, those enveloping critical normal structures and those with ill-defined borders, may have difficulties with technologies developed to pinpoint small, well-circumscribed targets.

Patients with tumor recurrences in close proximity to critical normal structures develop significant late toxicity even after conformal IMRT RRT. [41] For patients in these unique circumstances, charged particle therapy may offer uncompromised disease control without the untoward effects of photon irradiation. A sharp dose gradient at the end range of charged particles, called the Bragg peak, theoretically allows high-dose delivery at depth without exit dose. Two reports of patients with recurrent nasopharyngeal cancer, one from Loma Linda University Medical Center (CA, USA) [80] and one from The Lawrence Berkeley Laboratory (CA, USA), [81] treated with charged particle re-irradiation showed a 2-year OS of 50% and 3-year OS of 59%, respectively, with no significant late complications. In addition, 15 German patients tolerated RRT with carbon ions or protons predominantly for recurrent skull base tumors without significant acute toxicity. [82]

Systemic Therapy Considerations

Patterns of failure analyses suggest LRR remains the predominant mode of salvage treatment failure for recurrent HNC. The rationale then for concurrent chemotherapy is primarily as a radiosensitizer and secondarily for systemic disease control. No direct comparisons of RRT and CRRT have been completed, and the benefit of systemic therapy is not clearly established. Indeed, recently reported institutional series from The Netherlands evaluated modern RRT without chemotherapy and showed promising DFS and OS when compared with contemporary CRRT trials. [30,39]

A promising use of systemic therapy that has garnered considerable research interest is as a selection criterion when given as induction therapy prior to planned surgery or RRT. In the primary treatment of HNC, complete response to induction chemotherapy (IC) is associated with superior clinical outcomes. [8] Investigators at the University of Chicago studied IC as a selection metric to more accurately identify patients with previously irradiated recurrent HNC for surgical salvage. [83] IC consisted of gemcitabine (1500 mg/m 2) and pemetrexed (500 mg/m 2) every other week for 4 cycles. Surgery was then attempted if feasible. Subsequent CRRT consisted of 70 Gy (1.8–2.0 Gy q.d., 3DCRT or IMRT) with concurrent pemetrexed (500 mg/m 2) and carboplatin (area under the curve: 5–6) every 3 weeks. Eighteen out of 35 enrolled patients completed all protocol-directed therapy. Twenty of the 30 patients deemed resectable prior to IC underwent surgery. The 1 year rate of OS was 64% (95% CI: 30–85) for patients responding to IC and 35% (95% CI: 16–55) for those who did not (p = 0.019).

The classic radiobiological tenant that tumor hypoxia confers radioresistance has been confirmed clinically in HNC. [84] Prior radiotherapy, surgery and/or systemic therapy may worsen tumor hypoxia in recurrent HNC. A multi-institutional Phase II trial tested tirapazamine (TPZ), a selective hypoxic cell sensitizer, in combination with cisplatin concurrent with RRT. Twenty five patients received cisplatin (50 mg/m 2) and TPZ (260 mg/m 2) on weeks 1, 3 and 5 during daily RRT to a total dose of 72 Gy. Additional TPZ (160 mg/m 2) was given on days 1, 3 and 5 of week 2, and possibly week 4, based on randomization. Locoregional control was 56% overall and the 1- and 2-year rates of OS were 56 and 27%, respectively. Treatment-related toxicity was comparable with other CRRT trials. Given these promising results, study of additional hypoxia-directed therapies is warranted.

A variety of targeted agents have been studied as a component of CRRT. Bevacizumab was added to the FHX platform with median survival 10.3 months and high rates of fistula formation (11.6%) and soft tissue necrosis (9.3%). [85] EGF-receptor inhibitors have shown promise for primary HNC [86] and have also been studied in recurrent HNC. Both cetuximab, [72,87,88] a monoclonal antibody, and erlotinib, [89,90] a small molecule inhibitor, have been studied. A group at the NIH (MD, USA) evaluated bortezomib, a proteasome inhibitor, concurrently with RRT for recurrent HNC. [91] These and other novel agents require further study prior to more widespread adoption.

Expert Commentary & Five-year View

In the next 5 years, locally recurrent, previously irradiated HNC is likely to remain a significant challenge. Over the past 20 years, improvements in treatment outcomes have been limited. It is reasonable to expect continued incremental gains in clinical outcomes due to improved patient stratification and treatment advances. The treatment of primary HNC may schism due to the vastly different prognoses of human papillomavirus-positive and -negative HNC. It is unknown, however, how such a divide would affect the treatment of recurrent HNC within 5 years.

Radiotherapy techniques have evolved and will continue to do so over the next 5 years. While IMRT has already largely supplanted more conventional RT techniques, the next 5 years will likely provide additional evidence of improved disease control and lowered toxicity. Early experiences with SBRT will probably mature eventually, allowing meaningful comparisons of both treatment efficacy and late effects to fractionated treatment programs. Likewise, targeted systemic agents that improve the therapeutic ratio of CRRT may be identified. While outside the scope of this manuscript, the most significant advancement may come from surgeons as they continue to gain experience with robotic surgery for both primary and recurrent HNC. [92] Similarly, treatment advances are likely to improve primary HNC outcomes and potentially reduce the need for retreatment.

Strategies to better personalize therapy for patients with recurrent HNC are under study. It is quite likely that induction chemotherapy will be further studied in this setting as a possible selective screen. Novel functional imaging agents, such as 3′-deoxy-3′-[ 18F]-fluorothymidine or 18fluoro-misonidazole, may lend insight into tumor biology and allow tailored therapies. While gene signatures are now widely used in the treatment of breast cancer, it is unlikely that genetic or molecular profiling will affect treatment decisions for recurrent HNC within the next 5 years.

