| Japanese Journal of Clinical Oncology | Pages |
Prognosis After Salvage Chemotherapy for Locally Unresectable Recurrent Squamous Cell Carcinoma of the Head and Neck
Introduction
Materials And Methods
Results
Discussion
References
Prognosis After Salvage Chemotherapy for Locally Unresectable Recurrent Squamous Cell Carcinoma of the Head and Neck
Methods: T wenty-six patients with recurrent advanced head and neck cancer, were treated with one of two new regimens as second-line chemotherapy. The PEM regimen consisted of cisplatin 60 mg/m2 on day 1, etoposide 40 mg/m2 on days 1, 2 and 3 and mitomycin-C 7 mg/m2 on day 1. The long CF regimen consisted of cisplatin 8 mg/m2 on days 1-5, 8-12, 15-19 and 22-26 and 5-fluorouracil 300 mg/m2 as a 24 h infusion or oral administration of tegaful-uracil (UFT-E) 400 mg/m2 on days 1-28. Survival curves were calculated using the Kaplan-Meier method and compared by the log rank test.
Results: Of 24 patients evaluable for response, three complete responses (CR) and seven partial responses (PR) were achieved, with an overall response rate of 42%. Myelosuppression was the major side effect. One year survival was 100% for CR, 0% for PR and 20% for minor response (MR). All patients who failed to achieve a CR died within 12 months, except one patient with MR.
Conclusion: Our data suggest that with these salvage regimens survival benefit was demonstrated only in CR patients.
Key words: prognosis - salvage chemotherapy - unresectable recurrent cancer - head and neck
INTRODUCTION
In patients who have advanced squamous cell carcinoma of the head and neck with large nodal involvement, the expected 5-year survival is as low as 1-2% (1). Chemotherapy has been added to the standard regimen of surgery and radiotherapy in attempts to improve the outcome in such patients. A number of cytotoxic agents have been identified as active in the treatment of this disease. Currently, cisplatin (CDDP)-based combination regimens such as CDDP plus 5-fluorouracil (5-FU) or CDDP plus methotrexate (MTX) plus bleomycin (BLM) are widely used. These regimens produced a complete response (CR) rate of 30-60% and overall response rates (RR) of 80-100% (2-5). However, in previously treated patients, the overall and complete response rates have been disappointingly low (6-8). Patients who have already been treated with CDDP-based regimens and have shown recurrence or are refractory to these regimens ultimately die of their disease.
Based on this background we developed two new regimens which we designated PEM and L-CF. In our preliminary analysis we observed that these regimens were active as salvage treatments (9). In the present study we analyzed the impact of these salvage regimens on survival.
MATERIALS AND METHODS
Between May 1991 and December 1995, 26 sequential patients with histologically proven stage III and IV locally unresectable recurrent squamous cell carcinoma of the head and neck entered the study. All patients signed informed consent before enrollment in the study. All patients were required to have two-dimensionally measurable disease, normal renal function [blood urea nitrogen (BUN) <20 mg/dl and serum creatinine level <1.5 mg/dl] and hepatic function [serum glutamic oxaloacetic transaminase (SGOT) and glutamic pyruvate transaminase (SGPT) <40 units/dl and total bilirubin <1.5 mg/dl]. Staging classification was performed according to the International Union Against Cancer staging system. Performance status was recorded using the Eastern Cooperative Oncology Group (ECOG) criteria.
The chemotherapy regimens were as follows. The PEM regimen consists of CDDP 60 mg/m2 in 500 ml of normal saline as a 2 h infusion on day 1, etoposide 40 mg/m2 in 200 ml of normal saline as a 1 h infusion on days 1, 2 and 3 and mitomycin-C (MMC) 7 mg/m2 i.v. bolus on day 1. Patients were hydrated with 5% glucose with a half normal saline to ensure a urine output of more than 100 ml/h and premedicated with granisetron 40 mg/kg 30 min before the start of cisplatin infusion. The long CF (L-CF) regimen consisted of CDDP 8 mg/m2 in 500 ml of normal saline as a 2 h infusion on days 1-5, 8-12, 15-19 and 22-26 and 5-FU 300 mg/m2 in 1000 ml of nomal saline as a 24 h infusion or oral administration of tegaful-uracil (UFT-E) 400 mg/m2 on days 1-28. No hydration was required for administration of low doses of cisplatin. Patients were assigned randomly to either PEM or L-CF regimens. Both regimens were repeated at 3-4-week intervals as hematological toxicities permitted. Both regimens were given on an in-patient basis. The treatment was discontinued when a patient was found to have progressive disease (PD) or the toxicity exceeded the benefits of continued drug administration.
Response to treatment was assessed as the decrease in the total tumor area measured directly with calipers or through radiological features. Complete response (CR) was defined as the disappearance of all measurable and assessable disease for a minimum duration of 4 weeks. Partial response (PR) was defined as a [ge]50% reduction in the sum of the products of the perpendicular diameters of all measurable lesions without an increase in the size of any lesion or the appearance of new lesions for at least 4 weeks. Minor response (MR) was defined as a decrease of 25-50%. Stable disease (SD) was defined as a change in the sum of the products of the perpendicular diameters of all measured lesions of <25%. PD was defined as an increase of >25% in the sum of the products of the perpendicular diameters of all measured lesions from the point of maximum response or the appearances of new lesions. All patients not meeting the criteria for CR or PR were classified as non-responders. Duration of response was measured from the date of first documentation of response to the date of disease progression. Survival curves were calculated using the Kaplan-Meier method (10) and compared by the log rank test (11).
