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© 2003 American Society for Clinical Oncology Primary Chemotherapy in Resectable Oral Cavity Squamous Cell Cancer: A Randomized Controlled Trial
From the Istituto Nazionale Tumori, Milan, Italy. Address reprint requests to Lisa Licitra, Istituto Nazionale Tumori, Via Venezian 1, 20133 Milan, Italy; email: lisa.licitra{at}istitutotumori.mi.it.
Purpose: Prognosis of patients with advanced oral cavity cancer is worth improving. Chemotherapy has been reported to be especially active in oral cavity tumors. Here we repeat the results of a randomized, multicenter trial enrolling patients with a resectable, stage T2–T4 (> 3 cm), N0–N2, M0 untreated, squamous cell carcinoma of the oral cavity. Patients and Methods: Patients were randomly assigned to three cycles of cisplatin and fluorouracil followed by surgery (chemotherapy arm) or surgery alone (control arm). In both arms, postoperative radiotherapy was reserved to high-risk patients, and surgery was modulated depending on the tumor’s closeness to the mandible. Patients’ accrual was opened in 1989 and closed in 1999. It included 195 patients. Results: In the chemotherapy arm, three toxic deaths were recorded. No significant difference in overall survival was found. Five-year overall survival was, for both arms, 55%. Postoperative radiotherapy was administered in 33% of patients in the chemotherapy arm, versus 46% in the control arm. A mandible resection was performed in 52% of patients in the control arm, versus 31% in the chemotherapy arm. Conclusion: The addition of primary chemotherapy to standard surgery was unable to improve survival. However, in this study, primary chemotherapy seemed to play a role in reducing the number of patients who needed to undergo mandibulectomy and/or radiation therapy. Variations in the criteria used to select patients for these treatment options may make it difficult to generalize these results, but there appears to be room for using preoperative chemotherapy to spare demolitive surgery and/or radiation therapy in patients with advanced, resectable oral cavity cancer.
STANDARD TREATMENT for advanced oral cavity cancer consists of a multidisciplinary approach, including surgery and radiation therapy. However, tumor control and survival are unsatisfactory, because only one half of these patients are cured.1 To date, the addition of chemotherapy has not been proven effective. The combination of cisplatin and fluorouracil was shown to give high response rates in untreated patients. Toxicity was mild, and feasibility of both surgery and postoperative radiation therapy was not precluded.2,3 However, a positive effect on local regional control and survival was left to be demonstrated. Three meta-analyses, all published after this trial started, reviewed the use of chemotherapy in advanced head and neck cancer. All three concluded that, in general, chemotherapy was associated with a statistically significant advantage in survival, but that this benefit was small (4% to 6%).4–6 It is interesting to observe that randomized trials seem to show marginal tumoricidal activity of chemotherapy at distant sites, possibly implying that the regimens used were not strong enough. In addition to suboptimal chemotherapy regimens, available data are also difficult to be interpreted for other reasons, such as relaxed selection criteria in terms of tumor site, tumor extension, and local-regional treatment, as well as low statistical power.3,7,8 However, many clinicians do use preoperative chemotherapy in their practice, in the wake of its appealing high response rates.9 The present randomized trial, begun in 1989, focused on preoperative chemotherapy in a highly selected patient population, using a standard chemotherapy regimen. Indeed, randomized trials focusing on specific head and neck sites are very few, and to our knowledge, this is the first one that deals with advanced resectable oral cavity tumors only. The accrual for this multicenter randomized trial lasted 10 years, up to December 1999. The final results of the study are herein reported.
Eligibility of Patients The study was a randomized, multicenter, parallel group comparison trial, coordinated by Istituto Nazionale Tumori of Milan. A multidisciplinary team, including a medical oncologist, a head and neck surgeon, and a radiation oncologist, evaluated all eligible patients.
The study was open to patients who had a biopsy-proven, resectable, stage T2–T4, N0–N2, M0, previously untreated oral cavity squamous cell carcinoma. T2 lesions were included, if they were larger than 3 cm. Tumors extending into the oropharynx were accepted, provided that the lesion was contained within the oral cavity by more than 50%. Pretreatment tumor stage was categorized according to the Union Against Cancer TNM (tumor-lymph node-metastasis) Classification of Malignant Tumors (1987). Exclusion criteria were Karnofsky performance status less than 70, abnormal serum creatinine, white cell blood count Eligible patients were randomly assigned to either primary chemotherapy followed by surgery (chemotherapy arm), or to surgical standard treatment (control arm) after stratification by institution and nodal stage (N0, N1–N3). Randomization was performed on the phone by the Central Operations Office in accordance with stratified lists from permuted blocks of length four. Each patient gave informed consent before entering the study in accordance with the guidelines of the ethics committee of Istituto Nazionale Tumori, Milan.
