Annals of Surgical Oncology 8:644-650 (2001)
© 2001 Society of Surgical Oncology
Surgical Resection Is Necessary To Maximize Tumor Control in Function-Preserving, Aggressive Chemoradiation Protocols for Advanced Squamous Cancer of the Head and Neck (Stage III and IV)
H. Wanebo, MD,
P. Chougule, MD,
N. Ready, MD,
H. Safran, MD,
W. Ackerley, MD,
R.J. Koness, MD,
R. McRae, MD,
P. Nigri, MD,
L. Leone, MD,
K. Radie-Keane, MD,
P. Reiss, MD and
T. Kennedy, MD
From the Brown University Oncology Group (PR, TK), Miriam Hospital (HS), Rhode Island Hospital (PC, NR, WA, PN, RM, LL), and Roger Williams Medical Center (HW, RJK, KR-K), Providence, Rhode Island.
Correspondence: Address correspondence and reprint requests to Harold Wanebo, MD, Roger Williams Hospital, 825 Chalkstone Ave., Surgical Oncology, Providence, RI; Fax: 401-456-2035; E-mail: harold_wanebo{at}brown.edu
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ABSTRACT
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Background: The role of surgery in aggressive chemoradiation protocols for advanced head and neck cancer has been questioned because of the quoted high clinical response rates in many series.
Methods: The role of surgical resection was examined in an aggressive neoadjuvant protocol of weekly paclitaxel, carboplatin, and radiation for stage III and IV with completion of radiation to 72 Gy if biopsy at the primary site was negative after administration of 45 Gy. Of 43 patients enrolled, 38 completed the protocol. The clinical response was 100% (including 18 complete and 20 partial responses).
Results: The complete pathologic response (negative primary site biopsy at 45 Gy) was 25 of 38 (66%). Of patients who presented with N1 to N3 nodes, neck dissection revealed residual nodal metastases in 22%. Surgical resection of the primary site was required in 13 patients, including 5 with larynx cancer and 2 with base of tongue cancers. Four patients had resection with reconstruction for advanced mandible floor of mouth cancer, and one had resection of nasal-maxillary cancer. Functional resection was performed in 9 of 12 patients. The median progression free and overall survival was 64% and 68%, respectively, at median follow-up of 50 months. Nine patients developed recurrence (three local and six distant). There were no failures in the neck. Salvage surgery was performed in one patient with local and one with distant disease.
Conclusions: Surgical resection is an essential component of aggressive chemoradiation protocols to ensure tumor control at the primary site and in the neck.
Key Words: Head and neck • Surgical resection • Squamous cancer • Chemoradiation
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INTRODUCTION
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The role of surgery in aggressive chemoradiation protocols for advanced head and neck cancer has been questioned because of the high clinical response rate observed in many series.1–8 We have evaluated a series of neoadjuvant protocols in high-staged patients.9–11 One protocol combined radiation 45 Gy and cisplatin infusion (20 mg/m2/d for 4 days in weeks 1 and 4), followed by surgery in 4 to 6 weeks. This was associated with a high rate of complete or partial response at the primary site (92%) and a 95% clinical response at the nodal site.10 Thirty-six patients were treated without surgery, and 65 patients underwent curative resection. More than 80% of the primary tumor sites and 86% of the neck dissections were tumor free. A modification of this protocol, including preoperative cis-platinum and accelerated high-dose radiation, was associated with a high tumor response and control rate in patients with squamous head and neck cancer.11,12 Eighty-one percent of the primary sites showed a complete pathologic response, and 49% of nodal sites were pathologically free of tumor.
Paclitaxel is a unique radiation sensitizer that has prompted a series of studies by the Brown Oncology Group that explore the use of paclitaxel in a variety of solid tumors.13–23 Paclitaxel enhances microtubular assembly and prevents microtubal depolarization, thus synchronizing (blocking) cells in the G2 and M phases of the cell cycle. This study (Protocol Head and Neck 53) used weekly paclitaxel 60 mg/m2 and carboplatin 1 area under the curve to treat stage III and IV operable head and neck squamous cell cancer.21 A similar protocol also examines the response rate in patients with inoperable cancer.22 The goal in this study was to determine the clinical and pathologic response at the primary site and in the neck. If a biopsy of the primary site was negative after receiving 45 Gy of radiation, completion radiation (22–25 Gy) was given. Neck dissection was also performed only in those patients who presented with N1 to N3 disease. If the patient’s primary site biopsy was positive after 45 Gy, surgical resection of the primary site was performed along with neck dissection for N1 to N3 disease. This study addresses the clinical and pathologic response in the primary site and in the neck, the role of surgery to achieve tumor eradication, functionality of treatment, and the long-term local/regional and distant control rates.