Post-treatment follow-up differed according to the response to treatment and site of the primary tumor. Patients with CR underwent a physical examination every month during the 2 years after the end of treatment and every 2 months after the second year. Patients with PR, MR and SD were examined monthly.
RESULTS
Twenty-six patients were entered in this trial, of whom 15 received PEM and 11 L-CF. For the L-CF regimen, all 11 patients initially received 5-FU by 24 h continuous i.v. infusion. Then two of these patients were given tegaful-uracil orally, one in two and the other in three cycles. Follow-up was continued through January 1998. Two patients were disqualified from analysis because of protocol violation. Patients' characteristics are shown in Table 1. A majority of patients had been treated with 60-70 Gy of Linac or Telecobalt radiotherapy. Prior chemotherapy consisted of induction chemotherapy for five patients, induction plus salvage chemotherapy for 13 patients and six salvage chemotherapy including five patients with CDDP + 5-FU, one with CDDP + 5-FU plus CDDP + MTX + BLM plus CDDP + BLM, 12 with CDDP + 5-FU plus CDDP + MTX + BLM, two with CDDP + MTX + BLM plus CDDP + BLM, one with CDDP + MTX + BLM and three with CDDP + BLM. The mean number of cycles of treatment given was 3.0, ranging from 1 to 8. Responders had a longer interval between the end of first-line chemotherapy and the start of the second-line chemotherapy regimen (Table 2).
Table 1. Patients' characteristics (24 evaluable patients)
| Male:female | 20:4 |
| Age (years): median (range) | 61 (34-77 |
| Stage III/IV | 2/22 |
| PS | |
| 0 | 0 |
| 1 | 4 |
| 2 | 11 |
| 3 | 9 |
| Primary site | |
| Nasopharynx | 4 |
| Oropharynx | 5 |
| Hypopharynx | 5 |
| Oral cavity | 5 |
| Larynx | 5 |
| Prior surgery | 19 |
| Prior radiotherapy | 22 |
| Prior chemotherapy | 24 |
| CDDP + 5-FU | 18 |
| CDDP + MTX + BLM | 16 |
| CDDP + BLM | 6 |
Table 2. Treatment cycle and interval of chemotherapy
| Treatment cycle | Interval between 1st- and 2nd-line | Maximum response of 1st-line chemotherapy | |||
| Mean | Range | Mean | Range | ||
| Complete responders | 6.7 | 6-8 | 7.0 | 4-11 | CR 1, PR 2 |
| Partial responders | 3.4 | 2-5 | 6.6 | 2-14 | CR 2, PR 5 |
| Minor responders | 2.6 | 2-5 | 5.8 | 2-10 | PR 2, MR 2, SD 1 |
| Stable disease patients | 1.7 | 1-3 | 5.9 | 2-12 | PR 1, MR 3, SD 2 |
| Progressive disease patients | 1.3 | 1-2 | 3.3 | 2-5 | PR 1, SD 2 |
| Total | 3.0 | 1-8 | 5.9 | 2-14 | |
Of 24 patients evaluable for response, there were three CR, seven PR, five MR, six SD and three PD with an overall response rate of 42% (Table 3). All 10 CR and PR patients had previously responded to first-line chemotherapy. Complete responders are separately analyzed in Table 4. Four of six SD patients showed no response to initial chemotherapy.
Table 3. Response (24 evaluable patients)
| No. of patients | % | |||
| PEM | L-CF | Total | ||
| Complete response | 2 | 1 | 3 | 12.5 |
| Partial response | 4 | 3 | 7 | 29 |
| Minor response | 3 | 2 | 5 | 21 |
| Stable disease | 3 | 3 | 6 | 25 |
| Progressive disease | 2 | 1 | 3 | 12.5 |
Table 4. Analysis of complete responders
| No. | Age (years) | Gender | PS | Salvage regimen | Duration of response (months) | No. of courses | Primary site | Initial regimen | Maximal response | Interval* (months) | Survival (months) |
| 1 | 62 | M | 1 | PEM | 60+ | 8 | Mesopharynx | CDDP + BLM | PR | 6 | 60+ |
| 2 | 60 | M | 2 | PEM | 30 | 6 | Hypopharynx | CDDP + 5FU | CR | 11 | 36+ |
| 3 | 65 | M | 2 | L-CF | 20 | 6 | Nasopharynx | CDDP + BLM | PR | 4 | 24 |
*Interval between first- and second-line chemotherapy regimens.
Adverse reactions are listed in Table 5. Because of the small number of patients in each group, combined side effects are listed. The most frequently observed toxicities were nausea or vomiting. These side effects occurred in spite of premedication with granisetron. Myelosuppression was a major side effect and severe thrombocytopenia occurred in three patients. These three patients plus another two patients discontinued further chemotherapy owing to side effects. Mucositis was observed in previously irradiated patients.