Sidebar

Key Issues

  • Recurrent cancer in a previously irradiated head and neck cancer (HNC) patient is a challenging problem with poor prognosis.
  • When possible, patients should undergo surgical resection followed by adjuvant chemotherapy with reirradiation, regardless of pathologic risk factors for locoregional control and disease-free survival benefits.
  • Both reirradiation and chemotherapy with reirradiation are appropriate options for unresectable
  • When utilized, concurrent systemic therapy should be limited to standard agents. These include cisplatin, carboplatin, paclitaxel, hydroxyurea and 5-fluorouracil. Targeted agents and other cytotoxic chemotherapy should only be offered on trial.
  • Intensity-modulated radiotherapy may offer better locoregional disease control and late toxicity profile. Additional data are required before stereotactic body radiotherapy should be offered outside of a clinical trial.
  • Several studies have identified favorable prognostic factors for recurrent HNC including surgical salvage, second primary tumor, longer disease-free interval and higher radiotherapy dose.
  • Patients should be counseled regarding the potential for significant and possibly life threatening toxicity associated with any therapy for recurrent HNC.

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December, 2012|Oral Cancer News|

CMC gets $8M to study oral damage from radiation

Source: wcnc.com

by Karen Garloch / The Charlotte Observer

A research team in the Department of Oral Medicine at Carolinas Medical Center has received an $8 million grant from the National Institutes of Health to study tissue damage in patients who have received high-dose radiation for head and neck cancer. Hospital officials said it is the largest research grant ever awarded to CMC.

Dr. Michael Brennan, associate chairman of the oral medicine department, will be principal investigator for the Charlotte research site. Patients will also be enrolled at Harvard University, University of Pennsylvania, New York University and the University of Connecticut.

Brennan said the five-year study will help doctors develop evidence-based guidelines for the care of patients’ dental health before or after radiation therapy.

Patients with head and neck cancer often receive high-dose radiation therapy that results in lifelong damage to oral and facial tissues. Side effects include a decrease in saliva production, which increases the risk of tooth decay and tooth loss. Radiation can also impair bone healing, leading to an increased risk of infection around the teeth and increased risk of jaw fractures and pain that could require surgery.

Patients enrolled in the study will receive a standard dental assessment prior to radiation therapy, and follow-up visits will be conducted every six months for up to two years.

This news story was resourced by the Oral Cancer Foundation, and vetted for appropriateness and accuracy.

September, 2012|Oral Cancer News|

Oropharyngeal cancer patients with HPV have a more robust response to radiation therapy

Source: Eurekalert.org

(SACRAMENTO, Calif.) — UC Davis cancer researchers have discovered significant differences in radiation-therapy response among patients with oropharyngeal cancer depending on whether they carry the human papillomavirus (HPV), a common sexually transmitted virus. The findings, published online today in The Laryngoscope Journal, could lead to more individualized radiation treatment regimens, which for many patients with HPV could be shorter and potentially less toxic.

HPV-related cancers of the oropharynx (the region of the throat between the soft palate and the epiglottis, including the tonsils, base of tongue and uvula) have steadily increased in recent years, according to the National Cancer Institute, especially among men. At the same time, the incidence of oropharyngeal cancers related to other causes, such as smoking or alcohol consumption, is declining. HPV is the most common sexually transmitted infection in the United States; it can spread through direct skin-to-skin contact during vaginal, anal and oral sex.

The UC Davis study, conducted by Allen Chen, associate professor in the UC Davis Department of Radiation Oncology, examined patterns of tumor reduction during radiation treatment in two otherwise similar groups of patients with oropharyngeal cancer: those who tested positive for HPV and those who tested negative for the virus. None of the HPV patients in the study was a smoker, a leading risk factor for the disease.

Chen used CT scans acquired during image-guided radiation therapy (IGRT) and endoscopy (a tube with a small camera) to capture 3D images of the patients’ tumors and monitor their treatment progress. He found that within the first two weeks after starting radiation, the gross tumor volume decreased by 33 percent in HPV-positive patients, while the volume decreased by only 10 percent in HPV-negative patients.

Chen said the results demonstrate that HPV-positive patients have a more rapid and robust response to radiation treatments, confirming what clinicians have suspected for years.

“These HPV-related tumors literally melt before your eyes,” he said. “It is very gratifying to tell patients early on during treatment that their tumors are responding so quickly. Most of them are pleasantly relieved to hear such news.”

The rapid rate of tumor regression did not continue, however, after the second week of radiation treatment, and by the end of the seven-week regimen, the total tumor shrinkage in both groups of patients was nearly the same.

However, “the dramatic early response observed in the HPV-positive patients strongly implies that these tumors behave distinctly from a biological standpoint and could be approached as a separate disease process,” Chen said.

For example, the findings suggest that treatment for HPV-positive cancer may not need to be as intensive for it to be effective, Chen said, adding that a shorter, abbreviated treatment regimen would potentially lessen the side effects from radiation, which include sore throat, dry mouth, taste loss and swallowing difficulties.

“It is likely that treatment in the future will be individualized based on biomarkers present in the tumor, and HPV has the potential to do just that,” said Chen.

Chen said there is increasing evidence that HPV-positive patients who receive radiation treatments live longer and have higher cure rates. According to the NCI, 88 percent of the HPV-positive patients are still alive two years after their treatments, compared with 66 percent of the HPV-negative patients.

“Given the impressive outcomes for patients with HPV-positive cancer using currently aggressive treatments, how to de-intensify therapy while maintaining cure rates is definitely a hot topic right now,” said Chen.

