Can Synchronous Chemotherapy be Added to Accelerated Hypofractionated Radiotherapy in Patients with Base of Tongue Cancer?

Clinical Oncology 22 (2010) 185–191 Contents lists available at ScienceDirect

Clinical Oncology journal homepage: www.elsevier.com/locate/clon

Original Article

Can Synchronous Chemotherapy be Added to Accelerated Hypofractionated Radiotherapy in Patients with Base of Tongue Cancer? A. Jegannathen *, R. Swindell z, B. Yap *, L. Lee *, A. Sykes *, K. Mais *, P. Sanghera y, A. Hartley y, J. Glaholm y, N. Slevin * *

Department of Clinical Oncology, Christie Hospital NHS Foundation Trust, Manchester M20 4BX, UK Department of Clinical Oncology, University Hospital Birmingham NHS Foundation Trust, Queen Elizabeth Hospital, Birmingham, UK z Department of Medical Statistics, Christie Hospital NHS Foundation Trust, Manchester M20 4BX, UK y

Received 23 May 2009; received in revised form 9 October 2009; accepted 7 December 2009

Abstract Aim: To evaluate the tolerability of synchronous chemotherapy and accelerated hypofractionated radiotherapy in patients with locally advanced squamous cell carcinoma of the base of the tongue. Materials and methods: Between 1999 and 2004, 43 patients with stage II–IV squamous cell carcinoma of the base of the tongue were treated with a combined modality of radiotherapy (prescribed 55 Gy in 20 fractions), synchronous chemotherapy and in some cases surgical neck dissection. End points were acute and late toxicity, 3 year locoregional control, overall survival, cancer-specific survival and compliance. Results: The median follow-up for surviving patients was 3.9 years. All patients completed radiotherapy and 30% received neoadjuvant chemotherapy. The median time for the completion of treatment was 27 days (range 25–36). Overall, only 42% completed the prescribed synchronous chemotherapy. However, compliance increased to 60% in patients who did not receive neoadjuvant chemotherapy. Grade 3 mucositis developed in 90% of patients. Prolonged grade 3 mucositis (>4 weeks) was seen in 24/43 (56%) and none developed grade 4 mucositis. There were no toxic deaths. Feeding tube dependency at 1 year was 14%. The 3 year locoregional control, overall survival and cancer-specific survival were 70, 60 and 60%, respectively. Clinical T staging was most significantly associated with poor overall survival, cancer-specific survival and local control. Distant metastases occurred in 6/43 patients (14%), 5/6 without locoregional recurrence. Conclusion: The addition of synchronous chemotherapy to accelerated hypofractionated radiotherapy consistently led to grade 3 mucositis. Tumour control rates compare well with published outcomes. Higher mucosal toxicity and lower synchronous chemotherapy compliance compared with other series may suggest that this approach is at the limit of patient tolerability. However, the tumour site investigated and the choice of synchronous chemotherapy agent may also be important. Compliance may be improved using intensity-modulated radiotherapy and agents that do not enhance mucosal toxicity. Longer fractionation will probably increase compliance with chemotherapy, particularly when induction is used before synchronous treatment. Ó 2010 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved. Key words: Accelerated hypofractionated radiotherapy; base of tongue cancer; synchronous chemotherapy

Introduction Synchronous chemotherapy with radiotherapy is the non-surgical standard of care for most patients with stage III or IV head and neck cancer [1]. The addition of chemotherapy to radiotherapy significantly increases mucositis [2]. When conventional fractionation is used with 3 weekly cisplatin (100 mg/m2), the third cycle (week 7) is often omitted due to toxicity [2,3]. Alternative strategies have Author for correspondence: N. Slevin, Christie Hospital NHS Foundation Trust, Wilmslow Road, Manchester M20 4BX, UK. E-mail address: [email protected] (N. Slevin).

