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Head and Neck Cancer

RADPLAT: An Alternative to Surgery?

^a Department of Plastic Surgery, Canniesburn Hospital, Glasgow Royal Infirmary, Glasgow, United Kingdom; ^b Department of Otolaryngology/Head and Neck Surgery, VU University Medical Center, Amsterdam, The Netherlands; ^c Department of Plastic Surgery, Christie Hospital, Manchester, United Kingdom

Key Words. Head and neck cancer • RADPLAT • Targeted chemoradiation • Intra-arterial chemotherapy

Correspondence: Gary L. Ross, M.D., Department of Plastic Surgery, Christie Hospital, Southmoor Road, Manchester, United Kingdom. Telephone: 44-161-286-6534; Fax: 44-161-291-6381; e-mail: gary.ross{at}canniesburn.org

Received September 19, 2005; accepted for publication March 4, 2006.

	ABSTRACT

Top Abstract Evolution of Treatment for... Technique Study Outcomes Control of Nodal Disease RADPLAT in Other Centers Toxicity Predictors of Success Organ Preservation and Quality... Detection of Recurrence after... Surgery After Chemoradiation... Further Applications of the... Conclusions Disclosure of Potential... References

 
Head and neck cancer frequently presents at a late stage, leading to a poor prognosis despite optimal treatment with surgery and/or radiotherapy. Chemotherapy for advanced disease has shown little benefit as a single-modality treatment, and the use of concurrent chemoradiation is limited by problems with severe toxicity at higher doses. RADPLAT is the acronym used to describe a new technique, combining intra-arterial delivery of cisplatin with systemic neutralization by i.v. sodium thiosulphate, and concurrent radiotherapy. This allows very high cisplatin dose intensities to be used while potentially minimizing adverse systemic effects. Initial results suggest that excellent locoregional control rates are achievable in patients with unresectable disease, with a favorable side-effect profile when compared with conventional chemoradiation protocols. In addition, RADPLAT may potentially be of benefit in selected patients with resectable disease, allowing for preservation of organ function and quality of life without compromising locoregional control or survival. While current phase II data are encouraging, phase III randomized controlled trials are required in order to directly compare RADPLAT with i.v. chemoradiation therapy, the current standard of care. This article reviews the evolution of the RADPLAT concept, from initial clinical trials to its current application in the treatment of patients with advanced head and neck cancer.

	EVOLUTION OF TREATMENT FOR ADVANCED HEAD AND NECK CANCER

Top Abstract Evolution of Treatment for... Technique Study Outcomes Control of Nodal Disease RADPLAT in Other Centers Toxicity Predictors of Success Organ Preservation and Quality... Detection of Recurrence after... Surgery After Chemoradiation... Further Applications of the... Conclusions Disclosure of Potential... References

 
Cancer of the head and neck frequently presents at a late stage, when 5-year survival rates through surgery or radiotherapy, alone or in combination, frequently do not exceed 25% [1–3]. In addition, patients undergoing surgery for advanced local disease frequently require extensive resection of the larynx, pharynx, and/or tongue, leading to significant cosmetic and functional disabilities involving speech and swallowing. While radiotherapy alone has the advantage of organ preservation, its use in advanced disease only shows survival benefits in combination with surgical resection [4].

Chemotherapeutic agents, particularly cisplatin, have been shown to achieve high tumor response rates in the head and neck [5, 6] that have been shown to be dose related [7, 8]. However, cisplatin’s side effects, particularly nephrotoxicity, limit the useable dose in humans. Despite these promising initial results, chemotherapy has not been shown to improve survival when used alone or in the adjuvant/neoadjuvant setting for advanced head and neck cancer [9, 10], aside from one recent postoperative randomized trial targeting high-risk disease [11]. In addition, in a large prospective study of 332 patients with stage III or IV laryngeal cancer, induction chemotherapy followed by radiotherapy showed no difference in survival compared with laryngectomy and radiation therapy (p = .98) [12]. This suggests that an organ-preserving approach may be used without adversely affecting survival.

Potentiation of the cytotoxic effects of radiation occurs when chemotherapy is administered concurrently, a process termed radiosensitization. This effect, first noted in murine tumors [13], has demonstrated mixed tumor response rates with current chemoradiation protocols for head and neck cancer, in the range of 47%–84% [14–19]; a clear survival benefit over conventional treatment with surgery and postoperative radiotherapy has not been demonstrated in randomized trials [2, 12]. Concurrent chemoradiation appears to offer greater benefit than sequential treatment. In two recent phase III trials, chemoradiation demonstrated higher locoregional control rates than with radiotherapy alone in the postoperative setting [4, 20]. However, improvements in disease-free and overall survival times were observed in only one of these studies.

Acquired tumor resistance to cisplatin has been shown to occur after as few as two to four cycles [21, 22] and may explain in part the failure of chemotherapy to improve survival. It was previously demonstrated in vitro [7] and in vivo [8] that resistance may be overcome through the use of higher concentrations of cisplatin. However, in human subjects, the higher concentrations required could lead to devastating systemic toxicity—already a major problem with chemoradiation protocols, which also appear to aggravate radiation-induced mucositis [23]. Treatment delays and dose reductions are commonly reported in chemoradiation protocols, adversely affecting locoregional tumor control rates and overall survival.

The undesirable systemic side effects of i.v. chemotherapy can be partially circumvented through the use of regional chemotherapy techniques to deliver higher doses of chemotherapeutic agents directly into the tumor bed, allowing first-pass metabolism of the drug by the tumor. Head and neck cancers, which metastasize to distant sites infrequently, appear well suited to this approach.

Early attempts at intralesional injection of chemotherapy were largely unsuccessful because of problems with poor diffusion of the drug into tumor tissue, which led to the addition of adrenaline to improve local penetration. Initial reports are encouraging, with a reported 50% response rate and no dose-limiting toxicity in a series of 82 patients [20]. Another approach to improve the penetration of intra-lesionally injected chemotherapy is the use of electroporation therapy. Promising results have been reported in a series of 12 patients with oral cancer, of whom 10 patients had a complete response (CR) [24].

Intra-arterial infusion of chemotherapeutic agents was first carried out in the 1960s [25, 26]; however, technical difficulties and poor initial results prevented the technique from gaining popularity until the 1980s, when Lee et al. [27] reported a 91% tumor response rate in 24 patients treated with combined intra-arterial cisplatin and i.v. chemotherapy for advanced paranasal sinus carcinoma. Importantly, eight patients avoided craniofacial surgery as a result of their excellent response to treatment.

Several authors subsequently reported on the use of intra-arterial chemotherapy alone, but CR rates remained disappointingly low, in the range of 7.7%–33% [27–31]. The main criticism leveled at regional chemotherapy techniques was that there was no clear survival benefit over conventional systemic chemotherapy but a considerably greater risk of local toxicity. In addition, systemic distribution of cisplatin distal to the tumor site meant that systemic toxicity remained a considerable problem [32].

To address these problems, the RADPLAT protocol was developed at the University of California at San Diego and the University of Tennessee, Memphis. This technique involves four cycles of targeted intra-arterial cisplatin infusion with concurrent radiation therapy. Simultaneous with each intra-arterial infusion, the neutralizing agent sodium thiosulphate is infused into the systemic circulation and binds covalently with cisplatin to form a soluble, nontoxic compound [33]. This "neutralization" of cisplatin effectively increases the drug’s plasma clearance, allowing very high doses to be administered directly into the tumor tissue while minimizing systemic toxicity. Using the RADPLAT procedure, dose intensities up to 10 times those used in standard chemotherapy protocols may be administered [7, 8].

