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588
Phase II Study of Induction and Adjuvant
Chemotherapy for Squamous Cell Carcinoma of the
Head and Neck
A Long Term Analysis for the Illinois Cancer Center
Ilias Athanasiadis, M.D.1
Samuel Taylor IV, M.D.2
Everett E. Vokes, M.D.3
Harold J. Pelzer, M.D.4
Alfred Rademaker, Ph.D.5
Bharat B. Mittal, M.D.6
Natalia Ganzenko, M.D.1
Richard Blough, M.S.7
Eric P. Lester, M.D.3
Merrill S. Kies, M.D.1
BACKGROUND. In 1982, the Illinois Cancer Center initiated a Phase II trial in which
Address for reprints: Merrill S. Kies, M.D., Division of Hematology/Oncology, Northwestern
Medical Faculty Foundation, 233 East Erie, Suite
700, Chicago, IL 60611.
the following treatment was administered: Induction chemotherapy (cisplatin and
infusional 5-fluorouracil [5-FU]) was administered before definitive local therapy.
Definitive local therapy, consisting of surgery, radiation, or both, was followed by
three cycles of the same chemotherapy program.
METHODS. Eligible patients had Stage III or IV squamous cell carcinoma of the
head and neck with no distant metastases. Three cycles of induction chemotherapy
were given. Cisplatin, 100 mg/m2, was infused over 60 minutes on Day 1; thereafter,
5-FU (1000 mg/m2/day) was given continuously for 5 days. Cycles were repeated
at 3-week intervals. Local therapy was individualized, according to tumor stage
and site. Patients who responded were to receive an additional three cycles of
chemotherapy after surgery or radiation.
RESULTS. Eighty-one patients were entered into the trial, and 71 were considered both
eligible and evaluable. After induction chemotherapy, 59 patients (83%) responded, 23
of whom experienced complete response. Sixty-nine patients completed definitive local
treatment, but only 22 proceeded to the planned adjuvant cycles of treatment. Median
follow-up of surviving patients was 12 years. At last follow-up, 13 patients were alive
and free of malignancy, 9 of whom never had disease recurrence or a second primary
tumor. These 13 patients had an acceptable quality of life, were ambulating, and were
fully capable of caring for themselves. Overall, nine patients had second primary malignancies. Thirty-four percent of patients were alive at 5 years, and 21% were alive at 10
years. Of 58 deaths, 44 resulted from progressive disease and 8 resulted from second
primary cancers. Four patients died of unrelated causes, and two suffered lethal acute
toxicity from the chemotherapy program. Late toxicity was moderate. Among 23 patients
surviving at least 6 years, there were 3 cases of hypothyroidism, presumed to be secondary to radiation. Xerostomia was modest, consistent with usual radiation effects. Of the
13 patients who were alive and free of malignancy at last follow-up, none had clinical
manifestations of serious late end organ toxicity.
CONCLUSIONS. During long term follow-up after multimodal treatment of locally advanced squamous cell carcinoma, no obvious benefit was observed from the chemotherapy component of the treatment regimens rendered. Only 21% of patients achieved
10-year survival with the following causes of failure, in descending order of frequency:
disease recurrence, second malignancies, other medical problems, and treatment-related deaths. The results of this trial are consistent with the results of other induction
chemotherapy trials, indicating the need for innovative treatment strategies. These data
do not support the continued use of induction chemotherapy with the cisplatin and
infusional 5-FU program. Cancer 1997; 79:588?94.
q 1997 American Cancer Society.
Received September 27, 1996; accepted October 11, 1996.
KEYWORDS: squamous cell carcinoma, head and neck, chemotherapy, cisplatin, 5fluorouracil.
1
Department of Medicine, Northwestern University Medical School, Chicago, Illinois.
2
Department of Medicine, Illinois Masonic Cancer Center, Chicago, Illinois.
3
Department of Medicine, University of Chicago, Chicago, Illinois.
4
Department of Otolaryngology, Northwestern
University Medical School, Chicago, Illinois.
5
Division of Biometry, Northwestern University
Medical School, Chicago, Illinois.
6
Department of Radiology, Northwestern University Medical School, Chicago, Illinois.
7
Department of Medicine, Illinois Cancer Center, Northwestern University, Chicago, Illinois.
