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Keywords:

  • cisplatin;
  • methotrexate;
  • folinic acid;
  • 5-fluorouracil;
  • head and neck carcinoma

Abstract

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

BACKGROUND

Induction chemotherapy in locoregionally advanced squamous cell carcinoma of the head and neck (SCCHN) might improve survival with respect to radiation therapy alone. Furthermore, chemotherapy represents the only therapeutic option in metastatic head and neck carcinoma.

METHODS

To improve further the results that could be obtained with an induction regimen of cisplatin (CDDP) plus 5-fluorouracil (5-FU), the authors treated 50 patients with locally advanced or metastatic SCCHN with a combination of CDDP 65 mg/m2 on Day 1, methotrexate 500 mg/m2 on Day 1, levofolinic acid 250 mg/m2 on Day 2, and 5-FU 800 mg/m2 on Day 2. Cycles were repeated every 2 weeks. The authors' aim was to increase the activity of CDDP plus 5-FU (PF) using a regimen that combined the three most active drugs in SCCHN and provided an adequate biochemical modulation of 5-FU, which was administered as an intravenous bolus infusion.

RESULTS

Forty objective responses were observed among 50 evaluable patients (80%; 95% confidence interval [C.I.], 66–90%), including 7 complete responses (14%; 95% C.I., 5–27%), and 33 partial responses (66%; 95% C.I., 51–79%). Locoregional treatment, consisting of radiotherapy or surgery, was given at the end of chemotherapy. On completion of induction chemotherapy and locoregional treatment, 42 of 46 patients (91%) were rendered disease free. After a median follow-up of 20 months, the median duration of response was 10 months, the median failure free survival was 10 months, and the median overall survival was 21 months. The treatment was generally well tolerated. Grade 3–4 neutropenia occurred in 25 patients (50%), but it was febrile in only 3 patients. Nausea and vomiting were well managed with serotonin-3 blocking agents. Severe mucositis was seldom observed and easily manageable, and it never required hospitalization.

CONCLUSIONS

The high level of activity, the manageable toxicity, and the noteworthy survival data of this regimen compare favorably with most of the drug combinations used worldwide to treat similar patient populations, with the additional advantage of significantly lower cost. Cancer 1999;85:952–9. © 1999 American Cancer Society.

Squamous cell carcinoma of the head and neck (SCCHN) is an increasingly common cause of morbidity and mortality throughout the world1; it occurs particularly in an elderly patient population with heavy exposure to alcohol and tobacco. Approximately 10% of the patients show distant metastases at the time of initial presentation, and chemotherapy represents the only therapeutic option for this subset of patients. Nearly three-quarters of the patients are diagnosed with locoregionally advanced disease (Stage III–IV, M0). In the multidisciplinary treatment of this subset of patients, Phase III studies have established a role for chemotherapy when it is alternated with radiotherapy.2–4 The role of induction chemotherapy prior to local therapy is defined less clearly. In fact, an Italian study5 demonstrated that treatment with induction chemotherapy followed by radiotherapy resulted in improved survival compared with radiotherapy alone in patients with inoperable tumors. Furthermore, three randomized Phase III trials6–8 demonstrated that, in patients with advanced but resectable carcinoma of the larynx or hypopharynx, induction chemotherapy followed by radiotherapy provided organ preservation without reduction in survival compared with conventional surgery and postoperative radiation therapy. However, other randomized studies have failed to demonstrate an improvement in survival for induction chemotherapy followed by radiotherapy over radiotherapy alone.9, 10

There remains an unresolved issue with regard to the specific regimen of induction chemotherapy. Currently, the combination of cisplatin (CDDP) and a continuous infusion of 5-fluorouracil (5-FU)11, 12 is still considered the reference regimen. However, the combination of CDDP and bolus 5-FU may result in response rates comparable to the combination of CDDP and prolonged infusion of 5-FU.13

Clinical trials conducted throughout the world have focused on the modulation of 5-FU in the induction chemotherapy setting with the aim of increasing complete remission (CR) rates, because a significant correlation between CR and survival has been observed.14