The goal of intra-arterial infusion during RADPLAT is to target the portion of tumor considered to be bulky or infiltrative and likely to fail treatment with radiation therapy alone [34].

	TECHNIQUE

Top Abstract Evolution of Treatment for... Technique Study Outcomes Control of Nodal Disease RADPLAT in Other Centers Toxicity Predictors of Success Organ Preservation and Quality... Detection of Recurrence after... Surgery After Chemoradiation... Further Applications of the... Conclusions Disclosure of Potential... References

 
Patients are prehydrated with i.v. normal saline (2 l), 20 mmol potassium chloride (KCl), and 2 g magnesium sulphate (MgSO₄) prior to each cycle. Transfemoral carotid arteriography is carried out to assess vascular anatomy prior to superselective catheterization of the tumor’s dominant supply artery. Transaxial placement of the micro-catheter is accomplished under fluoroscopic guidance and allows rapid intra-arterial infusion of cisplatin (150 mg/m² over 3–5 minutes) with simultaneous i.v. sodium thiosulphate (9 g/m² over 15–20 minutes, followed by 12 g/m² over 6 hours). This allows the tumor bed to receive the maximum dose of cisplatin before thiosulphate, while the systemic organs receive protection by thiosulphate prior to cisplatin [35]. In patients with bulky disease crossing the midline, bilateral infusions may be carried out. Catheters are removed immediately postinfusion, and patients undergo rehydration with 1 l normal saline, 20 mmol KCl, and 2 g MgSO₄ over 2 hours. Intravenous or oral dexamethasone (4 mg) is also administered every 6 hours overnight.

Four cycles of targeted chemotherapy are administered on days 1, 8, 15, and 22, with radiotherapy commencing on day 1 and continuing for 5 days using opposed tangential fields and fractions of 2.0 Gy per day to a total planned radiation dose of 70–74 Gy, dependent on disease stage. Radiation to the neck is dependent on clinical involvement, with uninvolved necks treated to 50 Gy while positive necks are boosted with electrons to 60–66 Gy.

Planned neck dissection was initially carried out in all patients with bulky nodal disease (nodal [N] stage 2 or 3), regardless of response to RADPLAT. However, this policy was subsequently changed to salvage neck dissection when it became clear that clinical complete responders were also negative at pathologic evaluation of neck dissection specimens [36].

	STUDY OUTCOMES

Top Abstract Evolution of Treatment for... Technique Study Outcomes Control of Nodal Disease RADPLAT in Other Centers Toxicity Predictors of Success Organ Preservation and Quality... Detection of Recurrence after... Surgery After Chemoradiation... Further Applications of the... Conclusions Disclosure of Potential... References

 
The "decadose" effect is a term introduced by Robbins et al. [37] to describe a dose intensity approaching 10 times that of traditional cisplatin-based chemotherapy regimens. This was achieved through high-dose intra-arterial cisplatin delivery and systemic sodium thiosulphate neutralization, combined with a reduction in overall treatment time. In this phase I trial, 42 patients with stage III/IV disease underwent treatment with dose intensity schedules of 50, 100, 150, or 200 mg/m² per week. The maximum-tolerated cisplatin dose intensity was four cycles of 150 mg/m² per week, beyond which nephrotoxicity was the dose-limiting side effect. The observed response rates in that study suggested that acquired tumor resistance to cisplatin may be overcome through the use of these very high concentrations, with an 86% response in previously untreated patients (CR rate, 45%; partial response [PR] rate, 41%) and a 63% response rate in patients with recurrent disease (CR rate, 25%, PR rate, 38%). The patients who responded to treatment were subsequently found to have received a significantly higher average dose intensity than non responders (120.7 vs. 57.8 mg/m² per week; p = .031), suggesting that high tumor response rates can be achieved through the incorporation of decadose cisplatin therapy into multimodality treatment plans [8].

The RADPLAT protocol has since been shown to achieve impressive CR and PR rates and locoregional control (Table 1) while maintaining a favorable side-effect profile. Following on from their initial work, Robbins et al. [38] evaluated the response to treatment in 29 patients with previously untreated stage IV disease and observed complete pathologic responses in 23/24 evaluated patients (96%). Grade III or IV chemotoxicities occurred after only 14 of the 110 infusions carried out during the study (12.7%). At a median follow-up of 22 months, the projected 3-year overall and disease-free survival rates were 88% and 53%, respectively. Further studies from this group subsequently confirmed these promising response and survival rates, and extended the application of RADPLAT from patients with functionally inoperable disease only to an organ-preserving approach in patients with technically resectable disease [39, 40].

The reported CR rates following RADPLAT treatment appear to compare favorably with those observed in randomized trials of i.v. chemoradiation protocols [15, 41, 42]. In addition, the pattern of recurrence seen following RADPLAT treatment is unusual compared with previous head and neck cancer studies, in which locoregional failure predominates as the mode of death. It is likely that better local and regional control effectively unmask previously occult distant metastases, and this may require the addition of a systemic component to treatment in future studies using the RADPLAT protocol.

	CONTROL OF NODAL DISEASE

Top Abstract Evolution of Treatment for... Technique Study Outcomes Control of Nodal Disease RADPLAT in Other Centers Toxicity Predictors of Success Organ Preservation and Quality... Detection of Recurrence after... Surgery After Chemoradiation... Further Applications of the... Conclusions Disclosure of Potential... References

 
In most cases, targeted cisplatin infusions do not specifically target the regional lymph nodes. Despite this, patients treated with RADPLAT have demonstrated good regional as well as local control rates [43, 44]. Control of bulky (stage N2 or N3) nodal disease was recently examined in a prospective analysis of 52 patients with HNSCC. All patients received RADPLAT treatment, and all were offered neck dissection 8 weeks after completion of radiotherapy, in order to assess the efficacy of this combined approach. Thirty-five neck dissections were carried out. Of these, two were comprehensive (levels I–V), and 33 were selective. Thirty-three of the 60 involved neck sides demonstrated a CR (55%), with 21 (35%) PRs. Of the 35 neck dissections, 14 were positive for disease, and all of those patients were partial responders. One local (2%), one regional (2%), and 14 distant recurrences (26%) were observed at a median follow-up of 36 months, and the projected 3-year overall and disease-specific survival rates were 32% and 47%, respectively. The rate of locoregional control was 77% at 3 years. The results of this study showed that RADPLAT followed by selective neck dissection is highly effective for control of regional disease in patients with N2–N3 nodal involvement.

In a further study of 31 patients with stage N3 disease, Ahmed et al. [44] described survival and local and regional control rates following RADPLAT treatment. Nodal disease responded to treatment in 25 of 26 evaluated patients (96%). However, 21 of these (81%) were PRs, and most patients in the study (n = 19) went on to have salvage neck dissection at the time of restaging. Of the 23 patients rendered disease free, there was only one recurrence at the primary site and none in the neck at a median follow-up of 15 months. Distant metastases occurred in 11 patients (48%). The authors reported a projected 3-year overall survival rate of 41%, a disease-specific survival rate of 43%, and a locoregional survival rate of 67%.

