Chemotherapy as a substitute for surgery in the treatment of advanced resectable head and neck...

Chemotherapy as a Substitute for Surgery in the Treatment of Advanced Resectable Head and Neck Cancer

A Report From the Northern California Oncology Group

CHARLOTTE JACOBS, MD,' DON R. GOFFINET, MD,t LINDA GOFFINET, RN," MARSHA KOHLER, MSPH,* AND WILLARD E. FEE, MDS

This trial determines the feasibility for patients with resectable Stages III/IV head and neck cancer who achieved a complete response to induction chemotherapy of eliminating surgery from their treatment program. Thirty patients were treated with three cycles of cisplatin and 5-fluorouracil(5-FU), followed by reendoscopy and biopsy. Twelve patients achieved a complete pathologic response at the primary and received radiation (interstitial and/or external beam) only. The remainder underwent surgical resection and postoperative radiation. At 2 years, the relapse-free survival was 52%, and the survival was 53% for the entire group. For the 12 complete responders who had surgery eliminated, the relapse-free survival was 60%, and the survival was 70%. This pilot study suggests that for patients with resectable disease who achieve a complete pathologic response to induction chemotherapy at their primary, it is fasible to omit surgery and treat with primary radiation without compromise in survival. This approach warrants further study in a randomized trial.

Cancer 60:1178-1183,1987.

HE PROGNOSIS FOR patients with advanced, resect- T able squamous cell cancers of the head and neck region is poor, and the disease is associated with significant morbidity. Despite optimal combinations of surgery and radiation, at least 50% of the patients will recur, usually within the first 2 years.'-" Most recurrences are local, and few patients can be salvaged. Depending on site and stage of disease, patients with resectable Stages I11 and IV squamous cancers have 5-year survivals ranging from 10% to 50%. Attempts have been made to improve curability of advanced head and neck cancer by the addition of chemotherapy to standard surgery and

Although initial pilot data appeared en- couraging,'-" controlled trials to date have not demon- strated improvement in survival.'2,'3 Chemotherapy may not have reached its full potential and may prove more effective with advances in available chemothera-

peutic agents, intensity of regimens, and optimal se- quencing.

Besides improvement in survival, chemotherapy has a second potential role which needs to be explored. Those patients who are fortunate enough to survive their cancer often face a lifetime of significant morbidity because of cosmetic and functional debilities from surgical resection. Despite marked advances in reconstructive surgery and rehabilitation, patients who have undergone laryngectomy, glossectomy, or composite resection still have major debility. If the use of induction chemotherapy could result in modification or elimination of surgical resection, the quality of the patient's life may be improved, even if survival were equivalent. This trial investigates in a pilot study whether chemotherapy might substitute for surgical resection in those patients with advanced squamous cell carcinoma who achieved a complete response to induction chemotherapy.

From the *Division of Oncology, Department of Medicine; tDe- partment of Radiation Therapy; and §Division of Otolaryngology and Head and Neck Surgery, Department of Surgery; Stanford University School of Medicine, Stanford, California; and the $Northern Califor- nia Oncology Group, Belmont, California.

Supported in part by NIH grant CA 25862-05 and CA 21744. Address for reprints: Charlotte Jacobs, MD, Division of Oncology,

M-2 I 1, Stanford University School of Medicine, Stanford, CA 94305- 5306.

Accepted for publication March 30, 1987.

Methods

Eligible patients for this trial included those with pre- viously untreated, resectable squamous cell cancers, Stages 111 or IV arising in the oral cavity, oropharynx, hypopharynx, and larynx. Patients were required to have a pretreatment leukocyte count of 24,000/mm3,

1178

No. 6 CHEMOTHERAPY FOR HEAD AND NECK CANCER 0 Jacobs et al. 1179

platelet count 2 l O0,000/mm3, creatinine clearance 260 ml/minute, and Karnofsky performance status of >50.

Before treatment all patients had a complete history and physical examination, complete blood count, chemistry panel, chest x-ray, bone scan or liver scan, if indi- cated, computerized tomography (CT) scan of the head and neck, if appropriate, and pathologic review. Patients were further evaluated by triple endoscopy. Diagrams were made of the patient's tumor, and photographs were taken in the majority of patients. Patients were assigned a clinical stage according to the criteria of the American Joint Committee on C a n ~ e r . ' ~ Signed informed consent was obtained on all patients.

