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Concomitant Chemoradiotherapy in Pyriform Sinus Carcinoma
Jean-Michel Prades, MD, PhD;
Thierry M. Schmitt, MD;
Andrei P. Timoshenko, MD;
Pierre-Gilles Simon, MD;
Joanne de Cornulier, MD;
Marc Durand, MD;
Aline Guillot, MD;
Christian Martin, MD
Arch Otolaryngol Head Neck Surg. 2002;128:384-388.
ABSTRACT
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Objectives To test the effectiveness of concurrent chemoradiotherapy in patients
with pyriform sinus carcinoma and to demonstrate the feasibility of an organ
preservation approach.
Design Clinical trial phase 2.
Setting University Hospital Center, St-Etienne, France.
Patients The study population comprised 46 male patients with resectable stage
III and IV pyriform sinus carcinoma.
Methods Two successive chemoradiation regimens were investigated. In protocol
1 (24 patients), carboplatin was given on days 1 through 5 and 28 through
33, with an area under the curve dose of 5 mg/mL for 1 minute per day and
bifractionated radiotherapy (160 rad [1.6 Gy]/fraction) delivered on days
1 through 16 and 28 through 38. A treatment break was planned on days 16 through
27. In protocol 2 (22 patients), chemotherapy was given with the same dose
of carboplatin on days 1 and 21, and fluorouracil (750 mg/m2 per
day) on days 1 through 7 and 21 through 28. Radiotherapy with a single fraction
of 180 rad (1.8 Gy)/d was delivered during the first 2 weeks and then 150
rad (1.5 Gy) twice a day during the next 3 weeks.
Main Outcome Measures Patients were evaluated for tumor response, toxic reactions, and organ
preservation and survival rates. Statistical analysis of disease-free survival
and overall survival was performed using the Kaplan-Meier method.
Results A complete response was noted in 21 (88%) of the 24 patients following
protocol 1 and 16 (73%) of the 22 patients following protocol 2. After 2 years
of follow up, 16 patients (67%) (protocol 1) and 12 patients (55%) (protocol
2) retained their larynx without evidence of disease. During therapy, 15 patients
(63%) (protocol 1) and 19 patients (86%) (protocol 2) required unplanned hospitalization
for toxic effects. The overall survival and disease-free survival rates at
2 years were 58% (protocol 1) vs 53% (protocol 2) and 39% (protocol 1) vs
41% (protocol 2) (P = .80), respectively.
Conclusion Concomitant chemotherapy and bifractionated radiotherapy, although toxic,
leads to good locoregional control and therefore to a significant level of
laryngeal preservation.
INTRODUCTION
SQUAMOUS CELL carcinoma of the hypopharynx has one of the worst prognoses
of all upper aerodigestive tract cancers, particularly for tumors arising
in the pyriform sinus, the most frequent site of hypopharyngeal origin.1 Radiation therapy following surgery is the standard
therapy. The strategy of combined chemoradiotherapy in the treatment of advanced
resectable disease (to avoid mutilating surgery) is known as organ preservation.2 The objective of larynx preservation in patients with
pharynx and larynx carcinoma was studied in 3 randomized trials with combined
platinum-fluorouracil chemotherapy in a neoadjuvant setting: these regimens
were able to preserve the larynx in nearly 23% of patients after 5 years of
follow-up, with no significant difference in survival compared with the standard
treatment, ie, surgery and postoperative irradiation.3-5
Findings in laboratory and clinical studies suggest that concomitant administration
of platinum-based chemotherapy and irradiation seems to be more effective
than sequential treatment.6-7
Previous studies have found advantages to using multiple fractions per day
for radiation therapy.8-9 However,
the standard chemoradiotherapy regimen in these conditions remains to be determined.
PATIENTS AND METHODS
ELIGIBILITY CRITERIA
Forty-six male patients assigned with untreated stage III and IV squamous
cell carcinoma of the pyriform sinus were eligible to receive concomitant
chemoradiotherapy. Pretreatment evaluation included medical history, physical
examination, panendoscopy, and biopsy with general anesthesia and imaging
studies (ie, chest radiography and computed tomography). All patients were
required to have a Karnofsky Performance Status score of 60 or more. The examined
patients had disease limited to the head and neck (M0 tumors). Patients with
palpable cervical nodes were initially scheduled to undergo a planned pretreatment
neck dissection. The TNM staging who assigned according to the 1997 International
Union Against Cancer (Union Internationale Contre le Cancer [UICC]) staging
system.10 Two successive concomitant chemotherapy
and bifractionated radiotherapy regimens were investigated. A multidisciplinary
team supervised all treatments, and all patients gave written informed consent
for participation in the study.
