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Annals of Surgical Oncology 10:645-653 (2003)
© 2003 Society of Surgical Oncology

ORIGINAL ARTICLES

Carcinoma of the Head and Neck: A 5- to 20-Year Experience With Preoperative Chemotherapy, Uncompromised Surgery, and Selective Radiotherapy

John M. Loré, Jr, MD, Sol Kaufman, PhD, Nan Sundquist, RN and Kandala K. Chary, MD

From the Head and Neck Center (JML, NS, KKC), Sisters of Charity Hospital, Buffalo, New York; and State University of New York (SK), Buffalo, New York.

Correspondence: Address correspondence and reprint requests to: John M. Loré, Jr, MD, Department of Head and Neck Surgery, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY 14263; Fax: 716-845-8646.


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 CONCLUSION
 REFERENCES
 
Background: A 5- to 20-year evaluation of preoperative chemotherapy uncompromised surgery and selective radiotherapy in stage III/IV head and neck squamous cell carcinoma.

Methods: Eighty-two consecutive patients, single surgeon previously untreated, operable, and resectable for cure. Sites included the oral cavity, oropharynx, larynx, and hypopharynx. Two chemotherapeutic regimens were used: initial regimen (A), cisplatin/bleomycin (n = 45 patients); revised regimen (B), cisplatin/5-fluorouracil (n = 37 patients). The extent of surgery was carefully documented before chemotherapy—tattoo when feasible. This forms a strict guide for uncompromised surgery. Selective postoperative radiotherapy was based on specific criteria.

Results: Minimum follow-up was 5 years. Absolute survival: total group, 60%; regimen A, 46%; and regimen B, 77% (P = .004). Relative survival (correcting for life table mortality): total group, 66%; regimen A, 50%; and regimen B, 83% (P = .003). Recurrences: primary site, n = 9 (regimen A, n = 7 [16%]; regimen B, n =2 [5%]) and neck, n = 6 (13%, all in regimen A). Distant metastasis occurred in 12 patients (10 [22%] in regimen A and 2 [5%] in regimen B).

Conclusions: This study suggests treatment of advanced head and neck squamous cell carcinoma (resectable for cure) with preoperative chemotherapy (regimen B); resection of original tumor volume, regardless of response to chemotherapy; and selective (rather than routine) postoperative radiotherapy results in improved survival. More controlled studies are recommended.

Key Words: Head and neck cancer • Preoperative chemotherapy • Survival analysis • Treatment evaluation • Postoperative radiotherapy


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 CONCLUSION
 REFERENCES
 
Management of locally advanced squamous cell carcinoma of the head and neck (LASCCHN) continues to present a challenge because of relatively poor survival rates and a high incidence of functional impairment among survivors. Since the 1970s, the conventional treatment for resectable tumors has been surgery with postoperative radiotherapy (with 5-year survival rates ranging from 10% to 60%).1–6

In more recent years, significant strides have been made toward improved functional outcome, most notably preservation of speech, through the use of combined chemotherapy and radiotherapy (sequentially or concurrently), with surgery reserved for salvage of treatment failures,7–11 but the effect of this approach on overall survival rates remains to be fully clarified. A further concern with this approach is the development of significant surgical complications in irradiated tissues when salvage resection is subsequently required (a problem that beset head and neck surgeons in the 1950s and 1960s when preoperative radiotherapy was in vogue).

Reported studies on preoperative chemotherapy as an additional adjuvant or substitute for postoperative radiotherapy, although initially promising, have tended to be equivocal.12–15 From review of these earlier studies and from personal experience, the principal author of this article (J.M.L.) formulated an approach to preoperative chemotherapy that does not diminish the subsequent ablative resection. This led to a treatment protocol that places the highest priority on improved survival. Quality of life (particularly speech and deglutition), which remains a concern, is addressed primarily through improved reconstructive procedures and complementary therapies.

