Introduction

Chemotherapy (CT) followed by radical radiotherapy (RT) is proven to be a valid alternative to surgery in locally advanced operable head and neck cancer, involving the larynx. The overall results comparing surgery combined with RT versus CT followed by RT, tested in two large phase III randomized trials [1, 2], indicate that:

  1. 1.

    survival rate is comparable but not increased by CT–RT

  2. 2.

    preservation of laryngeal function is achieved in over 50% of patients

  3. 3.

    response to CT is predictive of RT response

  4. 4.

    CT–RT treated patients have decreased metastatic relapses.

Locoregional tumor control is likely to be affected by time elapsed from diagnosis and start of radical locoregional treatment but also by delay of definitive treatment (surgery and/or radiotherapy) due to the neoadjuvant CT.

Head and neck cancer potentially has a short doubling time and it will repopulate rapidly between the daily fractions of conventional fractionation RT: unconventional fractionation is able to reduce this fact. Furthermore, a reduction in both radiotherapy and chemotherapy treatment times might result in an increase of local tumor control.

In light of these findings, we have designed an institutional prospective phase II trial with a short course of neoadjuvant CT followed by unconventional fractionated RT (in the first period of the study we employed a hyperfractionated scheme and in the second an accelerated scheme). The objectives of the study were to assess the efficacy and evaluate the toxic effects of an intensive organ preservation modality, employing three CT cycles, with a week break, starting a few days after the diagnosis, followed by unconventional fractionated RT.

Materials and methods

Major eligibility criteria included previously untreated stages III–IV head and neck tumors, no evidence of distant metastases, World Health Organization(WHO) performance status of 0–2, age ≤ 75 years, adequate renal and hematological functions.

All patients required total laryngectomies either for local extension of disease or, in some non-compliant patients, to avoid the risk of inhalation due to the need to extend the surgical procedure to include the base of the tongue. All patients were evaluated by the “Head and Neck Committee” of Aviano National Cancer Institute consisting of a surgeon, a medical and a radiation oncologist.

Staging procedures included either computed tomography (CT) scan or magnetic resonance (MR) imaging of the head and neck region, a chest X-ray, a laryngo-pharyngoscopy, broncoscopy and esophagoscopy, with biopsy of suspected lesions, and liver ultrasound. A PET-CT was prescribed only when there was reasonable suspicion of distant metastases.

Patients were re-staged according to the 2002 UICC/TNM classification. At the time of esophagoscopy, the placement of a percutaneous endoscopic gastrotomy (PEG) was planned in patients with weight loss up to 10%. Dental status evaluation and fluoride-prophylaxis/prescription were carried out in all patients.

Treatment

CT schedule

Induction CT consisted of three courses of intravenous Cisplatin (100 mg/m²) and continuous 120-h infusion of 5-Fluorouracil (1,000 mg/m² per day). Chemotherapy was planned on days 1, 14, and 28. Response to CT was evaluated clinically and by CT-scan 10 days from the third CT cycle; criteria were evaluated according to WHO definitions. Patients with partial remission <50% at the primary site, underwent surgical resection followed by RT; all others received radical RT.

RT schedule

External beam RT was delivered with a 6 Mv Linear Accelerator after 2 weeks from the end of the CT cycles. From January 1998 to June 2002, the first group of 52 patients was treated with a hyperfractionated RT schedule consisting of a total 7,440 cGy delivered in 62 fractions(2 daily fractions of 120 cGy each) with a 6-h interval between fractions. Shrinking fields techniques were used; a boost of 2,400 cGy in 20 fractions delivered by a multiple co-planar field technique. The planned total treatment time was 6.5 weeks as previously reported [3].

From July 2002 to December 2006 due to logistical patients’ difficulties and outcomes reported in a RTOG study [4], a second group of 56 patients were treated by concomitant-boost RT: 180 cGy per fraction to 5,400 cGy in 30 fractions over 6 weeks to the gross tumor. At 3,240 cGy in 18 fractions, a second dose of 150 cGy by conformal RT at 6 h intervals, was given to the macroscopic tumor, for a total dose of 1,800 cGy in 12 fractions. On the whole, the primary tumor received 7,200 cGy in 42 fractions and uninvolved nodes received 5,400 cGy in 30 fractions in 6 weeks.

