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Combined-Modality Therapy for Locoregionally Advanced Head and Neck Cancer

Combined-Modality Therapy for Locoregionally Advanced Head and Neck Cancer

ABSTRACT: Traditionally, treatment for locally advanced resectable head and neck cancer has been surgical resection followed by postoperative radiation. In unresectable patients, primary radiation has been the mainstay of treatment. In an attempt to improve local control and survival, chemotherapy has been investigated as an adjunct to locoregional treatment. Induction or adjuvant chemotherapy in combination with primary surgical resection has failed to demonstrate an improvement in either local control or survival. Induction chemotherapy followed by radiation therapy is an acceptable alternative to surgical resection for organ preservation. A randomized trial in patients with advanced oropharyngeal carcinoma and another in advanced nasopharyngeal carcinoma have shown an improvement in survival with the use of concomitant chemotherapy and radiation compared to radiation alone. Other prospective randomized trials as well as three meta-analyses also demonstrate improved survival with the addition of concomitant chemotherapy for locally advanced disease. Newer chemotherapeutic agents are currently under investigation, particularly those with radiosensitizing properties. Chemotherapy as part of primary therapy, however, should be used judiciously, and should be based on an assessment of the potential risks and benefits to each patient. [ONCOLOGY 13(Suppl 5):83-91, 1999]


At presentation, 40% of newly diagnosed head
and neck cancer patients have only localized disease, 40% to 50% also
have regional disease, and less than 10% have distant metastases.[1]
The survival for those with early-stage disease (T1-2, N0, M0) is
acceptable, with 5-year survival rates of 70% to 90% with
single-modality therapy.[2] In this setting, the decision to use
surgical resection or definitive radiation is based on surgical or
radiation morbidity, cosmesis, and patient reliability.[3]

For patients who present with large primary tumors or regional
disease (American Joint Committee on Cancer stages III/IV),
historical therapy has been surgery followed by postoperative radiation.

Overall 5-year survival in this cohort is only 20% to 60% with this
approach. The majority of these patients fail locoregionally. Thus,
clinical investigations have centered on methods to decrease
locoregional relapse. Such approaches include neoadjuvant or adjuvant
chemotherapy, neoadjuvant or adjuvant radiation, and the concomitant
use of chemotherapy and radiation. This article will delineate the
current data available from clinical trials investigating
combined-modality therapy for locally advanced head and neck carcinoma.

Primary Surgery With Adjuvant Treatment

Surgery With Radiation

Locally or regionally advanced (T3-4, N0-3) disease has historically
been treated with combined-modality therapy to maximize local control
and survival. Radiation has been investigated in both preoperative
and postoperative settings. Advocates of preoperative radiation cite
a lower risk of positive surgical margins and therefore improved
local control and survival. In addition, lower doses of radiation can
be used preoperatively because of better tumor oxygenation, and tumor
downsizing with radiation can promote surgical resection with a
greater chance for function preservation. Advocates of postoperative
radiation suggest that surgical morbidity is lowest when operating on
nonirradiated tissue; tissue planes may also be easier to identify
and intraoperative frozen section analysis is more reliable. In
addition, postoperative radiation can be tailored according to
pathologic findings, such as nodal status, surgical margins, and
extent of tumor spread.[4]

The Radiation Therapy Oncology Group (RTOG) conducted a randomized
trial (RTOG 73-03) comparing preoperative 50 Gy to postoperative 60
Gy in 277 patients with locally advanced carcinoma of the
supraglottis and hypopharynx. With a median follow-up of 10 years,
postoperative radiation demonstrated superior locoregional control
(70% postoperative vs 58% preoperative, P = .04).[5] No survival
differences were seen (P = .15) (Table

In an attempt to determine the optimal dose of postoperative
radiation for both low-risk and high-risk patients, the University of
Texas M. D. Anderson Cancer Center (Houston) conducted a randomized
trial in the 1980s.[6] A total of 302 patients were assigned to
either low-risk or high-risk groups according to histopathologic
features, such as margin status, T stage, N stage, direct invasion of
tumor into adjacent structures, perineural spread, or extracapsular
nodal extension. Utilizing daily fraction sizes of 1.8 Gy
postoperatively, the study demonstrated that low-risk patients
receiving less than 54 Gy had a significantly higher failure rate
than those receiving at least 57.6 Gy (P = .02); 63 Gy is required
for patients with extracapsular spread. Higher doses than 63 Gy
increased toxicity but did not improve locoregional control.

Surgery With Chemotherapy

During the late 1970s and 1980s, investigators attempted to add
induction chemotherapy to surgery and postoperative radiation.
Theoretically, chemotherapy could convert inoperable tumors to
operable tumors by decreasing tumor bulk, allowing for organ function
preservation and the eradication of micrometastases, thereby
improving survival.

A number of randomized trials have been conducted comparing surgery
(with or without postoperative radiation) vs induction chemotherapy
and surgery. To date, no overall survival benefit has been
demonstrated, despite relatively high response rates to induction
chemotherapy.[7-18] Two trials have demonstrated improved overall
survival in select subsets only (Table
). However, confirmatory prospective randomized data have not
been obtained.

