• cisplatin;
  • outcomes;
  • radiotherapy;
  • head and neck cancer


  1. Top of page
  2. Abstract
  6. Conclusions


Both concomitant chemotherapy and altered fractionation radiotherapy (RT) have been shown to improve outcomes for patients with locoregionally advanced head and neck squamous cell carcinomas. However, both strategies also increase acute toxicity, and it is questionable whether the 2 can be safely combined. Traditional concomitant chemotherapy regimens include high-dose cisplatin given at 100 mg/m2 every 3 weeks. The authors' purpose was to report efficacy and toxicity after weekly cisplatin (30 mg/m2/wk) concurrent with altered fractionation RT.


One hundred twenty-one patients with American Joint Committee on Cancer stages II (3%), III (13%), or IV (84%) squamous cell carcinomas of the oropharynx (70%), hypopharynx (20%), or larynx (10%) were treated between 2000 and 2006 at the University of Florida with hyperfractionated RT (55 patients) or concomitant boost RT (66 patients) and concomitant cisplatin (30 mg/m2/wk).


Median follow-up was 2.9 years; median follow-up on survivors was 3.6 years. Seventy-nine percent of patients completed ≥6 cycles of chemotherapy; 94% received ≥7200 centigrays. Seven (6%) patients changed from cisplatin to carboplatin because of bone marrow toxicity. Gastrostomy tube feeding was required in 54% of patients either before (16%) or during RT (38%). Two (1.6%) patients died from therapy-related complications. The 5-year outcomes were: local control, 83%; locoregional control, 79%; distant metastasis-free survival, 88%; cause-specific survival, 76%; and overall survival, 59%. Seven (6%) patients had severe late complications. Three (3%) patients required a permanent gastrostomy tube.


Concomitant weekly cisplatin with altered fractionation RT is a safe and effective treatment regimen. Cancer 2010. © 2010 American Cancer Society.

Locoregional control and overall survival have improved for patients with locoregionally advanced head and neck cancers because of advancements in the delivery of radiotherapy (RT) and concomitant chemotherapy. Meta-analyses have shown that concomitant chemotherapy and RT improve outcomes compared with RT alone, maintenance chemotherapy, or historical regimens of induction chemotherapy.1-3 In addition, recent randomized trials have shown an advantage of altered fractionation over conventional once daily RT.3-6 The 2 regimens resulting in improved outcomes are hyperfractionated RT and concomitant boost RT, as demonstrated in the Radiation Therapy Oncology Group (RTOG) 90-03 trial.5 Yet whether altered fractionation can be successfully combined with concomitant chemotherapy to improve the therapeutic ratio without undue increased toxicity remains unknown.

Cisplatin is commonly used in the treatment of squamous cell carcinomas of the head and neck. It is synergistic when combined with RT. The most widely tested regimen for single-agent cisplatin in this population is 100 mg/m2 once every 3 weeks for 2 to 3 cycles.7-9 This high-dose regimen has been associated with grade 3-4 mucosal and hematologic toxicity exceeding 40% and sometimes requires RT treatment breaks or cessation of chemotherapy. Data suggest that treatment breaks are associated with reduced disease control, and some physicians have sought alternatives to the high-dose cisplatin regimen.10-12

Although the cumulative cisplatin dose remains unaltered at approximately 210 mg/m2, lower and radiosensitizing doses of cisplatin may minimize its toxicity. Daily doses of cisplatin at 6 mg/m2 concurrent with RT have been evaluated with success in Europe.12 Weekly doses of cisplatin are used with success in cervical cancer, but have not been tested prospectively for head and neck cancer.13 At the University of Florida, we used weekly cisplatin at 30 mg/m2/wk concurrent with altered fractionation RT (either hyperfractionation or the concomitant boost technique) in an attempt to reduce the mucosal, hematologic, and renal toxicities of concomitant chemotherapy while maintaining its therapeutic effect. Herein we report our experience with this treatment plan.


