M a x i m i z i n g L o c a l C o n t r o l a n d O r g a n P r e s e r v a t i o n i n S t a g e
I V S q u a m o u s C e l l H e a d a n d N e c k C a n c e r W i t h
H y p e r f r a c t i o n a t e d R a d i a t i o n a n d C o n c u r r e n t
C h e m o t h e r a p y
By David J. Adelstein, Jerrold P. Saxton, Pierre Lavertu, Lisa A. Rybicki, Ramon M. Esclamado, Benjamin G. Wood, Purpose: Results are reported from an aggressive
curred in 51%. Despite feeding tube placement in 35
chemoradiotherapy protocol for advanced squamous
patients (85%), the mean weight loss during chemora-
cell head and neck cancer.
diotherapy was 13.3% of initial body weight. One
Patients and Methods: Patients with advanced
patient died during treatment as a result of a pulmo-
squamous cell head and neck cancer were treated with
nary embolus. At a median follow-up period of 30
hyperfractionated radiation therapy (72 Gy at 1.2 Gy
months, the 3-year Kaplan-Meier projected overall sur-
twice per day) and two courses of concurrent chemo-
vival was 59%, disease-specific survival 69%, likeli-
therapy with fluorouracil (1,000 mg/m2/d) and cispla-
hood of local control without surgical resection 91%,
tin (20 mg/m2/d), both given as 96-hour continuous
and local control with surgical resection 97%. The like-
intravenous infusions during weeks 1 and 4 of radia-
lihood of distant disease control at 3 years was 74%,
tion therapy. Primary-site resection was reserved for
and distant metastases were present in eight of 13
residual or recurrent primary-site disease after chemo-
patients who died.
radiotherapy. Neck dissection was considered for N2
Conclusion: This chemoradiotherapy schedule pro-
or greater disease, irrespective of clinical response, and
duces considerable but manageable toxicity. Survival
for residual or recurrent neck disease after nonopera-
and organ preservation are excellent for this poor-
tive treatment.
prognosis patient cohort. Distant metastases are the
Results: Forty-one patients with stage IV disease
most common cause of treatment failure.
were treated. Toxicity was significant, with grade 3 to 4
J Clin Oncol 20:1405-1410. 2002 by American
mucositis in 98%, dysphagia in 88%, and skin reaction
Society of Clinical Oncology.
in 85%. Neutropenic fever requiring hospitalization oc-
THE PROGNOSIS for patients with stage IV squamous been examined with evidence of increased efficacy when cell head and neck cancer remains poor despite recent compared with conventional daily fractionation. Recent advances in multimodality management.1,2 Although pa- data from a large randomized Radiation Therapy Oncology tients may die as a result of distant metastatic disease, as a Group trial suggest that there is an improvement in both result of comorbid illness, or as a result of the development locoregional control and disease-free survival from several of a second primary neoplasm, the high frequency of local or regional recurrence poses the greatest threat.2,3 These These recent treatment innovations would be expected to locoregional failures highlight the inadequacy of even the most benefit patients with the most advanced locoregional most aggressive multimodality treatments.
disease. At the Cleveland Clinic Foundation, we explored During the past 20 years, systemic chemotherapy has an aggressive treatment protocol that used hyperfractionated been extensively tested in the management of this disease, radiation therapy with concurrent fluorouracil and cisplatin and many chemotherapeutic agents have been found to have chemotherapy as definitive treatment for patients with antineoplastic activity.1-3 The combination of fluorouracil advanced squamous cell carcinoma of the head and neck.