been adopted, including a change of cisplatin scheduling (weekly or daily) [4] or the use of different cytotoxic agents: taxanes [5], methotrexate [6], gemcitabine [7], capecitabine [8] and carboplatin [2], either as monotherapy or in combination. Accelerated schedules with hyperfractionation combined with chemotherapy are associated with severe mucositis compared with conventional treatment [9–11]. Accelerated hypofractionation is used in some centres in the UK, most commonly 55 Gy in 20 fractions over 4 weeks. Linear quadratic modelling predicts similar local control to 70 Gy conventional, but with decreased late effects [12]. This regimen has the theoretical advantage of

0936-6555/$36.00 Ó 2010 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.clon.2009.12.007

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treatment completion towards the end of the purported lag phase before the commencement of accelerated tumour clonogen repopulation [13]. When given with synchronous chemotherapy, this schedule has been shown to achieve high tumour control rates in locally advanced head and neck cancer [14]. This study was carried out to examine the tolerability of adding synchronous chemotherapy to accelerated hypofractionated radiotherapy treating the whole oropharynx in locally advanced base of tongue cancer.

Materials and Methods Data Collection Case records of all base of tongue cancer patients treated between 1999 and 2004 at Christie Hospital, Manchester and Queen Elizabeth Hospital, Birmingham using accelerated hypofractionated radiotherapy with synchronous chemotherapy were reviewed. All prospectively collected data from the notes were analysed retrospectively. The data collected included: age, gender, performance status, clinical and surgical staging, tumour grade, treatment details, acute toxicity, status of swallowing at 1 year, patterns of recurrence, and cause of death. When hospital information was incomplete, patient status was confirmed through general practitioners and the Cancer Registries. The tumour stage was recorded prospectively according to TNM classification. Toxicity was evaluated according to National Cancer Institute common toxicity criteria and the Radiotherapy Oncology Group scale for mucositis. The systematic recording of acute toxicity was collected from the weekly reaction clinic annotations. The data included onset and duration of grade 3 mucositis, compliance with chemotherapy, and incidence of prolonged grade 3 mucositis (greater than 4 weeks in duration). Outcome measures were: locoregional control (LRC) (primary and nodal), cancer-specific survival (CSS) and overall survival at 3 years. LRC was defined as the absence of either persistent or recurrent disease at the primary site or in the cervical lymph nodes. Radiotherapy All patients were treated supine, neck neutral and with immobilisation in a thermoplastic shell. Treatment was planned using two-dimensional simulation or threedimensional conformal methods using a lateral parallel opposed pair arrangement of fields. None was treated with intensity-modulated radiotherapy (IMRT). Radiotherapy was given using 4 or 6 MV photons, once daily fractionation for 5 days per week, 2.75 Gy per fraction, in two phases to a total of 55 Gy in 20 fractions delivered isocentrically (33 Gy in 12 fractions [Birmingham], 27.5 Gy in 10 fractions [Manchester] for phase 1). The typical field size for phase 1 measured 8–10 cm long, 11 cm wide for most of the patients, except 8/43 patients where the field length varied between 10 and 15 cm. The