  1. Top of page
  2. Abstract
  6. Conclusions

We retrospectively identified 121 consecutive patients with previously untreated squamous cell carcinomas of the head and neck curatively treated at the University of Florida with weekly cisplatin and concomitant RT between 2000 and 2006. Patients treated with definitive RT at our institution for stage III to IV head and neck squamous cell carcinomas are almost always treated with altered fractionation and concomitant weekly cisplatin, so that this represents a relatively unselected series. Only patients with oropharyngeal (70%), hypopharyngeal (20%), and laryngeal (10%) primaries were included. A prophylactic gastrostomy tube was placed in 19 (16%) patients before they started treatment. Patients were staged according to the 2002 American Joint Committee on Cancer staging system.14 Table 1 shows patient and tumor characteristics.

Table 1. Patient Characteristics
CharacteristicsNo. of Patients
Men104 (86%)
Women17 (14%)
Age, y57 (range, 25-81)
Follow-up, y 
 Overall2.7 (range, 0.1-7.9)
 Living patients3.6 (range, 1.1-7.9)
T classification 
 T117 (14%)
 T235 (29%)
 T334 (28%)
 T4a32 (26%)
 T4b3 (3%)
Overall stage 
 II3 (3%)
 III16 (13%)
 IV102 (84%)
Treatment sites 
 Oropharynx85 (70%)
 Hypopharynx24 (20%)
 Larynx12 (10%)


Sixty-six (55%) patients were treated with concomitant boost RT (7200 centigrays [cGy] in 42 fractions over 6 weeks), and 55 (45%) patients were treated twice daily (median 7440 cGy/62 fractions over 6.5 weeks). Eighteen (33%) of 55 patients treated with hyperfractionation received >74.4 Gy. During each cisplatin administration, patients received 1 L of saline and 10 to 20 potassium chloride before and after the cisplatin, which was administered in 500 mL to 1 L of saline. Patients also usually received 20 mg of furosemide (Lasix). Table 2 shows the treatment details. Intensity-modulated RT (IMRT) is used in lieu of conventional techniques in the treatment of head and neck cancer at the University of Florida if: 1) the target delineation requires a concave isodose distribution to spare a critical structure; 2) salivary preservation is an option in cases of unilateral adenopathy where we need to treat the retrostyloid nodes on the ipsilateral side of the tumor, but can avoid the contralateral retrostyloid nodes and thus spare the parotid; and 3) the primary tumor extends inferiorly below the level of the shoulders, and we need to avoid the shoulders to adequately irradiate the tumor.15 When IMRT is used, we prefer the concomitant boost treatment schedule for logistical purposes. The standard risk planning target volume (PTV) included areas at risk for subclinical disease and gross disease; the subclinical disease received 49.5 Gy at 1.65 Gy per fraction, and the gross disease received 54 Gy at 1.8 Gy per fraction. On treatment Days 19 through 30, the high-risk PTV containing the gross disease received 18 Gy at 1.5 Gy per fraction as a concomitant boost with a minimum 6-hour interfraction interval. Hyperfractionation was used with 1.2 Gy per twice-daily fraction with a minimum 6-hour interfraction interval for patients treated with conventional RT. The final dose was usually 74.4 Gy at 62 twice-daily fractions; 18 patients received >74.4 Gy. This schedule has been used at our institution since 1978.

Table 2. Radiotherapy Characteristics
CharacteristicNo. of Patients
  1. cGy indicates centigrays.

Median total dose7200 cGy (range, 5280-7680)
Patients who received ≥7200 cGy117 (97%)
 Twice daily55 (45%)
 Concomitant boost66 (55%)
 Conventional55 (45%)
 Intensity-modulated radiotherapy66 (55%)


Intravenous cisplatin was administered at a weekly dose of 30 mg/m2 for all 121 patients. Three patients received 20 mg/m2/wk because of medical comorbidities at the discretion of the medical oncologist. Weekly cisplatin began the first week of RT and continued weekly, typically for 6 to 6.5 weeks. In the case of grade 3-4 hematologic or mucosal toxicity, cisplatin is withheld with the specific intent of not interrupting RT.

Post-Treatment Assessment

Patients are formally evaluated by computed tomography (CT) and physical examination 4 weeks after completing treatment. Neck dissection is recommended if there is palpable residual lymphadenopathy, if cervical nodes measure >1.5 cm in the axial dimension, or if filling defects are present on a contrast-enhanced CT scan.16 If indicated, dissection is performed 6 weeks after completing chemoradiotherapy. Patients are then followed every 4 to 8 weeks during the first year, every 2 to 4 months for an additional 2 years, biannually until 5 years, and annually thereafter. Gastrostomy tubes are removed when patients are able to maintain their weight without the tube.