Patient Population
Table 1  shows the main patient’s and tumor’s characteristics. The two arms were well balanced for all such characteristics. Two patients in the chemotherapy arm were lost to follow-up: one after the occurrence of a second primary tumor at 88 months, and one without evidence of recurrence at 9 months, and another two patients in the control arm were lost to follow-up at 66 and 100 months without evidence of cancer recurrence. As of July 2000, the median follow-up time was 76 months.
Treatment Regimens Chemotherapy. Chemotherapy consisted of cisplatin 100 mg/m2 and fluorouracil 1,000 mg/m2, given as a 120-hour infusion, for three cycles every 21 days.
Before starting chemotherapy the patients underwent clinical examinations: a complete blood count and a biochemistry profile were performed for the assessment of toxicity and response. Toxicity and tumor response were evaluated according to the World Health Organization scale.10 A complete response was defined as the complete disappearance of the whole clinically evident tumor, and a partial response was defined as a Surgery. The resection volume was planned considering the tumor extention at the initial clinical evaluation, but the final surgical choice was left to the judgment of the responsible surgeon, also on the basis of the actual extent at the time of surgery. In any case, a macroscopic safe margin of at least 1.5 cm was mandatory. Surgical procedures included transoral, mandibular swing, pull-through, marginal, or segmental mandibulectomy approaches. In all cases, an ipsilateral neck dissection was associated. Bilateral neck dissection was performed when the tumor extended over the midline. Reconstruction was performed as needed by means of pedicled miocutaneous flaps. Microvascular free flaps, or local skin and/or mucosal flaps, were used in selected cases. Pathologic evaluation. After surgery, all gross specimens were carefully evaluated, and surface-labeled sections were taken. The response to chemotherapy was determined by a thorough examination that included 20 to 25 tumor sections. A complete pathologic remission was defined as the absence of any tumor cell. Microscopic residual tumor was assessed in the presence of scattered foci of a few tumor cells. Radiotherapy. After surgical resection, only high-risk patients received postoperative radiotherapy. High-risk patients were pathologically singled out as those with positive surgical margins and/or invasion of soft tissues of the face (cheek, chin) and/or more than three node metastases and/or extracapsular tumor spread.11–16 Radiation therapy started 4 to 5 weeks after surgery. The target volume in the case of positive surgical margins or soft tissue invasion was considered to be the whole oral cavity, and it was treated with high-energy photon beams with parallel opposite lateral fields up to 50 Gy (1.8 to 2 Gy per fraction, five weekly fractions), followed by a boost dose of 15 Gy to the highest-risk shrunk volume. The neck was treated with up to 45 to 50 Gy on both sides, normalized at 3 cm in 5 to 6 weeks with a large anterior field, shielding the spinal cord by a median block at 35 Gy. In case of well-identified extracapsular spread into the surrounding tissues, a boost dose of 10 to 15 Gy, preferably by electron beam, was administered. Follow-up. Patients were examined every 3 months for the first 2 years and every 6 months thereafter. Chest x-ray was performed every 6 months. Specific examinations were performed whenever signs and/or symptoms possibly related to either the disease, distant spread, and/or second primary was suspected. Statistical methods. The primary end point of the study was the occurrence of local-regional or distant tumor relapse. Another main end point was the incidence of deaths from any cause. Occurrence of second tumors was not considered as an efficacy end point. Time to occurrence of neoplastic events, whichever occurred first, and survival were computed from the date of randomization. Crude cumulative incidence curves of local-regional or distant tumor relapse were estimated as described by Kay and Schumacher,17 regarding second tumors as competing events. Survival curves were calculated by the Kaplan-Meier method. The log rank test was used to compare the hazard of combined local-regional or distant tumor relapse and overall survival in the two arms. The required sample size for the trial was 258 patients, equally divided in the two study arms. This was calculated by using the Freedman’s formula,18 based on the following assumptions: 50% 5-year risk of cancer recurrence in the control group, 5% type I error probability level (for a two-sided test), and 90% power to detect a 20% absolute risk reduction in the treatment arm.
Because of difficult patients’ accrual, the study was closed after enrolling 198 patients. The study power, conditional to the observed number of events, thus diminished to 78%. For this reason, we computed the probability of a Statistical analyses were carried out by using the SAS/STAT User’s Guide.20
Surgical Treatment All patients in the control arm underwent primary tumor resection and neck dissection. Six patients in the chemotherapy arm could not undergo the planned surgery because of death from toxicity,3 cardiac ischemia during chemotherapy,1 development of distant metastases during chemotherapy,1 or refusal of surgery.1 Another two patients underwent a primary tumor transoral resection without neck dissection because of increased surgical risks. In both cases the neck was treated with radiotherapy.