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MATERIALS AND METHODS
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Eligibility
The study was limited to patients with stage III and stage IV squamous cancer of the head and neck who had no previous chemotherapy or radiation to the head and neck. Also required were a Karnofsky performance status of >70 (Eastern Cooperative Oncology Group performance status of 0, 1, or 2), informed consent, and laboratory values consisting of an absolute polymorphonuclear cell count of 1800 cells per cubic millimeter, creatinine clearance of >30 ml/min, serum creatinine <1.5 mg/100 ml, hemoglobin of 9 g %, platelet >100,000, and bilirubin <2.3/100 ml.
Planned Treatment per Protocol
Patients were commonly staged by triple endoscopy, which included bronchoscopy, esophagoscopy, and a detailed laryngoscopy with direct biopsies, received a percutaneous endoscopy gastrostomy to augment nutritional support during the therapy, and had vigorous dental care initiated. The head and neck surgeon, the treating medical oncologist, and the radiation therapist evaluated each patient. A consent form acceptable to the participating institutions was signed, and the data were entered through the data manager. Patients were enrolled through the central Brown Oncology Group office. The patients received 45 Gy (180 cGy fractions) in 5 weeks of therapy with paclitaxel at 60 mg/m2/week given intravenously at the beginning of the week and carboplatin at an initial dose of l x (glomerular filtration rate)/min + 2 (Calvert formula; Fig. 1) This protocol was modified because of toxicity to give the area under the curve of +1 after the first five patients were entered. After the fifth week, the patients were re-evaluated by examination under anesthesia and had a biopsy of the primary site, and then a decision was made whether to proceed to surgery or to complete the chemoradiation. If a biopsy of the primary site was clear, the patient was directed to receive completion chemoradiation and subsequently to have the neck dissection after completion of radiation. The original radiation factors include 4500 cGy to the original volume, 180 cGy/fraction/day for 5 weeks. The patients who had complete pathologic response at the primary site had the area boosted by 2160 to 2700 cGy at 180 cGy/fraction/day for an additional 3 weeks. The total tumor dose ranged between 6660 and 7200 cGy. During this time, paclitaxel was given in the same dosing scheme. In such patients, neck dissection was performed 3 to 4 weeks after completion of radiation. McFee double transverse incisions were performed routinely in the performance of comprehensive neck dissection. Modified radical neck dissections were performed in all cases unless specific sites had been involved by tumor, in which case these sites in the neck were resected.
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RESULTS
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Forty-three patients were entered (33 men and 10 women, ages 37–81 years), of whom 38 were assessable for response at the primary site; 2 patients presented with unknown primary cancers (TxN3M0) and were assessable for overall response to therapy (Table 1). Patients were staged by TNM system for head and neck cancer.24 The study period was February 24, 1995, to June 6, 2000, and median follow-up was 50 months. Two patients were eliminated early (one patient canceled and one progressed). One patient was assessable for toxicity only. Performance status per the Eastern Cooperative Oncology Group was 0 in 17 patients, 1 in 24 patients, and 2 in 2 patients, and there were no patients with a performance status of 3 or 4. The stages in the total group included stage III (14 patients) and stage IV (29 patients). The primary tumor sites were floor of mouth (8 patients), tongue (8 patients), palate or tonsil (2 patients), oropharynx (5 patients), hypopharynx (4 patients), endolarynx (4 patients), supraglottic (9 patients), nasal cavity (1 patient), and unknown primary tumor (3 patients;Table 2). The major toxicities were grade 3 or 4 mucositis and stomatitis (63%), esophagitis (42%), infection (29%), skin breakdowns and rashes (20%), neutropenia (22%), and neuromuscular abnormalities (5%;Table 3).
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TABLE 1. Pretreatment T and N stage in patients receiving preoperative paclitaxel, carboplatin, and radiation for advanced head and neck squamous cancer
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Of the 38 patients assessable for response, 38 showed a clinical response (50% had complete pathological response). Among 20 patients with a clinical partial response, there were 10 patients who had residual cancer at the primary site and 10 patients who had negative biopsies. Of the 18 patients having a clinical complete response, there were 3 patients with residual cancer and 15 patients without cancer at time of rebiopsy (83% complete pathologic response). The total complete pathologic response was 66% (25 of 38) at the primary site (Table 4). Among the patients who had neck dissections after this therapy, 13 patients received preoperative radiation to the primary site (45 Gy); their rebiopsies were positive. These patients required resection of primary site plus neck dissection; one patient refused surgical resection and had completion irradiation. Of 23 patients who had received completion radiation to the primary site (69–72 Gy), 5 of 23 (19%) had positive nodes (Table 5). Among those presenting with clinically positive N1 to N3 nodes before therapy, only 9 of 29 (31%) had nodal metastases at neck dissection, suggesting a reduction in the incidence of nodal metastases by neoadjuvant therapy. Because not all patients had preoperative tissue confirmation of nodal metastases, the true regression rate is not known.