A great deal of in vitro and in vivo evidence exists that the cytotoxicity of 5-FU is increased by folinic acid, which significantly improves the response rate to 5-FU in colorectal carcinoma15 and in carcinoma of the head and neck.16 Folinic acid is a precursor of a reduced folate, 5,10-methylene-tetrahydrofolate (5,10-CH2-THF), which enhances the inhibition of thymidilate synthase (TS) induced by the 5-FU anabolite, 5-fluoro-2-deoxyuridine-5′-monophosphate (FdUMP), through the formation of a ternary complex (consisting of FdUMP, 5,10-CH2-THF, and TS), leading to the covalent binding of FdUMP to the enzyme.

In the past, methotrexate (MTX) has probably been the most commonly used drug for the palliation of patients with recurrent SCCHN; response rates were reported to average approximately 30%17 with acceptable toxicity. Also, MTX has been studied extensively as a means of achieving adequate biochemical modulation of 5-FU, and MTX inhibits purine synthesis, leading to intracellular accumulation of 5-phosphoribosyl-1-pyrophosphate (PRPP), which leads to an increased formation and subsequent incorporation into RNA of 5-FU-triphosphate (5-FUTP), the final 5-FU metabolite that inhibits RNA synthesis. Furthermore, the polyglutammated form of MTX is a strong TS inhibitor itself.

Cisplatin on its own does not have a very high or reproducible activity against carcinoma of the head and neck: In fact, although response rates average approximately 30% and vary between 0% and 41%, responses are often short lasting, and recurrent disease is often resistant to second-line chemotherapy18; however, both in vitro and in vivo studies suggest a 5-FU/CDDP synergism that can be explained mainly by the CDDP-induced increase in intracellular levels of reduced folates.19

In a previous Phase I study,20 we treated patients with locoregionally advanced and metastatic SCCHN with alternately escalating doses of bolus 5-FU plus CDDP, MTX, and L-folinic acid (LFA) every 2 weeks. The regimen was well tolerated, and a significant antitumor activity was observed at the dose level, which was selected for the present Phase II study.

PATIENTS AND METHODS

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

Patient Selection

Eligibility criteria for study entry included pathologically confirmed, inoperable, locally advanced or metastatic SCCHN; Eastern Cooperative Oncology Group (ECOG) performance status of 0–2; and adequate baseline organ function, defined as white blood cell count ≥ 3000/μL, platelets ≥ 100,000/μL, bilirubin ≤ 1.5 mg/dL, serum transaminases < 2 × upper limit of normal, creatinine clearance ≥ 60 mL/minute, and life expectancy of at least 3 months. A tumor was defined as unresectable if it was fixed to either a bone structure or lymph nodes or if it was too invasive to allow for a radical surgical removal. Patients were ineligible if they had received prior radiotherapy or chemotherapy. Patients with a history of congestive heart failure or severe coronary heart disease were also ineligible. In addition, pregnancy, uncontrolled infection, cerebral metastases, concurrent or previous malignancy, and severe neurologic disease also constituted exclusion criteria. The study was approved by the Ethics Committee of each participating center, and written informed consent was obtained from each patient.

Treatment Plan and Patient Evaluation

After vigorous intravenous hydration and urinary alkalinization with sodium bicarbonate, patients received CDDP at the dose of 65 mg/m2 diluted in 500 mL normal saline solution and MTX at the dose of 500 mg/m2 diluted in 1000 mL normal saline solution on Day 1; serotonin-3 (5HT3) blocking agents were used as antiemetic coverage. LFA was administered at the dose of 250 mg/m2 in 500 mL normal saline solution and was immediately followed by 5-FU administered at the dose of 800 mg/m2 as an intravenous bolus on Day 2. Five courses of chemotherapy were given. Toxic effects were graded according to World Health Organization criteria. Treatment was recycled every 14 days and was withheld for 1 week (until Day 21) if neutrophil count was <1500/μL, platelet count was <75,000/μL, or Hb was <9.5 mg/dL at the time of chemotherapy recycling. If full hematologic recovery did not occur within 2 weeks, then treatment was discontinued. In case of Grade 4 bone marrow toxicity, even after full recovery, drugs were administered with a reduction to 75% of the planned dose in subsequent courses. Granulocyte colony-stimulating factor (G-CSF) was not given prophylactically but was permitted in patients with Grade 4 neutropenia. In case of Grade 1 nephrotoxicity, CDDP dose was reduced by 25%. In case of higher grade renal toxicity, treatment was discontinued.