and cisplatin remains the best-studied and most active drugregimen.4-6 One advantage of this drug combination is thatboth agents are radiosensitizers,7,8 and attempts to exploit this From the Departments of Hematology and Medical Oncology, property have been successful. Several recent randomized Radiation Oncology, Otolaryngology and Communicative Disorders, phase III studies have convincingly demonstrated both a and Biostatistics, The Cleveland Clinic Foundation, Cleveland, OH. survival and locoregional control benefit for concurrent radia- Submitted June 29, 2001; accepted November 13, 2001. tion and chemotherapy regimens with fluorouracil, cisplatin, or Address reprint requests to David J. Adelstein, MD, Department of both when compared with radiation therapy alone.9-14 Hematology and Medical Oncology, Desk R35, The Cleveland ClinicFoundation, 9500 Euclid Ave, Cleveland, OH 44195; email: adelstd@ Altered fractionation radiation therapy is another ap- proach that has been studied in recent years in an effort to 2002 by American Society of Clinical Oncology. improve locoregional control.15-17 Several schedules have Journal of Clinical Oncology, Vol 20, No 5 (March 1), 2002: pp 1405-1410 with a full course of hyperfractionated radiation therapy, 1.2 Gy twicedaily to a total dose of 72 Gy in 6 weeks. Concurrently, two courses ofchemotherapy with 4-day continuous infusions of fluorouracil (1,000mg/m2/d) and cisplatin (20 mg/m2/d) were given during weeks 1 and 4of radiation therapy.
At the Cleveland Clinic Foundation, patients receiving this chemo- therapy regimen are hospitalized for hydration and antiemetic therapy.
No chemotherapy dose modifications were made, irrespective of nadirblood counts or the blood count at the time of treatment, although thesecond course of chemotherapy was delayed until recovery if aneutropenic fever had developed. Peripheral intravenous catheters wereused for drug administration. Megavoltage radiotherapy was generatedby a 6-MV linear accelerator. Opposed lateral fields generally wereused with an electron beam boost given to selected lymph node regions Fig 1. Treatment schema. 5FU, fluorouracil; DDP, cisplatin; RT, radiation
as indicated. There were no planned or toxicity-mandated breaks therapy; IV CI, continuous intravenous infusion.
scheduled during the administration of the radiation therapy, nor werethere any toxicity-mandated delays in the administration of the second We report our results in the subset of patients with the worst prognosis, those with stage IV disease, and assess end Patients were monitored at least weekly during their therapy in an effort to manage treatment-induced side effects, particularly mucositis points, including survival, locoregional control, and distant and myelosuppression. Neutropenia with fever resulted in mandatory metastatic disease control, in an effort to evaluate the effect hospitalization and appropriate antibiotic therapy. Hospitalization was also required when mucosal injury precluded an adequate oral intake.
Percutaneous endoscopic gastrostomy feeding tubes were placed as needed. Tracheostomies were performed in patients with significantly Eligibility for this clinical trial required a diagnosis of stage III or IV compromised airways, either at presentation or during the course of squamous cell carcinoma of the head and neck. Patients with primary sites in the nasopharynx, paranasal sinus, and salivary glands were excluded, as Between 6 and 12 weeks after completion of definitive chemoradio- were patients with metastatic disease involving neck but an unknown therapy, a formal response analysis was undertaken. This analysis primary site. Tumor and lymph node classifications were assigned accord- included an examination made while the patient was anesthetized ing to the 1992 staging system of the American Joint Committee on (when clinically appropriate) and biopsy of any abnormalities sugges- Cancer,19 and patients with hematogenous metastases (M1) disease were tive of disease. A complete response required the disappearance of all excluded. All patients were previously untreated and had an Eastern clinical, radiographic, and, if applicable, pathologic evidence of dis- Cooperative Oncology Group performance status of 0 or 1.
ease. Any response less than complete was considered to be a treatment Pretreatment evaluation in all patients included a medical history, an failure, and the patient underwent appropriate surgical resection if possible.
examination while the patient was anesthetized via panendoscopy, and Primary-site resection was reserved for patients with histologically a chest radiograph. Computed tomographic or magnetic resonance verified residual primary-site disease after completing chemoradiother- imaging scans of the involved head and neck region or other staging apy. Neck dissection was performed if clinical evidence of residual procedures for distant metastases were obtained if clinically indicated.
neck node disease was present after completion of nonoperative Pretreatment laboratory evaluation included a complete blood cell management. It was also recommended for patients with N2 or greater count and serum chemistry tests, including urea nitrogen, creatinine, disease at presentation, irrespective of clinical response, and for patients calcium, phosphorous, alkaline phosphatase, AST, albumin, total pro- undergoing primary-site resection. Salvage surgery was recommended for tein, bilirubin, and uric acid. Adequate hematologic renal and hepatic all patients if appropriate for local or regional disease recurrence.