Chen, in collaboration with colleagues, has recently launched a clinical trial of HPV-positive oropharyngeal cancer patients to evaluate outcomes when their radiation doses are reduced from seven weeks to either five or six, depending on their response to initial chemotherapy. This institutional trial, which is only available at UC Davis, just recently opened enrollment.

“Why subject a patient to seven weeks of radiation when five weeks of radiation could be just as effective?” Chen said. “Sparing select patients from this extra radiation could potentially prevent significant toxic side effects and improve quality of life, both in the short-term and long-terms.”

The current clinical trial also involves collection of oropharyngeal patient blood and tumor samples during treatment, so that researchers can precisely correlate HPV in these specimens with a patient’s rate of response to radiation therapy.

The dramatic increase in oropharyngeal cancers in recent years has been described as an “epidemic,” Chen said, due in large part to the increasing prevalence of HPV. In the United States, more than half of cancers currently diagnosed in the oropharynx are linked to HPV-16, according to the National Cancer Institute.

“Our trial was designed to help determine what the optimal treatment approach for these patients might be in the future,” Chen said.

Why HPV-positive tumors respond differently to radiation treatment is under investigation at UC Davis, as well. The thought is that HPV labels cancer cells with a foreign antigen, which stimulates an immune response, Chen said.

“The HPV hijacks the host cancer cell leading to expression of a viral antigen on the surface, causing the patient’s immune system to ramp up and fight the cancer,” Chen said. “By identifying which molecular pathways are up-regulated or down-regulated during radiation therapy, it is our hope that insight may be gained into why HPV-positive oropharyngeal cancer is so radiation sensitive. This could have tremendous implications for developing strategies to fight not just oropharyngeal cancer, but all tumors in the future.”

 

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Other authors were Judy Li and Laurel A. Beckett from the Division of Biostatistics of the Department of Public Health Sciences, Talia Zhara of the Department of Radiation Oncology, Gregory Farwell of the Department of Otolaryngology-Head and Neck Surgery, Derick H. Lau, associate professor of internal medicine, hematology and oncology, Regina Gandour-Edwards of the Department of Pathology and Laboratory Medicine, Andrew T. Vaughan, professor of radiation oncology, and James A. Purdy professor emeritus of the Department of Radiation Oncology and former director of the physics division.

UC Davis Comprehensive Cancer Center is the only National Cancer Institute-designated center serving the Central Valley and inland Northern California, a region of more than 6 million people. Its specialists provide compassionate, comprehensive care for more than 9,000 adults and children every year, and access to more than 150 clinical trials at any given time. Its innovative research program engages more than 280 scientists at UC Davis, Lawrence Livermore National Laboratory and Jackson Laboratory (JAX West), whose scientific partnerships advance discovery of new tools to diagnose and treat cancer. Through the Cancer Care Network, UC Davis collaborates with a number of hospitals and clinical centers throughout the Central Valley and Northern California regions to offer the latest cancer care. Its community-based outreach and education programs address disparities in cancer outcomes across diverse populations. For more information, visit cancer.ucdavis.edu.

This news story was resourced by the Oral Cancer Foundation, and vetted for appropriateness and accuracy.

September, 2012|Oral Cancer News|

Robots vs. radiation

Source: the-scientist.com
Author: Bob Grant

Source: Wikimedia Commons, Klem

Scientists at London, Ontario-based Lawson Health Research Institute have launched the first ever study of the comparative effectiveness of robotic-assisted surgery versus radiation therapy for the treatment of oropharyngeal cancer, or cancer of the back of the throat. Transoral robotic surgery (TORS), a new method for removing tumors from the throat developed in 2004, approved by the US Food and Drug Administration in 2010, and already used in many hospitals in the United States, may be a good way for throat cancer patients to avoid some of radiation therapy’s side effects, which include speech problems, hearing loss, skin discoloration, taste changes, difficulty swallowing, and dry mouth. “Early studies of TORS show it holds promise to provide good disease control, as well as offer good speech and swallowing outcomes for patients,” said London Health Sciences Center (LHSC) head and neck surgeon Anthony Nichols in a statement cialis otc. “However, it is important that we conduct a thorough comparison of the two treatments.”

Researchers conducting the so-called ORATOR trial will track quality of life, side effects, and survival in cancer patients randomly assigned to receive either TORS or radiation therapy. “Radiation has worked very well for the treatment of these cancers and has set a very high standard for treatment,” said LHSC radiation oncologist David Palma in a statement. “Before we can implement TORS, we need to prove that it meets that standard—are the cure rates just as good, and are the side effects less?”

Robotic Surgery Is Useful Option for Oral Cancer

Source: Onclive.com

transoral robotic surgeryMinimally invasive transoral robotic surgery (TORS), used alone or combined with adjuvant therapy, provides good functional and oncologic outcomes in patients with oropharyngeal squamous cell carcinoma (OPSCC), new research suggests.

The results were especially impressive in patients with human papillomavirus (HPV) infection, which is currently the most common cause of OPSCC in Europe and the United States.

Eric J. Moore, MD, associate professor of Otolaryngology at the Mayo Clinic in Rochester, Minnesota, and coauthors reviewed a prospective database of patients with previously untreated OPSCC arising in the tonsil or base of the tongue who underwent TORS at their institution during a recent 2-year period.

In 2011, about 12,000 individuals in the United States were diagnosed with OPSCC, according to the authors. The most common sites are the tonsillar fossa and base of the tongue. Customarily, OPSCC has been treated with combined modality therapy, including open surgical resection through mandibulotomy, neck dissection, and adjuvant radiation therapy or combined chemotherapy and radiation therapy. TORS was later introduced to improve access to these tumors.