At enrollment, patients were evaluated by a complete history and physical examination, performance status recording, complete blood cell count with differential, serum chemistries, urinanalysis, electrocardiogram, chest X-ray, thoracic and cervical computed tomography scan or magnetic resonance imaging, abdominal ultrasonography, bone scan, and upper aerodigestive tract endoscopy. Other examinations were performed only in the presence of a clinical indication. Laboratory tests were repeated before the start of each cycle. Evaluation for tumor response was performed at the end of the planned five courses of chemotherapy, with repetition of all tests that were abnormal at baseline. Primary tumor site and lymph node responses were scored separately. Complete response (CR) was defined as the disappearance of all symptoms and signs of all measurable disease lasting for at least 4 weeks, during which no new lesions appeared. Partial response (PR) was defined as a reduction of >50% in the sum of the products of the greatest perpendicular dimensions of all measurable lesions that lasted for at least 4 weeks, during which no new lesions appeared and no existing lesions became enlarged. Stable disease was defined as a less than 50% reduction and less than 25% increase in the sum of the products of two greatest perpendicular dimensions of all measured lesions and the appearance of no new lesions. Progressive disease was defined as an increase in the product of two greatest perpendicular dimensions of any measured lesion by more than 25% over the size present at entry on study or the appearance of new lesions. After chemotherapy, patients were offered locoregional treatment, which was discussed in each case by a multidisciplinary team, including the medical oncologist, the radiotherapist, and the head and neck surgeon. Surgery, if it was indicated, was undertaken within 4–6 weeks of the last course of chemotherapy. When radiation therapy was chosen as the modality of local treatment, it was started within 5 weeks of the last cycle of chemotherapy and was given in daily fractions of 2.0 grays (Gy). Wide treatment fields were planned to encompass the primary tumor and involved neck nodes, and a total dose of 52 Gy was reached in all cases. A boost to the primary tumor bed, which received at least 64 Gy, followed thereafter.

Statistical Methods

This study had a two-stage design, with 15 eligible patients to be enrolled during the first stage. If five or more objective responses were observed, then an additional 31 eligible patients would be accrued. Such a design would have an 80% power to detect an objective response rate of 50% rather than 30%. If the real but unknown objective response rate was 50%, then the study would have only a 5% chance of terminating after the first 15 eligible patients and declaring that the combination was inactive. The planned final sample size was 46 patients, and the hypothesis of 50% response rate would have to be accepted if at least 18 objective responses occurred.

Duration of response was calculated from the time of study entry to the first evidence of disease progression. Failure free survival (FFS) was calculated from the time of study entry to the documentation of disease progression (Fig. 1). Overall survival was determined from the time of study entry to the time of death or last follow-up. Survival curves were estimated by using the Kaplan–Meyer method.21

thumbnail image

Figure 1. Overall survival (OS) and failure free survival (FFS).

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RESULTS

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

Patient Characteristics

Between December 1995 and April 1997, 50 patients were entered onto this Phase II trial. Two patients discontinued treatment because of failure of hematologic recovery after two and three cycles, respectively, and one patient died of stroke before the fifth cycle, after a clinical response had been obtained in laterocervical nodes. These three cases, although they were not formally assessable for response, were considered as treatment failures according to the intention to treat analysis. Pretreatment characteristics of all patients are shown in Table 1. Median age was 55 years (range, 37–75 years). Performance status was 1 in the vast majority of patients. Oral cavity was the most frequent site of primary tumor location. Only 5 of 50 patients had relapsed after previous surgery, whereas the remaining 45 patients had never had any kind of treatment for their tumors. Of 50 patients, 48 had a locoregionally advanced disease (Stage III, IV, M0), whereas only 2 patients had distant metastases.