phase 2 photon field size measured 8–10 cm long, 7 cm wide with the posterior border through the mid-vertebral body. The posterior neck electron field measured 6–8 cm long and 4 cm wide (to include level 2b) (range 8–12 MeV prescribed to Dmax). The lower anterior split neck field with central spinal cord and larynx shielding measured about 16–17 cm wide, 6–7 cm long and received 45 Gy in 20 fractions at depth using 4–6 MV photons. The elective dose (photon þ electron) was 45 Gy in 20 fractions (Manchester) or 41.25 Gy in 15 fractions (Birmingham). The postoperative dose (photon þ electron) was 50 Gy in 20 fractions for the intermediate risk group and 52.50 Gy in 20 fractions for the high risk (extracapsular spread) group. Chemotherapy During the study period, four synchronous chemotherapy agents were used: cisplatin 80 or 100 mg/m2 weeks 1 and 4, carboplatin AUC5 weeks 1 and 4, methotrexate 100 mg/m2 weeks 1 and 3 with folinic acid rescue, capecitabine 500 mg/m2 twice daily for 4 weeks. Two courses of neoadjuvant chemotherapy with cisplatin 80 or 100 mg/m2 day 1 and 5-fluorouracil 1 g/m2 days 1–4 were given to 13 patients with stage IV disease before synchronous chemotherapy. The decision to use a particular agent was based on clinical and trial activity [6,8]. The chemotherapy choice selection was at the discretion of the treating oncologist. Follow-up All patients were assessed weekly during treatment and followed up monthly during the first year, 2 monthly for the second year, 3 monthly for the third year and 6 monthly thereafter. At each follow-up visit, a history was taken and a clinical examination, including laryngoscopy, was carried out. Statistical Analysis Data were analysed using SPSS version 15.0 for windows. Continuous data were assessed for normality and are presented as mean  standard deviation or median  interquartile range. A comparison based on different chemotherapeutic agents was carried out using ANOVA. The survival function was measured using Kaplan–Meier analysis and an intergroup comparison was carried out using the Log-rank test. Univariate analysis was used to determine predictive factors. Overall survival, CSS and LRC were calculated from the first day of radiotherapy treatment. Overall survival took all deaths into account. For CSS, patients dying from intercurrent disease were censored at the time of death. LRC was defined as the absence of either persistent or recurrent disease at the primary site or in the cervical lymph nodes; development of a second primary was censored. Statistical significance was assigned to P  0.05.

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Results

Table 2 TNM staging

Patient and Tumour Parameters Forty-three patients were treated (Manchester n ¼ 32; Birmingham n ¼ 11). Patient characteristics are presented in Table 1. TNM staging is presented in Table 2. Over 80% of patients had stage IV disease. The pathological tumour grading was as follows: well-differentiated squamous cell carcinoma (SCC) in 2/43 (5%), moderately differentiated SCC in 13/43 (30%) and poorly differentiated SCC in 28/43 (65%). The pre-radiotherapy haemoglobin level in all patients ranged between 10.2 and 16.0 g/l. The haemoglobin level was above 12 g/l in 90% (n ¼ 39/43) of patients. Chemotherapy and Compliance All patients received synchronous chemotherapy (cisplatin n ¼ 10; methotrexate n ¼ 8; capecitabine n ¼ 12; carboplatin n ¼ 13). Details of the chemotherapy are presented in Table 3. Forty-two per cent (18/43) of patients were able to complete the full course of prescribed chemotherapy. Two patients who received 100 mg/m2 cisplatin developed renal impairment (reduced glomerular filtration rate (GFR)) after the first course of synchronous chemotherapy. Their second course was changed to carboplatin. Thirteen of 43 (30%) patients received neoadjuvant chemotherapy, none of these completed their prescribed synchronous chemotherapy (statistically significant for synchronous chemotherapy compliance; P ¼ 0.008). The reasons for non-compliance in these 13 patients were as follows: grade 3 mucositis (10), neutropenic sepsis (two) and renal impairment (one). Sixty per cent of patients (18/30) treated with synchronous chemotherapy alone completed the prescribed chemotherapy.

Table 1 Patient characteristics Characteristic Age (years) Median Range Gender Male Female Performance status 0 1 2 UICC stage (2002) I II III IVA IVB UICC, International Union Against Cancer.

187

Value 56 43–74 40 (93%) 3 (7%) 17 (39.5%) 23 (53.4%) 3 (7%) 0 2 (4.6%) 6 (14%) 33 (76.8%) 2 (4.6%)

T1 T2 T3 T4

N0

N1

N2a

N2b

N2c

N3

0 2 2 3

2 2 0 1

1 1 1 3

4 4 3 4

0 3 1 4

1 0 0 1

In total, 22/36 node-positive patients underwent neck dissection. Data are presented in numbers. The numbers in bold involve stage IV disease.