Induction chemotherapy consisted of cisplatin 100 mg/m2 intravenous (IV) bolus with mannitol diuresis on day 1, followed by 5-fluorouracil(5-FU) 1 g/m2 per day by continuous infusion, days 1 through 5." Courses were repeated at 3 weeks for a total of three cycles. For the first six patients, bleomycin (1 5 mg/m2 IV push on day 3, followed by a 5-day infusion at 15 mg/m2 per day) was given, instead of 5-FU in the first chemotherapy cycle. Based on the excellent results of the Wayne State group,ll the regimen was modified to three cycles of cisplatin and 5-FU. Patients were examined weekly by a team of otolaryngologists, radiation therapists, and on- cologists. A complete blood count and serum creatinine were repeated weekly, and a creatinine clearance, chemistry profile and audiogram were obtained before each cycle. Acute toxicity was graded according to the criteria of the Northern California Oncology Group.

Tumor response was assessed weekly. A complete clinical response (CR) was defined as no visible or palpable disease. A partial response (PR) was defined as a >50% decrease in the product of the longest tumor diameter multiplied by its perpendicular diameter, as compared to the initial measurements. Stable disease was defined as tumor regression of less than 50% of the initial tumor size, and progressive disease was defined as any increase in disease or appearance of new lesions. Response data were recorded separately for the primary tumor and regional nodes. To obtain an overall response for each patient, the response at the primary tumor and regional nodes were combined, and the lesser response was taken as the overall response.

At the completion of three cycles of chemotherapy, patients judged to have less than a complete clinical response underwent surgery as originally planned (Fig. 1). All surgical resections were performed during the fourth week after the start of the third cycle of chemotherapy. The extent of the surgical resection was deter- mined by tumor size at initial evaluation and was not modified by tumor response to induction chemotherapy. If a patient had progressive disease on chemotherapy or failed to respond after two cycles of chemother-

CISPLATIN ,SURGERY -RADIATION

\ - BIOPSY RADIATION

FIG. 1. Schema of protocol. PR: partial response; CR: complete response.

apy, he proceeded to surgical resection. After surgical resection, patients were treated with postoperative radiation therapy.

If after three cycles of induction chemotherapy, the patient had a complete clinical response at the primary, endoscopy was repeated with multiple biopsies. If the biopsy specimen revealed microscopic residual disease, the patient underwent surgical resection and radiation therapy as originally planned with no modification for tumor response. If the patient had a complete pathologic response, surgery was eliminated at the primary. If there was a complete clinical response in the neck, neck dissection was eliminated, but if palpable disease remained in the neck, a neck dissection alone was performed. Pa- tients who achieved a pathologic CR were treated with primary radiotherapy.

Radiation therapy was delivered to the primary site or the resection bed via opposed lateral ports, using a 6-meV linear accelerator operating at 1 00-cm SSD. Supplemental anterior inferior cervical portals, calculated to a depth of 3.0 cm, also were used in all patients, except those with advanced laryngeal and hypopharyngeal cancers or multiple, enlarged, clinically positive neck nodes. These patients were treated by an anterior mediastinal T field (matched to the lateral fields to avoid spinal cord overlap), calculated to 5.0 cm depth. A daily radiation dose of 200 rad was used, five times per week, with all fields treated daily. The spinal cord was pro- tected at or before a total dose of 4000 rad.

Patients irradiated postoperatively received 5000 to 5400 rad to the primary site if the surgical margins were free of tumor. In those with close margins, 6000 rad were delivered, whereas patients with involved surgical margins received 6600 rad in 6.5 to 7 weeks. Inferior supplemental anterior neck portals also were used for these patients postoperatively. Iridium 192 implants were not performed in this group.