Table 1. Patient Characteristics (Total No. = 50)
CharacteristicNo.%
Age (yrs)
 Median55
 Range37–75
Sex
 Male3876
 Female1224
Performance status
 0510
 13774
 2816
Primary site
 Oral cavity2346
 Oropharynx1326
 Nasopharynx36
 Hypopharynx12
 Larynx1020
Previous surgery
 Yes510
 No4590
Stage
 III1020
 IV, M03876
 IV, M124

Response, Locoregional Treatment, and Survival

A total of 265 courses of chemotherapy were administered to 50 patients. The median number of courses per patient was 5 (range, 2–7). Of 50 objective responses, 40 were observed (80%; 95% confidence interval [C.I.], 66–90%), including 7 CRs (14%; 95% C.I., 5% to 27%) and 33 PRs (66%; 95% C.I., 51–79%). Ten patients were considered treatment failures, including six patients who had disease stabilization at the time of reevaluation, one patient with disease that progressed during treatment, and three patients who were not evaluable for response because of early treatment interruption (two patients) and death during chemotherapy (one patient).

The rates of response to chemotherapy were recorded separately for the primary tumor site and the neck lymph nodes. Among the patients with assessable primary site disease, 11 of 48 (23%) obtained a clinical CR at the primary tumor site, whereas 27 of 48 (56%) obtained a PR. The analysis of primary tumor site CR after chemotherapy showed that tumors of the oral cavity had a CR in 8 of 23 patients (35%), and tumors of the larynx had a CR in 3 of 10 patients (30%). No CRs were observed in tumors of the oropharynx, nasopharynx, or hypopharynx.

Among 36 patients with assessable neck disease, 29 (81%) had an objective response in the neck following our combination chemotherapy. In particular, 11 CRs (31%) and 18 PRs (50%) were recorded. Details on the impact of tumor stage and nodal stage on response to chemotherapy are shown in Tables 2 and 3, respectively.

Table 2. Impact of Tumor Stage on Response to Chemotherapy
Tumor stageNo. of patientsClinical response
CRPR
No.%No.%
  1. CR: complete response; PR: partial response; NA: not applicable.

T02NANANANA
T111100
T211327436
T31318862
T4236261565
Total5011232756
Table 3. Impact of Nodal Stage on Response to Chemotherapy
Nodal stageNo. of patientsClinical response
CRPR
No.%No.%
  1. CR: complete response; PR: partial response; NA: not applicable.

N014NANANANA
N111655545
N2204201155
N35120240
Total5011311850

Apart from the 1 patient who died during chemotherapy and the 2 patients with distant metastases, 47 patients (including the 2 patients who did not complete chemotherapy) were offered locoregional treatment. One patient with a T3-N2 lesion of the retromolar trigone refused any kind of further treatment after achieving a PR to chemotherapy and a meaningful symptomatic benefit. Seven patients (15%) were treated with surgery, which included primary site resection and neck dissection. The remaining 39 patients (85%) were treated with radiation therapy, which was started within 5 weeks from the last cycle of treatment. On completion of induction chemotherapy plus radiation therapy or surgery, 42 of 46 patients (91%) were rendered disease free. These included the 7 patients who achieved a CR after induction chemotherapy (6 who received subsequent radiotherapy and 1 who had surgery), all 31 patients who achieved a PR and who received locoregional treatment (25 who received radiotherapy and the remaining six who had surgery), 3 of 6 patients with no change after induction chemotherapy (all of whom received subsequent radiotherapy), and 1 patient who was not evaluable for response because of early discontinuation and who was treated subsequently with radiotherapy. After a median follow-up of 20 months, the median duration of response was 10 months, (range, 3–29+), the median FFS was 10 months, and the median overall survival was 21 months.