Table 5. Toxicities (24 evaluable patients)
| Effect | Grade | |
| I, II | III, IV | |
| Nausea or vomiting* | 9 | 1 |
| Leukopenia | 8 | 2 |
| Thrombocytopenia | 7 | 3 |
| Anemia | 6 | 2 |
| Mucositis | 4 | - |
| Diarrhea | 3 | 1 |
| Alopecia | 6 | - |
| Renal[dagger] | 2 | - |
| Skin pigmentation | 1 | - |
| Hyponatremia | 1 | - |
| Facial edema | 1 | - |
[dagger]Transient increases in serum creatinine.
Twenty-one patients have died of disease. One year survival was 100% for CR, 0% for PR, 20% for MR and 0% for SD and PD, respectively. One of three CR patients died in the second year and others are alive with local recurrence 36+ months and disease-free 60+ months (Fig. 1). Survival curves showed a significant difference in favor of the complete responders vs non-complete responders (P < 0.05).
Figure 1. Actuarial survival for 24 patients entered in the study. Survival curves were calculated using the Kaplan-Meier method. Significant differences were compared with the log rank test. Survival curves showed a significant difference in favor of the complete responders vs partial and non-responders (p < 0.05). This study demonstrates that patients with inoperable squamous cell carcinoma of the head and neck who had previously been subjected to cisplatin-containing chemotherapy respond to second-line cisplatin-containing regimens; however, survival advantages were seen only in complete responders. It has repeatedly been reported that in the treatment of head and neck carcinoma survival advantage was seen only in patients with responses (12,13). Our study extended this observation to salvage chemotherapy. The PEM regimen was conceived because topoisomerase II inhibitors such as etoposide were reported to be synergistic with CDDP (14). MMC was added because of its reported efficacy against hypoxic cells and of synergistic interaction with CDDP (15). We have previously shown that with the use of multicellular tumor spheroids (MTS), poor drug penetration into the core is a major hindrance governing the cell kill effect at a three-dimensional tumor mass level. Prior exposure to CDDP was effective in enhancing penetration of drugs known to be poor penetrants, such as doxorubicin (16). Indeed, our initial clinical trial of the PEM regimen showed a high response rate in previously untreated patients with head and neck cancer (17). The L-CF regimen was conceived as a means of dose intensification. Dose intensification of cytotoxic drugs has been positively correlated with increased clinical response (18). We questioned whether the use of low-dose prolonged 5-FU infusion and low doses of daily CDDP might permit the administration of increased amounts of drugs per unit time period. We observed that the L-CF regimen allowed the administration of 160 mg/m2/month of CDDP and 8400 mg/m2/month of 5-FU without major dose-limiting toxicities, doses much intensified as compared with conventional CDDP plus 5-FU regimens. In addition, our work with MTS demonstrated that there was a steep dose-response curve in favor of a prolonged 5-FU exposure time (19). Oral administration of tegaful-uracil produced a similar plasma level as 5-FU continuous i.v. infusion. At a molecular level, 5-FU continuous i.v. infusion on a schedule of 250 mg/m2/day and oral administration of tegaful-uracil on a schedule of 370 mg/m2/day are equivalent to 1.9 mmol/m2/day. The clinical effect of 5-FU is virtually correlated with the 5-FU area under the concentration versus time curve (AUC) value. Long-term administration resulted in no significant difference between AUC values in patients receiving 5-FU continuous i.v. infusion and oral tegaful-uracil (20). The daily tegaful-uracil dose as defined by the N1-(2'-tetrahydrofuryl)-5-fluorouracil dose was an approximately equimolar dose relative to 5-FU continuous i.v. infusion. Because a egaful-uracil capsule contains 100 mg of N1-(2'-tetrahydrofuryl)-5-fluorouracil, the calculated tegaful-uracil dose was rounded off to the nearest 100 mg. We observed that both the PEM and L-CF regimens were active in inducing tumor regression. Because of the small number of patients involved in each regimen, we carried out only a combined analysis. For patients who experienced grade III toxicity, further chemotherapy was stopped. However, these patients showed an adverse reaction after the end of scheduled chemotherapy, so all the patients were continued on the planned regimen. Several lessons can be learned from the present study. As expected, the response to salvage treatment was low. Nevertheless, responders to the salvage treatment had previously been exposed to CDDP and had responded. Therefore, it is likely that prior exposure to CDDP does not necessarily mean CDDP resistance. CDDP dose intensification may play a role in induction of the second response. The most important finding of the present study is the increases in survival observed among the CR patients in a salvage setting. Unfortunately, the CR rate was so low that the routine use of these two regimens does not appear to have added significantly to the overall survival of the study population. Since, however, the majority of courses were well tolerated and toxicity was limited, it is tempting, in order to increase the CR rate, to carry out further escalation of dose intensification by addition of hematopoietic growth factors and/or stem cell transplantation.
DISCUSSION
References
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Last modification: 1 Dec 1999
Copyright© 1999 Foundation for Promotion of Cancer Research.
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