Induction chemotherapy in the management of squamous cell carcinoma of the head and neck

Platinum-based chemotherapy administered concurrently with radiation has been adopted as the standard treatment for locally advanced head and neck squamous cell carcinoma. Historically, randomized trials using induction chemotherapy prior to radiation therapy alone have failed to demonstrate a clear survival advantage, and concurrent chemoradiation has delivered better results than previously obtained with radiation therapy alone, establishing the benefit of adding chemotherapy. This method of treatment, together with new modalities of therapy and novel agents, has reintroduced the question of induction chemotherapy before definitive chemoradiation. Systemic chemotherapy offers a better possibility of reducing systemic metastasis and improving cosmetic appearance. This article reviews developing trends using induction chemotherapy followed by chemoradiation in patients with head and neck squamous cell carcinoma.     

Induction chemotherapy in the management of squamous cell carcinoma of the head and neck

Platinum-based chemotherapy administered concurrently with radiation has been adopted as the standard treatment for locally advanced head and neck squamous cell carcinoma. Historically, randomized trials using induction chemotherapy prior to radiation therapy alone have failed to demonstrate a clear survival advantage, and concurrent chemoradiation has delivered better results than previously obtained with radiation therapy alone, establishing the benefit of adding chemotherapy. This method of treatment, together with new modalities of therapy and novel agents, has reintroduced the question of induction chemotherapy before definitive chemoradiation. Systemic chemotherapy offers a better possibility of reducing systemic metastasis and improving cosmetic appearance. This article reviews developing trends using induction chemotherapy followed by chemoradiation in patients with head and neck squamous cell carcinoma.     

Induction chemotherapy with cis-platinum and 5-fluorouracil for squamous cell carcinoma of the head and neck

One hundred and eight patients with squamous cell carcinoma of the upper aerodigestive tract (UADT) (T3, T4, NO-N3; 17% stage II, 54% stage III, 27% stage IV) were given three courses of chemotherapy before any local treatment. The regimen consisted of cis-platinum 100 mg m-2 on day 1 and 5-fluorouracil 1000 mg m-2 on days 2-6; drugs were administered by continuous infusion. The toxicity of this protocol was acceptable, as 82% of the patients were able to receive the initially scheduled drug dose. The overall response rate of 86.5% included a 35% rate of complete lesion regression. The effect of this regimen on primary tumours was especially remarkable--87.5% responses, including 47.5% complete responses. Results for lymph node metastases were not as good--66% responses, including 33% complete responses. The best results were obtained for tumours of the oropharynx and hypopharynx; oral cavity lesions were the most refractory. For those patients who were subsequently operated on, histological examination of the surgical specimen either confirmed sterilization or demonstrated the persistence of small disease foci. After local treatment, which consisted of radiotherapy alone for 69% of patients, the lesion control rate was 80%. At 18 months follow-up, the survival rate for patients who achieved a complete response with chemotherapy was significantly better than that for patients with a response of less than 50%.     

Induction chemotherapy with the EXTREME regimen in frail patients with locally advanced head and neck squamous cell carcinoma

Background

Induction chemotherapy (IC) with TPF (docetaxel, cisplatin, 5FU) for locally advanced head and neck squamous cell carcinoma (LAHNSCC) is limited to fit patients.

Objective

We conducted a retrospective cohort study to assess the use of the EXTREME regimen (platinum-based therapy, 5FU, cetuximab) as IC in frail patients with LAHNSCC.

Patients and methods

Retrospective analysis of all consecutive patients with unresectable LAHNSCC treated with the EXTREME regimen, with or without 5FU as IC, from two French centers from 2008 to 2015. We assessed the rate of completed sequence defined as at least two cycles of IC and definitive radiation therapy.

Results

We included 34 patients with a median age of 56 years [44-70]. The primary site of tumor development was the oropharynx (67%, n=23, all HPV negative), hypopharynx (21%, n=7) and the oral cavity (12%, n=4). At inclusion, patients presented: T4 76, 5% (n=26), N2c 41% (n=14), N3 26% (n=9), stage disease IVa 62% (n=21), IVb 38% (n=13), ECOG PS2 38% (n=13), decreased weight (10% in one month or 15% in 6 months) 74% (n=25). The sequence was achieved for 76% (n=26) of patients and 80% (n=27) presented a clinical response after the chemotherapy course with notably increased weight (40%, n=11) or general status (75%, n=26). Median PFS and OS were 5.7 and 15.5 months, respectively. Disease progression at 3 months was significantly associated with decreased median overall survival (13.6 versus 21.9 months, p=0.01).