Median follow-up for all patients was 2.7 years (range, 0.1-7.9 years); median follow-up on survivors was 3.6 years (range, 1.1-7.9 years).

Statistical Evaluation

All statistical analyses were performed with SAS and JMP software (SAS Institute, Cary, NC). The Kaplan-Meier product-limit method provided estimates of selected endpoints.17 For each endpoint, the log-rank test statistic provided an analysis of the prognostic significance of: T classification (T1-T2 vs T3-T4), overall stage (II-III vs IV), tumor site (larynx vs oropharynx vs hypopharynx), cycles of chemotherapy (< vs ≥6 cycles), and fractionation schedule (hyperfractionation vs concomitant boost). With the exception of fractionation schedule, these same prognostic factors were assessed in the multivariate analyses using Cox regression; a backward selection provided the most parsimonious final predictive model.18


  1. Top of page
  2. Abstract
  6. Conclusions

Ninety-seven (80%) patients were able to complete at least 6 cycles of weekly chemotherapy. Seven patients required a switch from cisplatin to carboplatin; 6 completed at least 6 cycles of chemotherapy. Reasons that patients did not complete the prescribed chemotherapy included: hematologic toxicity, 85%; nausea and vomiting, 8%; and 1 patient each with poor venous access and request to discontinue chemotherapy. There were no grade 3-4 renal toxicities.

One-hundred seventeen (97%) patients received ≥7200 cGy. Seventeen (14%) patients had RT treatment delay complications, most of which lasted 1 or 2 days (57%). The longest treatment delay was a 7-day treatment break because of admission to an outside hospital.

Grade 3 acute toxicities based on the RTOG Acute Radiation Morbidity Scoring Criteria were: anemia, 7 (6%) patients; thrombocytopenia, 3 (2%) patients; leucopenia, 33 (27%) patients; and >15% weight loss, 41 (34%) patients. The overall gastrostomy tube rate was 54%; 16% were planned before treatment, and 38% were required during the course of treatment.

Three patients experienced fatal toxicities. Two died before completing their treatment secondary to complications of bowel perforation with fatal peritonitis. The first had confirmed Clostridium difficile colitis before perforation, and the second had spontaneous bowel perforation and could not tolerate a surgical procedure secondary to thrombocytopenia. The third patient developed laryngeal necrosis, which responded poorly to conservative measures, including steroids and hyperbaric oxygen. He received 7200 cGy with the concomitant boost schedule and 6 cycles of weekly cisplatin followed 1 month later by a unilateral neck dissection. A tracheostomy was performed 7 months after completing chemoradiotherapy. A wound dehiscence developed followed by carotid artery blowout 1 month after tracheostomy and 8 months after completing chemoradiotherapy.

Indications for post-treatment neck dissection are discussed above. On the basis of these indications, 52 (43%) patients had a neck dissection; 45 were unilateral, and 7 were bilateral. Forty-two (81%) of 52 heminecks had no evidence of cancer on pathologic review. Of the patients with bilateral neck dissections, 2 had positive lymph nodes (positive unilaterally, 1 patient; positive bilaterally, 2 patients). Of the patients who had a neck dissection, 90% remained regionally controlled, and only 2 later failed in the neck.

The 5-year outcomes were: local control, 83%; locoregional control, 79%; distant metastasis-free survival, 88%; cause-specific survival, 76%; and overall survival, 59% (Figs. 1 and 2). Multivariate analyses of outcomes are depicted in Table 3. The only parameter that significantly influenced outcome was T classification.

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Figure 1. Survival at 5 years is shown.

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Figure 2. Locoregional control and distant metastasis-free survival at 5 years are shown.