The reported regional response and 3-year locoregional control rates suggest that the effects of targeted intra-arterial chemoradiation are not strictly confined to the local area infused, and it has been suggested that incomplete systemic neutralization of cisplatin by sodium thiosulphate may allow sufficient amounts to remain in the circulation and act as a radiosensitizing agent [40].

	RADPLAT IN OTHER CENTERS

Top Abstract Evolution of Treatment for... Technique Study Outcomes Control of Nodal Disease RADPLAT in Other Centers Toxicity Predictors of Success Organ Preservation and Quality... Detection of Recurrence after... Surgery After Chemoradiation... Further Applications of the... Conclusions Disclosure of Potential... References

 
The success of the Memphis group has encouraged other centers to undertake similar trials, and results have been largely encouraging. Balm et al. [45] reported high local (91%) and regional (90%) response rates in a prospective series of 79 patients with inoperable stage IV disease. Recurrences were seen in 27 patients (34%) at a median follow-up of 3.1 years. Of these, 10 (13%) were distant and 10 (13%) were local, and seven patients (9%) had recurrence in the neck. The estimated 1- and 3-year survival probabilities were 73% and 43%, respectively, with a median overall survival time of 2.2 years, and the locoregional control rates at 1 and 2 years were 82% and 69%, respectively. These figures are in keeping with earlier published results. However, the reported rates of grade III/IV toxicity were slightly higher in this study compared with the Memphis group’s experience. Gastrointestinal toxicity (57%), mucosal toxicity (43%), hematologic toxicity (38%), skin reactions (24%), nausea (20%), and subjective hearing loss (10%) were all observed, and three treatment-related deaths occurred (3.8%). Despite this significant side-effect profile, feasibility remained high, with 74 patients (94%) able to complete the RADPLAT protocol.

Feasibility, or the ability to deliver the full prescribed dose of both cisplatin and radiotherapy, was examined recently in the multicenter setting in a prospective phase II trial [46]. Eleven institutions participated, eight of whom were inexperienced in the delivery of RADPLAT. Sixty-seven patients were enrolled, of whom 61 were evaluated. RADPLAT was shown to be feasible at all sites, with 100% of patients at experienced centers completing the protocol. This number was only 83% at inexperienced centers, which was nevertheless above the 80% feasibility cutoff. Eighty-five percent of patients demonstrated a CR at the primary site, and 88% had a CR in the neck (80% overall). The 1- and 2-year overall survival rates were projected at 72% and 63%, with disease-free survival rates of 62% and 46%, respectively. Severe (grade III, IV, and V) toxicities were seen in 44%, 39%, and 3% or patients, respectively. However, there were significant differences in the rates of grade IV and V toxicity between experienced and inexperienced centers (grade IV, 14% vs. 47%; grade V, 0% vs. 4%; no p value given), and this held true for both hematologic and nonhematologic toxicities. The authors stated that developing toxicities may have been recognized earlier at the experienced centers, allowing for treatment to be temporarily halted. Failure to recognize developing toxic reactions at an early stage could account for the higher rate of severe toxicities observed at the inexperienced centers.

	TOXICITY

Top Abstract Evolution of Treatment for... Technique Study Outcomes Control of Nodal Disease RADPLAT in Other Centers Toxicity Predictors of Success Organ Preservation and Quality... Detection of Recurrence after... Surgery After Chemoradiation... Further Applications of the... Conclusions Disclosure of Potential... References

 
The synergistic effects of concurrent chemoradiation also extend to the potentiation of undesirable side effects. Severe toxicities are frequent, in particular radiation-induced mucositis [22]. Hypopharyngeal stenosis is another major complication of chemoradiation and may occur after a variable delay. Anterograde endoscopic dilatation through direct laryngoscopy or transgastric retrograde esophagoscopy (via gastrostomy) has been described. However, these procedures harbor the risk of perforation, infection of the abdominal wall, and stomal wall dehiscence [47]. It is likely that patients with posterior hypopharyngeal wall or postcricoid tumors have an increased risk of developing stenosis after chemoradiation. Therefore, this risk has to be kept in mind when selecting the treatment of choice. Further studies are needed to identify risk factors for development of stenosis after chemoradiation.

Initial experience with RADPLAT suggests that mucosal toxicity rates may be less than those observed in conventional chemoradiation protocols. In Robbins et al.’s [40] phase II trial of 60 patients with stage III/IV disease, grade III mucositis was encountered in only 12 patients (20%). It has been suggested that sodium thiosulphate may exert a radioprotective effect; the mechanism of this is not exactly known but may occur through scavenging of free radicals by the thiol compound.

Systemic neutralization of cisplatin by sodium thiosulphate diminishes the risk of systemic toxicity, potentially allowing a greater proportion of patients to complete the full course of treatment. Robbins et al. [40] reported that 90% of patients received all four cycles of chemotherapy, whereas 85% completed the full RADPLAT protocol. The grade III toxicities observed in that trial were hematologic (n = 6), gastrointestinal (n = 6), vascular (n = 4), neurological (n = 4), and mucosal, secondary to radiotherapy (n = 12; 20%). Most notable was the significant absence of grade IV–V nonhematologic toxicities in this group of 60 patients (only two grade IV gastrointestinal toxicities), unlike what is typically reported in virtually all chemoradiation trials. The absence of nephrotoxic events is attributed to the fact that sodium thiosulphate is extensively concentrated in the urine, providing additional protection to the kidneys.

The mild-to-moderate chemotoxic effects observed in some patients support the suggestion that small amounts of cisplatin may escape systemic neutralization by sodium thoisulphate, thereby entering the systemic circulation [40].

Chemotoxicity rates following RADPLAT appear to compare favorably with those of i.v. chemotherapy protocols, with reported overall incidences as low as 5.5% [39]. Gemmete [48] conducted a retrospective review of 105 patients undergoing 385 RADPLAT cycles and reported 41 grade III/IV chemotoxic events (10.6%). Of these, 29 were mucosal, nine were hematologic (two neutropenic sepsis), two were otologic, and one was gastrointestinal. These results were mirrored in a large prospective study of 213 patients [36], in which only 21 patients (10%) received less than three infusions as a result of problems with toxicity. One hundred thirty of 213 patients (61%) did not experience any grade III or IV reactions, and six treatment-related deaths were encountered (2.8%). This compares favorably with the 5%–18% mortality rate reported in other head and neck cancer chemoradiation trials [49, 50].

Complications related to the intra-arterial infusion technique may also arise, as reported by Gemmete [48]. Repeated catheterization may lead to groin-site complications, and two patients in this series (2%) required femoro-femoral bypass surgery secondary to external iliac artery occlusion. Vascular complications were observed in 25 patients (6.5%), while six patients (1.6%) experienced transient ischemic attacks (n = 3) or cerebrovascular accidents (n = 3). These rates are comparable with those reported following diagnostic angiographic procedures.

Ototoxicity is a well-documented complication of i.v. cisplatin-based chemotherapy, with reported rates as high as 81% [51]. In a prospective series of 70 patients treated with RADPLAT, Madasu et al. [52] demonstrated that the incidence of hearing loss is related to the cumulative cisplatin dose (ranging from 25% at 150 mg/m² to 60% at 600 mg/m²). However, the observed hearing loss was generally minimal (10–20 dB) and confined to frequencies greater than 2–3 kHz.