For patients with a complete response who were treated with interstitial implantation, the dose to the primary site was 5000 to 5400 rad in 5 to 5.5 weeks, followed 2 to 3 weeks later by a removable iridium 192 seed implant, which delivered an additional 2500 to 3000 rad to an isodose enclosing the tumor volume. These implant isodose distributions were correlated with computer derived tumor volumes, to minimize ex-

1180 CANCER Septem

TABLE 1. Patient Population

No. of patients

Site Oral cavity Oropharynx

Larynx Hypopharynx

stage 111

T2N 1 T3NO T3N 1

T2N2 T2N3 T3N2 T4NO T4N 1 T4N2 T4N3

IV

1 1 7 6 6

3 4 4

cessive radiation doses to normal tissues. Clinically involved cervical lymph nodes, which had responded completely after the chemotherapy were irradiated to a total dose of 6600 rad or more, If an implant was not performed, the primary site also received full dose irradiation.

Patients were followed in a combined modality clinic, with repeat physical examination, blood count, and chemistry panel every 2 months, and chest x-ray every 6 months. Follow-up data was collected on intraoperative and postoperative complications, and acute and chronic radiation toxicity. Statistical comparisons of response rates were made

between subgroups using the chi-square test. Survival (calculated from study entry to death) and relapse-free survival (calculated from date rendered disease-free to recurrence date) were plotted according to the Kaplan- Meier method.’’

TABLE 2. Clinical and Pathologic Response to Induction Chemotherapy

Overall

Primary Nodes +nodes) (primary

Clinical response Complete response 18 (60%) 12 (48%) 13 (43%) Partial response 9 (30%) 10 (40%) 12 (40%) Stable/progressive disease 3 ( 10%) 3 ( 12%) 5 ( 17%)

Complete + partial response 90% 88% 83%

Pathologic response Complete response 12 (40%) 10 (33%) Partial response 15 (50%) 15 (50%)

sber 15 1987 Vol. 60

Results

Patient Population

Between May 1982 and January 1985,30 consecutive patients entered trial. The mean age was 57 years with a range of 27 to 73 years. There were 19 men and 1 1 women with a mean Karnofsky performance status of 90 (range, 60-100). The sites of primary disease included the following: oral cavity, 1 1 ; oropharynx, seven; hypopharynx, six; and larynx, six (Table 1). Eleven patients had Stage 111 disease, and 19 patients had Stage IV disease. The histologic differentiation was described as well-differentiated in 1 1 patients, moderately differentiated in 12, and poorly differentiated in seven.

Response to Induction Chemotherapy

After induction chemotherapy, 60% of the patients achieved a complete clinical response at the primary, and 30% had a PR (Table 2). Forty-eight percent of patients who had nodal disease achieved a complete clinical response, and 40% achieved a PR in nodes. Thus, 43% of patients achieved a CR at both the primary and nodes, and 40% achieved a PR for an overall response rate of 83%. Seventeen percent of patients had stable or progressive disease in either the primary, nodes, or both.

After endoscopy and rebiopsy, six of 18 complete responders at the primary were found to have persistent disease, resulting in a complete pathologic response of 40% and an overall complete pathologic response of 33% (Table 2). Thus, of 30 patients entering trial, 13 achieved a clinical CR, and 10 achieved a pathologic CR. These ten patients had surgery eliminated from their treatment program. Two additional patients had a pathologic complete response at the primary but persistent neck disease and were treated with neck dissection only. These 12 patients will form the “no surgery” group for analysis. The surgical procedures that were eliminated by this protocol included the following: total laryngectomy, three; partial glossectomy, three; composite resection, six; and neck dissection, nine.

Analysis was performed of prognostic factors for overall tumor response. Those patients achieving a complete pathologic response were compared with those not achieving CR (Table 3). Forty-two percent of men achieved a complete response and only 18% of women. Assessing site of disease, the highest CR was achieved in patients with oropharyngeal primaries. Histologic differentiation had no impact. Lower CR rates were achieved in patients with more extensive or bulky disease: T4 or N3 or Stage IV. These may be important differences, but given the small numbers, tests of signifi-

No. 6 CHEMOTHERAPY FOR HEAD AND NECK CANCER - Jacobs et d. 1181

cance were negative. There was no difference in response rate in those few patients who received one cycle with bleomycin.