Conclusion

This is the first study to report the use of the EXTREME regimen as induction chemotherapy, and although this IC was used in a very frail population, the majority completed the sequence with significant clinical benefit.

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Induction chemotherapy with docetaxel,cisplatin and 5-fluorouracil followed by radiotherapy with cetuximab for locally advanced squamous cell carcinoma of the head and neck

PurposeTo determine the efficacy and feasibility of induction chemotherapy (ICT) with docetaxel, cisplatin and 5-fluorouracil followed by radiotherapy and cetuximab (C) in patients with locally advanced head and neck cancer.Patients and methodsForty-nine previously untreated patients with local advanced stage III and IV squamous cell carcinoma of the head and neck (SCCHN) received three courses of ICT consisting of docetaxel 75 mg/m² day 1, cisplatin 75 mg/m² day 1 and infusional 5-fluorouracil 750 mg/m²/day on days 1–5 followed by radiotherapy plus C at 250 mg/m²/week (after an initial loading dose of 400 mg/m²).ResultsAfter completion of ICT 44 of 49 patients received radiotherapy plus C. Three months after therapy completion tumour response was observed in 33 patients and after two years, 25 patients were in complete remission (CR). The most common grade 4 toxicity during the whole treatment period was dermatitis (30%), followed by mucositis (27%) and neutropenia (17%) without fever. One toxic related death was observed during ICT. Two-year progression-free survival (PFS) rate was 59% and two-year overall survival (OS) rate was 63%, respectively.ConclusionConcurrent radiotherapy plus C after three courses of ICT was feasible and was associated with promising CR, PFS and OS rates. Further optimisation of dose and sequence is warranted.     

Combination chemotherapy with high-dose methotrexate, bleomycin, and cisplatin in management of head and neck squamous cell carcinoma

Fifty-nine patients with stage IV head and neck squamous cell cancer were treated with an intensive induction chemotherapy consisting of high-dose methotrexate-leucovorin, bleomycin, and cisplatin. Forty-five patients had recurrent disease following surgery and/or radiation therapy. The response rate in this group was 22%, with a median response duration of 10 weeks and a median survival of 19 weeks. The median survival in responders was 20 weeks and in nonresponders 18 weeks. Fourteen previously untreated patients (13 T4 and one T2) received identical chemotherapy followed by radiation and/or surgery. The response to chemotherapy in previously untreated patients was impressively higher (93%). These patients had a median survival of 48 weeks, and 30% survived 2 years. The initial chemotherapy did not compromise the succeeding radiation therapy or surgery. Toxicities were frequent, but generally well tolerated. It is concluded that prior surgery and/or radiation therapy compromises the efficacy of subsequent chemotherapy in head and neck cancer. Responses to intensive chemotherapy prior to surgery and/or radiation therapy are excellent in patients with T4 tumors and provides a basis for further intensive treatment in attempts to augment cure rates.     

Concurrent radiotherapy and chemotherapy with cisplatin in inoperable squamous cell carcinoma of the head and neck. An RTOG Study