Supported in part by National Cancer Institute
Illinois Cancer Grant 2 P30-CA60553-03.
q 1997 American Cancer Society
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P
hase II studies of induction chemotherapy in previously untreated patients with advanced squamous cell carcinoma of the head and neck have repeatedly shown high response rates in the range of
60 ? 90%.1 The combination of cisplatin with infusional
5-fluorouracil (5-FU) (PF ) has been a widely used chemotherapy regimen.2 The strategy with induction chemotherapy programs has been to induce tumor response and thereby enhance local control after surgery
or radiation and to eradicate distant micrometastatic
disease, with the ultimate goal of improving patient
survival.
Concomitant or alternating chemoradiotherapy
has been shown to improve local control with a small
survival advantage over radiotherapy alone.3,4 Neoadjuvant and adjuvant chemotherapy have decreased the
incidence of distant metastases, but randomized trials
have failed to show prolongation of survival.5 ? 9 Another therapeutic goal has been organ preservation,
which was studied in a randomized fashion in the VA
Larynx Study, showing that larynx preservation is
achieved in 64% of patients without compromise of
survival.7
In 1982 the Illinois Cancer Center (ICC) initiated a
Phase II trial with induction PF for three cycles, before
definitive local therapy, followed by three cycles of the
same regimen for responding patients only. Accrual
was completed within 16 months between 9 participating institutions. In this article, the authors present
a mature analysis and discuss long term results after
induction and adjuvant chemotherapy.
MATERIALS AND METHODS
Eligible patients had histologically confirmed invasive
squamous cell carcinoma of the oral cavity, pharynx,
larynx, or paranasal sinuses, Stage III or IV, as defined
by the American Joint Committee on Cancer staging.
Patients were required to have no clinical or radiologic
evidence of distant metastases, have received no previous therapy, and have a performance status of 0 ? 2 by
Eastern Cooperative Oncology Group (ECOG) criteria.
Normal bone marrow, liver and renal functions were
required, with no clinical evidence of significant infection or other severe complicating medical illness. Pregnancy was an absolute contraindication. Obtaining
written informed consent was necessary prior to the
patient?s entry on study.
Each patient was evaluated by the Head and Neck
Surgery, Medical Oncology, and Radiation Oncology
units in the respective participating institutions. The
staging workup included panendoscopy and computed tomography (CT) imaging. Lesions were routinely tattooed to facilitate later assessment of response, and to serve as guideposts for surgery in patients achieving a major tumor regression after
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589
chemotherapy. After the initial evaluation, surgery
and/or radiation was planned for each patient. Patients then began drug treatment, as outlined below.
An indwelling central venous catheter was routinely
placed.
The treatment schema is shown in Table 1. Three
cycles of PF were planned at 21-day intervals. After
formal assessment of response, patients underwent
surgery and/or radiation therapy. Local therapy was
individualized according to tumor stage and site. After
recovery, all patients with partial response (PR) or
complete response (CR) to induction chemotherapy
were to receive three additional cycles of PF.
A cycle of chemotherapy was comprised of cisplatin, 100 mg/m2 infused over 60 minutes on Day
1, followed by 5-FU, 1000 mg/m2/day, continuously
infused over Days 1 ? 5. Hospitalization was required
for the administration of chemotherapy and for appropriate hydration, antiemetic therapy, and monitoring
of fluid balance and urine output. Prior to each cycle
of therapy, blood counts and serum creatinine were
determined. After discharge, patients were followed on
a weekly basis and monitored for drug-related toxicity.
Dose modification or treatment interruption was
required in the event of significant toxicities. A chemotherapy cycle was postponed for 1 week if the neutrophil count was �00/mL or if the platelet count was
�,000/mL. Cisplatin was discontinued for Grade 3
ototoxicity, if serum creatinine was elevated to 2 mg/
dL, or if creatinine clearance diminished to �/mL/
minute at the initiation of the next cycle. The duration
of 5-FU infusion was reduced by 1 or 2 days with the
occurrence of severe mucositis or myelosuppression
in the previous cycle. If intolerable toxicity occurred
or if there was disease progression noted during chemotherapy, patients proceeded to definitive local therapy.