function was required for the patient to enter the study. Patients with After the completion of therapy, patients were observed by all uncontrolled angina, active infection, or other uncontrolled malignancy members of the multidisciplinary team. Careful clinical examination was performed at 2- to 3-month intervals, and any suspected All patients were deemed appropriate for initial nonoperative man- locoregional or distant recurrence underwent biopsy. Radiographic agement. Patients with gross bone involvement that was considered studies were performed as clinically indicated. Survival times and potentially resectable were not approached in this fashion; instead, theyunderwent definitive surgical resection. Similarly, patients with oral times to specific events were calculated from the date radiation cavity lesions for whom there was a significant risk of radiation damage to therapy was initiated, and the results were analyzed as of March 1, the mandible were also in general not offered this treatment approach.
2001. No patient was lost to follow-up study. The Kaplan-Meier The study was approved and reviewed yearly by the Cleveland method was used to estimate the events of interest, including overall Clinic Foundation’s institutional review board. Written informed con- survival, disease-specific survival, distant control, local control sent was obtained from all patients before the initiation of treatment.
without surgery, and local control with surgery.20 Except for the Patient care was provided by a multidisciplinary management team, overall survival calculations, a patient was considered censored at which included head and neck surgeons and medical, radiation, and death if the event in question had not occurred. The patterns of nurse oncologists. All patients underwent a pretreatment dental evalu- failure analyses (local and distant control calculations) excluded the ation with appropriate care, and all received a pretreatment audiogram.
single patient who died during treatment and who therefore could The treatment schema is provided in Fig 1. All patients were treated CHEMO RT FOR STAGE IV HEAD AND NECK CANCER Table 1. Patient Characteristics (n ؍ 41)
Table 3. Chemoradiotherapy Toxicity (n ؍ 41)
single toxic death as a result of a pulmonary embolusoccurred during treatment.
The median follow-up period for patients at risk was 30 months (range, 6 to 62 months). The Kaplan-Meier pro-jected overall survival at 2 years is 80% and at 3 years is Between January 1996 and September 2000, 44 patients 59% (Fig 2). The projected disease-specific survival is 83% with advanced squamous cell head and neck cancer were at 2 years and 69% at 3 years (Fig 3), and this curve seems enrolled onto this clinical trial. Forty-one of these patients had stage IV disease at diagnosis and constitute the subject Among the 40 patients assessable for pattern of disease of this report. All patients were eligible, and all patients failure, 39 experienced a complete response at the primary were assessable for toxicity and survival. The clinical site after chemoradiotherapy. The single patient with resid- characteristics of these 41 patients and their tumors are ual primary-site disease after chemoradiotherapy underwent detailed in Table 1. Tumor and lymph node distribution is successful salvage surgery, resulting in all 40 assessable presented in Table 2. It should be noted that 35 (85%) of 41 patients achieving an initial local complete response. Two patients had either T3 or T4 primary tumors and that 32 delayed local recurrences developed. In one, successful patients (78%) were either T4 or N3 at presentation, confirm- salvage resection was possible. Thus, among the 40 patients ing the advanced locoregional disease present in this cohort.
assessable for pattern of failure, local control was achieved The toxicity from this treatment was significant and is without surgical resection in 37 and with surgical resection detailed in Table 3. Grade 3 or 4 mucositis, dysphagia, and in 39. Two of the three patients who experienced local skin reaction occurred in almost all patients but were persistence or recurrence received successful surgical sal- reversible. Sixty-eight percent of patients experienced atleast one episode of neutropenia (Ͻ 1,000/mm3), and 21(51%) of the 41 patients required an unplanned hospitaliza-tion for management of neutropenic fever. Despite feedingtube placement in 35 (85%) of the 41 patients, the meanweight loss during treatment was 10.9 kg (range, 0 to 24.7kg), or 13.3% of initial body weight. Long-term feedingtube maintenance was required by only one patient. Renalinsufficiency was infrequent and entirely reversible. A Table 2. Tumor (T) and Lymph Node (N) Distribution (n ؍ 41)
Fig 2. Kaplan-Meier projected overall survival in stage IV patients.