Radiotherapy Compliance Forty-two of 43 patients received the planned dose of radiotherapy. One patient received 57.94 Gy in 22 fractions due to an unscheduled gap secondary to tumour bleeding and completed radiotherapy in 36 days. The remaining 42 patients completed radiotherapy to the 55 Gy prescribed; in 25 days (8/43), 27 days (26/43), 28 days (5/43), 30 days (2/43) and 31 days (1/43). The median time for the completion of treatment was 27 days (range 25–36). Neck Dissection Planned neck dissection was carried out before synchronous chemotherapy in 20 patients and after synchronous chemotherapy in two patients. Twelve of the 20 pre-synchronous chemotherapy patients showed extracapsular nodal spread. In total, 22 of 36 patients with node-positive disease underwent neck dissection. Acute Toxicity Grade 3 mucositis developed in 39 of 43 (90%) patients. One patient with T3N0 disease who had received 6/20 fractions, with synchronous capecitabine, developed bleeding from the tumour site requiring temporary tracheostomy. Grade 3 palmoplantar erythema developed a week later. Grade 3/4 haematological toxicity developed in two patients (4.6%). Both patients (both cT4N2c) became neutropenic and anaemic after receiving one course of cisplatin 100 mg/m2 and one course of carboplatin (AUC5), respectively. There were no toxic deaths. A feeding tube was inserted in 36/43 patients (84%). Eleven patients (26%) underwent percutaneous feeding gastrostomy before radiotherapy. The remaining 25 patients (23 during synchronous chemotherapy and two after synchronous chemotherapy) required nasogastric tube feeding during the course of treatment. The mean time to the onset of grade 3 mucositis was 16.7  6.1 days, with a mean duration of 48  24.6 days. Prolonged mucositis was present in 24/43 (56%) patients. Late Toxicity Three patients required intervention for late effects from treatment. One required tracheostomy and gastrostomy at 14 months after primary treatment. A second patient

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Table 3 Chemotherapy given by type, dose level and number of doses Drug (n)

Dose level

Completed full course

Reasons for not completing (n)

Neoadjuvant chemotherapy

Cisplatin (13) (neoadjuvant chemotherapy in 9)

80 mg/m2 (n ¼ 3) 100 mg/m2 (n ¼ 10)

0 1

3 4 1 1

Methotrexate (8)

100 mg/m2

6

Capecitabine (12) Carboplatin (10) (neoadjuvant chemotherapy in 4)

500 mg/m2 (bid) AUC5

6 5

Grade 3 mucositis (3) Grade 3 mucositis (6) Neutopenic sepsis (1) Renal impairment (1) Social (1) Sepsis (1) Grade 3 mucositis (1) Grade 3 mucositis (6) Neutropenic sepsis (1) Renal impairment (1) Grade 3 mucositis (3)

1 3

The reasons for non-compliance in the 13 neoadjuvant chemotherapy patients were as follows: grade 3 mucositis (10), neutropenic sepsis (2) and renal impairment (1).

required percutaneous feeding gastrostomy at 5 months after treatment due to severe dysphagia. The third underwent partial mandibulectomy for osteoradionecrosis which followed tooth extraction 4 years after the completion of treatment. At 6 months, 39% (n ¼ 17) of patients were able to eat a normal diet. Late feeding dysfunction, as determined by tube dependency at 12 months, was seen in 14% (n ¼ 6). Locoregional Control The patterns of treatment failure are illustrated in Fig. 1. Three year LRC was 70.2% (95% confidence interval 53.3– 82). LRC was higher for T1/T2 disease (80%, 95% confidence interval 69.2–99.3) compared with T3/T4 disease (47.8%, 95% confidence interval 25.7–67.0) at 3 years (Fig. 2). Nodal dissection affected neither locoregional recurrence nor the outcome (nodal dissection 5/22 vs non-nodal dissection 7/21 P ¼ 0.51). Distant Metastasis

(Table 4; Fig. 3). The only significant variable associated with overall survival (Fig. 4), CSS and LRC was T stage (Fig. 2).