Toxicity

Of the 265 courses, 185 were administered at full dose, whereas, in the remaining 80 courses, the doses of the four drugs were reduced by 25% because of Grade 4 neutropenia. Twenty-five courses were delayed by 1 week. The mean delivered dose intensity was 28.3 mg/m2/week for CDDP, 218 mg/m2/week for MTX, and 350 mg/m2/week for 5-FU. One patient died during treatment following a clearly documented stroke; however, the stroke had a correlation with treatment that was questionable. Neutropenia was the most common toxic effect. In fact, 25 of 50 patients (50%) developed Grade 3 (13 patients) or Grade 4 (12 patients) neutropenia during therapy. Other severe hematologic toxicities included Grade 3 anemia in two patients (4%) and Grade 3 thrombocytopenia without clinical sequelae in one patient (2%). Five packed red cell transfusions were given to two patients, although platelet transfusions were never required. Mucositis was a common toxic effect but reached Grade 3 in only four patients (8%), never resulting in significant dehydration or hospitalization. Nausea and vomiting never reached Grade 3; however, 5HT3 receptor inhibitors were used routinely as antiemetic prophylaxis. Diarrhea was clinically significant in two patients but never required hospitalization. Grade 1 neurotoxicity was observed in only five patients; nephrotoxicity was fairly frequent, but it never exceeded Grade 1 nor was it ever the only toxic effect determining chemotherapy dose reduction. Details on toxicity are provided in Table 4.

Table 4. Toxicity
ToxicityWHO grade
01234
  1. WHO: World Health Organization.

Neutropenia58121312
Thrombocytopenia37661
Anemia271562
Nausea and vomiting182012
Nephrotoxicity4010
Mucositis2412104
Diarrhoea3992
Neurotoxicity455

DISCUSSION

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

The vast majority of patients with newly diagnosed SCCHN present with locoregionally advanced disease. This subset of patients represents a therapeutic challenge; in fact, conventional radiotherapy, which has been considered thus far as standard treatment for unresectable SCCHN, is highly palliative because of the risk of local and distant recurrences.18 Recently, a role for chemotherapy as induction therapy before surgery or radiotherapy or alternated with radiotherapy2–4 has been demonstrated in Phase III studies. In particular, a large Phase III trial5 demonstrated an improved survival for patients with inoperable or unresectable disease treated with chemotherapy and radiotherapy compared with those treated with radiotherapy alone. However, other randomized trials have failed to achieve similar results.9, 10 The role of induction chemotherapy in patients with operable lesions is better established; in fact, in these patients, trials of induction chemotherapy with strategies for primary tumor site preservation have demonstrated that organ preservation is possible for tumors of the hypopharynx or larynx, with clear functional and cosmetic advantage, without a different survival outcome with respect to conventional treatment, including surgery and radiotherapy.6–8 The rationale for application of neoadjuvant chemotherapy includes better delivery of drugs to tumors with an intact vascular supply, better utilization of local therapy in a debulked tumor, and better tolerance of higher doses of chemotherapy by previously untreated patients. Also, in tumors characterized by rapid development of drug resistance, such as SCCHN, early application of combination chemotherapy at optimal dose intensity may prevent the development of resistant cell clones in the primary tumor or in clinically latent micrometastases.

The combination of CDDP and continuous infusion 5-FU represents a widely used regimen for induction chemotherapy in locally advanced SCCHN,11, 12 although no survival benefit has been observed in randomized trials comparing this combination with either MTX alone22 or other combinations of active drugs.23 The PF regimen was reported initially as having a clinical CR rate of 54% in 61 patients with advanced but operable and resectable SCCHN.24 However, subsequent evaluation indicated that the true CR rate after three courses was lower, i.e., between 20% and 35%.8 Because the achievement of a CR to the induction chemotherapy has been demonstrated to have a favorable impact on survival,14 the identification of regimens that may result in higher CR rates has achieved a high priority. Among the treatment strategies that have been experimented with to accomplish this goal (multiple courses of therapy, high CDDP and/or 5-FU dosages, increased dose delivery intensification through weekly CDDP administration, combination with other agents25–28), the adequate biochemical modulation of 5-FU with agents like MTX, hydroxyurea, α-interferon, and folinic acid seems to be the most promising.16, 29–31 Four studies have now been completed with the combined use of CDDP, 5-FU, and leucovorin (PFL) as induction chemotherapy in locally advanced SCCHN,16, 32–34 with objective response rates ranging between 45% and 90% and with CR rates ranging between 23% and 54%. In all of these trials, 5-FU has been administered by continuous infusion at doses between 500 mg/m2 and 1000 mg/m2 for 5 days. The 54% CR obtained by Clark et al.34 in 102 patients looks particularly favorable, because it is associated with excellent FFS and overall survival after subsequent locoregional treatment (51% and 52% 5 years after the study onset, respectively).