In patients who have locally advanced and inoperable head and neck cancer, the achievement of initial local control (complete response) of the disease with initial definitive treatment with radiotherapy (RT) with or without chemotherapy, is an important prognostic factor for overall survival. Cisplatin 100 mg/M2-intravenously (IV) with hydration and mannitol diuresis was given every 3 weeks for three doses concurrently with definitive radiotherapy (followed by salvage surgery [if possible] for persistent disease) was activated by the Radiation Therapy Oncology Group (RTOG) in 1981. One hundred thirty-four patients were initially registered and 124 were eligible and analyzed for this report. Eighty-two percent of the patients had Stage IV disease and greater than 50% of the primary sites were in oropharynx (39%), nasopharynx (22%), and oral cavity (18%). Eighty-seven percent of the patients are known to have finished the planned RT greater than 6450 cGy and 60% received three courses of cisplatin. Overall, 60% finished the planned combined treatment. Complete response to initial treatment occurred in 69% and an additional one patient (1%) was rendered disease-free after radical node dissection. Severe toxicities were as follows: leukopenia, 11%; anemia, 8%; nausea and vomiting, 6%; stomatitis, 31%; and renal, 6%. One toxic death occurred when a nephrotoxic antibiotic was administered at the same time. All patients were evaluated for total disease and survival regardless of compliance to the treatment or the cause of death. At 1 year, an estimated 51% of the patients had their disease totally controlled and an estimated 66% were alive. Incidence of initial complete response by various patient characteristics also were analyzed. The authors concluded that the combination of cisplatin and radiotherapy is an effective and safe treatment in patients with advanced head and neck cancer and needs to be tested against radiotherapy alone.     

Induction chemotherapy with cisplatin/docetaxel versus cisplatin/5-fluorouracil for locally advanced squamous cell carcinoma of the head and neck: a randomised phase II study

A combination of cisplatin and 5-fluorouracil (PF) is considered the standard induction chemotherapy regimen for squamous cell carcinoma of the head and neck (SCCHN). The present study compares the efficacy and safety of a new combination of cisplatin/docetaxel versus the PF regimen. A total of 83 chemotherapy-naive patients with locally advanced SCCHN were randomised to receive every 21 d (i) docetaxel 85 mg/m2 i.v. on day 1 and cisplatin 40 mg/m2 i.v. on days 1 and 2 (arm A) or (ii) cisplatin 100 mg/m2 i.v. on day 1 followed by 5-fluorouracil 1000 mg/m2 in 24 h continuous infusion for 5 d (arm B). A total of 287 cycles (range 1-3 per patient) were administered. Among 76 patients evaluable for response, the overall response rate in arm A was 70% (complete response (CR) 26%, partial response (PR) 44%) and in arm B 69% (CR 16%, PR 54%), respectively. Median survival in arm A was 7.6 months (95% CI: 5.8-11.1) and 9.9 months (95% CI: 7.4-14.6) for arm B. The most frequent grade 3/4 toxicity in arm A was neutropaenia (34.1%) and diarrhoea (9.8%) versus mucositis (29.3%) and neutropaenia (19.5%) in arm B. Both schedules present a similar efficacy, with different but acceptable toxicity patterns.     

Phase II Trial of docetaxel and cisplatin combination chemotherapy in patients with squamous cell carcinoma of the head and neck.

PURPOSE: To assess the antitumor activity and toxicity of docetaxel plus cisplatin chemotherapy in patients with recurrent or incurable squamous cell carcinoma of the head and neck (SCCHN). PATIENTS AND METHODS: Patients with recurrent or incurable SCCHN were eligible if they were chemotherapy naive or if they had received one prior regimen as neoadjuvant or concurrent treatment with radiation. Patients who had received chemotherapy for recurrence or prior taxanes were ineligible. Patients received docetaxel 75 mg/m(2) and cisplatin 75 mg/m(2) on day 1; cycles were repeated every 21 days. RESULTS: Toxic effects and length of survival were assessable in 36 patients and tumor response was assessable in 32, for whom the overall response rate was 40% (13 of 32) (6% complete response and 34% partial response). Median time to response was 5 weeks, and median duration was 4.9 months. In the intent to treat population (n = 36), median time to disease progression was 4 months. Median survival (n = 36) was 9.6 months, and the 12-month survival rate was 27%. Grade 4 neutropenia was observed in 71% of patients. Two patients (6%) experienced serious fever during grade 4 neutropenia (without documented infection) that required intravenous antibiotics, and an additional four patients had grade 3 infection. Other severe (grades 3 and 4) toxic effects were asthenia (25%), nausea (11%), fever (8%), vomiting (8%), severe hypersensitivity reactions (8%), and diarrhea (8%). Severe stomatitis (grade 3) occurred in only one patient. CONCLUSION: Docetaxel plus cisplatin is an effective regimen with an acceptable safety profile for palliation of recurrent SCCHN. Relative to the standard regimen of cisplatin/fluorouracil, this regimen may offer higher tumor response and survival rates with short outpatient administration and a lower incidence of severe mucosal toxicity.     

