Three weekly versus weekly concurrent cisplatin: a matter of safety in head and neck cancer

doi:10.21203/rs.3.rs-403139/v1

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Three weekly versus weekly concurrent cisplatin: a matter of safety in head and neck cancer

https://doi.org/10.21203/rs.3.rs-403139/v1

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Background

Radio-chemotherapy with CDDP is the standard for H&N squamous cell cancer. CDDP 100mg/m²/q3 is the standard; alternative schedules are used to reduce toxicity, mostly 40mg/m²/q1.

Methods

Patients were treated from 1/2010 to 1/2017 in two Radiation Oncology Centres. Propensity score analysis (PS) was retrospectively used to compare these two schedules.

Results

Patients analyzed were 166. Most (114/166) had 1w-CDDP while 52 had 3w-CDDP. In the 3w-CDDP group, patients were younger and with better performance status; disease extent was smaller and nodal involvement was more common than in the 1w-CDDP. Acute toxicity was similar in the groups. Treatment compliance was lower in the w-CCDP. OS before PS was better for female, for oropharyngeal disease and for 3w-CDDP group. After PS, survival was not related to the CDDP schedule.

Conclusions

3w-CDDP remains the standard for fit patients, weekly schedule could be safely used in selected patients.

Oncology

H&N cancer

radiotherapy

chemotherapy

weekly-CDDP

3weekly-CDDP

From decades, CDDP has been used in the management of locally advanced squamous cell carcinoma of the head and neck (LAHNSCC) in order to enhance the tumoricidal activity of radiation. Among the various CDDP schedules proposed, differing in frequency, dose, and administration, there is level 1 evidence for improvement in loco-regional control and/or overall survival, achieved by three-weekly high-dose (100 mg/m²) cisplatin concurrently with conventional external beam radiotherapy, when compared with radiotherapy alone. The supporting data originate from four large randomized phase III trials investigating the role of cisplatin in both the definitive and postoperative settings ^{(1, 2, 3, 4)}.

Since three-weekly chemotherapy (3w-CDDP) causes significant acute toxicity in more than three quarts of patients, many patients are likely to receive sub-optimal cumulative cisplatin dose and dose intensity. This could hamper treatment outcomes and require a proper patient’s selection.

Weekly low-dose cisplatin (1w-CDDP) regimes have gained large clinical acceptance, replacing the standard 3w-CDDP schedule at many institutions in daily clinical practice. The background of this choice is the assumption that low-dose, 1w-CDDP could increases treatment compliance maintaining dose intensity and avoiding interruptions of radiotherapy.⁽⁵⁾ It could also reduce chemotherapy-related acute and late side effects, facilitate dose adjustments according to clinical conditions during the treatment and therefore outpatient management, with lower hospitalization rates. Several retrospective and small prospective studies ^{(6, 7)} and different systematic reviews and meta-analysis ⁽⁸⁾⁽⁹⁾ compared 1w- and 3w- schedules obtaining conflicting and inconclusive results, mostly in relation with survival outcomes. Moreover, different prospective randomized trial are actually ongoing in curative setting of both LAHNSCC and nasopharyngeal cancer (NCT03998696, NCT03649048, NCT01171781, JPRN-jRCTs031180135). Weekly 1w-schedules has also be included in de-intensification trials for human papilloma virus-related tumors (NCT01530997, NCT01687413). Therefore, waiting for definitive results, there is an unmet need to provide literature data on homogenous cohorts of patients treated with 1w-CDDP to guide the daily clinical practice.

In this contest, the main objective of this retrospective analysis is to compare, in a real-life setting, two chemotherapy schedules (1w-CDDP 40 mg/m² vs 3w-CDDP 100 mg/m²) concomitant to radical radiotherapy in locally advanced head and neck cancers, in terms of acute and overall and relapse free survival. The Propensity Score matched analysis should help to reduce the selection biases that are usually present in a retrospective series.

Patients enrolled in this retrospective analysis have been treated between January 1st, 2010 and January 30th, 2017 for LAHNSCC (oropharynx, hypopharynx and larynx) at the Radiation Oncology Departments of the Brescia University (“O. Alberti”, ASST-Spedali Civili - IRA) and of the European Institute of Oncology (IEO IRCCS)/University of Milan, Italy.

All patients had concomitant CDDP-based radical chemo-radiotherapy. Two different CDDP schedules were used in the two Institutions: 100 mg/m² every three weeks (3w-CDDP, IEO) and weekly 40 mg/m² (1w-CDDP, IRA). In order to reduce the variability related to the patient’s body surface differences, the dose was considered as dose/m² (ratio of total CDDP dose received by each patient and his/her body surface).

Data were retrospectively collected using a database where all the clinical and therapeutic features were entered.

The ethical committee of the two Institutions approved/notified the study.