Discussion The acute normal tissue dose-limiting end point of synchronous chemoradiotherapy in this review was grade 3 mucositis in most patients. Clinically we would wish to avoid grade 4 acute toxicity and any gaps in the radiotherapy delivery. We observed a higher rate of mucosal toxicity (90% grade 3) and a lower rate of synchronous chemotherapy compliance (42%) compared with other published series. This study has shown that despite heterogeneity of the chemotherapy delivered, synchronous chemotherapy can be added to some extent to accelerated hypofractionated radiotherapy and that tumour control rates compare well with published outcomes. If induction chemotherapy is used, compliance with synchronous

Distant metastasis occurred in 6/43 (14%) patients. Five of 43 (11%) patients developed distant metastasis without locoregional recurrence. The incidence of isolated distant metastasis was not affected by neoadjuvant chemotherapy (3/30 without neoadjuvanct chemotherapy vs 3/13 with neoadjuvant chemotherapy P ¼ 0.35).

Primary failure

7

Second Primary Cancers Five patients (11%) developed a second primary cancer: cervical oesophagus (n ¼ 1), lung (n ¼ 2), prostate (n ¼ 1) and pancreas (n ¼ 1) at 4 years.

1

3

Disease-free Survival, Cancer-specific Survival and Overall Survival Both overall survival and CSS at 3 years were 60% (95% confidence interval 43.6–73). Disease-free survival was 60.4% (95% confidence interval 44.2–73.3) at 3 years

0 0

Nodal failure

1

5

Distant metastasis

Fig. 1. Patterns of treatment failure in the form of a Venn diagram.

100

100

80

80

% Free of event

% Locoregional control

A. Jegannathen et al. / Clinical Oncology 22 (2010) 185–191

60

40

189

60

E v e nt s 12 19 21 19

40

Local Regional DFS Overall Survival Cancer Survival

T1,2 T3,4 20

20

P=0.004 0 0

1

2

3

4

0

5

1

0

Time in Years 1, 2 20

18

18

12

5

3

3, 4 23

16

12

9

5

1

Fig. 2. Locoregional control by T-stage of the disease. The percentage of locoregional control is presented in the y-axis and the time in years in the x-axis.

chemotherapy is particularly poor; if compliance is regarded to be crucial then consideration should be given to a longer conventional radiotherapy fractionation. There are no specific randomised studies on base of tongue cancer looking at the tolerability and efficacy of various synchronous chemoradiotherapy schedules. A collective review of studies on the oropharynx with a high proportion of base of tongue cases has been included for a comparison of the results and discussion (Table 5). In a meta-analyses of chemotherapy added to locoregional treatment of head and neck SCC, Pignon et al. [1] noted a significant survival benefit with synchronous chemotherapy compared with adjuvant or neoadjuvant chemotherapy. However, acute mucosal reactions in the oropharynx are dose limiting for accelerated schedules [15]. The high dose planning target volume may affect the tolerability of accelerated schedules [16]. Evaluating the acute tolerance of adding chemotherapy to 55 Gy in 20 fractions given to a consistently large volume is useful as radiobiologically this schedule is predicted to give equivalent tumour control with less late side-effects than 70 Gy in 7 weeks.

2

3

4

5

Time in Years LR 43 DFS 4 3 OS 43

34 33 40

30 29 33

21 22 22

10 11 11

4 4 4

CA

40

33

22

11

4

43

Fig. 3. Locoregional control, disease-free survival, overall survival and cancer-specific survival for all patients.

Ninety per cent of patients were able to complete radiotherapy within 4 weeks. However, the chemotherapy compliance was poor compared with other schedules, including other accelerated hypofractionated series (Table 5). Compliance was especially poor after neoadjuvant chemotherapy. The incidence of grade 3 mucositis was high (90%) compared with concurrent chemoradiotherapy using 1.8–2.0 Gy per fraction [2,3,5,9,11,17], but may also be related to the specific agents used in this study. However, a subgroup analysis according to chemotherapy agent used could not be reliably carried out because of small patient numbers. This may have led to the higher incidence of tube feeding (83.4%). Despite poor compliance with these chemotherapy regimens, the outcome measures at 3 years are acceptable and comparable with other series [2,5,17–19]. IMRT may decrease toxicity and improve synchronous chemotherapy compliance by reducing the volume of mucosa irradiated while maintaining tumour control. Recent reports of IMRT with synchronous chemotherapy have shown

Table 4 Three year overall survival, local control and disease-free survival Variable

Overall survival (%)

Local control (%)

Disease-free survival (%)

All patients T1–T2 T3–T4 Stage III Stage IVA Stage IVB

60 80 43.5 100 65.7 43.5

70.2 95 47.8 100 81.9 45.4

60.4 80 43.5 100 66.7 41.2

(43.6, 73) (55.3, 91.9) (23.4, 62.1) (100, 100) (38.6, 83.1) (23.4, 62.1)

Data are presented as a percentage with 95% confidence intervals.