Functional outcomes of the study included gastrostomy tube dependence and tracheostomy dependence. Oncologic outcomes included local, regional, and distant control and disease-specific and recurrence-free survival.

Overall, 66 patients who underwent TORS as their primary treatment were followed for a minimum of 2 years. Sixty-four patients, or 97%, were able to tolerate an oral diet and maintain their nutritional needs before initiating adjuvant therapy at 4 weeks. Only 3 patients, or 4.5%, required long-term gastrostomy tube use, and one (1.5%) had long-term tracheotomy.

Three-year recurrence-free survival was achieved in 92.4% of patients, and 95.5% were alive and disease-free at the latest assessment.

Importantly, the analysis also demonstrated a strong correlation between disease control and HPV status. The 3-year survival rate was 92% in protein 16 assay (p16)-positive patients versus 52% in p16-negative patients. Most patients in the study had HPV-associated OPSCC.

The authors cited numerous advantages of TORS as primary therapy in OPSCC, including “the ability to stage the tumor adequately, to eradicate the primary tumor and the involved lymph nodes reliably and completely in a single setting, and to add adjuvant therapy in a rational and individually designed manner.” In addition, the ability to preserve normal tissue and neurovascular supply helps patients heal faster and recover oropharyngeal function.

“The authors cited numerous advantages of TORS as primary therapy in OPSCC.”

The authors said that the major study limitation was the lack of an alternative treatment group for comparative analysis. Selection bias represented an additional drawback, given that patients with higher T-stage tumors that cannot be exposed or resected using a transoral approach were ineligible for the study.

This news story was resourced by the Oral Cancer Foundation, and vetted for appropriateness and accuracy.

April, 2012|Oral Cancer News|

Prognostic Significance of HPV Status in Oropharyngeal Cancer

OncologySTAT Editorial Team

Dr. Maura Gillison is Professor of Medicine, Epidemiology, and Otolaryngology at Ohio State University in Columbus.

OncologySTAT: The results of the Radiation Therapy Oncology Group (RTOG) 0129 trial showed that the human papillomavirus (HPV) is an independent prognostic factor in oropharyngeal cancer. Could you tell us about the rationale for this study?

Dr. Gillison: Over the last 10 years, our research has shown that cancers of the oropharynx are actually 2 completely different diseases that can look quite similar. One subset is caused HPV infection, and the other is more closely associated with long-term use of alcohol and tobacco.

Initial studies suggested that the presence of HPV in a patient’s tumor had prognostic significance, but study limitations made that conclusion dubious. We set out to determine whether or not HPV was indeed an independent prognostic factor in head and neck cancer. To show whether there was a direct relationship between HPV infection and head and neck cancer, we needed to prospectively study a uniformly treated and uniformly staged patient population. Thus, we used the study population from the trial conducted by the RTOG. We divided the patients into 2 groups—those whose tumors were caused by HPV and those whose tumors were not—and we compared survival outcomes for the 2 groups.

The results showed that HPV status was the single most important predictor of patient outcome, even more so than disease stage and other well-known prognostic factors such as performance status and presence of anemia. In fact, after accounting for 6 other nonprognostic factors, patients with HPV-positive cancer had less than half the risk of dying from their cancer as did patients whose cancer was HPV negative. At 5 years, that translated into a 30% absolute difference in survival.

On the basis of these results, we can state definitively that HPV is a strong and independent prognostic factor for oropharynx cancers. Currently, tumor HPV status is determined for all patients with head and neck cancer prior to enrollment into a clinical trial. I believe that HPV-positive oropharynx cancer is a completely different disease from traditional head and neck cancer, to the extent that we need to design separate clinical trials that are specific for the HPV-positive patient, as distinct from the HPV-negative patients.

Unfortunately, we have not made true progress over the last 15 to 20 years in therapy for patients with head and neck cancer. The major advances have been in our understanding of the underlying etiology of the disease and its inherent biologic responsiveness. Patients with HPV-negative head and neck cancer, in particular, are still doing extraordinarily poorly. Even with the use of intense, concurrent chemoradiation, as was done in the RTOG trial, 5-year survival is only about 30%.

OncologySTAT: Now that we can stratify patients by HPV status, it will be possible to separate out people who have head and neck cancer related to tobacco use and conduct separate trials on those patients, or investigate different therapies for them.

Dr. Gillison: Exactly. Our data indicate that patients with HPV-positive tumors do extraordinarily well. Some still do die of their cancer, but about 80% are alive and doing well 5 years later. Many of these patients are quite young; it’s not unusual to see patients in their 30s or 40s. If they’re expected to survive their cancer, then they will have to deal with the consequences of the therapy for 30, 40, or 50 years.

OncologySTAT: Are they surviving longer?

Dr. Gillison: They are surviving longer. Now we need to focus on improving their outcomes. The more aggressive approaches being used in head and neck cancer, such as combination therapy with multiple agents, together with standard chemotherapy, biologics, and radiation therapy, all should be studied in HPV-negative patients. The increased toxicity of combined therapies may be warranted in terms of the risk-benefit analysis because these patients have such poor survival. At present, it would be inappropriate to use such therapies for the HPV-positive group.

OncologySTAT: Will you be following the HPV-positive patients over the long term? Patients with head and neck cancer are at risk for second cancers later on.

Dr. Gillison: We analyzed second cancers in our trial and found that they were significantly less likely to occur in HPV-positive patients than in HPV-negative patients. The difference was largely explained by a difference in rates of smoking in the 2 groups of patients. The rate of second cancers is approximately 20% among HPV-negative patients, whereas it’s about 5% in the HPV-positive group.

OncologySTAT: Are there any follow-up studies planned or underway right now?