Table 2
No postoperative death occurred. Postoperative morbidity was not substantially different in the two arms (Table 3 ). Hospitalization time was similar in both groups: 21 and 23 days on average for the chemotherapy and the control arm, respectively.
Chemotherapy Sixty-three (64%) of 98 patients in the chemotherapy arm received three full-dose cycles. A dose reduction had to be made in eight patients, whereas drug administration was interrupted in 27 cases, because of lack of response to chemotherapy (11), patient’s refusal (three), toxicity (12), and protocol violation (one; chemotherapy schedule not conforming to the study protocol). Ninety-three patients (95%) developed some chemotherapy toxicity that was severe (grade 3 and 4) in 36 cases (37%) and fatal in three cases (3%): two cardiac accidents and one sepsis. Types and grades of toxicity are reported in Table 4 .
Response to Primary Chemotherapy Eighty-five patients who received at least two cycles of chemotherapy were considered evaluable for clinical response to chemotherapy. Three of these patients were not operated on, because of a cardiac accident (1), development of distant metastases during chemotherapy (1), or refusal of surgery (1), so that only 82 patients were evaluable for pathologic response to chemotherapy. A clinical complete remission (primary tumor and neck nodes) was recorded in 23 patients (27%) treated with chemotherapy. Tongue tumors responded in 56% of cases, whereas lesions of the floor of the mouth responded in 68% of cases. A clinical complete response was observed in 45%, 19%, and 27% of stage II, III, and IV tumors, respectively. Complete or partial clinical regression of the primary tumor was observed in 28 (33%) and 42 (49%) patients, respectively, for a total of 82% objective response rate. A pathologic complete response of the primary tumor was observed in 22 patients (27%), and persistence of microscopic residual disease at the T site was recorded in 15 cases (18%). If considering both primary tumor and regional nodes, 27 patients (33%) had a complete pathologic response or microscopic residual tumor. These results were observed in 63%, 27%, and 18% of stage II, III, and IV tumors, respectively.
Patterns of Relapse and Survival
Patient survival status information is reported in Table 5 . Forty-six patients died in the chemotherapy arm compared with 47 in the control group. Overall survival curves are shown in Fig 4. Five-year overall survival estimates were 55% (95% CI, 45% to 66%) in the treatment arm and 55% (95% CI, 44% to 65%) in the control arm. The log rank test failed to yield any significant result (P = .767).
For exploratory purposes, we broke down the relapse-free survival curve according to response to chemotherapy. Patients achieving a complete clinical response had a 5-year disease-free survival rate equal to 78% (95% CI, 61% to 95%), versus 57% (95% CI, 41% to 74%) and 40% (95% CI, 19% to 61%) in those obtaining a partial or no response at all, respectively: the difference was statistically significant (P = .041). Accordingly, patients with either a pathologic complete response or with minimal residual disease (microscopic residual foci) had a 5-year disease-free survival rate of 85% (95% CI, 71% to 99%), versus 49% (95% CI, 35% to 63%) of cases with evident persistent disease (P = .001).
In this randomized controlled trial, selectively targeted to resectable oral cavity cancer, primary chemotherapy did not add evident benefit to local regional treatment alone. Indeed, significant preoperative downstaging was observed in the chemotherapy arm, which in our hands translated into less demolitive surgery and less postoperative radiation, without compromising either local control or survival. Currently available evidence does not support the use of chemotherapy in addition to surgery in head and neck cancer, although chemotherapy has an established role in organ-preserving integrated approaches based on radiation therapy. In particular, as far as oral cavity cancer is concerned, standard treatment is surgery, followed by radiation therapy in advanced cases. Preoperative chemotherapy has been investigated in head and neck cancer, but the results are still inconclusive, if not negative. Our study is the only randomized trial on primary chemotherapy in operable oral cavity cancer, and its rough conclusions do not support the incorporation of medical treatment in the therapeutic strategy. The long-term activity of chemotherapy as assessed in this study is superimposable on that observed in other studies, which excludes a possible lack of activity of the regimen used, which is, in fact, considered as the standard regimen in head and neck cancer. However, in this study we used less demolitive surgery in the chemotherapy arm (31% v 52% in the control group) without detecting any increased number of positive surgical margins, and less postoperative radiotherapy (33% v 46%). The 95% CI of the difference between the two protocol arms (ranging from 7% to 34%) clearly favors the chemotherapy arm in terms of less demolitive surgery. This occurred at the expense of a toxic death rate of 3% and a reasonable incidence of serious adverse events. In oral cavity cancer patients, demolitive surgery entails mandibulectomy, which translates into significant functional impairment. Although not formally assessed, some effect on quality of life is plausible. Also, radiation therapy has unfavorable functional consequences, particularly