After the planned three cycles of chemotherapy,
repeat endoscopy and formal assessment of response
status were performed. Definition of clinical response
is outlined as follows:
CR: The disappearance of all endoscopically visible
and palpable tumor for at least 28 days. A histologic CR
required either surgical resection with no pathologic
evidence of tumor or convincing biopsies of the tumor
bed that were free of malignancy.
PR: Shrinkage of measurable disease by at least 50%
of the product of the two longest perpendicular dimensions of the indicator lesion, lasting 28 days or
longer.
Disease progression: Increase by at least 25% in the
size of the indicator lesion, or the appearance of new
lesions or death while the patient was on study.
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TABLE 1
Treatment Schema
Diagnosis r
Staging r
PF 1 3 r
Surgery and/or radiation r
PF 1 3
PF � Cisplatin, 100 mg/m2 on Day 1 and
5-FU, 1000 mg/m2/day on Days 1-5
by continuous i.v. infusion (cycle
repeats every 3 weeks)
PF: combination of cisplatin plus infusional 5-fluorouracil; 5-FU: 5-fluorouracil; i.v.: intravenously.
Stable disease (SD): Less than a partial response, but
without evidence of disease progression.
After completion of therapy, patients were followed regularly with physical examination and repeated endoscopies. CT scans were performed if clinical indications developed. Overall survival was calculated from the time of enrollment on the study to the
date of death or to the date of the last clinical evaluation. Progression free survival was calculated from the
time of enrollment on the study to the time of documentation of progressive disease, or treatment-related
death. Development of a new primary cancer constituted a failure and was clinically considered in the
calculation of progression free survival. Finally, patients were evaluated for the development of late toxicity.
RESULTS
Between February 1982 and June 1983, 81 patients
with locally advanced squamous cell carcinoma of the
head and neck were enrolled by the 9 participating
institutions.
Four patients were considered ineligible because
they had poor performance status and did not meet
the eligibility criteria. Six patients interrupted therapy
after one or two cycles of induction and were considered inevaluable for response: two declined therapy,
three were lost to follow-up during induction, and one
underwent surgery after one cycle of induction chemotherapy. This was considered to be a major protocol violation. Patient characteristics for the remaining
71 eligible and evaluable patients are described in Table 2. All patients had an ECOG performance status of
0, 1, or 2 and the most common primary site was the
oropharynx. Two patients died with septic complications during induction and were considered to be
treatment failures. After induction chemotherapy, 23
patients were considered to be in CR and 36 patients
in PR. The CR status was confirmed histologically in
15 of 23 patients. Five patients had negative biopsies of
the tumor bed and ten patients had surgical specimens
that were histologically free of tumor.
Definitive local therapy was given to 69 patients.
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TABLE 2
Pretreatment Characteristics of Evaluable Patients (n � 71)
Gender
Male
Female
Age (yrs)
Range
Median
Stage
III
IV
T2
T3
T4
Site
Oral cavity
Oropharynx
Hypopharynx
Larynx
Sinuses
52 (73%)
19 (27%)
34?78
59
22 (31%)
49 (69%)
N0
0
15
13
N1
5
2
6
N2
4
7
8
N3
3
7
1
14
28
15
10
4
Eight patients had surgery only, 38 had surgery followed by radiotherapy, and 23 had radiotherapy alone.
There was no recognized increase in perioperative
complications and no deaths associated with the local
therapy. At the completion of surgery and/or radiotherapy, 54 patients were clinically and radiologically
free of disease. As noted above, 23 patients had CR to
neoadjuvant chemotherapy and 31 patients achieved
disease free status only after local therapy.
After local therapy, adjuvant chemotherapy was
administered in 22 patients and 18 completed the total
of 3 planned cycles. By protocol design, all 59 responders should have been treated with further chemotherapy, but this was compromised by reluctance of patients and physicians to resume chemotherapy, even
after a substantial earlier response. The high percentage of patients noncompliant to the adjuvant program
is similar to the experiences reported by Ervin et al.10
and the Head and Neck Contracts Program.5
With an overall median follow-up of 30 months
(range, 1 ? 160 months), there were 13 patients alive
and free of malignancy. Eleven presented with stage IV
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Chemotherapy of Squamous Cell Carcinoma of the Head and Neck/Athanasiadis et al.
FIGURE 1. Overall survival.