Dr. Gillison: The National Cancer Institute (NCI) steering committee has adopted my recommendation to design separate clinical trials for HPV-positive and HPV-negative patients. We also hope to conduct clinical trials with the European Organisation for Research and Treatment of Cancer (EORTC) and the French Head and Neck Oncology and Radiotherapy Group. This work will focus on how best to treat patients with HPV-positive head and neck cancer. We don’t know the best treatment strategy, because HPV-positive cancer wasn’t recognized until recently as a unique disease entity.

In the United States, incidence rates of HPV-positive cancer are rising dramatically. NCI data for 2000 put the incidence at 10% per year, but this rate is expected to double in the current decade. Thus, in the future, the alcohol- and tobacco-related cancers are going to be the rare cancers.

We need to figure out as rapidly as possible the standard of care for this cancer. Together with RTOG and the Eastern Cooperative Oncology Group (ECOG), we are in the process of designing a large, randomized phase II study specific to HPV-positive patients. We estimate enrolling 800 to 1,000 patients. Endpoints will include quality of life and toxicity outcomes. Because HPV-positive patients respond so well to therapy, the question now is whether we can reduce the use of intense therapy and thereby decrease the long-term consequences of the therapy. Some therapies used during the last 15 years for head and neck cancer have yielded only a 5% to 8% absolute benefit in 5-year survival, but they have contributed to a 500% increase in morbidity over the long term. Many patients end up not being able to swallow food and are therefore dependent on gastrostomy tubes, which has significant social and quality-of-life implications.

So the goal of that trial is to compare standard-of-care therapy, as it was developed in RTOG 0129, with 2 other treatment algorithms involving reduced-intensity therapy. Hopefully, we will find that reduced-intensity therapy does not compromise survival. We hope we can get answers sooner rather than later.

OncologySTAT: Do you think vaccination is going to have a role in reducing the incidence of HPV-related head and neck cancers over time?

Dr. Gillison: I certainly hope so. Half of my research program involves work on oral HPV infection, looking at its prevalence in the US population, predictors, and the natural history. Soon we will be starting a clinical trial that evaluates whether the currently approved HPV vaccines can more effectively prevent oral HPV infections. We hope to have answers in 5 years.

HPV vaccines are extraordinarily effective (nearly 100%) in preventing cervical dysplasia and cancer among women. Both the Food and Drug Administration and the Centers for Disease Control and Prevention report virtually no evidence of any severe toxicities or negative outcomes from the vaccine. However, only 1 out of 4 parents in the United States have made the decision to have their daughters vaccinated.

OncologySTAT: Pediatricians appear to be proponents of vaccination against HPV.

Dr. Gillison: Yes. I understand that there are social implications to the vaccine, as well as cost-benefit considerations, because the vaccine is expensive. However, my patients look at it this way: If they had the option, in retrospect, of getting 3 vaccines in their teens instead of having to deal with the consequences of a cancer diagnosis for themselves and their families later on, they say it would have been an easy decision.

For HPV-related cancers, we’ve found the Achilles heel, in that HPV is necessary for these cancers, causing about 20,000 cases in the United States every year. The vaccine appears to be fairly effective at every site where it’s been tested. My concern is that, if we can’t make the appropriate decisions on a policy level that could eliminate a cancer for which we’ve identified a single cause, what will we do for all these other cancers, the genetics of which are much more complex? Cancers such as colon cancer and breast cancer are tremendously heterogeneous in terms of genetic predisposition. There’s probably not going to be an Achilles heel for those cancers. In my opinion, potentially 20,000 US families are affected each year by a cancer for which the HPV vaccine holds promise. Worldwide, that’s more than a million cases.

OncologySTAT: What are the implications of your results for community-based oncologists?

Dr. Gillison: The patient population that gets HPV-related head and neck cancer is highly educated; they tend to be of high socioeconomic status. This is a different population than head and neck cancer patients in the past, who, because of their protracted alcohol and tobacco abuse, maybe didn’t advance as well in society as these patients, who tend not to smoke and drink. Patients we see tend to be Internet savvy, and when they read about the profound prognostic significance of the HPV test, they demand it.

If you knew that you had been diagnosed with a cancer for which there was a test that could determine whether you had an 85% chance of 5-year survival as opposed to a 30% chance, you’d probably demand it, too, because you’d want to make plans for your life. Community oncologists should be aware of these data, because any patient with an oropharynx cancer who does not have traditional risk factors probably has an HPV-related cancer.

Unfortunately, a lot of medical oncologists in the community are still unaware of the relationship between HPV and oropharynx cancer. They need to be made aware of the relationship so that they can counsel their patients appropriately. Many patients are completely stumped as to why they’ve gotten this cancer. Community oncologists need to know that HPV testing is available in at least 2 institutions, Johns Hopkins and Ohio State University.

All clinical trials conducted by ECOG and RTOG will now require determination of HPV status for eligibility. Oncologists in the community who refer patients for clinical trials need to be aware of this and know how to counsel their patients when the results come back. There is still a social stigma to having a cancer caused by a sexually transmitted infection, and community oncologists need to be sensitive to that. In my clinical practice, I’ve seen marriages dissolve over the blame game, and relationships strained because of guilt feelings in one partner or the other. Community oncologists need to educate themselves about HPV so that they can handle this difficult counseling.

OncologySTAT: That’s an interesting aspect that we don’t often think about in terms of participation in a clinical trial.

Dr. Gillison: Telling someone that they have a cancer caused by a sexually transmitted infection can have social implications. In my opinion, there should be no stigma associated with it. As an HPV biologist, I recognize that 80% of individuals will have an HPV infection at some point in their life. That may even be an underestimation, as it is based solely on data for cervical cancer. Anal HPV infection and oral HPV infection didn’t factor into those previous estimates.