On the whole, morbidity following the RADPLAT procedure appears to be relatively low, comparing favorably with the existing literature for "conventional" chemoradiation protocols. However, the clinician should be aware of the potential for additional complications related to the technical aspects of intra-arterial cisplatin delivery, and the apparent learning curve for institutions new to the procedure.

	PREDICTORS OF SUCCESS

Top Abstract Evolution of Treatment for... Technique Study Outcomes Control of Nodal Disease RADPLAT in Other Centers Toxicity Predictors of Success Organ Preservation and Quality... Detection of Recurrence after... Surgery After Chemoradiation... Further Applications of the... Conclusions Disclosure of Potential... References

 
RADPLAT treatment appears to offer better locoregional control and survival than conventional nonsurgical treatment [36, 43, 44]. Consequently, variables previously reported to influence outcome may not be equally applicable to this new treatment modality.

Robbins et al. [53] addressed this issue in their prospective series of 240 patients treated with RADPLAT for stage III or IV disease. At a median follow-up of 58 months, the authors reported an excellent 5-year local control rate (210/240, 83%). Factors found to significantly influence this outcome included the total dose of radiotherapy, number of nodal levels involved, and persistence of nodal disease after treatment. Tumor (T)-stage classification was found to be a significant predictor of local control only when stage T2 tumors were included in the analysis. No difference was seen between the stage T3 and T4 groups (p = .089), indicating that T stage may not be the optimal means of risk stratification for this patient group.

In a smaller study of 64 patients, primary tumor volume greater than 19.6 mm³ was strongly associated with a higher local recurrence rate (94% vs. 57%; p = .001) and lower 5-year survival rate (14.1% vs. 41.5%; p = .018) [54]. The authors postulated that this may be related to the poorly vascularized areas of central necrosis frequently seen in large tumors, preventing effective intra-arterial delivery of chemotherapy [55].

The reported improvements in locoregional control rates have been partially offset by the unmasking of distant metastases in a significant proportion of patients undergoing treatment with RADPLAT [36]. It is therefore of paramount importance to recognize and address significant risk factors for distant failure in order that the choice of treatment may be tailored appropriately.

In a large prospective series, Doweck et al. [56] reported recurrence of disease in 84 of 250 patients treated with the RADPLAT protocol (33.6%). Of these, 45 (18%) had distant metastases and 39 (15.6%) had locoregional metastasis. Reported risk factors for distant metastasis included N stage (p = .02), primary tumor in the hypopharynx (p = .01), lower neck involvement (p = .002), number of neck levels involved (p = .001), and bilateral nodal disease (p = .02). Similar results were described by van den Broek et al. [57] in a series of 92 patients, with tumor volume (p = .003), lowest involved neck level (p = .007), pretreatment weight loss >10% (p = .02), and associated comorbidity (p = .01) all found to significantly influence survival following RADPLAT treatment.

Based on these results, variables such as age and T-stage classification appear to be of secondary importance to tumor volume and nodal status. It is apparent that the variables influencing local and distant control, and therefore survival, following RADPLAT treatment may differ considerably from those known to affect outcomes following conventional treatment. Specific biologic markers of response to chemoradiation may be helpful in predicting outcomes of RADPLAT. Studies to analyze the predictive value of different markers are ongoing.

	ORGAN PRESERVATION AND QUALITY OF LIFE FOLLOWING RADPLAT

Top Abstract Evolution of Treatment for... Technique Study Outcomes Control of Nodal Disease RADPLAT in Other Centers Toxicity Predictors of Success Organ Preservation and Quality... Detection of Recurrence after... Surgery After Chemoradiation... Further Applications of the... Conclusions Disclosure of Potential... References

 
Following the early success of the RADPLAT protocol, its application was subsequently extended to include patients with resectable disease. The organ-preserving approach in these patients has the potential to preserve functions of speech and swallowing, with potential resultant improvements in quality of life (QoL).

Robbins et al. [39] first described RADPLAT as an alternative to major resection in a series of 42 patients with advanced laryngeal and pharyngeal cancer and reported a CR in 36 patients (86%). Only five recurrences were observed at a median follow-up of 13 months, and the 2-year locoregional control rate was estimated at 86%. Overall and disease-specific survival rates at 2 years were 64% and 76%, respectively. Importantly, 28 of 31 surviving patients (90%) retained their larynx, 27 (87%) maintained oral food intake, and all the surviving patients were able to speak.

The preservation of organs does not necessarily ensure preservation of organ function, and problems with swallowing, speech, and breathing may also occur following nonsurgical treatment [58]. Staton et al. [59] conducted a retrospective chart review of 45 patients with stage III–IV laryngeal carcinoma enrolled into a RADPLAT protocol study in order to determine predictors of functional outcome following larynx-preserving RADPLAT treatment. At 6 months post-treatment, 10 patients (22%) required tracheostomy and gastrostomy, three patients required tracheostomy alone (6.7%), and three patients required gastrostomy alone (6.7%). Poor functional outcome was positively predicted by the presence of vocal cord fixation by the tumor at initial presentation (p = .0065), while stage T4 status and massive cartilage invasion showed strong trends toward association (p = .149 and p = .14, respectively). Age, tumor site, comorbid chronic obstructive pulmonary disease, neck dissection, and nodal status were not found to affect functional outcomes. The authors concluded that the ability to predict a poor functional outcome of organ-preserving RADPLAT treatment can assist in the selection of treatment modality for patients in this population.

Newman et al. [60] assessed the ability to eat normally in a series of 47 patients treated with RADPLAT for advanced head and neck cancer and found that swallowing ability was markedly improved (72% reported normal swallowing post-treatment, compared with 38% pretreatment). At 18 months of follow-up, percutaneous endoscopic gastrostomy (PEG) tubes were required in six patients (13%), compared with four patients (9%) pretreatment. A mean weight loss of 10% body weight was observed on initiation of treatment, after which weight remained stable. This trend has been previously noted in patients undergoing radiotherapy alone [61].

In a further study carried out by the same group, Murry et al. [62] used patient questionnaires to determine that both swallowing ability and QoL were diminished prior to RADPLAT treatment for advanced cancer and decreased further during the treatment cycle (p < .05). However, QoL subsequently improved and exceeded the pretreatment level at 6 months after completion of treatment.

Similar results were reported in a series of 26 patients with stage IV disease by Ackerstaff et al. [63], with a decline in QoL observed at 6 weeks post-treatment and a subsequent improvement to exceed pretreatment values in terms of functional ability and head and neck symptoms (p < .001). At a 12-month follow-up, 16 of 26 patients (62%) reported little or no problems with mastication, while 19 patients (73%) had no problems with swallowing. Five patients (19%) required PEG tube feeding at 1 year. Twenty-three patients described their voice as normal (n = 16; 61%) or somewhat normal (n = 7; 27%), whereas only three patients (12%) reported severe voice-related problems. The most frequently reported problem post-treatment was xerostomia, with all patients experiencing a decrease in volume or thicker consistency of saliva.

The results of these studies indicate that RADPLAT is associated with high rates of function preservation and improved QoL in patients with advanced cancer of the head and neck.