Patients with at least 1 lymph node >3 cm at the original diagnosis and patients with clinical residual mass persistence in the neck at 2 months from the end of RT, underwent a selective neck dissection. Clinical examinations with a fiber-optic laryngoscope were performed weekly during RT treatment to define toxicity and response. Patients were followed up every 2 months for the first 6 months; every 3 months in years 1–3, every 6 months in years 3–5, and annually thereafter.

No routine biopsy procedures were employed to confirm complete remission; they were obtained in case of suspected relapse or disease persistence only.

Statistics

Overall survival was calculated from the date of CT start to the time of death (including all types of death) or last active follow-up. Cancer-specific survival was calculated from the date of CT start to the time of death from head and neck cancers or last follow-up.

Disease-free survival (DFS) was computed from the date of clinical complete remission (CR) to date of relapse. Patients who failed to reach CR were excluded from the analysis.

Kaplan–Meier method [5] and a log-rank test was used to test differences in clinical characteristics between subgroups. In all cases, statistical significance was claimed for P ≤ 0.05.

Results

A total of 115 patients with respectable, only with laryngectomy, biopsy proven, squamous cell carcinoma of the oropharynx, hypopharynx and larynx, were evaluated to enter into the accelerated CT–RT trial between January 1998 and December 2006. Seven patients failed to complete the planned therapeutic program and were lost to evaluation for the combined CT–RT regimen. Two of the seven non-evaluable patients died during the first 2 weeks after study initiation: one from massive pulmonary thromboembolism and the other from diabetic imbalance. Five patients did not receive RT given no response to CT after chemotherapy. They received salvage surgery according to protocol specification and they were included for statistical analysis in the group of patients who had no larynx preservation. A total of 108 patients, object of the study, completed the therapeutic program fully.

Of these evaluable patients, 100 were men and 8 were women. Average age at diagnosis was 59 (range 38–77). A previous clinical history of malignancy was reported in 5.5% of the patients which were truly considered cured.

The primary cancer site was the hypopharynx in 45 patients (87% pyriform sinus), larynx in 37 and oropharynx in 26 patients (52% base of tongue). Clinical patients’ characteristics, tumor stage and histological grade are reported in Tables 1 and 2: 79% had tumors classified as T3–T4 and 61% as N2–N3;84% had a stage IV disease. In 60% of the patients, the tumor grade was classified as G3–G4 according to the WHO classification [6].

Table 1 Characteristics of the patients
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Table 2 Primary tumor and nodal stage
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CT evaluation

A total of 333 CT cycles were administered: the median time from histological report date to start of CT and from first medical examination to start of CT were 32 and 9 days, respectively. The third Cisplatin/5-Fluorouracil cycle was deleted in 5 patients and in 15 the dose was reduced by 25% due to toxicity (4 patients did not receive a third cycle due to toxicity). Overall, 82% of the patients received CT according to the protocol. At 2 weeks from the end of CT, a complete remission in the primary site was observed in 22 patients (20.3%) and 17 patients (15.7%) achieved a complete node remission. The chemotherapy-related toxicity was well managed by adequate supportive care: grade G3–G4 leucopenia, anemia, and thrombocytopenia were reported in only 4.5, 6.5 and 3% of the patients, respectively. Grade 3–4 mucositis developed in 17.5% and conventional cardiovascular toxicity occurred in 20%, with tachyarrhythmias and sinus bradycardia (inferior to 59 heart rate beats/min) reported in 36 cycles. Severe symptomatic bradycardia (sinus heart rate < 39 beats/min) occurred in two patients and one patient had a myocardial ischemia.

RT evaluation

Of the 108 patients receiving RT, 52 were treated consecutively by hyperfractionated schedule (7,440 cGy in 62 fractions) and 56 by concomitant boost technique (7,200 cGy in 42 fractions): all concluded the planned RT treatment. The median interval between end of CT and start of RT was 17 days (range 12–30) and median duration of RT was 44 days (range 41–67).