PROTOCOL 1
The chemotherapy regimen included carboplatin with an area under the
curve (AUC) dose of 5 mg/mL for 1 minute per day on days 1 through 5 and on
days 28 through 33. The AUC dose was calculated with the Calvert formula.
The chemotherapy infusions were administrated 2 hours before each radiotherapy
fraction. Bifractionated radiotherapy delivered 160 rad (1.6 Gy) twice a day
on days 1 through 16 and on days 28 through 38. There was a treatment break
scheduled on days 16 through 27. The planned total dose of radiation therapy
was 6720 rad (67.2 Gy).
PROTOCOL 2
The chemotherapy regimen included carboplatin (AUC dose of 5 mg/mL for
1 minute per day) given on days 1 and 21, and continuous perfusion of fluorouracil
(750 mg/m2 per day on days 1 through 7 and 21 through 28). Radiotherapy
with a single fraction of 180 rad (1.8 Gy) per day was delivered in patients
during the first 2 weeks, followed by bifractionated radiation therapy (150
rad [1.5 Gy] twice a day) over the next 3 weeks. There was no treatment break.
The planned total dose of radiation was 6300 rad (63 Gy). In both protocols,
all patients underwent a clinical evaluation for tumor response by means of
an endoscopy and biopsy under general anesthesia 6 to 8 weeks after completion
of chemoradiotherapy. No residual tumor on pathologic examination was required
for definition of a complete tumor response.
TOXIC EFFECTS AND STATISTICAL METHODS
Acute and late reactions to the treatment were scored by grade in the
patients according to the World Health Organization classification system.
Survival curves were calculated from the date of onset of therapy using the
Kaplan-Meier method, and were compared using the log-rank test. No patient
was lost to follow-up.
RESULTS
POPULATION
The protocol 1 group comprised 24 patients with a mean age of 53 years
(range, 35-69 years); 14 patients had positive nodes for cancer on pathologic
examination, and 10 of the 14 patients presented with a ruptured capsule.
The protocol 2 group comprised 22 patients with a mean age of 57 years (range,
38-70 years). In protocol 2, 10 patients had positive nodes on pathologic
examination, and 5 presented with a ruptured capsule. Table 1 summarizes the clinical distribution of the disease by T
and N stage.
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Table 1. Distribution of Disease by TNM Staging*
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TUMOR RESPONSE
A complete tumor response occurred in 21 patients (88%) in the protocol
1 group and 16 patients (73%) in the protocol 2 group. Progression of neck
disease during chemoradiation was seen only in 1 patient (protocol 2). However,
a minimal persistent local disease associated with a chondronecrosis of the
larynx was detected in 2 patients in each protocol. These patients required
salvage surgery by total pharyngolaryngectomy. Additionally, a progression
of neck disease after chemoradiotherapy manifested in 1 patient (protocol
2).
PATIENT STATUS
After 2 years of follow-up, 16 patients (67%) in the protocol 1 group
and 12 patients (55%) in the protocol 2 group were alive with no evidence
of disease. All these patients retained their larynx (grade 1 or 2 laryngeal
radiation reactions), maintained oral nutrition, and were able to speak and
communicate. In the protocol 1 group, 5 patients had local or regional recurrence
of disease, 3 of whom died of tumor progression; 3 other patients with distant
metastases (lung, bone, and liver) died without locoregional recurrence of
disease. In the protocol 2 group, 5 patients had local or regional recurrence
of disease, which caused 3 lethal cases because of disease progression; 3
other patients died due to distant metastases but without any local recurrence
of disease, and another 2 patients died after a local recurrence associated
with lung metastasis.
TOXIC EFFECTS
The toxic effects of these treatments are illustrated in Table 2. Nasoenteric and/or gastrostomy tube feeding because of
severe mucositis (grade 3 or higher) was required in 11 (46%) of the 24 patients
following protocol 1 and 17 (77%) of the 22 patients following protocol 2.
Grade 2 laryngeal radiation reactions were observed in 7 protocol 1 patients
(29%) and 7 protocol 2 patients (32%). One patient died of a cardiac cause
during treatment with protocol 2. An unscheduled treatment break between 8
and 15 days was required for 6 protocol 1 patients (25%) and 5 protocol 2
patients (23%); 15 protocol 1 patients (63%) and 19 protocol 2 patients (86%)
required additional unplanned hospitalization for combinations of insufficient
oral intake, dehydration, febrile neutropenia, or septicemia. Because of late
chondronecrosis of the larynx, 1 protocol 1 patient and 3 protocol 2 patients
required a total pharyngolaryngectomy 6 months (protocol 1) and 6 to 10 months
(protocol 2) after treatment, respectively.