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TABLE 4. Preoperative therapy for advanced head and neck cancer: response at the primary site after chemotherapy/radiotherapy (45 Gy)
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Among the 23 patients who had a complete pathologic response to therapy, there were 10 with laryngeal cancers, 8 with oropharynx, 5 with tongue, and 2 with hypopharynx cancers; 2 patients had unknown primary cancer (Table 6). These patients all received 69 to 72 Gy radiotherapy to the primary site (or presumed site in case of the two patients with unknown primary sites). Thirteen patients had residual cancer at the primary site after 45 Gy and were scheduled for definitive resection of the primary site. These included four with central or lateral mandible involvement, five laryngeal cancers, two base of tongue cancers, and two nasal cavity or maxilla cancers. These were generally high T stage and had more bulky lesions (Table 7). The mandible resections all had foci of cancer in the bone. One additional patient, who had positive rebiopsy of gum/mandible at the 45-Gy time period, had no tumor on final partial mandible resection. In all but one patient, who refused surgery, disease was completely removed as initially confirmed by frozen section with ultimate confirmation of clear margins by permanent section. Two patients (one with nasal cavity cancer and one with an invaded mandible) required additional resection because of positive margin at permanent histology. Temporary tracheostomy was required in eight patients and permanent tracheostomy in three. A permanent tracheostomy was required in one patient treated with chemoradiation alone because of extensive fibrosis and a nonfunctioning larynx.
Protocol Violations
Protocol violations (seven patients) included one patient who had a radiation implant in addition to the resection of the base of tongue cancer; this implant was not sanctioned in the protocol. One patient had radiation boost delayed by the performance of the neck dissection before the radiation (scheduled to be a posttherapy procedure). Chemotherapy doses were incomplete in one patient because of patient refusal, and in one patient a supraglottic laryngectomy was performed instead of the radiation boost.
Surgical Toxicity
One patient developed necrosis of the trachea at the tracheostomy site after a laryngeal resection and required extended pharyngeal laryngectomy. A second patient developed partial failure of a flap. A third patient developed a tracheal arterial fistula approximately 3 weeks after resection. This fistula led to the patient’s death. In that case, the wound was totally intact and seemed secondary to an internal fistula from the innominate artery in the tracheotomized patient. The patient was essentially receiving rehabilitation in a low-intensity care subacute unit. There were no wound healing problems with performance of neck dissection per se in 29 patients. Among all of the patients with gastrostomy tubes, all but three were able to eliminate the feeding tube.
Survival
With minimum follow-up of 45 months (range, 45–60 months) the progression-free survival was 64%, and the overall survival was 68% (Figs. 1 and 2). Thirteen patients’ tumors have recurred, 11 are dead of disease, and 2 are living with disease. First sites of recurrence include local (n = 3), regional (n = 3), and distant (n = 8;Table 7). Retrieval surgery was performed on one patient with local recurrence, and one patient with distant metastases required a lobectomy.
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DISCUSSION
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Preoperative therapy with weekly paclitaxel and carboplatin and concurrent radiation is associated with a high clinical response rate approaching 100% and a 66% rate of complete pathologic response at the primary site. There was also a high clinical response rate in the neck among the patients who had palpable disease. In the 36 patients who presented with clinical nodal metastases in N1 to N3 nodes, only 9 (31%) had nodal metastases documented at time of neck dissection. This suggests significant downstaging in these patients. Of even greater significance is the complete pathologic response that occurred at the primary site in 25 patients who had negative rebiopsy at 45 Gy, thus allowing them to forego surgery and to undertake completion therapy by radiation (69–72 Gy). This provides a high degree of organ preservation, certainly equivalent to any other published protocol. Thirteen patients were found to have residual cancer at the time of primary site rebiopsy (one with larynx cancer refused surgery and was irradiated), and 12 were subjected to resection of the primary site in conjunction with a neck dissection that took place 4 weeks after the radiation. In 10 of 12 patients, there was still residual cancer at the primary site, and in 2 patients there was no longer viable tumor at the primary site. This suggests that the biopsy at 45 Gy was correctly representative of the tumor status 83% of the time and justified the timing of the mandatory biopsy (at 45 Gy). These patients comprised a group having high-risk features that included cancers involving central mandible in three patients, alveolar ridge and floor of mouth from symphysis to retromolar trigone in one patient, larynx in six patients, base of tongue tumors in two patients, and nasal cavity or maxilla in two patients. These patients generally had tumors that had extended to the margins or involved bone and were not controlled by the radiation and chemotherapy. Of interest, however, was the limited tumor in these patients at the time of resection compared with the initial stage, which suggests that the chemoradiation had induced a near complete response even though there was microscopic residual tumor at rebiopsy at 45 Gy. This raises a question of whether the 45-Gy treatment point is an appropriate time for conducting a biopsy, because the demonstration of biopsy-proved disease at this point may underestimate the true effect of chemoradiation. Indeed, in one patient the final resection of the bone and mandible was clear of cancer despite a positive biopsy at the 45-Gy time point. The protocol writing committee agreed on the timing of the biopsy and the use of the pathologic finding to dictate the mode of completing the treatment, either by radiation or surgery. The selection of the 45-Gy biopsy checkpoint also permitted a return to chemoradiation to complete treatment and thus maintained the intensity of therapy and minimized the chance of tumor regrowth.