All patients in the study experienced a grade 2–3 (WHO) mucositis except nine in whom it was reported as grade 4; in four patients treatment was interrupted due to radiotherapy-related toxicity (range 7–25 days). Moreover, 23 patients needed hospitalization: 14 to receive parenteral nutrition as well as supportive care to treat dehydration and electrolyte imbalance for a median of 29 days (range 4–52), 10 only for logistic reasons (difficulty of administering 2 daily-fractions).

The median overall treatment time from the first day of CT to the last day of RT was 101 days (range 83–122).

Two months after RT, 97.2% of patients had a clinical complete remission in the primary site and only three patients required salvage surgery for tumor persistence at clinical evaluation, confirmed by CT scan or MR. The rate of complete response was not significantly different between the two radiotherapy regimens measured by univariate analysis [chi-square (log-rank test) = 0.01; P = 0.94). At the end of RT, clinically complete response in neck-nodes was recorded in 95 patients (87.7%): 13 patients underwent neck dissection on residual node-disease and, according to protocol direction, other 25 patients were submitted to adjuvant surgery given initial lymph node stage.

Figures 1, 2 and 3 show the 5-year overall survival, 5-year cancer-specific overall survival, and disease-free survival, at the median follow up of 58 months (range 14–84), respectively. Figure 4 shows the disease-free survival by RT schedule.

Fig. 1
figure 1

Overall survival of 108 patients with locally-advanced head and neck cancer time (months) probability

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Fig. 2
figure 2

Cancer specific survival of 108 patients with locally-advanced head and neck cancer time (months) probability

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Fig. 3
figure 3

Disease free survival of 105 clinical complete remission patients with locally-advanced head and neck cancer time (months) probability

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Fig. 4
figure 4

Disease free survival of 105 clinical complete remission patients with locally-advanced head and neck cancer by radiotherapy schedule (continuous lines concomitant boost vs. discontinuous lines hyperfractionation) time (months) probability

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At the time of analysis, 67 patients (62.6%) are alive and free of disease, 23 patients died from cancer, 15 died from intercurrent disease or a second primary tumor and three patients are alive but with continued presence of the disease and undergoing CT. Overall organ preservation rate was 73.5%. The data in Table 3 summarize our study outcome: the cumulative rate of locoregional persistent disease after CT–RT was 15.0% (16 patients). From the end of RT, the median time for local relapse was 8 months (range 4–32); evidence of progression was noted in only three patients after 2 years: one in the neck and two at distant sites.

Table 3 Results and toxicity
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An univariate analysis was performed to identify the covariables determining the disease free survival and overall specific survival. We analyzed: primary site, histological grade, “T” and “N” stage, lymph node characteristics, elapsed time between time of diagnosis and start of CT, overall time of CT–RT, elapsed time between end of CT and start of RT, response to CT and RT. Only the site of primary tumor presentation was of borderline significance for larynx cancer versus hypopharynx or oropharynx (P = 0.06): all other possible prognostic factors were not significant.

Discussion

Avoiding larygectomy in locally advanced squamous cell head and neck cancer involving the larynx remains a challenge. The combined induction cisplatin-chemotherapy obtained a high response rate but multiple randomized trials [7–9] have failed to demonstrate any significant improvement in the overall survival. The only reported result after neoadjuvant CT appears to be a decrease in the development of distant metastatic disease, with an estimated reduction of approximately 65–45% [10]. Despite these encouraging results on distant metastases, in the randomized studies [11–13], lack of a good overall survival was determined by locoregional failure. For this reason, more effective RT–CT combination regimens, and particularly an unconventional RT schedule associated with a more aggressive CT, are advisable.

Our schedule intended to face a series of relevant problems:

  1. 1)

    The use of an optimal CT scheme (Cisplatin–5FU) delivered to full dosage in the shortest time to avoid delay of locoregional treatment, also aimed to decrease chemotherapy clone-resistant cells and prevent their rapid growth.