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Table 2. Toxic Effects of Concomitant Chemoradiotherapy*
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LARYNX PRESERVATION
In both protocols, 28 (61%) of the 46 patients were free of disease
with a functional larynx. There was an advantage in the laryngeal preservation
rate for protocol 1 (66% of cases) vs protocol 2 (55% of cases). In the protocol
1 group, 8 patients underwent a pharyngolaryngectomy (1 after the first evaluation
for persistent disease, 1 after 6 months for chondronecrosis of the larynx,
and 6 after a local or a locoregional recurrence). In the protocol 2 group,
10 patients required salvage pharyngolaryngeal surgery (2 for persistent disease
at week 8, 3 for laryngeal necrosis at months 6 or 10, and 5 after a local
or a locoregional recurrence). Thus, 18 of 46 patients required salvage surgery,
mainly for a recurrent T4 tumor (10 of 11 patients) (Table 3).
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Table 3. Number of Patients Who Underwent Salvage Pharyngolaryngectomy*
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SURVIVAL
The overall 2-year survival rate of patients was 58% for the protocol
1 group and 53% for the protocol 2 group (Figure 1). At 2 years, the disease-free survival rate of patients
was 39% (protocol 1) and 41% (protocol 2) (Figure 2). There was no statistically significant difference between
the 2 protocols.
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Figure 1. Kaplan-Meier overall survival
curves. The 2-year overall survival rate was 58% (protocol 1) and 53% (protocol
2). There was no statistically significant difference between the protocols
(P = .85, log-rank test).
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Figure 2. Kaplan-Meier disease-specific
curves. At 2 years, disease-specific survival rates were 39% (protocol 1)
and 41% (protocol 2). There was no statistically significant difference between
the protocols (P = .80, log-rank test).
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COMMENT
Randomized trials of neoadjuvant chemotherapy failed to improve survival
rates but suggested important potential benefits, such as organ preservation.3-5 The next therapeutic
step after induction chemotherapy was the concurrent administration of radiation
and chemotherapy to enhance radiosensitization provided by chemotherapy. In
the first meta-analysis,11 it was revealed
that the addition of chemotherapy to the locoregional treatment led to a statistically
significant increase in the survival rate of the treated patients. Findings
from an analysis of the timing of chemotherapy suggested no significant benefit
of adjuvant (after conventional locoregional therapy) or neoadjuvant (before
conventional locoregional therapy) chemotherapy, but they did suggest a significant
benefit of concomitant chemotherapy (a benefit at 2 and 5 years of 8%). Several
concurrent platinum-based protocols of chemoradiotherapy yielded an improved
relapse-free survival rate compared with induction chemotherapy and radiotherapy
in the 2-armed studies12-13 and
indicated that all relapses seen during a 4-year period occurred within the
first 17 months.12 Platinum-based chemotherapy
can be used as a single treatment given simultaneously with radiation therapy.14-15 A new strategy has been identified
incorporating high-dose intensity intra-arterial cisplatin infusions combined
with radiation therapy, which could offer patients an improved survival outcome
avoiding major loss of organ function.16
Pretreatment neck dissection may be open to criticism, but no treatment
delay or wound complication has been observed in our study. Persistent viable
tumors in the neck have been observed in 50% of patients with residual palpable
disease after chemoradiotherapy and 25% of complete clinical responders.17 Few studies have evaluated the impact of chemoradiation
on the complication rate of any subsequent neck surgery. It should be noted
that even for isolated neck dissection there was a considerable incidence
of wound complications.18 Surgical salvage
for tumor persistence, tumor recurrence, or larynx necrosis was also notable
in our series (Table 3): of the
patients assigned stage IV tumors, 5 of 6 patients following protocol 1 and
all patients following protocol 2 required salvage surgery. In our experience,
stage IV patients do not have the benefit of our laryngeal preservation strategy.
Only 8 (23%) of 35 stage III patients required salvage pharyngolaryngectomy.
When patients had local and/or regional recurrence, the prognosis for overall
survival decreased: among our patients only 2 (11%) of the 18 patients who
underwent salvage surgery are currently alive and disease free.