FIGURE 2. Progression free survival.
disease, and 9 of these patients had N2/3 involvement.
Median follow-up in survivors was 12 years (range,
8.5 ? 13.3 years). Nine of the 13 patients never experienced progression or second primary cancer. Two patients had successful surgical salvage for second local
cancers (at 28 months and 89 months, respectively).
One patient had both recurrence of the primary tumor
(38 months) and a second primary lung carcinoma (20
months), that were surgically salvaged. There were no
survivors with clinical evidence of malignancy at the
last follow-up.
Overall survival for the entire group of 71 patients
was 34% at 5 years and 21% at 10 years, with a median
survival of 30 months (Fig. 1). Progression free survival
was 24% at 5 years and 17% at 10 years, with a median
time to failure of 22 months (Fig. 2).
There have been 58 deaths: 44 from progressive
disease, 8 from second primary malignancies, 4 from
unrelated causes, and 2 from chemotherapy-induced
toxicity.
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591
Second primary malignancies were noted in 9 patients and were observed at a median time of 36
months (range, 8 ? 70 months). There were four second
primary lung carcinomas and three second primary
head and neck carcinomas. Esophageal carcinoma
and malignant ascites with adenocarcinoma of an unknown primary tumor accounted for the other two
second primary tumors. There was incomplete information regarding posttreatment tobacco use patterns.
Overall survival and progression free survival were
not different among patients who had CR versus those
with PR versus those with no response to induction
(Fig. 3). However, the latter group was small. Of note,
no differences emerged between patients who received or did not receive adjuvant chemotherapy (Fig.
4).
Chemotherapy-related toxicity is described in Table 3. There were two treatment-related septic deaths
with induction chemotherapy, whereas there were no
toxic deaths with adjuvant therapy. Otherwise, toxicities were similar for the neoadjuvant and the adjuvant
components, and they are analyzed together.
Myelosuppression and mucositis were the most
common toxicities. Renal toxicity also was observed,
mostly in the form of tubular dysfunction, with electrolyte wasting. Although azotemia was documented
briefly after cisplatin chemotherapy, it was mostly reversible, and dialysis was not required in any of the
patients. Dermatitis and nausea were less common.
Late toxicity was moderate. Among 23 patients
surviving at least 6 years after enrollment, there have
been 3 cases of hypothyroidism requiring thyroid hormone supplementation. This occurred presumably
secondary to radiation effects. Xerostomia was consistent with usual radiation effects, and not incapacitating. According to record review, nine patients were
alive with an acceptable quality of life by ECOG performance standards (0/1) without significant swallowing
or speaking problems, or clinical manifestations of
other serious late toxicity. Four patients with similar
good quality of life were last seen at 102, 104, 117, and
132 months of follow-up.
DISCUSSION
A mature analysis of 81 prospectively evaluated and
treated patients with locally advanced squamous cell
carcinoma of the head and neck is presented. Treatment involved a sequential multimodality therapy
schedule. Induction PF resulted in an 83% response
rate with CRs observed in 32% of patients and histologically confirmed in the majority of these patients. The
response rates were similar to those reported in other
studies of induction PF. Local therapy was completed
without an appreciable increase in complications or
deaths. Adjuvant chemotherapy was administered to
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CANCER February 1, 1997 / Volume 79 / Number 3
FIGURE 3. (A) Overall survival by response status. (B) Progression free survival by response status.
FIGURE 4. (A) Overall survival by adjuvant treatment. (B) Progression free survival by adjuvant treatment.
TABLE 3
Chemotherapy-Induced Toxicity-Number of Patients by Most Severe
Grade Toxic Effect
Toxicity
Grade:
Dermatitis
Mucositis
Myelosuppression
Nausea/emesis
Nephrotoxicity
Ototoxicity/neurotoxicity
Thrombocytopenia
1-2
3
4
1
16
18
12
3
5
1
1
13
11
13
1
0
0
0
0
5
0
0
0
0
a minority of patients, primarily because of poor compliance by both patients and physicians. The acute
toxicity of the entire treatment program was predictable and acceptable.
The reported median survival of 30 months with
15% of patients alive with no evidence of malignancy
at long term follow-up was consistent with survival
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expected in patients treated with local therapy only.