(53.3, 73) (69.2, 99.3) (25.7, 67) (100, 100) (53.6, 93.8) (20.9, 67.1)

(44.2, 73.3) (55.3, 91.9) (23.4, 62.1) (100, 100) (40.4, 83.4) (18.7, 62.6)

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a considerably lower incidence of acute and late toxicity with excellent LRC [20,21]. The other alternative is to use longer fractionation with synchronous chemotherapy when neoadjuvant chemotherapy is given. Concerns remain about whether neoadjuvant chemotherapy undermines the intensity of synchronous chemotherapy delivery [22] and several clinical trials are underway to assess this approach [23]. Conventional fractionation may accommodate the combined usage of neoadjuvant and synchronous chemotherapy better than the 4 week schedule. Whether there is a gain in tumour control is unknown. In conclusion, chemotherapy can be added to some extent to accelerated hypofractionated radiotherapy provided there is appropriate supportive care. Tumour control rates were encouraging and late toxicity was acceptable. Accelerated hypofractionated chemoradiotherapy schedules using IMRT, in combination with neoadjuvant chemotherapy, merit further investigation. Consideration could be given to longer fractionation if both synchronous and neoadjuvant chemotherapy are given.

100

% Survival

80

60

40

T1,2 T3,4 20

P=0.035 0 0

1

2

3

4

5

5 6

3 1

Time in Years 1, 2 3, 4

20 23

20 20

19 14

12 10

Fig. 4. Overall survival by T-stage of the disease.

Table 5 Trials using concurrent chemoradiotherapy on patients with predominantly locally advanced (stages III and IV) oropharynx cancer that included carcinoma of the base of the tongue (BOT) Reference

Tumour site

n

Chemotherapy

Conventional radiotherapy (70/35 7 weeks) [23] Oropharynx 48 Cisplatin/5-FU BOT 54% 3 weekly [18] BOT 62% Hypopharynx 49 Cisplatin 3 weekly [6] Oropharynx 63 Docetaxel weekly BOT 38% 295 Cisplatin 3 weekly [19] Various sites Oropharynx 54% [5] Oropharynx BOT 62% 53 Paclitaxel weekly [2] Oropharynx 226 Carboplatin/5-FU BOT 37% 3 weekly Accelerated hyperfractionation [10] Various sites Oropharynx 60%

384

MMC/5-FU

[9]

494 224

Carboplatin/5-FU 3 weekly Cisplatin

240

Carboplatin/5-FU

[3] [11]

Various sites Oropharynx 73% Various sites Oropharynx 53% Various sites Oropharynx 74%

Accelerated hypofractionation [14] Various sites Oropharynx 46%

81

Methotrexate Carboplatin

5-FU, 5-fluorouracil; MMC, mitomycin C. The tube dependency rate is at 1 year or the quoted time point. The outcome figure is at 3 years or the quoted time point. The figures quoted are for the treatment group only.

Chemotherapy compliance

Mucositis grade 3/4

Tube dependency

Outcome (3 years)

87%

84%

37% (3 months)

Overall survival 52%

74% 95%

84%

0%

Overall survival 64% Overall survival 47%

43%

NA

Overall survival 37%

66% 65%

98% 71%

12% NA

Overall survival 70% Overall survival 51% Disease-free survival 42%

90% Locoregional control 52%

66%

NA

Overall survival 37%

71%

NA

59%

NA

68%

30% (2 years)

Overall survival 22% (5 years) Overall survival 59% (2.5 years) Locoregional control 58% (2 years)

79%

11%

71%

78% 74%

Overall survival 72% Disease-free survival 69% Locoregional control 75% (all 2 years)

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