Induction chemotherapy for squamous cancer of the head and neck

This paper reviews the efficacy and hazard of sequential combined treatment programs for squamous cell carcinoma of the head and neck. These regimens consist of initial systemic chemotherapy, known as neoadjuvant or induction chemotherapy, followed by radiation with or without concomitant chemotherapy.     

Paclitaxel and cisplatin in patients with recurrent and metastatic head and neck squamous cell carcinoma

The purpose of this phase II trial was to investigate the use of paclitaxel and cisplatin in patients with recurrent and/or metastatic head and neck squamous cell carcinoma (HNSCC), to evaluate tumor response, time to progression, survival, and toxicity of this regimen. Patients with recurrent and/or metastatic HNSCC received 175 mg/mq paclitaxel (PTX) administered as a 3-h intravenous infusion on day 1 and 75 mg/mq cisplatin (CDDP) as a 30(') intravenous infusion on day 2; cycles were repeated every 21 days. From February 1997 to February 2000, 36 patients (18 with locoregionally recurrent disease, 8 with deemed inoperable locally advanced disease, and 8 with metastatic disease) with a median age of 60 years (range 38-73 years) were enrolled. The patients evaluable were 34 for toxic effects, length of survival, and tumor response. The overall response was 41.1%, with two (5.8%) complete responders (CR) and 12 (35.3%) partial responders (PR), 10 (29.4%) patients had stable disease and 10 (29.4%) progressed. The median time to progression (TTP) was 5 months (range 1-49 months), and the median overall survival was 11 months (range 1-53 months). The 1-year-, the 2-year-, and the 3-year-survival rate were 38.2, 17.6 and 14.6, respectively. Up to date of the statistical evaluation four patients were still alive. According to the World Health Organization (WHO) criteria, transient G3 neutropenia and anaemia occurred in seven (20.5%) and four (11.7%) patients, respectively. The predominant non-haematologic toxicities were alopecia and fatigue: Twenty-three (67.6%) patients had G3 alopecia, two patients (5.8%) G3 fatigue and 10 (29.4%) G2, eight (23.5%) G2 myalgia, eight (23.5%) G2 nausea/vomiting, and two (5.8%) G2 mucositis. There were no G4 toxicity and any treatment-related death. Paclitaxel plus cisplatin combination is an active regimen with an acceptable safety profile in recurrent/metastatic HNSCC. This regimen, according to our opinion, is a valid alternative to infusional fluorouracil (5FU)/cisplatin. In fact up to date we can confirm, in taxane era, that paclitaxel, as single agent or in combination, produce response rates similar to cisplatin/5FU regimen, but with more manageable toxicity, especially in the subset of patients with 0-1 ECOG-PS and incurable or locoregional recurrent HNSCC, with short outpatient administration too.     

Results and failures with or without cisplatin containing induction chemotherapy in the treatment of squamous cell carcinoma of the head and neck

This prospective randomised study was undertaken to assess the effects and effectiveness of cisplatin in a pre-operative setting. Thirty-eight patients were treated with stage II-IVa (AJCC) squamous cell cancer of the oral cavity and oropharynx. Nineteen patients received a combination of bleomycin, vincristine, methotrexate (BVM; group I.), 19 received BVM and cisplatin (group II). Patients underwent surgery within 3 weeks after chemotherapy. Biopsy and surgical specimens were compared. A clinical complete response was seen in five patients in group I (26.3%) and in four patients in group II (21.1%). Partial response was noted in 11 patients in group I (57.8%) and in 13 patients in group II (68.4%). There was no statistical difference in clinical response between the two groups. Microscopic response was better in the cisplatin treated group. Median follow up of patients is 52 (36-70) months. Disease free survival showed a significant difference, favouring the no cisplatin group (P = 0.03). There was no significant difference in overall survival (P > 0.6). Cisplatin in combination with BVM showed significantly higher levels of microscopic response, but the lower disease free survival is mostly due to a higher rate of regional neck failure.     

Induction chemotherapy in advanced squamous head and neck carcinoma with high-dose cis-platinum and bleomycin infusion.