after major surgery. In addition, it has been associated with an increased risk of stroke.21 Therefore, a more conservative local approach might represent a clinically relevant benefit in this patient population, which, in principle, could justify the incorporation of chemotherapy in the treatment strategy, at least in selected patients. This would be in line with the organ- and function-preserving approaches currently used in other head and neck cancers. In oral cavity cancer, the benefit would essentially be functional, in terms of better mastication, and cosmetic. It cannot be overlooked that this issue may be a field of controversy, inasmuch as the extent of surgery and the indications to postoperative radiation therapy in oral cavity cancer are still under discussion. Particularly in Europe, systematic postoperative radiotherapy in advanced oral cavity cancer is not universally accepted. It is generally used in the case of positive or close resection margins, soft tissue invasion, nodal extracapsular spread, and/or if there are more than three metastatic nodes.11,16,22–26 In the absence of these risk factors, local control is reported to be fairly good with surgery alone.15,27,28 Moreover, it has already been observed that in patients with advanced resectable cancer, treated with induction chemotherapy, postoperative radiation could be not systematically indicated.29 Even in this study, we used postoperative radiotherapy selectively, only in patients presenting risk factors. For this reason, our study may be viewed as a demonstration that, as long as pathologic risk factors are used to select patients for radiation therapy, chemotherapy may help use radiation therapy less extensively. In regard to segmental mandibulectomy, in this study, a safe margin of 1.5 cm toward the mandible was pursued. This is the reason why downstaging of the tumor in the chemotherapy arm led to less demolitive surgery. Again, surgical policy may vary from center to center, and so there may be substantial variations as to how much preoperative tumor response can affect the extent of surgery. Moreover, surgery has already been recognized as easier and surgical planes as more obvious after preoperative chemotherapy in several cancers and also in head and neck tumors.29 Technical progress may favor less demolitive surgery. Indeed, the local benefit from preoperative chemotherapy is difficult to document in several cancers. Suffice it to mention the value of preoperative chemotherapy in osteosarcoma. In osteosarcomas, chemotherapy increases overall survival; if administered preoperatively, it primarily contributes to make demolitive surgery less frequent, independent of preoperative tumor response. Again, this study can be taken as a demonstration that, as long as our criteria are followed, mandibular-sparing surgery can be resorted to more often after chemotherapy. At least this observation may be useful for some subgroups of patients with a more extensive disease. Of course, all this could be also viewed from a reverse perspective. The potential benefit of primary chemotherapy in terms of survival might have been lost just because less radiation therapy and less surgery were used in the chemotherapy arm, because of the downstaging. However, the evidence supporting this hypothesis is as weak as the controversy is on these subjects within the international community of experts. Indeed, as already known in head and neck cancer,30 a clinical and pathologic complete response proved a strong prognostic factor in this study, predicting a long-term survival rate around 80%. This should let the surgeon feel less uneasy about carrying out more limited surgery after optimal response to preoperative chemotherapy. It is possible that this attitude could leave some room for use of preoperative chemotherapy, at least in those patients with more advanced, or more critically located, disease. In this regard, this study would exclude any detrimental effect of primary chemotherapy, which was suggested by some authors, because of the delay in local-regional therapy and/or the selection of more aggressive cancer cells.31–33 In conclusion, this study could not prove a favorable effect on long-term local control of disease and survival by the addition of primary chemotherapy to a multidisciplinary strategy comprising primary surgery and postoperative radiotherapy in high-risk oral cavity cancer patients. However, present results may indicate the possibility of using primary chemotherapy as a guide for a less-aggressive local approach, at least in selected oral cavity cancer patients. We believe that this possibility may be worth further exploration.
Supported in part by CNR-ACRO, Grant no. 92.02336.pf39, and AIRC (Associazione Italiana Ricerca Cancro). Both L.L. and C.G. contributed equally to this work. Participating institutions and investigators: Ospedale Niguarda Ca Granda, Milan, Italy: E. Colombo, G. Gelosa; Melegnano Hospital, Milan, Italy: F. Zibordi; Centro di Riferimento Oncologico, Aviano Pordenone, Italy: L. Barzan.
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Copyright © 2003 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
4,000 per cubic millimeters, platelet count 
50% reduction in the sum of the product of the longest diameter and the perpendicular one for at least 3 weeks. Patients with either progressive or stable disease after two cycles were addressed for surgical resection. Patients received the third cycle only when a 