The essential aspects of this treatment protocol are preoperative chemotherapy, surgery uncompromised by any favorable response to the chemotherapy, and selective postoperative radiotherapy based on specific criteria. The primary tumor sites targeted are the larynx, hypopharynx, oropharynx, and oral cavity. The underlying rationale for this approach derives from the following observations:

  1. Chemotherapeutic agents appropriate for LASCCHN can cause appreciable, even dramatic, reduction in gross tumor (and, by implication, in microscopic distant disease).
  2. Shrinkage of gross tumor is not necessarily accompanied by corresponding control of all microscopic disease in the region of shrinkage.
  3. Postoperative radiotherapy can cause significant sequelae that often impair patient functional status and complicate subsequent salvage resections.

The protocol commenced in 1979 and continues to date. Details of the protocol and early results were published in 1995.16 This article is a 5- to 20-year evaluation and follow-up of patients entered between 1979 and 1994. A total of 93 patients were entered during this period. However, five patients refused resection after completion of chemotherapy, and six patients were deemed medically inoperable after chemotherapy (although their tumors remained resectable). Hence, 82 patients completed the protocol and represent the principal subjects of this report.


   PATIENTS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
RESULTS
 DISCUSSION
 CONCLUSION
 REFERENCES
 
All patients entered onto the study were consecutive and those of a single surgeon and presented with previously untreated stage III or IV squamous cell carcinoma of the oral cavity, oropharynx, larynx, or hypopharynx. All were deemed operable and resectable for cure.

Chemotherapy
Regimen A used a combination of bleomycin and cisplatin (cisplatin 80 mg/m2 intravenously [IV] day 1—considered the appropriate dose at that time—and bleomycin 15 mg/m2/day IV days 1 to 5 by continuous infusion). As evidence regarding the relative efficacy of chemotherapeutic agents in LASCCHN accumulated, regimen B was adopted; it replaced bleomycin with 5-fluorouracil (cisplatin 80 mg/m2 IV day 1 and 5-fluorouracil 1000 mg/m2/day IV days 1 to 5 by continuous infusion). Most patients received two courses of this combination separated by a 3-week interval. During the last few years of patient entry, the cisplatin dose was increased to 100 mg/m2 and the number of courses was increased to three or more to reflect evolving practice. Most patients receiving regimens A and B were treated without dose modification. When dose reductions were required because of neutropenia or other toxicity, standard criteria were pursued. Of the 82 patients who completed the protocol, 45 were treated according to regimen A and 37 according to regimen B (Table 1).


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  		TABLE 1. Distribution by site, stage, and treatment regimen
 
Surgery
The resections—including all ablative procedures (no significant portion was conducted by a resident, fellow, or other attending surgeon) and 95% of the reconstructive procedures—were performed by a single surgeon (J.M.L.). Follow-up of all patients was performed primarily by the operating surgeon monthly the first year, every 2 months the second year, every 3 months the third year, every 4 months the fourth year, every 5 months the fifth year, and every 6 months thereafter. Resection was based on meticulous pretreatment evaluation of the primary cancer by the surgeon. The T stage was predicated on ulceration and the extent of the firm, submucosal indurated mass. Computed tomographic and magnetic resonance imaging scanning were used. Palpation was considered a very important feature of physical examination. Areas of edema and fullness were included in wide resection of the primary tumor but did not alter the T classification.

The critical task of documenting the extent of the primary tumor before chemotherapy was conducted by tattoo, photography, or both and was recorded on stamps or printed diagrams. The operation was planned intending no modification or compromise in the extent of resection after induction chemotherapy, although the resection might be extended if indicated in the course of the procedure.