	DETECTION OF RECURRENCE AFTER CHEMORADIATION

Top Abstract Evolution of Treatment for... Technique Study Outcomes Control of Nodal Disease RADPLAT in Other Centers Toxicity Predictors of Success Organ Preservation and Quality... Detection of Recurrence after... Surgery After Chemoradiation... Further Applications of the... Conclusions Disclosure of Potential... References

 
It is of utmost importance that organ preservation be carried out without compromising locoregional disease control. Patients should be carefully observed throughout the course of treatment and during follow-up so that surgery can be undertaken as soon as resistant or recurrent disease is suspected. Clinical evaluation of the response to nonsurgical treatment is difficult, with post-treatment induration and fibrosis obscuring accurate clinical assessment. Anatomic imaging techniques, such as computed tomography (CT), magnetic resonance imaging (MRI), and ultrasonography, all fall short of consistently demonstrating persistent or recurrent tumor following chemoradiation. Biopsies in previously treated areas may produce false negatives as a result of sampling error that misses focally dispersed residual tumor. One potential method of improving the discrimination of clinical assessment is by functional imaging with positron emission tomography (PET). ¹⁸Fluoro-2-deoxy-glucose (FDG)-PET has previously been shown to correlate with clinical response to concurrent chemoradiation [64]. Kubota et al. [65] recently compared the sensitivity and specificity of FDG-PET, MRI, and CT with histology in the evaluation of 36 patients suspected of having a recurrence following intra-arterial chemoradiation therapy. The reported sensitivity (88%) and specificity (78%) of FDG-PET were significantly higher than those of MRI or CT (sensitivity, 75%; specificity, 30%). Six patients had false-positive results, and three of these were a result of post-therapy inflammation. The authors suggested that the high reported negative predictive value of FDG-PET (91.3%) may mean that further invasive investigation is unnecessary if FDG-PET is negative

	SURGERY AFTER CHEMORADIATION TREATMENT

Top Abstract Evolution of Treatment for... Technique Study Outcomes Control of Nodal Disease RADPLAT in Other Centers Toxicity Predictors of Success Organ Preservation and Quality... Detection of Recurrence after... Surgery After Chemoradiation... Further Applications of the... Conclusions Disclosure of Potential... References

 
In some patients, surgical treatment may be an option following complications or failure of chemoradiation therapy, and in some institutes, planned neck dissections are performed. Extensive fibrosis is an untoward outcome observed in many patients who undergo surgery after radiation therapy. These chronic soft tissue toxic events are more likely to occur after chemoradiation than after radiation alone. Delayed wound healing of the surgical incision and potential wound breakdown with flap necrosis and great vessel exposure may result from surgery after chemoradiation.

Postoperative complications after en bloc salvage surgery for head and neck cancer occur in more than half of the patients, and one third of these patients experiences major complications [66, 67]. In a retrospective study at Memorial Sloan-Kettering Cancer Center, postoperative complications were compared among patients undergoing primary total laryngectomy, salvage laryngectomy after radiotherapy, or salvage laryngectomy after chemoradiation. Chemoradiation was found to be an independent predictor of local complications and pharyngocutaneous fistula [68].

Two thirds of patients with local and/or regional recurrence after larynx preservation with chemoradiation are candidates for salvage surgery. Moreover, negative surgical margins appear to be more difficult to obtain during salvage laryngectomy than during primary laryngectomy [69]. Although this is in part related to the selection of more aggressive tumors, it is likely that difficulties in macroscopic differentiation between recurrent tumor and post-chemoradiation changes during surgery also play a role.

The decision to perform a neck dissection following chemoradiation is clear when patients have proven residual neck disease. However, distinguishing between residual metastasis and chemoradiation sequelae is difficult in most cases with a residual neck mass because post-treatment induration and fibrosis obscure accurate clinical assessment. Therefore, in some institutes, routine planned neck dissections have been performed because no reliable clinical parameters are available to predict pathological status after chemoradiation [70, 71].

Performing a neck dissection after chemoradiation runs the risk of wound-healing problems; pedicled pectoralis major muscle flaps may be used if wound healing problems are anticipated, at the expense of greater morbidity. Complication rates of 26%–35% have been reported for planned neck dissection after chemoradiation [70]. Some centers perform selective neck dissection or lumpectomy instead of radical neck dissection to minimize the surgical wound bed and consequently the risk for wound-healing problems [71].

Viable tumor cells are found in only 30%–50% of neck dissection specimens [43, 45]. Moreover, controversy surrounds the use of planned neck dissection in patients with a CR to chemoradiation because the vast majority of these patients have negative neck dissection specimens on histopathological examination [70]. The difficulty in evaluating for recurrence has made salvage neck surgery less effective, and late recurrences in the neck are rarely surgically salvageable [72].

Because salvage treatment after chemoradiation has a questionable prognosis and a high incidence of complications, RADPLAT may not be the choice of treatment in all patients with advanced-stage disease. A reliable pretreatment probability model for predicting outcome after RADPLAT is needed to select patients with resectable tumors who are likely to benefit from chemoradiation. If RADPLAT is unlikely to cure patients with resectable tumors, these patients should instead be treated with primary surgery [57].

	FURTHER APPLICATIONS OF THE RADPLAT TREATMENT PROTOCOL

Top Abstract Evolution of Treatment for... Technique Study Outcomes Control of Nodal Disease RADPLAT in Other Centers Toxicity Predictors of Success Organ Preservation and Quality... Detection of Recurrence after... Surgery After Chemoradiation... Further Applications of the... Conclusions Disclosure of Potential... References

 
As a relatively new treatment modality, the full utility of targeted chemoradiation has yet to be determined. Reports of novel applications continue to emerge, and promising results have been reported in a number of difficult-to-manage patient groups.

Samant et al. [73] described the use of RADPLAT in a series of 135 patients with stage T4 disease, 45 of whom had evidence of bone or cartilage invasion. The authors noted that the CR rate did not differ significantly between patients with or without invasion (66.7% vs. 71.1%; p = .71), and the same was true for the 2-year overall survival rate (46.3% vs. 36.9%; p = .36). They concluded that the RADPLAT protocol can be used as a viable treatment option in patients with advanced head and neck cancer invading bone or cartilage, a patient group for whom organ preservation approaches have traditionally been contraindicated.

Neo-RADPLAT is the acronym given to the use of targeted intra-arterial chemoradiation cytoreduction prior to surgery, as recently described by Robbins et al. [74] in a series of 25 patients with stage T2 or T3 oro/oropharyngeal tumors. A CR was demonstrated at the primary site in 20 patients (80%) and at the neck in 10 patients (79%). PRs were observed in all remaining patients. Fourteen patients subsequently underwent tumor nidusectomy, five of whom had involved margins and required conventional resection. Nine patients (11 neck sides) also had a selective neck dissection because of clinical evidence of residual nodal disease, three of whom were found to be positive. At a median follow-up of 56 months, the estimated 5-year overall survival, disease-specific survival, and locoregional control rates were 54%, 64%, and 74%, respectively. Recurrences were observed in five patients, all of which occurred at the primary site. The authors found that the use of triple-modality therapy was feasible and efficacious in patients with stage T2–T4 oro/oropharyngeal carcinoma, and that presurgical cytoreduction reduced the extent of resection, allowing greater preservation of function. In addition, the total radiation dose in that study was reduced to 50 Gy (10 Gy/week) without adversely affecting response rate. The authors suggested that the maximum radiation dose may not be required in the context of multimodality treatment, and further study of this is required.

A similar triple-therapy approach was described by Madison et al. [75] in the treatment of 11 patients with advanced sinonasal malignancy. The authors reported that the presurgical reduction in size achievable with targeted chemoradiation allows for surgical management of otherwise unresectable tumors, and improvements in local control and survival with a low complication rate are achievable with this approach.