The patients having complete responses at the primary site included those with tumors of the larynx, oral cavity (exclusive of bone and mandible), hypopharynx, and tongue base. The patients who required resection were generally those with large lesions of the mandible or nasal cavity with bone invasion or who had large laryngeal cancers that did not completely respond to the chemoradiation. In these cases, however, near-complete responses were obtained, and the patient could have a more limited resection with reconstruction and with the achievement of an excellent functional result.
The type of surgery that is required in this type of patient deserves comment. Because of the high rate of completion radiation being delivered, we had made a decision to complete the radiotherapy first and then to provide the patients with neck dissection as needed. Indeed, if a neck dissection is performed within 4 to 5 weeks of the completion of therapeutic radiation (69–72 Gy), this is tolerable and carries minimal surgical toxicity. In patients who received only 45 Gy, the toxicities were fully acceptable and were actually reasonably minimal. A free-tissue transfer was essential in patients with lesions of the central mandible, and we made liberal use of this technique in reconstruction for these patients. Free-tissue transfer for mandible replacement, replacement of soft tissue defects of floor of mouth, nasal cavity or maxilla, and lesions were all used in more than half of the 14 patients who required re-resection. Free-tissue transfer allowed the radiation site to be constructed with fresh tissue and minimized the wound breakdown hazard of resection with local flap reconstructions.
The long-term survival in the patients requiring surgical resection was similar to that of those who had a completion radiation. This suggests that planned surgical resection on the basis of the completeness of the pathologic response to chemoradiation may afford the maximum tumor control at the primary site and in the neck. The use of a biological checkpoint to determine the optimal therapy in this type of chemoradiation protocol would seem to select out patients whose biology is more favorable to control by chemoradiation and also permits early and planned surgical salvage of those who do not respond. We believe that control by surgical resection may be more definitive and predictable without incurring the adverse affects of high-dose radiation without guarantee of final control. A phase II trial is needed to settle the point.
An overriding issue of this protocol is the toxicity of preoperative therapy. In 32 of the 38 patients, there were significant preoperative grade 3 and 4 toxicities, including stomatitis or mucositis in 63% of patients, esophagitis in 44%, leukopenia in 22%, infections in 47%, and neutropenia in 22% of patients. Because of anticipation of nutrition obstacles in these malnourished and debilitated patients, we generally mandated placement of a percutaneous endoscopy gastrostomy tube, which successfully permitted nutritional support to continue even during the worst of the toxicity problems. Although in general these toxicities were manageable, they did require frequent delay in treatment, and one would perhaps envision a lower dose of paclitaxel to achieve a lower toxicity rate without compromising the chemotherapy rate.
Major surgical complications that occurred in three patients included a tracheostomy necrosis in one patient, a flap failure in one patient, and a tracheal arterial fistula after a mandible resection that led to a patient death. Again, these types of toxicities are associated with the aggressive nature of this protocol and suggest that modifications are in order. We currently are in the process of modifying this protocol to reduce toxicity without compromising the antitumor effect of the modalities.
The next protocol will focus on modifying the dose and, perhaps, the schedule of paclitaxel. Paclitaxel is known to have very profound effects on switching the cell cycle, which optimizes radiation but may also increase toxicity in normal tissues. Our ultimate goal is to refine this protocol so as to maintain the clinical and pathologic complete response rate without the price of current toxicity levels and then to conduct a phase III comparison of preoperative chemoradiation with paclitaxel and carboplatin versus radiation and cisplatin, which was successfully used in our earlier protocols.
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Footnotes
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Presented at the 53rd Annual Meeting of the Society of Surgical Oncology, New Orleans, Louisiana, March 16–19, 2000.
Received for publication March 18, 2000.
Accepted for publication June 6, 2001.
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ABSTRACT
INTRODUCTION