Oral cavity primary tumors were resected with margins of 1 to 2 cm. With unilateral palatal tumors, the uvula and portions of the contralateral palate were removed, along with dissection of the ipsilateral parapharyngeal space, as indicated. In the oropharynx, margins were 1.5 to 2.5 cm and continued into the parapharyngeal space. Often, portions of the palate and juxtaposed tongue were included. Tongue-base tumor margins were generally >1.5 to 2.5 cm because a lack of fascia in tongue muscles allows deep invasion of the muscle. All stage III/IV tumors of the larynx required total laryngectomy and, at times, portions or all of the hypopharynx. Stage III/IV tumors of the hypopharynx usually required total hypopharyngectomy and total laryngectomy. A narrow strip of mucosa was not preserved for the gullet.

For patients with clinical cervical nodal metastases, a classical radical neck dissection (RND) was performed. The RND was modified with preservation, repair, or nerve grafting of the spinal accessory nerve when there was no disease at level II and/or V and with preservation of the contralateral internal jugular vein in bilateral neck dissection. RNDs were performed in 77 patients, 3 of whom had concomitant contralateral suprahyoid neck dissections. Two patients had suprahyoid neck dissection alone, and three were treated without neck dissection. No functional or other selective neck dissections were performed.

Cervical skin and platysma reconstructive flaps were used only after a concomitant neck dissection. Deltopectoral flaps were used initially for soft tissue defects but were subsequently supplanted by pectoralis major myocutaneous flaps, which were also used for reconstruction of the hypopharynx and proximal cervical esophagus. Posterior tongue flap and dermal graft were also used for the hypopharynx. Levator scapula muscle flaps were sometimes applied to cover carotid vessels, and forehead flaps were used early in the series for cheek and intraoral reconstruction. Segmental resections of the mandible were generally reconstructed with double-bent pins. Reconstruction plates were occasionally used. Only two microvascular free tissue reconstructions were performed.

Routine frozen-section analyses of margins of both the operation site and the specimen were performed during the resection and were evaluated by both the surgeon and pathologist. If frozen-section analyses showed tumor involvement, the area was re-resected until it was clear of disease. Five hundred frozen sections were performed on 80 of the 82 patients, with 285 frozen sections at the primary site and 215 of the neck.

Radiotherapy
Criteria for selective postoperative radiotherapy were adapted, with modifications, from the head and neck cancer management guidelines published in 1979 by the National Institutes of Health,17 as follows:

  1. Highest or lowest neck dissection node positive.
  2. Margins positive (on permanent section).
  3. Extracapsular nodal spread.
  4. Extension of disease beyond the fascial planes of the neck.
  5. Invasion of deep cervical musculature.
  6. Recurrence within 6 weeks.

Statistical Analysis
Survival curves were estimated by the Kaplan-Meier method. Standard errors for confidence bounds and t-tests were calculated by using Greenwood’s formula. Overall differences between two survival curves were evaluated with the Mantel-Haenszel (log-rank) test.18 Survival time was measured from the start of chemotherapy to patient death (regardless of cause) or was censored as of the patient’s last follow-up date. This yields an estimated absolute probability of survival from all causes of death.

To focus on the effect of disease on survival, the expected mortality of the patients (had they not had the disease) was removed via an adjustment for normal age/sex mortality based on the National Center for Health Statistics 1997 life table.19 A second set of Kaplan-Meier survival curves was thereby generated and labeled "relative survival." These curves may be interpreted as an estimate for the probability of surviving the disease itself (unaffected by competing causes of death).


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
DISCUSSION
 CONCLUSION
 REFERENCES
 
Survival
The median follow-up of patients alive at last follow-up was 7.6 years (regimen A, 12.9 years; regimen B, 6.3 years). Absolute survival for the entire study group from the start of preoperative chemotherapy is shown in Fig. 1. The results for regimens A and B separately are shown in Fig. 2. Analogous results for estimated relative survival are shown in Figs. 3 and 4Go. Most cancer-related deaths seem to take place during the first 6 years of follow-up. After 6 years, the mortality seems similar to that from sex-and age-specific mortality for the overall US population.