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Table 3. Multivariate Analysis Endpoint P Values
VariableLocal ControlLocal Regional ControlDistant Metastasis-Free SurvivalCause-Specific SurvivalOverall Survival
T classification.0280.0400.4131.0172.0090
Overall stage.5968.9166.3816.1499.2639
Tumor site.4830.6260.2776.4668.0433
Cycles of chemotherapy.1865.2740.4794.7831.4740
Fractionation schedule.9043.7516.8799.1914.2968

Late toxicity was graded according to the Common Terminology Criteria for Adverse Events v 3.0 scale.19 Overall, 6% of patients had a grade 4 late complication of soft tissue, cartilage, or bone requiring surgical repair or hyperbaric oxygen. One patient developed external auditory canal stenosis with bone exposure requiring surgical repair with a split thickness skin grafting. After neck dissection, 1 patient had a wound dehiscence with necrosis and was effectively treated with hyperbaric oxygen and surgical repair. Five others also developed necrosis: 2 oropharyngeal mucosal necrosis, 2 laryngeal cartilage necrosis, and 1 clavicular head necrosis. Treatments included hyperbaric oxygen and/or surgical resection of necrotic tissue. Three of the patients with necrosis received >7600 cGy, given by hyperfractionation. The patient with clavicular head necrosis received 5000 cGy to the lower neck, given as 200 cGy per fraction once daily with a single anterior-posterior low anterior neck field. He received a right neck dissection at 6 weeks, which was negative. He continued to smoke cigarettes and cigars after treatment. The necrosis was surgically excised 1 year after completing chemoradiotherapy; he did not have further complications with treatment.

Three patients required a permanent gastrostomy tube that was present >1 year after treatment.


  1. Top of page
  2. Abstract
  6. Conclusions

The ideal treatment for patients with locoregionally advanced squamous cell carcinoma of the head and neck remains unknown. Several lessons have been learned from 50 years of prospective randomized trials and multiple recent meta-analyses. Table 4 compares our outcomes to 3 other trials of altered fractionation and concomitant cisplatin chemotherapy.

Table 4. Comparison of Treatment Outcomes
Jeremic et al20 (5-year follow-up)RTOG-991422 (4-year follow-up)RTOG-012923University of Florida (5-year outcomes)
Chemoradiotherapy regimen6 mg/m2/d HFX and 77 Gy100 mg/m2 × 2 cycles CB and 72 Gy30 mg/m2/wk CB or HFX and ∼72-76 Gy
  • HFX indicates hyperfractionated radiotherapy; Gy, grays; CB, concomitant boost radiotherapy; NR, not reported; G-tube, gastrostomy tube; a/w, associated with.

  • a

    Includes grade 3 toxicity.

Local-regional control58%64%NR79%
Disease-free survival50%48.5%NR76%
Overall survival46%54%NR59%
Distant metastases13%21%NR12%
G-tube rate at end of treatmentNR83%68%54%
G-tube rate at 1 yearNR41%30%3%
Grade 4 late complications11%15.5%20%a6%
Death a/w treatment, <30 days03.9%3%2%
Death a/w treatment, >30 days01%1%

Altered Fractionation

The rationale for altered fractionation is based on the dissociation between acute and late effects. The goal is to improve the likelihood of a cure and decrease the probability of a late complication. Pure hyperfractionated RT consists of multiple, small (1.1-1.3 Gy) daily fractions to achieve a greater total dose within the same time as conventionally fractionated RT. Accelerated RT consists of multiple, daily fractions using the same dose per fraction, to achieve an equivalent dose within a shorter treatment time. In practice, most altered fractionation schedules are a hybrid of hyperfractionation and accelerated fractionation.

The landmark RTOG 90-03 study randomized patients to hyperfractionated RT (HFX, 81.6 Gy at 1.2 Gy per twice-daily fraction over 7 weeks), accelerated split-course RT (67.2 Gy at 1.6 Gy per twice-daily fraction over 6 weeks), accelerated concomitant boost RT (72 Gy at 1.8-1.5 Gy per fraction over 6 weeks with twice-daily RT given over the last 12 treatment days), or standard RT (70 Gy in 35 once-daily fractions over 7 weeks).5 Patients treated with HFX and accelerated concomitant boost RT had significantly better locoregional control and disease-free survival rates compared with those treated with standard RT. Disease-free survival rates at 5 years were 21%, 30.7%, and 28.9% for standard RT, HFX, and accelerated concomitant boost RT, respectively. There was a trend toward improved overall survival for the HFX arm (37.1% vs 29.5%; P = .063). All 3 altered fractionation schedules resulted in increased acute toxicity compared with standard RT. There was a trend toward increased late effects after accelerated concomitant boost RT compared with standard RT (33.3% vs 25.2%; P = .066). The rates of late effects for HFX (27.4%) and accelerated split-course RT (26.8%) were similar to those observed in the control arm. Because hyperfractionation is more costly and labor-intensive, the RTOG has recommended accelerated concomitant boost RT as the new standard in this patient population.