Fig 3. Kaplan-Meier projected disease-specific survival in stage IV
Fig 5. Kaplan-Meier projected local control with surgery in stage IV
vage treatment. Figure 4 presents the Kaplan-Meier projec- the 12 patients with clinical evidence of residual adenopa- tion of local control without the need for surgery. This curve thy. It should also be pointed out that among the nine N2, plateaus at 91%. The local control rate is 97% if surgical N3 patients who underwent neck dissection despite being clinically free of neck disease, three (33%) proved to have A clinical complete response was achieved in the neck in residual pathologic evidence of cancer in the neck at the 24 of the 36 assessable patients with neck nodes identified time of surgery. Among the entire patient cohort, only one at presentation. Neck dissection was performed in 21 of the patient experienced regional disease recurrence. This was a 34 patients with N2, N3 disease at diagnosis, including all patient who initially presented with N3 disease and subse- 12 patients with residual palpable neck disease after che- quently underwent a neck dissection for palpable and moradiotherapy and nine of the 24 patients who achieved a pathologically demonstrated disease persistence after che- complete response in the neck. The results of neck node moradiotherapy, who nonetheless experienced recurrence management are detailed in Table 4. Thirteen of the 21 patients undergoing neck dissection had no residual evi- Contrary to the usual pattern of failure, distant metastases dence of disease in the neck. This included seven (58%) of were relatively common, occurring in eight of the 40assessable patients. All eight died, including two whosubsequently developed hematogenous dissemination to thebrain. Thirteen of the 41 patients described herein havedied, including the eight who developed distant metastases,one patient who died during treatment, two patients whodied as a result of second primary aerodigestive tractmalignancies, and two who died as a result of comorbidillnesses. The patient with unresectable local disease recur- Table 4. Neck Node Management (n ؍ 40)
Fig 4. Kaplan-Meier projected local control without surgery in stage IV
Abbreviation: CR, complete response.
CHEMO RT FOR STAGE IV HEAD AND NECK CANCER rate of Յ 64% achieved in less advanced larynx/hypophar-ynx cancer after sequential chemotherapy and radiation,21,22suggesting an additional benefit from the concurrent treat-ment. The recently reported results from the Intergroupsecond-generation larynx preservation trial (Radiation Ther-apy Oncology Group 91-11) confirm this observation.23 Regional control proved more problematic. Residual pathologic evidence of neck node disease was found in eightof the patients enrolled onto this trial, some of whom had noclinical evidence of residual cancer in the neck. Althoughthe majority of patients undergoing neck dissection in thisseries had no residual tumor at the time of surgery, we wereunable to accurately identify these patients preoperatively.
We therefore continue to recommend neck dissection for allpatients with N2 or N3 disease at diagnosis, irrespective of Fig 6. Kaplan-Meier projections of local control without surgery and
their clinical response after chemoradiotherapy, and in all distant control in stage IV patients.
patients with residual clinical evidence of nodal involve-ment after nonoperative treatment.24 Even when a primary nonoperative treatment approach is rence and the patient with regional disease recurrence both chosen, the importance of ongoing surgical involvement in died with distant metastases. This striking reversal in the the management of these patients cannot be overstated. The usual pattern of failure is illustrated in Fig 6. The projected clinical evaluation of the primary site is often difficult after likelihood of local control without surgery at 3 years is 91% chemoradiotherapy, requiring repeated examinations while compared with the projected 3-year likelihood of distant the patient is anesthetized as well as multiple biopsies.