Postoperative chemotherapy has theoretical advantages over a
neoadjuvant approach because (1) the definitive surgical procedure is
not delayed; (2) the number of tumor clonogens is reduced so
resistance is less likely to develop; (3) tumor margins are best seen
by the surgeon de novo, before chemotherapy is administered; and (4)
a substantial number of patients refuse surgery after symptoms
subside with tumor response to induction chemotherapy.

Adjuvant chemotherapy has been evaluated in a number of large
prospective randomized trials. An overall survival advantage has not
been demonstrated, although a number have reported a decrease in
distant metastases. However, many of these trials have statistical or
design flaws. Two recent well-conducted trials confirm the lack of
efficacy of adjuvant chemotherapy. In Japan, 424 patients with
locally advanced head and neck carcinomas were randomized to 1 year
of adjuvant uracil and tegafur (in a molar ratio of 4:1 [UFT]) or
resection alone.[19] Despite a high compliance rate with
chemotherapy, no survival advantage was observed. The RTOG sponsored
an intergroup trial of 442 stage III and IV patients comparing
immediate postoperative radiation to three cycles of cisplatin
(Platinol) and fluorouracil followed by postoperative radiation. No
overall difference was observed in actuarial 4-year survival (44% vs
48%), disease-free survival (38% vs 46%), or locoregional failure
(29% vs 26%).[20] However, chemotherapy-treated patients developed
fewer distant metastases (15% vs 23%, P = .03).

Surgery With Adjuvant Concomitant Chemoradiation

The addition of chemotherapy to postoperative radiation has the
theoretical advantage of utilizing radiosensitization to improve the
efficacy of radiation. Several conflicting randomized trials have
been reported.

Bauchaud et al randomized 88 postoperative patients with
extracapsular nodal disease to receive postoperative radiation alone
or in combination with cisplatin 50 mg weekly.[21] Median and 5-year
survival were significantly improved with the addition of cisplatin
(median survival, 40 vs 22 months; 5-year survival, 36% vs 13%, P <
.01). In addition, a trend toward improved locoregional control was
observed (77% vs 59%, P = .08). Overall, 15% of patients who received
radiation alone (RTOG grade > 2) and 20% of chemoradiation-treated
patients experienced severe complications.

Haffty et al reported improvement in 5-year local recurrence-free
survival (87% vs 67%, P < .015) and disease-free survival (67% vs
44%, P < .03) with the addition of mitomycin C.[22] No overall
survival advantage was seen (56% vs 41%, P = ns).

In a study by Domenge et al, 287 patients with high-risk,
extracapsular nodal extension received postoperative radiation with
or without cisplatin, bleomycin (Blenoxane), and methotrexate.[23]
Patients on the adjuvant chemotherapy arm had significantly worse
overall survival despite an improvement in locoregional control.

In order to clarify the role of chemotherapy given concomitantly with
postoperative radiation, the RTOG is randomizing high-risk
postoperative patients (extracapsular spread, multiple involved
nodes, positive surgical margins) to 60 Gy alone in 30 fractions or
the same radiation with cisplatin 100 mg/m² given on days 1, 22,
and 43. Accrual is anticipated to be completed in early 2000.

Primary Radiation With Adjuvant Treatment
Induction Chemotherapy

A large number of phase II trials have shown the feasibility of
administering single-agent or combination chemotherapy prior to
definitive radiation. The most widely used induction combination has
been cisplatin and fluorouracil, as initially reported by Wayne State
University (Detroit, Mich) in 1982.[24] In 26 evaluable patients, the
most common toxicity was nausea and vomiting, and 26% of patients
developed grade 3 or grade 4 leukopenia. A 19% complete response rate
and a 70% partial response rate (overall response rate, 89%) was
reported using two induction cycles. Similar results have been
demonstrated by other investigators using this combination.

Currently, novel chemotherapy combinations are being evaluated in the
induction setting with the goal of increasing complete response rates
and decreasing toxicity. The most promising new agents at this time
are paclitaxel (Taxol) and docetaxel (Taxotere). Both have
demonstrated single-agent overall response rates of 30% to 50% in
patients with metastatic or locally recurrent head and neck carcinoma.[25,26]

In the induction setting, taxane-based regimens have demonstrated
excellent overall and complete response rates. Investigators at Dana
Farber Cancer Institute (Boston, Mass) conducted a phase I/II trial
evaluating three cycles of induction docetaxel, cisplatin,
fluorouracil, and leucovorin in 23 patients with locally advanced
squamous carcinoma of the head and neck.[27] The maximum tolerated
dose with granulocyte colony-stimulating factor support was docetaxel
60 mg/m² with cisplatin 25 mg/m² administered by continuous
intravenous infusion (CI) for 5 days, leucovorin 500 mg/m² (CI
× 5 days), and fluorouracil 700 mg/m² (CI × 4 days).
Toxicity was substantial. At the maximum tolerated dose, the
incidence of grade 3 or 4 mucositis was 46%, of grade 3 or 4 febrile
neutropenia was 10%, and toxicity-related hospitalization was 35%.
The complete response rate was 61% (14/23), and the partial response
rate was 39% (9/23), for an overall response rate of 100%.