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  		FIG. 1. Estimated absolute survival for the total study group (n = 82) with 95% confidence intervals.

 


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  		FIG. 2. Estimated absolute survival in regimens A and B.

 


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  		FIG. 3. Estimated relative survival for the total study group (n = 82) with 95% confidence intervals.

 


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  		FIG. 4. Estimated relative survival in regimens A and B.

 
Five- and 10-year survival probabilities are listed in Table 2. Selection of regimen was not predicated on patient or disease characteristics, and other facets of management were similar, so the relative effectiveness of the two regimens may be compared. In comparison of 5-year intervals, regimen B showed superior survival compared with regimen A (P = .003 and .004, respectively). However, 10-year survivals did not differ significantly. Statistical power here is limited by the small number of regimen B patients followed up for 10 years.


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  		TABLE 2. Selected survival probabilities
 
Survival analysis of the stage III (n = 24) and stage IV (n = 58) subgroups of the 82 patients revealed no significant difference. Estimated 5-year absolute survivals by major primary tumor site classification were larynx, 72%; hypopharynx, 36%; oropharynx, 52%; and oral cavity, 72%.

An alternative subgrouping was analyzed on the basis of the observed chemotherapy response. When patients had clinically positive nodes, a summary chemotherapy response was computed by averaging responses at the primary tumor site and in the neck. The 82 patients were partitioned into 4 groups:

  1. Maximal responders (>=90%; n = 18; 8 with regimen A and 10 with regimen B).
  2. Partial responders (50%–90%; n = 44; 22 with regimen A and 22 with regimen B).
  3. Minimal responders (<50%; n = 18; 13 with regimen A and 5 with regimen B).
  4. Response data missing (n = 2).

Two patients with tumor progression were included among minimal responders. Five-year absolute survival estimates for the first three groups were 70%, 68%, and 27%, respectively. The difference between partial and minimal responders was statistically significant (P = .002).

Complications
Significant complications due to chemotherapy are listed in Table 3. Three patients experienced 1- to 3-week delays in resection because of hypokalemia, myelosuppression, and pancreatitis. Sixty-six patients received two courses, seven received three or more courses, and nine received only one course. Two patients underwent resection because of progression during the first course.


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  		TABLE 3. Chemotherapy toxicities/complications affecting therapy
 
Life-threatening surgical complications included one intraoperative death from myocardial infarction, one respiratory failure, and one perforated gastric ulcer, with recovery. Additional surgical complications are listed in Table 4 and do not differ from those anticipated without preoperative chemotherapy.16,20 Two patients required repeat dilation of stricture.


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  		TABLE 4. Surgical complications (non–life-threatening; N = 82)
 
Virtually all patients had tracheotomies and feeding tubes. Four patients had temporary tracheotomies maintained from 20 days to 4 months. Thirty-one patients had permanent stomas associated with total laryngectomy (18 larynx, 9 hypopharynx, and 4 oropharynx). Gastrostomies were required in three patients.

Vascular Involvement
Two patients had unresectable metastatic disease about the internal and common carotid arteries. No carotid artery resections were required, in contrast to the principal author’s (J.M.L.) prior experience.21

Radiotherapy
Nineteen patients (23%) received radiotherapy. Eight patients (10%) received it within 6 weeks of resection for protocol-specified indications, as detailed in Table 5. Twelve patients received radiation at intervals exceeding 6 weeks to treat recurrence. Details are listed in Table 6.


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  		TABLE 5. Early selective postoperative radiotherapy N = 8
 

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  		TABLE 6. Late postoperative radiotherapy N = 12
 
Recurrences
Nine patients had recurrence at the primary tumor site, as shown in Table 7. There was a significantly higher recurrence rate for oropharyngeal tumors in comparison to all other sites (P = .02).


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  		TABLE 7. Primary tumor site recurrences N = 9
 
All six neck recurrences occurred in regimen A patients (13%). This differed significantly from the zero neck recurrence rate in regimen B (P = .03). All six patients died of disease.