Previous studies have found advantages to the use of multiple fractions
per day in radiation therapy.9, 19-20
Wang et al9 showed that patients with advanced
head and neck carcinoma treated with bifractionated radiotherapy experienced
an improved locoregional control rate of 15% to 20% compared with monofractionated
radiotherapy. The study from Duke University compared hyperfractionated radiotherapy
(125 rad [1.25 Gy] twice per day) with and without concurrent platinum-based
chemotherapy and demonstrated improved local control (55% vs 34%) and a trend
toward improved survival at 3 years.21 Concomitant
chemoradiation for head and neck cancer is an intensive treatment associated
with frequent, severe, and long-lasting toxic effects. Regimens with high
toxicity must often exclude some patients and are associated with reduced
patient compliance.22
Because the design of our protocols was aimed at maximizing the efficiency
of therapeutic agents and minimizing adverse toxic reactions, a 2-week break
was included in protocol 1 during the concurrent chemoradiotherapy for organ
preservation as suggested by Koch et al.2 Patients
with myelosuppression and severe mucositis, attributed sometimes to the addition
of fluorouracil, often demanded extended breaks in therapy, perhaps accounting
for a lower response rate.11 Hospitalization
and medical surveillance with nutritional and psychosocial support played
an important role in our treatment approach. Previous studies reported the
incidence of severe mucositis between 50% to 85% using a chemoradiation therapy
for advanced head and neck carcinoma.15, 17, 23
De Serdio et al24 reported a 17% reduction
in the compliance rate using a bifractionated radiochemotherapy protocol for
advanced head and neck carcinoma. In our study, only 4 (9%) of 46 patients
did not receive the full course of therapy, and 34 (74%) of the 46 patients
required unplanned hospitalization. Although toxic reactions of the mucosa
have been common adverse effects, 90% of treated patients were able to receive
all the intended concomitant chemoradiation. Monitoring patients undergoing
concurrent chemoradiation therapy via a quality of life questionnaire and
swallowing assessment manifests the patient's ability to tolerate the therapy.16-17,25
CONCLUSIONS
Concomitant chemoradiotherapy with irradiation twice a day leads to
high locoregional control with organ preservation in patients with pyriform
sinus carcinoma, particularly for stage III tumors, but not for stage IV tumors.
However, these regimens have also been shown to result in increased toxic
effects. Medical surveillance with nutritional and psychosocial support plays
an important role in improving patient compliance. The optimal strategy for
this combined therapy needs further investigations.
AUTHOR INFORMATION
Accepted for publication October 26, 2001.
This study was presented at the annual meeting of the French Head and
Neck Oncology Society, Toulouse, France, November 19, 1999.
We thank Anna Milan, BSc, PhD, Research Fellow from the University of
Liverpool, Liverpool, England, and Alexander Timoshenko, PhD, Postdoctoral
Fellow from the University of Western Ontario, London, for revising the English
manuscript and assistance.
Corresponding author and reprints: Jean-Michel Prades, MD, Department
of Otolaryngology, Head and Neck Surgery, Bellevue Hospital, St-Etienne University
Hospital Center, Boulevard Pasteur, 42055 Saint-Etienne CEDEX 2, France (e-mail: christian.martin{at}chu-st-etienne.fr).
From the Departments of Otolaryngology–Head and Neck Surgery
(Drs Prades, Timoshenko, Simon, Durand, and Martin), Radiation Oncology (Drs
Schmitt and de Cornulier), and Medical Oncology (Dr Guillot), Saint-Etienne
University Hospital Center, Bellevue Hospital, St-Etienne, France.
REFERENCES
| |
1. Pingree TF, Davis RK, Reichman O, et al. Treatment of hypopharyngeal carcinoma: a 10-year review of 1362 cases. Laryngoscope. 1987;97:901-904.
ISI
| PUBMED
2. Koch WM, Lee DJ, Fisele DW, et al. Chemoradiotherapy for organ preservation in oral and pharyngeal carcinoma. Arch Otolaryngol Head Neck Surg. 1995;121:974-980.
ABSTRACT
3. The Department of Veterans Affairs Laryngeal Cancer Study Group. Induction chemotherapy plus radiotherapy compared with surgery plus
radiation in patients with advanced laryngeal cancer. N Engl J Med. 1991;324:1685-1690.
ABSTRACT
4. Lefebvre JL, Chevalier D, Luboinski B, Kirkpatrick A, Collette L, Sahmoud T. Larynx preservation in pyriform sinus cancer: preliminary results of
a European organization for research and treatment of cancer phase III trial. J Natl Cancer Inst. 1996;88:890-899.
FREE FULL TEXT
5. Richard JM, Sancho-Garnier M, Pessey JJ, et al. Randomized trial of induction chemotherapy in larynx carcinoma. Oral Oncol. 1998;34:224-228.