In the present trial, we tried to combine three active drugs in carcinoma of the head and neck while exploiting the biochemical modulation of 5-FU by the double pretreatment with MTX and LFA, in agreement with our wide experience in advanced gastrointestinal carcinoma.35, 36 Patients with distant metastases were included in our trial as well. The schedule of drug administration was chosen in keeping with experimental and clinical data, which suggest that an adequate interval should elapse between MTX and 5-FU administration,37 whereas a relatively high dose of folate is indicated immediately before the administration of 5-FU. We preferred to use a regimen that included intravenous bolus 5-FU administration, because it could be administered entirely on an outpatient basis, thus substantially lowering cost and improving patient compliance. Previous data confirming the activity of the drug when it is administered as intravenous bolus in this setting13 encouraged us in the choice of this treatment schedule.

The treatment used in the current study was generally well tolerated. The biweekly schedule allowed the concurrent administration of three active drugs with a high dose intensity at the expense of a toxicity that is significantly lower than that reported in similar studies.

In fact, only one death occurred during the treatment, and its correlation to the treatment itself is at least questionable. Neutropenia represented the most frequent toxic effect, occurring in nearly all patients and reaching Grade 3–4 in 50% of them; however, febrile complications were unusual and never required hospitalization, because they were always managed at home with appropriate intravenous antibiotics. Patients were never admitted to the hospital before their planned time for chemotherapy recycling because of overwhelming toxicities of any kind. Nausea and vomiting were very well managed with 5HT3 blocking agents. The incidence of both mucositis and diarrhea was much lower than that reported in other studies with PFL combination34 in which frequent dose reductions of fluorouracil and leucovorin were required to avoid these toxicities. Alterations of renal function were always minor, and peripheral neuropathy never represented a major problem.

The response rate of our combination was 80%, which is in keeping with data reported in studies with PFL regimen, although the CR rate is substantially lower than that reported by Clark et al.34 Patients who achieved an objective response to chemotherapy obtained a CR to subsequent radiotherapy in 100% of cases; on the other hand, only 3 of 6 patients who did not have a response to chemotherapy obtained a CR to subsequent radiotherapy. This observation, although it is devoid of statistical significance due to the low number of patients, lends support to the idea that response to induction chemotherapy might be a predictive factor for response to subsequent radiotherapy. In the current trial, the percentage of patients who were rendered disease free after systemic plus locoregional treatment was considerable and was even higher than that reported by Clark et al.34; this is in keeping with our survival data, which look quite encouraging; in fact, after a median follow-up of 20 months, the median overall survival was 21 months. These survival data compare favorably with the generally accepted figures for these patients,38 even though they look less impressive than those reported by Clark et al.34 However, in their study, 5-FU was administered by continuous infusion at a dose of 800 mg/m2 for 5 days, and frequent dose reductions were required to improve control of toxic effects; furthermore, the incidence of oral stomatitis, diarrhea, and unanticipated hospitalization added significantly to the treatment-related morbidity experienced by these patients. Our schedule is associated with significantly lower toxicity and is far less costly, because it does not require pumps or other expensive devices for drug administration, it can be administered entirely on an outpatient basis, and it is accepted better by patients. We think that the cost effectiveness of our regimen is well worth emphasizing, not only compared with different schedules of similar regimens but also compared with regimens that include new active drugs, such as taxanes.

We conclude that our combination chemotherapy regimen definitely deserves further evaluation; in particular, our next plan is to integrate our regimen within a program of alternating radio/chemotherapy, which has previously provided a survival advantage when compared with neoadjuvant chemotherapy followed by definitive radiotherapy2. In this trial, adequate dose intensity will be maintained by concurrent cytoprotection with amifostine.

REFERENCES

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES
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