Forty patients with advanced head and neck cancer were treated with combined Cis-platinum-Bleomycin chemotherapy. Cis-diammine dichloroplatinum (DDP) 120 mg/m2 iv was given after prehydration, with mannitol diuresis on Day 1. On Day 3, an initial loading dose of Bleomycin 15 mg/m2 was given by rapid iv push followed by continuous 24 hour intravenous infusion of Bleomycin 15 mg/m2 Day 3 through Day 10. DDP 120 mg/m2 iv was administered again on Day 22. The patients were evaluated for tumor response and resectability between Day 29 to Day 35. Of 39 patients who were evaluable, there were 8 complete responses or CR (20%) and 22 partial responses or PR (56%), for a major response rate of 76%. Nineteen patients had surgery (14 patients whose lesions were initially inoperable and 5 patients who were initially operable). Chemotherapy toxicity in 40 patients included alopecia (40), vomiting (39), mucositis (11), skin rash (10), fever (17), weight loss of more than 5 lbs. (25), WBC less than 3,000 (2), platelets less than 100,000 (1), peak serum creatinine of 2 mg% (3), severe-hearing loss (1), hypersensitivity reaction (2). Surgical complication in 19 patients were pharyngocutaneous fistulae (2), wound dehiscence (1), meningitis and brain abscess (1). There was one death secondary to nephrotoxicity. This particular combination chemotherapy when given as initial treatment, appears very effective in reduction of tumor bulk. Long-term follow-up and randomization is necessary to determine effect upon survival.     

Pretreatment with 5-FU enhances cisplatin cytotoxicity in head and neck squamous cell carcinoma cells

PURPOSE: In the treatment of head and neck malignancy, cisplatin and 5-FU have been used the most as chemotherapeutic agents. The difference in efficacies of these is unclear and controversial. To investigate more effective schedule, we analyzed the cytotoxicity in different treatment sequence with two agents in vitro and the mechanism for different effectiveness. METHODS: UM-SCC-23 and UM-SCC-81B, head and neck squamous cell carcinoma cell lines, were analyzed for cellular killing in alternative sequence treatment with cisplatin and 5-FU. The treatment schedule was designed based on the clinical regimen. To determine the mechanism for the difference of cytotoxicity with each schedule, cell cycle distributions of both cells after 5-FU treatment with various durations were analyzed by flow-cytometry and immunostaining with anti-PCNA and anti-BrdU. RESULTS: 5-FU pretreatment followed by cisplatin treatment showed higher cell killing in both types of cells than the reverse treatment schedule. In the cell cycle analysis and immunostaining after the treatment of 5-FU, the rate of PCNA-positive cells was increased from 24 to 144 h in both cells. The rate of BrdU-positive cells of UM-SCC-81B in flow-cytometry was also increased, while that of UM-SCC-23 was gradually decreased. These data suggested that the cells treated with 5-FU for more than 144 h were still in the S-phase with or without DNA synthesis. CONCLUSIONS: In head and neck carcinoma cells, we showed 5-FU pretreatment enhanced cisplatin cytotoxicity. The result of cell cycle analysis and immunostaining showed S-phase arrest by treatment of prolonged 5-FU treatment. The very long arrest in S-phase might be a mechanism to enhance cisplatin cytotoxicity by 5-FU pretreatment. We thus suggest pretreatment with 5-FU to enhance the effectiveness of cisplatin-based chemotherapy.     

Treatment of squamous cell carcinoma of the head and neck with multi-drug chemotherapy and radiotherapy

Multi-drug chemotherapy containing cisplatin has been reported to be one of the most active chemotherapy regimens in advanced or recurrent head and neck squamous cell carcinoma. In this study, the current status of clinical investigation of combination chemotherapies is reviewed. And our data are presented in head and neck cancer with multi-drug chemotherapy containing cisplatin. Thirty-five patients of stage 3-4 and 70 patients with recurrent and/or metastatic head and neck squamous cell carcinoma were treated by multi-drug chemotherapy containing cisplatin, and radiotherapy and/or operation. The overall response rate was 71.4%, with 17.1% complete remission in previously untreated, locally advanced patients and 31.4% in recurrent or metastatic patients. Problems of chemotherapy combined with radiotherapy and future direction of clinical study in locally advanced or recurrent head and neck cancer are discussed.     