Similarly, the algorithms for neck management suggest theimportance of an ongoing surgical presence and a planned neck dissection in appropriate patients if optimal treatment Several important points emerge from this analysis. First, results are to be achieved. Although the likelihood of organ it is apparent that the toxicity of aggressive concurrent preservation in this patient cohort is exciting, we cannot lose chemotherapy and hyperfractionated radiation therapy is sight of the fact that the overall treatment goal is cure. Surgical significant. Almost all patients experienced severe mucosal management remains important in the achievement of that end.
and skin toxicity, and more than half required hospitaliza- These kinds of results, however, suggest that cure is a tion for neutropenic fever. More important, however, was reasonable and attainable goal, even in patients with ad- the transient nature of this acute toxicity and the effective- vanced locoregional tumors. Aggressive multimodality ness of current supportive measures. No patient died as a treatment strategies, with appropriate supportive care, by an result of these treatment-related side effects. The single experienced management team can produce a significant toxic death reported resulted from a pulmonary embolus.
improvement in results when compared with historical Aggressive follow-up care, early hospitalization and antibi- experience. Although these patients may die for many otic therapy for neutropenic fever, and prompt nutritional reasons, the overwhelming cause of death in this cohort was intervention with gastrostomy placement was critical in distant metastatic disease, not locoregional tumor, comor- maintaining the dose intensity of this treatment regimen and bidity, or second primary neoplasms. Other investigators was in large part responsible for the success achieved.
who used similar aggressive locoregional treatments have Although the toxicity encountered was formidable, it was made this same observation,25 and attention must now be manageable and would seem justifiable given these results.
focused on the prevention of these distant metastases.
Future attention will be directed to the potential long-term Interventions might include the use of additional multiagent toxicities that may develop in this patient cohort.
chemotherapy given as either induction or adjuvant treat- Second, despite the initial presentation with advanced ment, or the use of other, nonchemotherapeutic systemic locoregional tumors, local control of disease was excellent.
approaches. The complexity of these treatment regimens Organ preservation, or local control without the need for and the effect on patient compliance remain a significant surgical resection, was possible in 91% of these stage IV concern. Similar attention should also be directed toward patients. One can contrast this with the organ preservation possible toxicity modification, if this can be accomplished without a compromise in overall treatment results. Initial experienced supportive care team. The survival, local con- efforts with agents such as amifostine26 and pilocarpine27 trol, and organ preservation were excellent despite the advanced stage of these patients at diagnosis. Distant We conclude that this chemoradiotherapy schedule pro- metastases have now become the most common cause of duces considerable toxicity and requires management by an treatment failure at our institution.
1. Dimery IW, Hong WK: Overview of combined modality thera- 14. Brizel DM, Albers ME, Fisher SR, et al: Hyperfractionated pies for head and neck cancer. J Natl Cancer Inst 85:95-111, 1993 irradiation with or without concurrent chemotherapy for locally ad- 2. Adelstein DJ, Tan EH, Lavertu P: Treatment of head and neck vanced head and neck cancer. N Engl J Med 338:1798-1804, 1998 cancer: The role of chemotherapy. Crit Rev Oncol Hematol 24:97-116, 15. Ang KK: Altered fractionation trials in head and neck cancer.
3. Vokes EE, Weichselbaum, RR, Lippman SM, et al: Head and 16. Mendenhall WM, Parsons JT: Altered fractionation in radiation neck cancer. N Engl J Med 328:184-194, 1993 therapy for squamous-cell carcinoma of the head and neck. Cancer 4. Forastiere AA, Metch B, Schuller DE, et al: Randomized com- parison of cisplatin plus fluorouracil and carboplatin plus fluorouracil 17. Hu KS, Harrison LB: Altered fractionation in the treatment of versus methotrexate in advanced squamous-cell carcinoma of the head head and neck cancer. Curr Oncol Rep 1:110-123,1999 and neck: A Southwest Oncology Group study. J Clin Oncol 10:1245- 18. Fu KK, Pajak TF, Trotti A, et al: A Radiation Therapy Oncology Group (RTOG) phase III randomized study to compare hyperfraction- 5. Jacobs C, Lyman G, Velez-Garcia, et al: A phase III randomized ation and two variants of accelerated fractionation to standard fraction- study comparing cisplatin and fluorouracil as single agents and in ation radiotherapy for head and neck squamous cell carcinomas: First combination for advanced squamous cell carcinoma of the head and report of RTOG 9003. Int J Radiat Oncol Biol Phys 48:7-16, 2000 19. Beahrs OH, Henson DE, Hutter RVP (eds): Manual for Staging 6. Adelstein DJ: Induction chemotherapy in head and neck cancer.
of Cancer (ed 4). Philadelphia, PA, Lippincott, 1992 Hematol Oncol Clin North Am 13:689-698, 1999 20. Kaplan EL, Meier P: Nonparametric estimation of incomplete 7. Vietti T, Eggerding F, Valeriote F: Combined effect of x- observations. J Am Stat Assoc 53:457-481, 1958 radiation and 5-fluorouracil on survival of transplanted leukemic cells.