Distant Metastasis
Distant metastases occurred in 12 patients (15%): 10 (22%) of 45 patients treated according to regimen A and 2 (5%) of 37 patients treated according to regimen B (P = .03). Patients with carcinoma of the hypopharynx had a 40% incidence of distant metastases; this was significantly greater than that of all other sites (P = .015)

Patients Excluded From the Study
Outcomes for the five patients who refused resection after the completion of chemotherapy are listed in Table 8, and those for the six patients who proved inoperable (on medical grounds) after chemotherapy are listed in Table 9.


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  		TABLE 8. Noncompliersa (n = 5)
 

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  		TABLE 9. Medically inoperable patientsa (n = 6)
 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
CONCLUSION
 REFERENCES
 
An objective of this treatment protocol was to ascertain whether preoperative chemotherapy followed by the originally needed resection plus the selective addition of postoperative radiotherapy improved survival compared with surgery followed by routine postoperative radiotherapy (the latter combination was widely recognized as standard treatment for LASCCHN at the time of the initiation of this study). Within the confines of the principal author’s (J.M.L.) practice, this was the case. In our first report,16 a more limited assessment was attempted via a comparison of a subset of 37 patients with 37 controls from the Head and Neck Contracts Program14 who were retrospectively matched by site and stage. The resulting 5-year survival of 62% for our patient subset compared with 35% in the Contracts Program controls seemed substantial but proved equivocal (P = .07). Objective assessment of the entire series is not possible because the experience does not reflect a randomized, controlled trial (RCT). Additionally, "The nature of the RCTs is that they are difficult to use to evaluate surgical techniques."22 However, regimen B’s 5-year absolute survival of 77%, compared with the range of 10% to 60% reported in the literature,1–6 suggests the promise of a treatment paradigm that warrants further investigation.

It is not possible to definitively explain the markedly improved survival under regimen B relative to regimen A. Possible considerations are (1) greater effectiveness of 5-FU over bleomycin for LASCCHN, (2) a shift to a higher cisplatin dose and to three courses of chemotherapy (which took place toward the end of the study period), (3) disparities in the distribution of primary tumor sites, tumor-node-metastasis classifications, and staging between the two regimens, and (4) advances in supportive care. Regimen A had a higher proportion of poorer-prognosis patients with oropharyngeal and hypopharyngeal tumors. Regimen B had a higher proportion of stage IV patients (76%) than did regimen A (67%; data not shown). The nearly equivalent survival rates observed in the stage III and IV subgroups could be because more patients with poorer-prognosis stage IV disease were treated through the more effective regimen B. Additional advantages in substituting preoperative chemotherapy for routine postoperative radiotherapy were that (1) radiotherapy was available in the event of nonresectable recurrence and (2) pretreatment tracheostomy was reduced essentially to zero.

The emergence of combined chemotherapy and radiotherapy (either sequentially or concurrently) over the past decade forms an accepted alternative treatment for LASCCHN. The focus of this approach is on organ preservation to enhance quality of life.7–11 In treatment of head and neck cancer, organ preservation has been most closely identified with preservation of the larynx and normal speech. With respect to the quality of life, inability to swallow probably represents a more serious problem than loss of laryngeal speech. In this respect, combination chemotherapy with radiation may not necessarily provide better swallowing than surgical resection, because patients are placed at increased risk for late sequelae, including radiation-induced fibrosis and neuropathy,23 as well as persistent mucositis.