As discussed above, hyperfractionation and the concomitant boost technique are used with equal frequency at our institution. Fractionation is determined by whether IMRT will be used. In addition, we avoid using the concomitant boost schedule for lesions involving the skull base, such as the nasopharynx and paranasal sinuses, because of the increased risk of late complications observed in the RTOG-90-03 study. A previously published report discusses our experience with IMRT in head and neck cancer.15

Univariate analysis showed no difference regarding a relationship between fractionation and our control or survival outcome parameters. Likewise, late toxicities were distributed evenly between those who received hyperfractionation and the concomitant boost schedule. However, those patients treated with hyperfractionation who had a late complication were treated with 7680 cGy and ≥6 cycles of chemotherapy. No patient treated to 7440 cGy with hyperfractionation had a severe late complication. Thus, 7440 is our recommended dose for those treated with hyperfractionation and concomitant chemotherapy. This dose effect may explain the difference in toxicity seen between our review and the Jeremic study, which evaluated hyperfractionation to 7700 cGy with concurrent daily cisplatin.20 The standard arm in that study (hyperfractionation without chemotherapy) had a 6% rate of severe late complications.

Adjuvant Chemotherapy

Chemotherapy is administered with RT to improve locoregional control and survival in patients with stage III-IV advanced head and neck cancer. The MACH-NC meta-analysis of 63 randomized trials (10,741 patients) published between 1965 and 1993 revealed that adjuvant chemotherapy provided a 4% improvement (P < .0001) in 5-year overall survival.1 This benefit was limited to those who received concomitant chemotherapy (8%; P < .001) and was not observed in patients who received induction or maintenance chemotherapy. This report was criticized for its heterogeneity and was recently updated2 to include 24 new trials, 85% of which explore concomitant chemotherapy. The results were unchanged: 1) there was an 8% improvement in overall survival with concomitant chemotherapy; 2) maintenance and induction schedules did not offer a significant survival benefit; 3) all tumor sites benefited; 4) platinum-containing regimens showed the greatest benefit (an 11% 5-year overall survival advantage); and 5) there was no difference between poly- and monochemotherapy.

Budach and coworkers published a meta-analysis of modern chemotherapy regimens and curative intent RT doses (>60 Gy). The analysis included 32 trials (10,225 patients) published between 1975 and 2003.3 Their report showed an overall survival benefit of 12 months for chemotherapy concurrent with conventional or altered fractionation RT.

Recent RTOG studies (RTOG-9914 and -0129) evaluate 2 cycles of high-dose cisplatin, at a cumulative dose of 200 mg/m2, combined with concomitant boost RT.21, 22 The long-term outcomes of the phase 2 RTOG-9914 study were published, and a toxicity report is available for RTOG-0129. The results of RTOG-9914 show that 86% of patients completed the protocol treatment. The 4-year local control, disease-free survival, and overall survival were 64.4%, 48.5%, and 53.6%, respectively. There was a 21% incidence of distant metastases.

Nonstandard cisplatin regimens used to achieve the same cumulative dose (200 mg/m2) given at lower, radiosensitizing doses are intriguing. Jeremic and coworkers have performed 2 prospective trials showing an advantage for low-dose daily cisplatin (6 mg/m2) with RT compared with RT alone.12, 20 Their second study randomized patients to hyperfractionation (1.1 Gy twice daily to 77 Gy) with concurrent low-dose daily cisplatin versus hyperfractionation alone. The 5-year locoregional control rates were 58% versus 40% (P = .0013), and the overall survival rates were 46% versus 25% (P = .0075), for the chemoradiation arm and RT-alone arms, respectively. They note a 49% versus 42% incidence in all acute grade 3-4 toxicities and 12% versus 6% incidence of grade 3-4 late toxicities, respectively.