Combination chemotherapy with methotrexate, bleomycin, and vincristine with or without cisplatin in advanced squamous cell carcinoma of the head and neck

A total of 185 eligible patients with advanced inoperable squamous cell carcinoma of the head and neck were randomized into two groups; the cisplatin, methotrexate, bleomycin, and vincristine (CABO) group received cisplatin (50 mg/m2; day 4), methotrexate (40 mg/m2; days 1, 15), bleomycin (10 mg; days 1, 8, and 15), and vincristine (2 mg; days 1, 8, and 15) and the ABO group received methotrexate, bleomycin and vincristine in the same doses on days 1, 8, and 15. After three courses, patients in both arms received weekly methotrexate as maintenance therapy; those 34 patients with previously untreated locoregional disease went off the study because of subsequent locoregional treatment in form of radiotherapy +/- surgery. The complete response rate was 16% in patients receiving CABO, compared with 5% among patients given ABO. The corresponding overall response rates were 50% and 28%, respectively (P = 0.003). Among patients with recurrent or metastatic disease, progression was delayed in patients receiving CABO (median, 18 weeks) compared to those receiving ABO (median, 14 weeks) (P = 0.07), but there was no difference in survival time. Myelosuppression consisted mostly of leukopenia, which was seen in 67% of the CABO patients versus 47% in the other arm. Myelosuppression-associated infection and hemorrhage led to death in two patients in the CABO treatment group and six patients in the ABO treatment group. Nausea and vomiting, mostly of grades 1 or 2, occurred in 93% of the patients given CABO and 44% of those receiving ABO. Other toxic effects--neuropathy, alopecia, stomatitis, constipation, fever/chills, diarrhea, cutaneous alterations, and renal impairment--occurred equally in the two treatment groups. This study underlines the role of cisplatin in head and neck cancer, although no impact on survival could be demonstrated. It also supports indirectly the superiority of combination chemotherapy over single-agent treatment for this disease.     

Induction chemotherapy with paclitaxel, cisplatin and 5-fluorouracil for squamous cell carcinoma of the head and neck: long-term results of a phase II trial.

BACKGROUND: The aim of this study was to evaluate the efficacy and toxicity of a combination of paclitaxel, cisplatin and 5-fluorouracil (PPF) as induction chemotherapy in patients with locally advanced squamous cell carcinoma of the head and neck (SCCHN). METHODS: Seventy patients with previously untreated stage III-IV SCCHN were included in this phase II trial. Induction treatment consisted of a maximum of three outpatient courses of paclitaxel 175 mg/m(2) as a 3-h infusion on day 1, cisplatin 100 mg/m(2) on day 2, and 5-fluorouracil (5-FU) 500-750 mg/m(2)/day as a 24-h continuous infusion on days 2-6, repeated every 3 weeks. The 5-FU dose was reduced from 750 mg/m(2)/day to 500 mg/m(2)/day due to the excessive toxicity observed in the first 14 patients enrolled. Local treatment consisted of radiotherapy and/or surgery. RESULTS: Two-hundred-and-one cycles were administered to 70 patients. The main toxicities of PPF were neutropenia (grade 4, 14%; febrile neutropenia, 4%), peripheral neuropathy (grade 2-3, 14%) and catheter-associated venous thrombosis (7%). There were three early deaths (two from neutropenic sepsis and one from pulmonary embolism), and 13 patients required hospitalization due to toxicity. Other side effects included mucositis, anorexia, diarrhea, myalgias and alopecia. The overall response rate to PPF was 88%, including 59% complete responses (CR) and 29% partial responses. The CR rates at the primary tumor and neck lymph nodes were 74% and 62%, respectively. With a median follow-up of 51 months (range 40-63 months), the estimated 5-year time-to-disease progression and overall survival rates were 56% and 44%, respectively. CONCLUSIONS: The PPF regimen has major antitumor activity and is associated with manageable toxicity as induction treatment in SCCHN patients. The high complete response rate and favorable long-term outcome justify further evaluation of this chemotherapy combination.