I see HPV infection as a consequence of being human. Nearly all people who get an HPV infection can handle it immunologically, without developing any health consequences. We don’t know what’s different about the 0.01% of people who develop cancer from the virus and those who don’t. I try to educate people about the high prevalence of HPV infection. Education can help remove the social stigma.

A lot of my patients feel relieved when I tell them how common the infection is. There’s also a perception that HPV infection is an indication of promiscuity, which is not correct. A study done at the University of Washington followed college-aged women from their freshman year forward to assess the incidence of HPV infection. The analysis was restricted to women who were virgins at entry into the study. The women were followed only through their first sexual partner, after which they were censored. By the end of 1 year, 25% of the women had contracted an HPV infection. By the end of 2 years, the incidence had risen to one-third. Men are remarkable reservoirs for HPV infection. An estimated 63% of men in the United States have a genital HPV infection.

So it’s best to think of HPV infection as a consequence of being human and having evolved with the virus for a long time. With this viewpoint, people won’t attach such a stigma to it.

OncologySTAT: It will also be important to determine which patients can have good outcomes despite receiving less aggressive therapy. This could spare them some of the speech and eating problems that result from head and neck cancer.

Dr. Gillison: As the principal investigator on the planned RTOG study, I know some of the comparisons we will be looking at. Less intensive radiation is one option for less aggressive therapy. Most of the complications from therapy are related to patients’ receiving chemotherapy and radiation at the same time; an alternative approach might be to administer these treatments sequentially. Or, if given together, they could be given at lower doses. These are some of the different options being considered for this study.

This news story was resourced by the Oral Cancer Foundation, and vetted for appropriateness and accuracy.

April, 2012|Oral Cancer News|

Nobel Laureate Makes Strong Case for Vaccinating Young Males Against HPV to Prevent Cervical Cancer in Females

Source: Therapeutics Daily

AUSTIN, Texas, March 26, 2012 /PRNewswire-USNewswire/ — Nobel Prize winner Harald zur Hausen called for vaccinating both young males and females for human papilloma virus (HPV) in an achievable quest to eradicate cervical cancer, which is the second leading type of women’s cancer worldwide. Zur Hausen made his remarks at a gathering of more than 1,600 members of the Society of Gynecologic Oncology during its 43rd Annual Meeting on Women’s Cancer® in Austin.

“If we wish to eradicate these types of infections – then theoretically we can do it,” zur Hausen said. “And if we wish to achieve this (eradication of HPV) in a foreseeable period of time, then we should vaccinate both genders globally.”

He pointed out that educational, cultural and religious barriers contribute to the lack of knowledge or willingness to address or discuss the subject by public health officials, teachers, parents and even some physicians. Zur Hausen also said that if society were to vaccinate just one gender to prevent the spread of cervical-cancer causing HPV, it would be more effective to vaccinate just males, highlighting the potential medical value of male HPV vaccinations. Zur Hausen also noted that research shows that early fears of the side effects of the HPV vaccine were overblown, and Australian research shows that there is about one adverse reaction in 100,000 vaccinations, which confirms the safe nature of the vaccine.

Keynote speaker for this year’s Annual Meeting on Women’s Cancer, Harald zur Hausen was awarded the Nobel Prize in Medicine in 2008 for his pioneering discovery of the role of human papilloma virus (HPV) in the development of cancer of the cervix. He currently is professor emeritus, after having served as Chairman of the Management Board and Scientific Director of the German Cancer Research Center, Heidelberg, Germany.

Zur Hausen said approximately 275,000 women die each year of cervical cancer, some 85 percent in economic-constrained countries, with more than 500,000 new cases appearing in women globally each year.

About the SGO
The Society of Gynecologic Oncology (SGO) is a national medical specialty organization of physicians and allied healthcare professionals who are trained in the comprehensive management of women with malignancies of the reproductive tract. Its purpose is to improve the care of women with gynecologic cancer by encouraging research, disseminating knowledge that will raise the standards of practice in the prevention and treatment of gynecologic malignancies, and cooperating with other organizations interested in women’s health care, oncology and related fields. The Society’s membership, totaling more than 1,600, is primarily comprised of gynecologic oncologists, as well as other related medical specialists including medical oncologists, radiation oncologists, nurses, social workers and pathologists. SGO members provide multidisciplinary cancer treatment including chemotherapy, radiation therapy, surgery and supportive care. More information on the SGO can be found at www.sgo.org.

This news story was resourced by the Oral Cancer Foundation, and vetted for appropriateness and accuracy.

March, 2012|Oral Cancer News|

Oral Complications After Head/Neck Radiation ‘Underreported’

Source: Elsevier Global Medical News

Late oral effects of head and neck cancer therapy are “multiple, underreported, and under-appreciated. “That is the perspective of Joel Epstein, D.M.D., who has worked extensively with head and neck cancer patients experiencing severe dental and other oral problems following radiation therapy.

“The acute complications of head and neck cancer therapy are pretty well known, but the late complications are underappreciated,” Dr.  Epstein, director of oral medicine at City of Hope National Medical Center, Duarte, Calif., told attendees at the symposium. As head and neck cancer treatments have advanced and patients are living longer, the spectrum of treatment complications has shifted, he explained. In a 5-year, prospective longitudinal study of 122 patients with oral carcinoma, dry mouth, sticky saliva, speech changes, dental problems, and sleep disturbance were reported by all patients except those treated only with surgery. These complications persisted at 1 and 5 years and affected quality of life (Head Neck 2008;30:461-70).