Stage classification was carried out in accordance with the TNM classification system, VII Ed. ⁽¹⁰⁾

Acute radiation and chemotherapy-related toxicities were analyzed weekly and registered as the higher score occurred during and 3 months after radiotherapy, according to the Common Toxicity Criteria for Adverse Effects (CTCAE) v.4.03.

The RT completion was chosen as reference for survival. Relapse Free Survival (RFS) was the time between the end of treatment and occurrence of local/distant relapse or last follow up, for not relapsed patients; Overall Survival (OS) was the time from the end of radio-chemotherapy to death for any cause or last follow up, for living patients.

STATISTICAL ANALYSIS

The differences between the two treatments were investigated through the χ² test.

OS and RFS were calculated through the Kaplan-Meier method and the differences evaluated with the Log-Rank Test.

The Propensity Score matched analysis (PS) (OS and RFS) was introduced to minimize the effect of confounding factors ant to create two homogeneous populations (w-CDDP vs 3w-CDDP). The variables to match the patients (2:1) were age, disease stage and performance status (Karnofsky Performance Status, KPS). At the end, 160 patients were evaluable after the match (114 and 46 patients respectively in the 1w and 3w-CDDp group).

The multivariate analysis was done (OS and RFS), with Cox Regression model, both before and after PS, including all the variables included in the univariate one.

The statistical analysis was made using the IBM® SPSS Statistics® v25.0; the p-values were considered significant when p = < 0.05.

One hundred sixty-six patients were included in the analysis. Seventy-five percent (n = 125) were male, 140 (84%) aged < 70 years, 109 in good general conditions (KPS = 90–100, 66%). Almost 50% (n = 84) were tobacco smokers and had a current use of alcohol (n = 90). The patient’s features for the series are shown in Table 1.

Table 1

Patients features in relation with chemotherapy schedule.
Characteristics of patients	1w-CDDP (n = 114)	3w CDDP (n = 52)	χ²	Entire serie n (%)
Gender Male Female	92 (80.7%) 22 (19.3%)	33 (63.5%) 19 (36.5%)	0.0017	125 (75.3%) 41 (24.7%)
Age < 70 yrs > 70 yrs	90 (78.9%) 24 (21.1%)	50 (96.2%) 2 (3.8%)	0.005	140 (84.3%) 26 (15.7%)
Baseline KPS 90–100 70–80 60	60 (52.6%) 52 (45.6%) 2 (1.8%)	49 (94.2%) 3 (5.8%) 0 (0%)	0.000	109 (65.7%) 55 (33.1%) 2 (1.2%)
Tobacco use Currently < 10 cigarettes/die Currently 10–20 cigarettes/die Currently > 20 cigarettes/die Stopped smoking > 5 years Never smoking	14 (12.3%) 27 (23.7%) 31 (27.2%) 22 (19.3%) 20 (17.5%)	4 (7.7%) 5 (9.6%) 3 (5.8%) 10 (19.2%) 30 (57.7%)	0.000	18 (10.8%) 32 (19.3%) 34 (20.5%) 32 (20.5%) 50 (30.1%)
Alcohol Currently Past Never ND	75 (65.8%) 17 (14.9%) 22 (19.3%) 0 (0%)	15 (28.8%) 1 (1.9%) 29 (55.8%) 7 (13.5%)	0.000	90 (54.2%) 18 (10.8%) 51 (30.7%) 7 (4.2%)
Legend: 1w-CDDP: weekly Cisplatin; 3w-CDDP: three-weekly Cisplatin; KPS: Karnofsky Performace Status; ND: not declared

The distribution of the clinical characteristics was not homogeneous in the two groups (Table 1). Patients treated with 1w-CDDP were significantly older (p = 0.005), in worse general conditions (p = 0.000) and more frequently actual smokers and alcohol consumers (p = 0.000).

Primary disease site was oropharynx in 119 patients (71.7%). In 129 cases, the disease was in stage IV (77.7%). Human Papilloma Virus status (HPV) was determined in 36.14% (60) of cases. (Table 2)