	CONCLUSIONS

Top Abstract Evolution of Treatment for... Technique Study Outcomes Control of Nodal Disease RADPLAT in Other Centers Toxicity Predictors of Success Organ Preservation and Quality... Detection of Recurrence after... Surgery After Chemoradiation... Further Applications of the... Conclusions Disclosure of Potential... References

 
Patients treated with the RADPLAT protocol as an alternative to surgery for advanced head and neck cancer appear to demonstrate high locoregional control rates, with an apparent survival benefit over radiation alone and an acceptable side-effect profile. In inoperable HNSCC, RADPLAT is often the only option available to achieve locoregional control.

RADPLAT may also be of benefit in the treatment of selected patients with resectable disease, with preservation of swallowing and speech following RADPLAT treatment demonstrating significant improvements in terms of patient QoL. However, careful patient selection is required in order to minimize the problems associated with salvage surgery after chemoradiation.

Future refinements to the RADPLAT protocol may involve altered radiation fractionation [76] or the addition of a systemic therapy component in order to target occult distant metastases [40]. Current phase II data are encouraging, and new applications for RADPLAT continue to emerge. However, phase III randomized controlled trials are required in order to directly compare RADPLAT with i.v. chemoradiation therapy, the current standard of care [46, 77]. The first results of such a trial in The Netherlands are expected at the end of this year. It can be concluded that RADPLAT is a viable alternative to surgery, but careful selection of suitable patients is of utmost importance.

	DISCLOSURE OF POTENTIAL CONFLICTS OF INTEREST

Top Abstract Evolution of Treatment for... Technique Study Outcomes Control of Nodal Disease RADPLAT in Other Centers Toxicity Predictors of Success Organ Preservation and Quality... Detection of Recurrence after... Surgery After Chemoradiation... Further Applications of the... Conclusions Disclosure of Potential... References

 
The authors indicate no potential conflicts of interest.

	REFERENCES

Top Abstract Evolution of Treatment for... Technique Study Outcomes Control of Nodal Disease RADPLAT in Other Centers Toxicity Predictors of Success Organ Preservation and Quality... Detection of Recurrence after... Surgery After Chemoradiation... Further Applications of the... Conclusions Disclosure of Potential... References

 