According to Dr. Epstein, the data illustrate the need for better collaboration between oncologists and dentists. “While people discuss  the concept of multidisciplinary [and] interdisciplinary teams for the benefit of our patients, it is unfortunate that dentistry developed  separately from physicians and surgeons. So while we need to interact, we’re not really well prepared to do so, particularly in the  community,” he said.

Clinically, it’s important to evaluate oral care, including brushing, flossing, fluoride, and tobacco abstinence, at all head and neck cancer treatment follow-up visits. Patients should be assessed for xerostomia, speech, swallowing, mucosal sensitivity, and taste. Head and neck and oral exams should include assessments for saliva (wet mucosa), exposed bone, infection, and new lesions or recurrent cancer, and a dental exam (for plaque, caries, and periodontal health), Dr. Epstein recommended.

Dry mouth, in particular, can lead to a host of other chronic problems related to swallowing, eating, sleeping, and dental health. When the 50-item Vanderbilt Head and Neck Symptom Survey was administered to a total of 70 patients, 67 reported having dry mouth at more than 6 months’ follow up (Head Neck 2011 Aug. 24 [doi:10.1002/hed.21816]).

The majority reported that dry mouth makes chewing/swallowing difficult (65) and that it affects their ability to sleep (67) and  talk (64). With regard to eating and swallowing, similar majorities reported trouble eating solids (67) and drinking liquids (68), with food getting stuck in their mouth (66) and throat (67).

And, of concern, the same numbers of patients reported the sensation of choking or strangling on solids (66) and liquids (68). “The impact on function from the lack of saliva and the change in quality of saliva are issues we need to be more ready and willing to address,”  Dr. Epstein commented.

Taste and smell may also be profoundly altered. In the Vanderbilt survey, most patients reported altered taste (68), a decreased desire to eat (68), altered food choices (66), and a decrease in food eaten (66). A change in sense of smell was reported by 69 patients.

Such alterations often result in changes in diet, including decreased consumption of high-fiber food and of vitamins and other nutrients,  along with increased consumption of fats, caffeine, and sugar. All of these factors increase the risk for dietary deficiencies, as well as  dental caries.

Yet, altered taste sensation is not something patients might think to mention. “Half of patients experience altered taste sensation. But if  they think you’re not interested or you don’t ask, you may not know,”  Dr. Epstein commented.

Periodontal health is often compromised by hyposalivation, which can lead to inflammation, bone/attachment loss, oral infection, and necrosis. Dental demineralization and cavitation may develop as early as 2-3 months after cancer treatment and progress rapidly, leading to fractures of the gum line, tooth loss, and necrosis.

Demineralization appears as a change to white, which may not be recognized as a problem because of the belief that white teeth are  healthy. However, recognition at this stage is critical in order to prevent further dental damage, he said.

“The white change near the gum line and the tips of the teeth represent demineralization, and [in] time reversal can be accomplished  prior to structural breakdown. Once cavitation has occurred, fillings are needed and prevention must be instituted or the cavities will  recur and progress,” Dr. Epstein said in an interview.

In the Vanderbilt survey, reported dental problems included difficulty chewing because of teeth/dentures (54 of the 70 patients); tooth  sensitivity to hot, cold, or sweet foods (52); teeth feeling looser (51); teeth cracking/chipping (50); and trouble with dentures (24).

Oral candidiasis is another common problem, affecting approximately 39% of head and neck cancer patients during treatment and 33% afterward. One common clinical mistake is prescribing these patients antifungals that contain sugar, such as nystatin. “Nystatin is very high in sugar, and one of the [most commonly] used antifungals. The message is to avoid sugar-sweetened products in dry mouth patients and utilize alternatives,” Dr. Epstein said in the interview.

Mucosal sensitivity and pain is also frequent. In a meta-analysis of 22 studies published between 1990 and 2008, the prevalence of trismus was 25.4% in patients who received conventional radiotherapy and 5% for the few intensity-modulated radiation therapy studies that were included, suggesting that the newer radiation modality might diminish the problem (Support. Care Cancer 2010;18:1033-8).

Data suggest that the radiation effect on mandibular movement correlates with the radiation dose to the mastication muscles, with a  steep dose-response curve. Onset is typically 2-6 months post treatment and is ongoing. Concurrent chemotherapy may increase the  incidence and/or severity of mandibular immobility (Oral Surg. Oral Med. Oral Pathol. Oral Radiol. Endod. 1999;88:365-73).

In the Vanderbilt survey, most patients reported burning in the throat or mouth (69); sensitivity to hot, spicy, or acid food (67);  sensitivity to dryness (69); and changes in food intake because of mucosal sensitivity (67); most patients also reported that mucosal  sensitivity prevents tooth brushing (63). “Mucosal sensitivity is a quality of life issue,” Dr. Epstein said.

The Vanderbilt survey was particularly illuminating, Dr. Epstein commented. Studies that utilize claims data probably underrepresent  the problem of long-term oral complications because dental and medical insurance are separate and the data are not easily combined, he added.

“Late oral effects are best diagnosed [and] managed in a multidisciplinary team with close communication between medical and  dental providers. … We really need to come together.”

The Multinational Association of Supportive Care in Cancer is developing tools to improve communication between dentistry and  medicine. These could be available for beta testing as early as this fall.

Dr. Epstein said he had no relevant financial disclosures.

This news story was resourced by the Oral Cancer Foundation, and vetted for appropriateness and accuracy.

 

March, 2012|Oral Cancer News|

Connected nodes in throat cancer signal poor prognosis

Source: OncologyNurseAdvisor.com

The presence of “matted” lymph nodes in persons with oropharyngeal squamous cell carcinoma (SCC)—that is, nodes that are connected together—was associated with a 3-year survival rate of 69%, compared with 94% among patients without matted nodes. Such a marker could help clinicians identify patients who are at heightened risk for metastasis and who might benefit from additional systemic therapy. Conversely, a person without matted nodes could be a candidate for less therapy, which would in turn reduce uncomfortable side effects.