Toxicity

The major toxicity was vomiting, with 30% exper- iencing grade 3 vomiting, defined as up to three times daily. Thirty percent of patients had grade 2 mucositis, defined as patchy mucositis. Thirty percent of patients had a 20 to 40 decibel loss in hearing in the 8000 Hz range, and 12% had a greater than 40 decibel loss in the 8000 Hz range. Two patients had serum magnesium levels less than 1.5 mg%. Two patients had leukocyte counts of less than 2000/mm3, and one patient had a platelet count less than 50,000/mm3. There were no associated infections or bleeding episodes. One patient had an elevation of serum creatinine to 4 mg%, which returned to normal after discontinuation of cisplatin. Only five patients failed to receive three cycles of chemotherapy at full dose. Three of these patients had progressive disease, and surgery was performed after two cycles of chemotherapy; one patient with renal dysfunc- tion had one cycle of chemotherapy; one patient had cardiovascular bypass surgery for unstable angina after two cycles of chemotherapy. This patient had underly- ing cardiovascular disease, and it is unclear if 5-FU pre- cipitated the angina.I6

All patients underwent surgery and radiotherapy in a timely manner, except for one patient who, after achieving a PR, refused surgery and was treated with radiotherapy only. Five patients had positive margins at surgical resection and were treated with a boost of radiotherapy to that region. There were no unusual or unexpected postoperative complications: one patient developed a low-grade flap infection; and two patients had chronic aspiration, one requiring conversion from a supraglottic laryngectomy to total laryngectomy. Of the 12 patients who achieved a CR at the primary, eight received interstitial implants. One refused further radiation, and three could not be implanted due to (1 ) medical considera- tions or (2) inaccessibility of site to brachytherapy. These three received 6600 rad external beam. During radiotherapy, five patients developed grade 3 mucositis, described as moist desquamation or confluent mucositis.

Recurrence and Survival Data

At follow-up, ranging from 16 to 48 months, 13 patients have relapsed, four in the “no surgery” group and nine in the “surgery” group. Seven recurrences were locoregional, three were distal, and three were local and

TABLE 3. Predictive Factors for Complete Pathologic Response at the Primary

Complete reswnse (%)* Factor (n)

Male ( 19) Female ( I 1) Site

Oral cavity ( I 1 ) Oropharynx (7) Hypopharynx (6) Larynx (6)

Histologic type Well ( 1 1 ) Moderate ( 12) Poor (7)

T2 (10) T3 (14) T4 (6) NO ( 5 ) N l (9) N2 (13) N3 (3) I I I ( l l ) IV (19)

Stage

42 18

36 57 17 17

36 33 29

30 43 17 60 22 38 0

45 26

* P value for comparisons of response rates between subgroups all >o. I .

distal. There was no difference in recurrence pattern between those who did and did not have surgery.

At 2 years, the relapse-free survival (Fig. 2) and survival (Fig. 3) for the entire group were 52% and 53%, respectively, both with 10% standard errors. The me- dians have not yet been reached. For the group of 12 patients who had primary surgery eliminated, the relapse-free survival (Fig. 4) and survival (Fig. 5 ) were 60% and 70%, respectively, at 2 years. Standard errors of

‘1

L7 LL

8 M I 11 IP bi IS 04 ii PI ;I w 3) 01 31 w H n H M

TlHl IN m FIG. 2. Relapse-free survival of entire group (n = 30).

1182 CANCER September 15 1987 Vol. 60

: 0- I

- . L I b

FIG. 3. Probability of survival of entire group (n = 30).

these estimates are 14% for relapse-free survival and 13% for survival. Of the patients who died, all except one had head and neck cancer as the cause of death. One patient died from a pulmonary embolus a year after completion of therapy; autopsy revealed no evidence of cancer. One patient developed a second primary neo- plasm at another head and neck site.

Discussion

This trial has shown the feasibility of omitting surgical resection in those patients with advanced head and neck cancer who achieved a complete pathologic response to chemotherapy, without diminishing their survival. Using three cycles of cisplatin and 5-FU as an induction regimen, the excellent response rates reported by the Wayne State group were confirmed." However, in head and neck cancers, the ability to judge response is often hindered by areas of residual induration and edema.