The focus of our protocol is on improved survival while striving by other means to minimize the debilitating effects of treatment. These methods include (1) limiting radiotherapy (which is recognized as a source of long-term complications and as an impediment to subsequent salvage surgery); (2) using reconstructive surgery, implants, and prosthesis; and (3) using supportive services from speech pathologists, prosthodontists, and physiatrists. Hence, this protocol and the chemotherapy/radiation approaches do not necessarily conflict. They may offer choices to patients with widely different values concerning the importance of survival alone in comparison to preserving nearly normal appearance and function.24

The development of this paradigm in 1979 was based on the premise that surgery is the mainstay of treatment for squamous cell carcinoma of the head and neck, with adjunctive roles for other modalities.25 These tenets are still widely accepted: "the most satisfactory treatment is, of course, to completely excise the tumor at the first operation, and perioperative frozen section histological examination is helpful in achieving this end,"26 and "Aggressive surgical resection is the cornerstone of therapy, with increasing roles for both radiation and chemotherapy, especially for organ preservation."27

Bounding the Disease
Documentation of the extent of disease is of great importance if one is to rely on surgery as the backbone of treatment after induction chemotherapy. Tattooing is the preferred method because the time lapse between the original evaluation and resection may exceed 6 weeks. This is too long a time to depend on memory, even when there is a minimal response to the preoperative chemotherapy. Figure 5 demonstrates a lesion with a 90% response to regimen B. The mucosa is intact, but deep to it are viable tumor cells (arrow) that would have been left behind if not for the tattoo, which outlined the pretreatment extent of cancer. Clinical complete response obscuring deep microscopic disease is also observed at other organ sites, e.g., in the rectum: "A significant percentage of clinical complete responders have persistent deep tumors or nodal involvement."28 Despite the substantial number of patients with maximal tumor response to chemotherapy, only one surgical specimen was found to be disease free on pathologic examination.



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  		FIG. 5. Photomicrograph of viable tumor cells (<-) deep to regenerated mucous membrane in patient who had a 90% response (stain, hematoxylin and eosin; magnification, low power).

 
Frozen Section
The regular use of frozen section is supported in the literature.25,29,30 A total of 500 frozen-sections analyses were performed on all but 2 patients. Fifty-eight of these specimens (from 26 patients) were involved with tumor and necessitated further resection.

Local Control
Oropharyngeal sites showed a significantly higher rate of local recurrence. This suggests that resection of a primary oropharyngeal neoplasm should be undertaken with a thorough evaluation of the extent of disease and potentially wider resection. In contrast, the low rate of oral cavity recurrence may be due to more readily accomplished pretreatment evaluation of the extent of disease. Tattooing is more easily accomplished and may be based on inspection, palpation, and cross-sectional imaging studies.


   CONCLUSION
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 CONCLUSION
REFERENCES
 
A multidisciplinary management plan for LASCCHN involving (1) preoperative adjuvant chemotherapy with a combination of cisplatin and 5-fluorouracil; (2) surgical resection as the mainstay of treatment, uncompromised by tumor response to the chemotherapy; and (3) selective postoperative radiotherapy with defined indications seems to reduce the incidence of local recurrence, neck recurrence, and distant metastases and to improve survival. Pursuit of additional corroborative studies is recommended.


   ACKNOWLEDGMENTS
 
The authors thank Dr. Ernesto Diaz-Ordaz, Head and Neck Attending Surgeon, for his helpful evaluation of data.

The acknowledgments are available online at www.annalssurgicaloncology.org.


   FOOTNOTES
 
In a study group of 82 stage III/IV patients, a subgroup of 37 patients treated with cisplatin/5-fluorouracil demonstrated 5-year and 10-year absolute survivals of 77% and 46%. Throughout follow-up, recurrence rates were 9% local, 0% in the neck, and distant metastasis rate was 5%.

Received for publication June 25, 2001. Accepted for publication March 10, 2003.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 CONCLUSION
 REFERENCES
 

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  16. Loré JM Jr, Diaz-Ordaz E, Spaulding M, et al. Improved survival with preoperative chemotherapy followed by resection uncompromised by tumor response for advanced squamous cell carcinoma of the head and neck. Am J Surg 1995; 170: 506–11.[CrossRef][Medline]
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