1. Marcial VA, Pajak TF. Radiation therapy alone or in combination with surgery in head and neck cancer. Cancer 1985;55:2259–2265.[CrossRef][Medline]
2. Laramore GE, Scott CB, al-Sarraf M et al. Adjuvant chemotherapy for resectable squamous cell carcinomas of the head and neck: report on Intergroup Study 0034. Int J Radiat Oncol Biol Phys 1992;23:705–713.[Medline]
3. Hart AA, Mak-Kregar S, Hilgers FJ et al. The importance of correct stage grouping in oncology. Results of a nationwide study of oropharyngeal carcinoma in The Netherlands. Cancer 1995;75:2656–2662.[CrossRef][Medline]
4. Robertson AG, Soutar DS, Paul J et al. Early closure of a randomized trial: surgery and postoperative radiotherapy versus radiotherapy in the management of intra-oral tumours. Clin Oncol (R Coll Radiol) 1998;10: 155–160.
5. Rooney M, Kish J, Jacobs J et al. Improved complete response rate and survival in advanced head and neck cancer after three-course induction therapy with 120-hour 5-FU infusion and cisplatin. Cancer 1985;55: 1123–1128.[CrossRef][Medline]
6. Dreyfuss AI, Clark JR, Wright JE et al. Continuous infusion high-dose leucovorin with 5-fluorouracil and cisplatin for untreated stage IV carcinoma of the head and neck. Ann Intern Med 1990;112:167–172.[Abstract/Free Full Text]
7. Robbins KT, Hoffman RM. "Decadose" effects of cisplatin on squamous cell carcinoma of the upper aerodigestive tract. I. Histoculture experiments. Laryngoscope 1996;106:32–36.[CrossRef][Medline]
8. Robbins KT, Storniolo AM, Hryniuk WM et al. "Decadose" effects of cisplatin on squamous cell carcinoma of the upper aerodigestive tract. II. Clinical studies. Laryngoscope 1996;106:37–42.[CrossRef][Medline]
9. El-Sayed S, Nelson N. Adjuvant and adjunctive chemotherapy in the management of squamous cell carcinoma of the head and neck region. A meta-analysis of prospective and randomized trials. J Clin Oncol 1996;14:838–847.[Abstract/Free Full Text]
10. Pignon JP, Bourhis J, Domenge C et al. Chemotherapy added to locoregional treatment for head and neck squamous-cell carcinoma: three meta-analyses of updated individual data. MACH-NC Collaborative Group. Meta-Analysis of Chemotherapy on Head and Neck Cancer. Lancet 2000;355:949–955.[Medline]
11. Bernier J, Domenge C, Ozsahin M et al. Postoperative irradiation with or without concomitant chemotherapy for locally advanced head and neck cancer. N Engl J Med 2004;350:1945–1952.[Abstract/Free Full Text]
12. Induction chemotherapy plus radiation compared with surgery plus radiation in patients with advanced laryngeal cancer. The Department of Veterans Affairs Laryngeal Cancer Study Group. N Engl J Med 1991;324: 1685–1690.[Abstract]
13. Zak M, Drobnik J. Effect of cis-dichlorodiamine platinum (II) on the post-irradiation lethality in mice after irradiation with X-rays. Strahlentherapie 1971;142:112–115.[Medline]
14. Murthy AK, Taylor SG 4th, Showel J et al. Treatment of advanced head and neck cancer with concomitant radiation and chemotherapy. Int J Radiat Oncol Biol Phys 1987;13:1807–1813.[Medline]
15. Marcial VA, Pajak TF, Mohiuddin M et al. Concomitant cisplatin chemotherapy and radiotherapy in advanced mucosal squamous cell carcinoma of the head and neck. Long-term results of the Radiation Therapy Oncology Group study 81-17. Cancer 1990;66:1861–1868.[CrossRef][Medline]
16. Al-Sarraf M, Pajak TF, Marcial VA et al. Concurrent radiotherapy and chemotherapy with cisplatin in inoperable squamous cell carcinoma of the head and neck. An RTOG Study. Cancer 1987;59:259–265.[CrossRef][Medline]
17. Taylor SG 4th, Murthy AK, Caldarelli DD et al. Combined simultaneous cisplatin/fluorouracil chemotherapy and split course radiation in head and neck cancer. J Clin Oncol 1989;7:846–856.[Abstract]
18. Adelstein DJ, Sharan VM, Earle AS et al. Long-term results after chemo-radiotherapy for locally confined squamous-cell head and neck cancer. Am J Clin Oncol 1990;13:440–447.[Medline]
19. al-Sarraf M, Pajak TF, Cooper JS et al. Chemo-radiotherapy in patients with locally advanced nasopharyngeal carcinoma: a Radiation Therapy Oncology Group study. J Clin Oncol 1990;8:1342–1351.[Abstract]
20. Malhotra H, Plosker GL. Cisplatin/epinephrine injectable gel. Drugs Aging 2001;18:787–793; discussion 794–785.[CrossRef][Medline]
21. Andrews PA, Murphy MP, Howell SB. Characterization of cisplatin-resistant COLO 316 human ovarian carcinoma cells. Eur J Cancer Clin Oncol 1989;25:619–625.[CrossRef][Medline]
22. Andrews PA, Jones JA, Varki NM et al. Rapid emergence of acquired cis-diamminedichloroplatinum(II) resistance in an in vivo model of human ovarian carcinoma. Cancer Commun 1990;2:93–100.[Medline]
23. Vokes EE, Weichselbaum RR. Concomitant chemoradiotherapy: rationale and clinical experience in patients with solid tumors. J Clin Oncol 1990;8:911–934.[Abstract]
24. Burian M, Formanek M, Regele H. Electroporation therapy in head and neck cancer. Acta Otolaryngol 2003;123:264–268.[CrossRef][Medline]
25. Klopp CT, Smith DF, Alford TC. Palliation achieved in carcinoma of the head and neck with intra-arterial chemotherapy. Am J Surg 1961;102: 830–834.[CrossRef][Medline]
26. Sullivan RD. Continuous intra-arterial infusion chemotherapy of head and neck cancer. Trans Am Acad Ophthalmol Otolaryngol 1962;66: 111–117.[Medline]
27. Lee YY, Dimery IW, Van Tassel P et al. Superselective intra-arterial chemotherapy of advanced paranasal sinus tumors. Arch Otolaryngol Head Neck Surg 1989;115:503–511.[Abstract/Free Full Text]
28. Forastiere AA, Baker SR, Wheeler R et al. Intra-arterial cisplatin and FUDR in advanced malignancies confined to the head and neck. J Clin Oncol 1987;5:1601–1606.[Abstract/Free Full Text]
29. Cheung DK, Regan J, Savin M et al. A pilot study of intraarterial chemotherapy with cisplatin in locally advanced head and neck cancers. Cancer 1988;61:903–908.[CrossRef][Medline]
30. Mortimer JE, Taylor ME, Schulman S et al. Feasibility and efficacy of weekly intraarterial cisplatin in locally advanced (stage III and IV) head and neck cancers. J Clin Oncol 1988;6:969–975.[Abstract/Free Full Text]
31. Frustaci S, Barzan L, Caruso G et al. Induction intra-arterial cisplatin and bleomycin in head and neck cancer. Head Neck 1991;13:291–297.[Medline]
32. Eckman WW, Patlak CS, Fenstermacher JD. A critical evaluation of the principles governing the advantages of intra-arterial infusions. J Pharma-cokinet Biopharm 1974;2:257–285.[CrossRef][Medline]
33. Elferink F, van der Vijgh WJ, Klein I et al. Interaction of cisplatin and carboplatin with sodium thiosulfate: reaction rates and protein binding. Clin Chem 1986;32:641–645.[Abstract/Free Full Text]
34. Kumar P, Robbins KT. Treatment of advanced head and neck cancer with intra-arterial cisplatin and concurrent radiation therapy: the ‘RADPLAT’ protocol. Curr Oncol Rep 2001;3:59–65.[Medline]
35. Howell SB, Taetle R. Effect of sodium thiosulfate on cis-dichlorodiammi neplatinum(II) toxicity and antitumor activity in L1210 leukemia. Cancer Treat Rep 1980;64:611–616.[Medline]
36. Robbins KT, Kumar P, Wong FS et al. Targeted chemoradiation for advanced head and neck cancer: analysis of 213 patients. Head Neck 2000;22:687–693.[CrossRef][Medline]
37. Robbins KT, Storniolo AM, Kerber C et al. Phase I study of highly selective supradose cisplatin infusions for advanced head and neck cancer. J Clin Oncol 1994;12:2113–2120.[Abstract/Free Full Text]
38. Robbins KT, Vicario D, Seagren S et al. A targeted supradose cisplatin chemoradiation protocol for advanced head and neck cancer. Am J Surg 1994;168:419–422.[CrossRef][Medline]
39. Robbins KT, Fontanesi J, Wong FS et al. A novel organ preservation protocol for advanced carcinoma of the larynx and pharynx. Arch Otolaryngol Head Neck Surg 1996;122:853–857.[Abstract/Free Full Text]
40. Robbins KT, Kumar P, Regine WF et al. Efficacy of targeted supradose cisplatin and concomitant radiation therapy for advanced head and neck cancer: the Memphis experience. Int J Radiat Oncol Biol Phys 1997;38:263–271.[CrossRef][Medline]
41. Adelstein DJ, Li Y, Adams GL et al. An intergroup phase III comparison of standard radiation therapy and two schedules of concurrent chemoradiotherapy in patients with unresectable squamous cell head and neck cancer. J Clin Oncol 2003;21:92–98.[Abstract/Free Full Text]
42. Calais G, Bardet E, Sire C et al. Radiotherapy with concomitant weekly docetaxel for stages III/IV oropharynx carcinoma. Results of the 98-02 GORTEC phase II trial. Int J Radiat Oncol Biol Phys 2004;58:161–166.[CrossRef][Medline]