Y

O D t M I 00 1B 08 I S Ob 10 8) 15 t0 18 Ot 38 OO 14 68 I S 60

TIME IN MOlllHS

FIG. 4. Relapse-free survival ofthose patients in whom surgery at the primary was eliminated (n = 12).

0 0 6 tt I w I0 60 I5 @O 3 b% ;S 68 i4 0% 35 0% 18 tt !I PO

TIHE IN tMHS

FIG. 5. Probability of survival of those patients in whom surgery at the primary was eliminated (n = 12).

After meticulous reexamination with endoscopy and biopsy, three of 13 patients who were judged to have a complete clinical response at the primary were found to have residual disease on endoscopy. There was accept- able toxicity with this induction regimen without an increased number of complications from subsequent surgery or radiotherapy.

The goal of induction chemotherapy in prior studies has been to improve curability by reducing tumor size before surgery or radiation and thereby improving the efficacy of these modalit ie~.~,~ Another theoretical ad- vantage is to eliminate microscopic metastatic disease early on. The number of randomized trials testing induction chemotherapy is small, and none to date has shown improvement in disease-free survival or survival. Advocates of induction chemotherapy have pointed out that these early randomized trials did not use the most effective induction regimens.

The major objective of this trial was to determine if patients who achieved a complete pathologic response could have surgery eliminated and be treated with primary radiotherapy without compromising survival. Ten of our patients had all surgery (laryngectomy, partial glossectomy, or composite resection) eliminated because of complete pathologic response, and two patients had neck dissections only because of residual palpable neck disease. Survival for the entire group was 53% at 2 years. This outcome is similar to that of the Head and Neck Contracts Pro~gam. '~ In that trial, there were 462 patients of similar stages and sites, one third of whom were treated with standard surgery and postoperative irradiation. At 2 years, the disease-free survival was 55%, and the survival was 59%. These results are comparable to our current trial and suggest that, as a whole, patient longevity was not compromised by our protocol therapy. The group of patients who had surgery eliminated

No. 6 CHEMOTHERAPY FOR HEAD AND NECK CANCER Jacobs et al. 1183

had a better survival; 70% at 2 years. The Wayne State group reported in a pilot trial that complete responders to induction chemotherapy lived longer than nonresponders, and they suggested that chemotherapy response may improve survival.” Others have cautioned that this difference may not result from chemotherapy response, but rather from the selection of a favorable subgroup. Taylor noted in his trial of induction chemotherapy that the same factors that affected prognosis were those that affected response to chemotherapy.’2 When he corrected for imbalances in the expected 3- year disease-free survival of patients based on disease site and stage, the differences between responders and nonresponders disappeared. He concluded that response to chemotherapy is not an independent factor which influences disease outcome.

In our trial, chemotherapy response may have oc- curred in those patients with Stages 111 and IV disease who were already destined to have a good outcome. However, if response to chemotherapy can select this favorable subgroup of patients, then surgery might be eliminated from their treatment program, probably resulting in improved quality of life. We sought to identify prognostic factors which might predict tumor response. Although lower CR rates were observed in women, in patients with laryngeal and hypopharyngeal primaries, and in patients with more extensive disease (T4,N3), our numbers were not large enough to predict with statistical confidence a favorable group of patients. Wolf et al. reported for the Head and Neck Contracts Program that response to induction chemotherapy in 29 1 patients was associated with primary tumor size and extent of nodal disease.I8

There is the concern that while those patients who achieved a CR had excellent outcome, those who at- tained only a PR to chemotherapy might, in fact, have their survival diminished by a delay before standard surgery and irradiation. These questions can only be answered in a randomized trial comparing this approach to standard treatment. Such a trial is currently in prog- ress by the Veterans Administration (VA) Cooperative Group.

In conclusion, the results of this novel approach to patients with advanced resectable head and neck cancer suggest that there may be subgroups of patients in whom surgery could be eliminated without compromising survival. However, one must caution that this group of patients was followed weekly by a research team con-

sisting of otolaryngologists, radiotherapists, medical on- cologists, and a research nurse. Before advocating such an approach outside the clinical trial setting, it must be tested further in a randomized trial.

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