This Phase II study failed to indicate that systemic
therapy provided major benefit. Responders to induction chemotherapy did not exhibit better long term
outcome than nonresponders. Also, there was no difference in outcome between patients who received or
did not receive adjuvant therapy, although the small
number of patients analyzed may have prevented a
significant conclusion regarding this issue. Moreover,
the patients who actually received adjuvant chemotherapy would have been expected to be a favorable
group, both from the standpoints of compliance and
general performance. Of the 13 patients alive and disease free, 11 had Stage IV disease; thus, summary stage
did not relate to prognosis in this study, and the numbers are insufficient to identify prognosis according to
site.
Notably, nine patients with disease that was otherwise controlled developed second primary malignancies. The pattern was of tobacco-related processes:
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Chemotherapy of Squamous Cell Carcinoma of the Head and Neck/Athanasiadis et al.
four lung carcinomas, three head and neck carcinomas, and an esophageal carcinoma. The median observed time to these events was 3 years and long term
survivors were clearly at high risk, which may escalate
with time. This is in contrast to the incidence of tumor
recurrence, which declines after 2 years.
The small number of patients who remained disease free at last follow-up enjoyed good quality of life.
Although side effects were observed and organ preservation was not an objective in this study, none of the
surviving patients had unexpected significant sequelae
of chemotherapy or radiotherapy. Xerostomia and hypothyroidism were observed. Late neurologic deficits
were not noted. The surviving patients had no other
evident treatment-related dysfunction and they were
able to return to work or to usual daily activities.
Almost 15 years after the design of this study,
well conducted randomized trials have been completed, and the long term efficacy of neoadjuvant
and adjuvant chemotherapy has been studied.11 The
Head and Neck Contracts Program5 accrued a large
number of patients with locally advanced head and
neck carcinoma. Induction with cisplatin for one cycle was suboptimal and response rates were unacceptably low. Overall survival benefit with chemotherapy was not shown. In another randomized
study,6 the Southwest Oncology Group used a more
active induction regimen and the overall response to
induction was 70%. Patients who received induction
had decreased incidence of distant metastases, but
additional survival for the experimental arm was not
observed.
The VA Larynx Study7 and the Italian Cooperative
Group9 applied the PF induction regimen, for three
and four cycles, respectively. The incidence of distant
metastases was decreased but there was no improvement in survival. A subset analysis of unresectable patients in the Italian Cooperative Study showed that
four cycles of induction therapy achieved a small but
statistically significant prolongation of survival.
Adjuvant chemotherapy has not been extensively studied in patients with head and neck carcinoma. A randomized study of 448 patients, in which
PF was administered after surgery in the experimental arm, failed to show a significant survival benefit
despite a decreased incidence of distant metastases
as the first manifestation of failure.8 Also, in the National Cancer Institute-sponsored Head and Neck
Contract Program, one-third of the enrolled 462 patients were randomized to receive six cycles of adjuvant cisplatin.11 Despite poor compliance, the adjuvant arm had a decreased incidence of distant metastases, suggesting systemic biologic activity for
adjuvant chemotherapy in head and neck carcinoma, but with no impact on local control. Success-
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593
ful preservation of the larynx in two-thirds of the
patients in the VA Larynx Study argues for major
efforts for organ preservation and has introduced
quality of life as a significant endpoint in head and
neck carcinoma studies. Neither local control nor
long term survival are improved with PF. Further
study of induction chemotherapy does allow for the
evaluation of new drug combinations. Vokes et al.
modified the basic PF schedule and recently reported a Phase II trial of cisplation, 5-FU, and leucovorin and interferon-a has achieved 100% response
rates in previously untreated patients.12,13 In addition, the combination of cisplatin with paclitaxel as
a 24-hour infusion is currently being investigated by
ECOG in a study of dose escalation.14 These regimens would be appropriate for further investigation
of neoadjuvant or adjuvant chemotherapy. Concomitant or alternating chemoradiotherapy appears to
improve local control and is a promising alternative
strategy that is another focus of current trials.15
This ICC trial is consistent with the results of other
induction chemotherapy trials, with a mature analysis
revealing 21% survival at 10 years. Current investigations are directed toward the identification of more
active chemotherapy, concurrent chemoradiation
schedules, and chemoprevention.
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