43. Robbins KT, Wong FS, Kumar P et al. Efficacy of targeted chemoradiation and planned selective neck dissection to control bulky nodal disease in advanced head and neck cancer. Arch Otolaryngol Head Neck Surg 1999;125:670–675.[Abstract/Free Full Text]
44. Ahmed KA, Robbins KT, Wong F et al. Efficacy of concomitant chemoradiation and surgical salvage for N3 nodal disease associated with upper aerodigestive tract carcinoma. Laryngoscope 2000;110:1789–1793.[CrossRef][Medline]
45. Balm AJ, Rasch CR, Schornagel JH et al. High-dose superselective intra-arterial cisplatin and concomitant radiation (RADPLAT) for advanced head and neck cancer. Head Neck 2004;26:485–493.[CrossRef][Medline]
46. Robbins KT, Kumar P, Harris J et al. Supradose intra-arterial cisplatin and concurrent radiation therapy for the treatment of stage IV head and neck squamous cell carcinoma is feasible and efficacious in a multi-institutional setting: results of Radiation Therapy Oncology Group Trial 9615. J Clin Oncol 2005;23:1447–1454.[Abstract/Free Full Text]
47. Sullivan CA, Jaklitsch MT, Haddad R et al. Endoscopic management of hypopharyngeal stenosis after organ sparing therapy for head and neck cancer. Laryngoscope 2004;114:1924–1931.[CrossRef][Medline]
48. Gemmete JJ. Complications associated with selective high-dose intraarterial cisplatin and concomitant radiation therapy for advanced head and neck cancer. J Vasc Interv Radiol 2003;14:743–748.[Medline]
49. Garden AS, Glisson BS, Ang KK et al. Phase I/II trial of radiation with chemotherapy "boost" for advanced squamous cell carcinomas of the head and neck: toxicities and responses. J Clin Oncol 1999;17:2390–2395.[Abstract/Free Full Text]
50. Rosen F, Vokes EE, Lad T et al. Phase II study of amonafide in the treatment of patients with advanced squamous cell carcinoma of the head and the neck. An Illinois Cancer Center study. Invest New Drugs 1995;13: 249–252.[CrossRef][Medline]
51. Laurell G, Jungnelius U. High-dose cisplatin treatment: hearing loss and plasma concentrations. Laryngoscope 1990;100:724–734.[Medline]
52. Madasu R, Ruckenstein MJ, Leake F et al. Ototoxic effects of supradose cisplatin with sodium thiosulfate neutralization in patients with head and neck cancer. Arch Otolaryngol Head Neck Surg 1997;123:978–981.[Abstract/Free Full Text]
53. Robbins KT, Doweck I, Samant S et al. Factors predictive of local disease control after intra-arterial concomitant chemoradiation (RADPLAT). Laryngoscope 2004;114:411–417.[CrossRef][Medline]
54. Doweck I, Denys D, Robbins KT. Tumor volume predicts outcome for advanced head and neck cancer treated with targeted chemoradiotherapy. Laryngoscope 2002;112:1742–1749.[CrossRef][Medline]
55. Galmarini FC, Galmarini CM, Sarchi MI et al. Heterogeneous distribution of tumor blood supply affects the response to chemotherapy in patients with head and neck cancer. Microcirculation 2000;7:405–410.[CrossRef][Medline]
56. Doweck I, Robbins KT, Vieira F. Analysis of risk factors predictive of distant failure after targeted chemoradiation for advanced head and neck cancer. Arch Otolaryngol Head Neck Surg 2001;127:1315–1318.[Abstract/Free Full Text]
57. van den Broek GB, Rasch CR, Pameijer FA et al. Pretreatment probability model for predicting outcome after intraarterial chemoradiation for advanced head and neck carcinoma. Cancer 2004;101:1809–1817.[CrossRef][Medline]
58. Lazarus CL, Logemann JA, Pauloski BR et al. Swallowing disorders in head and neck cancer patients treated with radiotherapy and adjuvant chemotherapy. Laryngoscope 1996;106:1157–1166.[CrossRef][Medline]
59. Staton J, Robbins KT, Newman L et al. Factors predictive of poor functional outcome after chemoradiation for advanced laryngeal cancer. Otolaryngol Head Neck Surg 2002;127:43–47.[CrossRef][Medline]
60. Newman LA, Vieira F, Schwiezer V et al. Eating and weight changes following chemoradiation therapy for advanced head and neck cancer. Arch Otolaryngol Head Neck Surg 1998;124:589–592.[Abstract/Free Full Text]
61. Johnston CA, Keane TJ, Prudo SM. Weight loss in patients receiving radical radiation therapy for head and neck cancer: a prospective study. JPEN J Parenter Enteral Nutr 1982;6:399–402.[Abstract/Free Full Text]
62. Murry T, Madasu R, Martin A et al. Acute and chronic changes in swallowing and quality of life following intraarterial chemoradiation for organ preservation in patients with advanced head and neck cancer. Head Neck 1998;20:31–37.[CrossRef][Medline]
63. Ackerstaff AH, Tan IB, Rasch CR et al. Quality-of-life assessment after supradose selective intra-arterial cisplatin and concomitant radiation (RADPLAT) for inoperable stage IV head and neck squamous cell carcinoma. Arch Otolaryngol Head Neck Surg 2002;128:1185–1190.[Abstract/Free Full Text]
64. Wong RJ, Lin DT, Schoder H et al. Diagnostic and prognostic value of [(18)F] fluorodeoxyglucose positron emission tomography for recurrent head and neck squamous cell carcinoma. J Clin Oncol 2002;20:4199–4208.[Abstract/Free Full Text]
65. Kubota K, Yokoyama J, Yamaguchi K et al. FDG-PET delayed imaging for the detection of head and neck cancer recurrence after radio-chemotherapy: comparison with MRI/CT. Eur J Nucl Med Mol Imaging 2004;31:590–595.[CrossRef][Medline]
66. Agra IM, Carvalho AL, Pontes E et al. Postoperative complications after en bloc salvage surgery for head and neck cancer. Arch Otolaryngol Head Neck Surg 2003;129:1317–1321.[Abstract/Free Full Text]
67. Sassler AM, Esclamado RM, Wolf GT. Surgery after organ preservation therapy. Analysis of wound complications. Arch Otolaryngol Head Neck Surg 1995;121:162–165.[Abstract/Free Full Text]
68. Ganly I, Patel S, Matsuo J et al. Postoperative complications of salvage total laryngectomy. Cancer 2005;103:2073–2081.[CrossRef][Medline]
69. Leon X, Quer M, Orus C et al. Results of salvage surgery for local or regional recurrence after larynx preservation with induction chemotherapy and radiotherapy. Head Neck 2001;23:733–738.[CrossRef][Medline]
70. Kutler DI, Patel SG, Shah JP. The role of neck dissection following definitive chemoradiation. Oncology (Williston Park) 2004;18:993–998; discussion 999, 1003–1004, 1007.
71. Robbins KT, Ferlito A, Suarez C et al. Is there a role for selective neck dissection after chemoradiation for head and neck cancer? J Am Coll Surg 2004;199:913–916.[CrossRef][Medline]
72. McHam SA, Adelstein DJ, Rybicki LA et al. Who merits a neck dissection after definitive chemoradiotherapy for N2–N3 squamous cell head and neck cancer? Head Neck 2003;25:791–798.[CrossRef][Medline]
73. Samant S, Robbins KT, Kumar P et al. Bone or cartilage invasion by advanced head and neck cancer: intra-arterial supradose cisplatin chemotherapy and concomitant radiotherapy for organ preservation. Arch Otolaryngol Head Neck Surg 2001;127:1451–1456.[Abstract/Free Full Text]
74. Robbins KT, Samant S, Vieira F et al. Presurgical cytoreduction of oral cancer using intra-arterial cisplatin and limited concomitant radiation therapy (Neo-RADPLAT). Arch Otolaryngol Head Neck Surg 2004;130:28–32.[Abstract/Free Full Text]
75. Madison ML 2nd, Sorenson JM, Samant S et al. The treatment of advanced sinonasal malignancies with pre-operative intra-arterial cisplatin and concurrent radiation. J Neurooncol 2005;72:67–75.[CrossRef][Medline]
76. Eisbruch A, Marsh LH, Martel MK et al. Comprehensive irradiation of head and neck cancer using conformal multisegmental fields: assessment of target coverage and noninvolved tissue sparing. Int J Radiat Oncol Biol Phys 1998;41:559–568.[CrossRef][Medline]
77. Robbins KT. The evolving role of combined modality therapy in head and neck cancer. Arch Otolaryngol Head Neck Surg 2000;126:265–269.[Free Full Text]
78. Fountzilas G, Skarlos D, Kosmidis P et al. Radiation therapy and concurrent cisplatin administration in locally advanced head and neck cancer. A Hellenic Co-operative Oncology Group study. Acta Oncol 1994;33: 825–830.[Medline]
79. Huguenin P, Beer KT, Allal A et al. Concomitant cisplatin significantly improves locoregional control in advanced head and neck cancers treated with hyperfractionated radiotherapy. J Clin Oncol 2004;22:4665–4673.[Abstract/Free Full Text]
80. Jeremic B, Shibamoto Y, Milicic B et al. Hyperfractionated radiation therapy with or without concurrent low-dose daily cisplatin in locally advanced squamous cell carcinoma of the head and neck: a prospective randomized trial. J Clin Oncol 2000;18:1458–1464.[Abstract/Free Full Text]
81. Cooper JS, Pajak TF, Forastiere AA et al. Postoperative concurrent radiotherapy and chemotherapy for high-risk squamous-cell carcinoma of the head and neck. N Engl J Med 2004;350:1937–1944.[Abstract/Free Full Text]

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