  2. 2)

    The adoption of an unconventional, more effective RT schedule (hyperfractionated or concomitant boost RT regimen).

  3. 3)

    A reduction of the CT–RT overall treatment time sequence.

  4. 4)

    Homogeneity in total laryngectomy prescription by the same Head and Neck surgical team.

In our Department, the waiting time from the first Head and Neck Committee medical examination to the start of RT treatment is on average 35 days (range 15–56) due to the number of patients treated daily which may influence local tumor control. In fact, at an International Federation of Head and Neck Oncologic Society Meeting (27 June–1 July 2006, Prague, Czech Republic) [14], Overgaard presented a study to determine the impact of waiting time on tumor growth in head and neck cancer patients: in 53 patients, two scans at a median interval of 28 days during waiting radiotherapy time (range 5–125) were evaluated and he reported that 57% of the patients had increases of tumor volume, 30% progressive disease and 19% progressed to higher stages. We have postulated that starting an intensive schedule of CT immediately after the first clinical examination is necessary to kill the maximal number of tumor cells and allow a stabilization of tumor volume, and simultaneously begin the locoregional radical treatment in the shortest time possible.

In our study, at the end of CT cycles, we obtained 20.3% complete remission and an 87% total response rate, achieving a 97.2% complete response after RT treatment.

We emphasize that CT began within 9 days from our first clinical examination (range 5–18). Therefore, no patients developed an increase in tumor volume during the waiting/combined-treatment time, and this should be considered an improvement in prognosis and disease probability control [15, 16].

In recent years, prospective randomized studies showed that the association of CT–RT obtained higher locoregional control and overall survival rates compared with RT alone or neoadjuvant CT associations [17–24].

A large metaanalysis of 63 trials and 10,741 patients reported a 4% absolute survival advantage at 5 years (CT plus RT) but only for the concomitant modality and no benefit was reported for adjuvant and/or neoadjuvant CT. Moreover, an abstract presented at the 2006 ASCO meeting,regarding results of Intergroup RTOG 91–11 [11] with a long follow up period (6.9 years),reported a comparable rate of improvement in laryngectomy-free survival (LFS) both with neoadjuvant and concomitant RT–CT, but without any advantage in overall survival. On the other hand, the superior efficacy of concurrent CT–RT is associated with considerable toxic effects such as high grade mucositis with dysphagia and weight loss requiring the interruption of treatment, supportive care, and hospitalization.

In our patient-group, 60% of tumors were poorly differentiated, 42% of patients presented a hypopharyngeal primary site cancer and 63% had advanced lymph node disease classified as stage N2–N3: all these patients were categorized at greatest risk of developing distant metastases and therefore candidates for systemic therapy.

Major issues in head and neck cancer treatment are to reach a high local control to avoid laryngectomy, but simultaneously to improve specific overall survival. The published data regarding concomitant RT–CT reported survival between 24 and 68% at 3–5 years [17, 18, 22]. Using a schedule employing neoadjuvant CT followed by concomitant CT–RT, the 3-year overall survival was 51–70% [25–28], with a locoregional relapse rate of 7–25% and a distant progression rate of 7–17%.

In our study, we reported a 55% of overall survival and a 73% cause-specific overall survival, with a disease free survival of 65% at 5 years and an organ preservation rate of 73.5%.

Our data using an unconventional CT–RT combination in a consecutive, unselected, patient population reported comparable results to published studies using different timing of CT–RT associations [29–32]. The sequential, accelerated CT followed by unconventional fractionated RT was well tolerated; only four patients temporarily interrupted RT treatment for severe mucositis.

In conclusion, we confirm a good efficacy for the combined CT–RT regimen in locally advanced head and neck tumors whose objective is laryngeal preservation, even with sequential CT–RT. However, the problem of locoregional disease control can still be improved; the development of new pharmaceutical products combined with radiotherapy is the innovative solution for a better therapeutic outcome [33]. This outcome can be further improved by using dose-intensity radiotherapy with the IMRT technique delivered either with a Linac or Tomotherapy equipment.