Concurrent Cisplatin and Altered Fractionation Radiotherapy

Weekly cisplatin, given 30 mg/m2/wk to a cumulative dose of 180 to 210 mg/m2 concurrent with RT, has not been prospectively tested in head and neck cancer, but has been used with success in other squamous cell carcinoma disease sites.13 In our report, treatment tolerability and overall efficacy compare favorably to both the Jeremic study of daily cisplatin with hyperfractionation as well as the RTOG-9914 and RTOG-0129 studies (see Table 4). Seventy-nine percent of our patients were able to complete the chemotherapy treatment course; 95% were able to receive >7200 cGy.

Improvements in treatment outcomes must be weighed against toxicity. Toxicities with weekly cisplatin are quite low. We observed no cases of grade 3-4 renal impairment. Ang et al reported a 12% rate of grade 3-4 renal impairment and 1 grade 5 renal-associated toxicity in patients treated with a high-dose cisplatin regimen.23 Leucopenia has been seen in all of the cisplatin dosing schedules.12, 20, 21, 23 With mucosal or hematologic toxicities, our preference is to continue RT and defer chemotherapy until its acute effects are appropriately resolved. An advantage to weekly administration is that it enables the chemotherapy to be discontinued if there is significant toxicity. Titrating chemotherapy to avoid a severe acute toxicity reduces the risk of a severe late complication.

With respect to toxicity evaluation and scoring, we are sensitive to the inherent observational bias of retrospective studies. However, if properly recorded, outcomes such as gastrostomy tube rate, surgical interventions, and utilization of hyperbaric oxygen may be useful in spotting trends associated with a treatment schedule. We have a low rate of gastrostomy tube placement at the end of treatment, and it is markedly lower at 1 year. IMRT was not allowed in the RTOG studies, whereas half of our patients were treated with IMRT. Success with swallowing rehabilitation may be associated with sparing of the pharyngeal constrictor muscles coincidental to contralateral parotid-sparing techniques. In addition, our institution is proactive with its swallow rehabilitation program, which is a planned component of each patient's treatment course, and coaches patients to have gastrostomy tubes removed in a timely manner.

Grade 4 toxicities in this report included soft-tissue, cartilage, and bone necrosis. An analysis by the RTOG reviewed factors associated with severe late toxicity after concurrent chemoradiation for head and neck cancer.24 They showed that significant correlates with the development of severe late toxicities are older age, advanced T classification, larynx/hypopharynx primary site, and neck dissection after chemoradiotherapy. The same factors are shared by patients who experienced late toxicities in our cohort. The most preventable among these was toxicity associated with neck dissection. As demonstrated above, 81% of our patients had no pathologic evidence of disease at the time of neck dissection, highlighting our excellent locoregional control rates and, more importantly, the need for diagnostic improvements to spare patients the potential morbidity associated with neck dissection. Most late toxicities observed are manageable, and most patients will accept the risks of toxicity for an improved chance at cure.


  1. Top of page
  2. Abstract
  6. Conclusions

Altered fractionation RT with concurrent weekly cisplatin is safe and effective in this patient population. We recommend concurrent weekly cisplatin (30 mg/m2) and altered fractionation RT. An RT dose >7440 cGy is associated with increased toxicity. A concomitant boost prescription (72 Gy/42 fractions/30 treatment days) is used with IMRT when the goal is salivary preservation or when the PTV extends below the level of the shoulders. Otherwise, hyperfractionation to 7440 cGy is recommended, given at 120 cGy twice daily. Patients whose medical comorbidities are a contraindication for cisplatin are evaluated for concurrent cetuximab or carboplatin. In the event of grade 3-4 toxicity, chemotherapy is postponed to avoid RT treatment breaks. Computed tomography (CT) is obtained 1 month post-RT to determine whether to add a planned neck dissection if the risk of residual regional disease is thought to exceed 5%. Patients suspected of harboring residual regional disease may be considered for positron emission tomography-CT 3 months post-RT to determine whether the planned neck dissection can be safely withheld.


  1. Top of page
  2. Abstract
  6. Conclusions
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    Pignon JP, Le Maitre A, Bourhis J. Meta-Analyses of Chemotherapy in Head and Neck Cancer (MACH-NC): an update. Int J Radiat Oncol Biol Phys. 2007; 69: S112-S114.
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    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.
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