The Vanderbilt Cancer Center (Nashville, Tenn) has reported its
experience with induction therapy using carboplatin (area under the
concentration-time curve [AUC in mg/mL • min] 6.0 to 7.5) and
paclitaxel (135 to 175 mg/m²).[28] The complete response rate
with two to four cycles (median, three) was 53% (10/19), and the
partial response rate was 42% (8/19). The toxicity profile was
favorable: Three patients experienced grade 3 or 4 leukopenia, and
one patient experienced grade 3 thrombocytopenia. One grade 5
toxicity occurred in a noncompliant patient. The cause of death was
presumably nadir sepsis.

Induction chemotherapy has been used prior to definitive radiation in
three distinct settings: In resectable patients for organ
preservation, in patients with unresectable squamous carcinoma, and
in patients with stage III/IV cancer of the nasopharynx. Induction
chemotherapy followed by radiation has become an accepted treatment
option in patients who would otherwise have substantial loss of organ
function with definitive surgical resection. This approach has been
used most commonly in patients with laryngeal, hypopharyngeal, and
base-of-tongue tumors. Phase II data indicate that induction
chemotherapy followed by radiation has acceptable toxicity,
comparable survival outcome to historical surgical controls, and
reasonable rates of organ preservation.

Two sentinel phase III studies have compared induction chemotherapy
with radiation to primary surgery with postoperative radiation. The
Veterans Affairs Laryngeal Cancer Study Group randomized 332 patients
with stage III/IV laryngeal cancer to total laryngectomy with
postoperative radiation or induction chemotherapy with three cycles
of cisplatin and fluorouracil followed by definitive radiation (66 to
76 Gy). Local recurrences were increased in the induction
chemotherapy/radiation arm (P = .0005), although distant metastases
were fewer (P = .016). Nonetheless, the 2-year survival was 68% for
both treatment arms. The larynx preservation rate was 64% with
induction chemotherapy and radiation.[29]

An analogous result was shown by the European Organization for
Research and Treatment of Cancer in 194 patients with locally
advanced hypopharyngeal cancer.[30] Patients went on to 70 Gy
irradiation only after a clinical complete response to induction
cisplatin and fluorouracil. The median survival obtained with
induction chemotherapy and radiation was 44 months vs 25 months for
immediate surgery (P = NS). At 3 years, 42% of patients receiving
induction chemotherapy and radiation retained a functional larynx.
Treatment failures at local, regional, and second primary sites
occurred at the same frequency (12%, 19%, and 16%, respectively, for
surgery, and 17%, 23%, and 13%, respectively, for induction chemotherapy/radiation).

These trials have been criticized because they lack a third treatment
arm with radiation alone. For this reason, an intergroup phase III
trial is ongoing to determine if induction chemotherapy is an
essential component of organ preservation.[31] Treatment arms include
radiation alone (70 Gy), induction cisplatin and fluorouracil
followed by radiation, and concomitant cisplatin with radiation.
Accrual is scheduled to be completed in the next few months.

In the unresectable patient population, the role of induction
chemotherapy is less clear. Paccagnella et al reported the results of
a phase III trial of initial chemotherapy in stage III/IV head and
neck cancer patients.[18] Patients were segregated into two groups:
Those who could undergo primary surgical resection, and those who
were to receive primary radiation. Within each cohort, patients were
randomized to receive induction chemotherapy with four cycles of
cisplatin and fluorouracil or no induction therapy. Results indicate
no survival advantage with induction chemotherapy in patients
undergoing primary surgery. The overall 3-year survival in patients
receiving primary radiation, however, was statistically improved with
induction chemotherapy (24% vs 10%, P = .04).

Similarly, a prospective randomized study comparing radiation
preceded by continuous intra-arterial methotrexate (3 mg/day to 5
mg/day; total dose, 90 mg to120 mg) to radiation alone showed
improvement in overall 5-year survival with the addition of
methotrexate (43% vs 25%, P < .05).[32] In contrast, other trials
investigating induction regimens have failed to consistently
demonstrate an improvement in survival over radiation alone (Table

A third setting in which the role of induction chemotherapy has been
investigated is locally advanced nasopharyngeal cancer. The
International Nasopharyngeal Cancer Study Group recently reported the
results of a phase III trial in 339 patients randomized to radiation
(70 Gy) alone vs three cycles of induction bleomycin 15 mg
intravenous bolus (day 1), plus 12 mg/m²/day CI (days 1 to 5),
epirubicin (Ellence) 70 mg/m² IV (day 1), and cisplatin 100
mg/m² (day 1), followed by radiation.[36] Disease-free survival
was improved in patients receiving induction chemotherapy (41% vs
30%, P < .002). However, no survival advantage was noted (median,
52 months for induction chemotherapy vs 39 months for radiation
alone, P = NS).


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