21. Wolf GT, Hong WK, Fisher SG, et al: Induction chemotherapy plus radiation compared with surgery plus radiation in patients with 8. Douple EB: Platinum-radiation interactions. Natl Cancer Inst advanced laryngeal cancer. N Engl J Med 324:1685-1690, 1991 22. Lefebvre JL, Chevalier D, Luboinski B, et al: Larynx preserva- 9. Jeremic B, Shibamoto Y, Stanisavljevic B, et al: Radiation tion in pyriform sinus cancer: Preliminary results of a European therapy alone or with concurrent low-dose daily either cisplatin or Organization for Research and Treatment of Cancer phase III trial.
carboplatin in locally advanced unresectable squamous cell carcinoma of the head and neck: A prospective randomized trial. Radiother Oncol 23. Forastiere AA, Berkey B, Maor M, et al: Phase III trial to preserve the larynx: Induction chemotherapy and radiotherapy versus 10. Jeremic B, Shibamoto Y, Milicic B, et al: Hyperfractionated concomitant chemoradiotherapy versus radiotherapy alone, Intergroup radiation therapy with or without concurrent low-dose daily cisplatin inlocally advanced squamous cell carcinoma of the head and neck: A Trial R91-11. Proc Am Soc Clin Oncol 20:2a, 2001 (abstr 4) prospective randomized trial. J Clin Oncol 18:1458-1464, 2000 24. Lavertu P, Adelstein DJ, Saxton JP, et al: Management of the 11. Adelstein DJ, Adams GL, Li Y, et al: A phase III comparison of neck in a randomized trial comparing concurrent chemotherapy and standard radiation therapy (RT) versus RT plus concurrent cisplatin radiotherapy with radiotherapy alone in resectable stage III and IV (DDP) versus split-course RT plus concurrent DDP and 5-fluorouracil squamous cell head and neck cancer. Head Neck 19:559-566, 1997 (5FU) in patients with unresectable squamous cell head and neck 25. Vokes EE, Kies MS, Haraf DJ, et al: Concomitant chemoradio- cancer (SCHNC): An Intergroup study. Proc Am Soc Clin Oncol therapy as primary therapy for locoregionally advanced head and neck 12. Adelstein DJ, Saxton JP, Lavertu P, et al: A phase III random- 26. Brizel DM, Wasserman TH, Henke M, et al: Phase III random- ized trial comparing concurrent chemotherapy and radiotherapy with ized trial of amifostine as a radioprotector in head and neck cancer.
radiotherapy alone in resectable stage III and IV squamous cell head and neck cancer: Preliminary results. Head Neck 19:567-575, 1997 27. Scarantino CW, LeVeque FG, Scott CB, et al: A phase III study 13. Wendt TG, Grabenbauer GG, Rodel CM, et al: Simultaneous of concomitant oral pilocarpine to reduce hypo-salivation and mucosi- radiochemotherapy versus radiotherapy alone in advanced head and tis associated with curative radiation therapy in head and neck cancer neck cancer: A randomized multicenter study. J Clin Oncol 16:1318- patients: RTOG 9709. Proc Am Soc Clin Oncol 20:225a, 2001 (abstr


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Sedative and Hypnotic Withdrawal Worksheet Instrument: Modified CIWA-A Patient: The trigger point for this protocol is 6. Symptoms & Intoxication Signs: Nystagmus Give only one score for each block. Withdrawal Signs: Hallucinations DBP > 100 Sitting/Standing Orthostasis Sedative and Hypnotic Withdrawal Worksheet Instrument: Modified CIWA-A Inst

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