FULL TEXT
|
ISI
| PUBMED
6. Coughlin CT, Richmond RC. Biologic and clinical developments of cisplatin combined with radiation:
concepts, utility, projections for new trials and the emergence of carboplatin. Semin Oncol. 1989;16(suppl 6):31-43.
7. Vokes EE, Weichselbaum RR. Concomitant chemoradiotherpy: rationale and clinical experience in
patients with solid tumors. J Clin Oncol. 1990;8:911-934.
ABSTRACT
8. Million RR, Parsons JT, Cassisi NJ. Twice-a-day irradiation technique for squamous cell carcinomas of the
head and neck. Cancer. 1985;55:2096-2099.
FULL TEXT
|
ISI
| PUBMED
9. Wang CC, Blitzer PM, Suit H. Twice-a-day radiation therapy for cancer of the head and neck. Cancer. 1985;55:2100-2104.
FULL TEXT
|
ISI
| PUBMED
10. Sobin LH, ed, Wittekind C, ed (International Union Against Cancer [UICC]). TNM Classification of Malignant Tumours. 5th ed. Baltimore, Md: Wiley-Liss; 1997.
11. Pignon JP, Bourhis J, Domenge C, et al. Chemotherapy added to locoregional treatment of head and neck squamous
cell carcinoma: three meta-analyses of updated individual data. Lancet. 2000;355:949-955.
ISI
| PUBMED
12. Adelstein DJ, Sharan VH, Earl AS, et al. Simultaneous versus sequential combined technique therapy for squamous
cell head and neck cancer. Cancer. 1990;65:1685-1691.
FULL TEXT
|
ISI
| PUBMED
13. Taylor SG, Murphy AK, Vannetzel JM, et al. Randomized comparison of neoadjuvant cisplatin and fluorouracil infusion
followed by radiation versus concomitant treatment in advanced head and neck
cancer. J Clin Oncol. 1994;12:385-395.
ABSTRACT
14. Volling P, Staar S, Achterrath W, et al. Carboplatin plus radiation therapy in head and neck cancer. Semin Oncol. 1991;18(1, suppl 2):17-22.
15. Schnabel TR. Combined radiochemotherapy with carboplatin in the treatment of advanced
head and neck carcinomas. Oncology. 1993;50 Suppl 2:16-22.
16. Robbins KT, Fontanesi J, Wong F, 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
17. Lavertu P, Adelstein DJ, Saxton JP, et al. Aggressive concurrent chemoradiotherapy for squamous cell head and
neck cancer: an 8-year single-institution experience. Arch Otolaryngol Head Neck Surg. 1999;125:142-148.
FREE FULL TEXT
18. Weisman RA, Robbins KT. Management of the neck in patients with head and neck cancer treated
by concurrent chemotherapy and radiation. Otolaryngol Clin North Am. 1998;31:773-784.
FULL TEXT
|
ISI
| PUBMED
19. Horiot JC, Le Fur R, N'Guyent T, et al. Hyperfractionation versus conventional fractionation in oropharyngeal
carcinoma: final analysis of a randomized trial of the EORTC cooperative group
of radiotherapy. Radiother Oncol. 1992;25:231-241.
FULL TEXT
|
ISI
| PUBMED
20. Dobrowsky W, Dobrowsky E, Naude J, et al. Conventional versus accelerated fractionation in head and neck cancer. Br J Cancer Suppl. 1996;27:S279-S281.
21. Brizel DM, Albers ME, Fisher SR, et al. Hyperfractionated induction with and without concurrent chemotherapy
for locally advanced head and neck cancer. N Engl J Med. 1998;338:1798-1804.
FREE FULL TEXT
22. Yu L, Vikram B, Malamud S, et al. Chemotherapy rapidly alternating with twice a day accelerated radiation
therapy in carcinomas involving the hypopharynx and esophagus: an update. Cancer Invest. 1995;13:567-572.
ISI
| PUBMED
23. Shirinian MH, Weber RS, Lippman SM, et al. Laryngeal preservation by induction chemotherapy plus radiotherapy
in locally advanced head and neck cancer: the M. D. Anderson Cancer Center
experience. Head Neck. 1994;16:39-44.
ISI
| PUBMED
24. De Serdio JL, Villar A, Martinez JC, et al. Chemotherapy as a part of each treatment fraction in twice-a-day hyperfractionated
schedule: a new chemoradiotherapy approach for advanced head and neck cancer. Head Neck. 1998;20:489-496.
FULL TEXT
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ISI
| PUBMED
25. 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
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