The study, led by Matthew E. Spector, MD, a resident in the department of otolaryngology – head and neck surgery at the University of Michigan Health System in Ann Arbor, focused on 78 previously untreated persons with stage III or IV oropharyngeal SCC. All patients were undergoing chemotherapy in combination with intensity-modulated radiation therapy (IMRT) as part of a clinical trial.

The 3-year disease-specific survival rate for the 16 patients presenting with matted nodes was 69%, compared with 94% among the 61 other patients. Matted nodes were found to be a poor prognostic factor independent of tumor classification, human papillomavirus (HPV) status, epidermal growth factor receptor (EGFR), and smoking status. Matted nodes did appear to be an especially strong indicator of increased risk among HPV-positive persons, despite the fact that these patients had better overall outcomes than did those who were HPV-negative. The best outcomes were seen among HPV-positive nonsmokers.

The investigators, who reported their findings in Head & Neck, say the reasons for the survival differences between persons with and without matted nodes are unclear.

This news story was resourced by the Oral Cancer Foundation, and vetted for appropriateness and accuracy.

February, 2012|Oral Cancer News|

Newer radiation technology improves head and neck cancer patients’ long-term quality of life

Source: Eurekalert.org

Patients treated with IMRT for head and neck cancer report an increasingly better quality of life post-treatment when compared to patients receiving other forms of radiation therapy, according to a study presented at the Multidisciplinary Head and Neck Cancer Symposium, sponsored by AHNS, ASCO, ASTRO and SNM.

Intensity modulated radiation therapy, or IMRT, is a highly specialized form of external beam radiation therapy that allows the radiation beam to better target and conform to a tumor. It is a newer treatment that has become widely adopted for treating head and neck cancer. Prior studies have shown that IMRT decreases the probability of radiation therapy related side effects, including dry mouth and chewing and swallowing problems, but no study has been conducted to measure long-term quality of life in head and neck cancer patients treated with various forms of radiation therapy.

Investigators from the University of California, Davis, School of Medicine, prospectively administered the University of Washington Quality of Life instrument, a standardized, previously validated questionnaire that patients complete after radiation therapy, to 155 patients undergoing treatment for cancers of the head and neck and analyzed the scores over time. Fifty-four percent of patients were initially treated with IMRT and 46 percent were treated with non-IMRT techniques.

The researchers showed that the early quality of life gains associated with IMRT not only are maintained but become more magnified over time. At one-year post-treatment, 51 percent of IMRT patients rated their quality of life as very good or outstanding compared to 41 percent of non-IMRT patients. However, at two-years after treatment, the percentages changed to 73 percent and 49 percent, respectively. Also, 80 percent of patients treated with IMRT reported that their health-related quality of life was much better or somewhat better compared to the month before developing cancer. In contrast, only 61 percent of patients treated by non-IMRT techniques felt similarly.

Although the researchers acknowledged that quality of life is somewhat of a subjective concept, they nonetheless believe their findings support the widespread use of IMRT for head and neck cancer.

“Hopefully, these results provide some reassurance to patients that radiation therapy using contemporary techniques in the hands of expert specialists can maintain their function and long-term quality of life, while still curing them of cancer,” Allen Chen, MD, lead author of the study and director of the radiation oncology residency training program at the University of California, Davis School of Medicine in Sacramento, Calif., said.

“Radiation therapy for head and neck cancer is without a doubt an intensive process and very intimidating to most patients. Folks think about the prospects of six to seven weeks of radiation and naturally expect the worst. It is nice to know that technological advances have made the treatment much more tolerable than in the past.”

About the American Head and Neck Society

The American Head and Neck Society (AHNS) is the single largest organization in North America for the advancement of research and education in head and neck oncology. The purpose of the AHNS is to promote and advance the knowledge of prevention, diagnosis, treatment, and rehabilitation of neoplasms and other diseases of the head and neck; to promote and advance research in diseases of the head and neck; and to promote and advance the highest professional and ethical standards.

About the American Society of Clinical Oncology

The American Society of Clinical Oncology (ASCO) is the world’s leading professional organization representing physicians who care for people with cancer. With more than 30,000 members, ASCO is committed to improving cancer care through scientific meetings, educational programs and peer-reviewed journals. ASCO is supported by its affiliate organization, the Conquer Cancer Foundation, which funds ground-breaking research and programs that make a tangible difference in the lives of people with cancer. For ASCO information and resources, visit www.asco.org. Patient-oriented cancer information is available at www.cancer.net.

About the American Society for Radiation Oncology

The American Society for Radiation Oncology (ASTRO) is the largest radiation oncology society in the world, with more than 10,000 members who specialize in treating patients with radiation therapies. As the leading organization in radiation oncology, biology and physics, the Society is dedicated to improving patient care through education, clinical practice, advancement of science and advocacy. For more information on radiation therapy, visit www.rtanswers.org. To learn more about ASTRO, visit www.astro.org.

About SNM—Advancing Molecular Imaging and Therapy

SNM is an international scientific and medical organization dedicated to raising public awareness about what molecular imaging is and how it can help provide patients with the best health care possible. SNM members specialize in molecular imaging, a vital element of today’s medical practice that adds an additional dimension to diagnosis, changing the way common and devastating diseases are understood and treated.

This news story was resourced by the Oral Cancer Foundation, and vetted for appropriateness and accuracy.

January, 2012|Oral Cancer News|