Table 2

Disease characteristics in relation with chemotherapy schedule in relation to chemotherapy schedule.
Disease Characteristic	1w-CDDP (n.114)	3w-CDDP (n.52)	p=	Entire serie (%)
Histology Squamous Other histology	109 (95.6%) 5 (4.4%)	52 (100%) 0 (0%)	0.125	161 (97%) 5 (3%)
Site of the disease Oropharynx Hypopharynx Larynx	72 (63.2%) 23 (20.2%) 19 (16.7%)	47 (90.4%) 2 (3.8%) 3 (5.8 %)	0.001	119 (71.7%) 25 (25.1%) 22 (13.3%)
Staging T (TNM 7th Ed) T1-T2 T3-T4	52 (45.6%) 62 (54.4%)	32 (61.3%) 20 (38.5%)	0.057	84 (50.6%) 82 (49.4%)
Staging N (TNM 7th Ed) N0 N1 N2 N3	16 (14%) 17 (14.9%) 80 (70.2%) 1 (0.9%)	2 (3.8%) 6 (11.5%) 40 (76.9%) 4 (7.7%)	0.024	18 (10.8%) 23 (13.9%) 120 (72.3%) 5 (3%)
Stage (AJCC 7th Ed) II III IV	5 (4.4%) 28 (24.6%) 81 (71.1%)	1 (1.9%) 3 (5.8%) 48 (92.3%)	0.009	6 (3.6%) 31 (18.7%) 129 (77.7%)
HPV Positive Negative ND	12 (10.5%) 11 (9.6%) 91 (79.8%)	32 (61.5%) 5 (9.6%) 15 (28.8%)	0.000	44 (26.5%) 16 (9.6%) 106 (63.9%)
Legend: HPV: Human Papilloma Virus; TNM: Tumor, Node, Metastases; AJCC: American Joint Committee on Cancer; 1w-CDDP: weekly Cisplatin; 3w-CDDP: three-weekly Cisplatin;

The two treatment groups appear to be non-homogeneous, with a statistically significant prevalence of oropharyngeal tumors (90% vs 65%, p = 0.001) and N2-3 disease (84.7% vs 71%, p = 0.02) in 3w-CDDP group, and an excess of T3-4 disease (54% vs 38%; p = 0.05) among w-CDDP patients. A higher rate of HPV determination and positivity is also evident in 3w-CDDP group. (p = 0.000) (Table 2).

One hundred fourteen patients were treated with w-CDDP (40mg/m²) and 52 with 3w-CDDP (100mg/m²). The CDDP/m² doses was 200–250 mg in 25.4% in w-CDDP and 23.1% in 3w-CDDP; >250 mg/ m² in 2.6% and 50% respectively in w- and 3w-CDDP (p = 0.000). No patients had neo-adjuvant chemotherapy. CDDP was interrupted in 49.5% patients: 56.1% and 34.6% in w and 3w groups respectively (p = 0.012). CDDP was mostly interrupted in patients treated with dose/fraction > 2 Gy (59.6% vs 44%; p = 0.052) and in the w-CDDP.

All patients were treated with radical radiotherapy using different fractionations in relation to the clinical institutional use, assuming the same biological curative effect in combination with chemotherapy⁽¹¹⁾: 10 (6%) patients had 69 Gy (dose/fraction, 2.3Gy/die); the others had 2Gy/fr (109 pts – 66%) or a slightly higher daily fractionation 2.1–2.12 Gy/die (47 pts 28%). Dose/fraction > 2Gy was used in the weekly-CDDP group. Almost all patients had IMRT. (Table 3)

Table 3

Treatment in relation to chemotherapy schedule
Treatment Characteristic	1w-CDDP (n.114)	3w-CDDP (n.52)	p=	Entire serie (%)
Cumulative CDDP/m² dose <= 200 mg/m² 200-250mg/m² > 250 mg/m²	82 (71.9%) 29 (25.4%) 3 (2.6%)	14 (26.9%) 12 (23.1%) 26 (50%)	0.000	96 (57.8%) 41 (24.7%) 29 (17.5%)
Median CDDP/m²	175.9 mg/m²	248.1 mg/m²	0.026
CDDP interruption YES NO	64 (56.1%) 50 (43.9%)	18 (34.6%) 34 (65.4%)	0.012	82 (49.4%) 84 (50.6%)
RTT dose 69 Gy > 69 Gy and < 70 Gy 70Gy	10 (8.8%) 47 (41.2%) 57 (50%)	0 0 52(100%)	0.000	10 (6%) 47 (28%) 109 (66%)
RTT dose/fraction 2.3 Gy/fr 2.1–2.2 Gy/fr 2 Gy/fr	10 (8.8%) 47 (41.2%) 57 (50%)	0 0 52(100%)	0.000	10 (6%) 47 (28%) 109 (66%)
RTT technique 3D IMRT (VMAT) Helical IMRT	3 (2.6%) 53 (46.5%) 58 (50.9%)	4 (7.7%) 48 (92.3%) 0 (0%)	0.000	7 (4.2%) 101 (60.8%) 58 (34.9%)
Legend: 1w-CDDP: weekly Cisplatin; 3w-CDDP: three-weekly Cisplatin, RTT: radiotherapy; IMRT: Intensity Modulated Radiation Therapy; VMAT: Volumetric Modulated Arch Therapy, fr: fraction

Two sub-analysis were conducted on groups of patients with homogeneous KPS. In the group with KPS < 90 (n = 57) no differences are evident between patients submitted to different chemotherapy schedules (age, smoking habits, site of disease). No differences neither are evident in terms of interruption or dose of CDDP/m².

On the contrary, in the group with KPS 90–100 (n = 109), the patients treated with the different schedules are homogeneous only for age. A higher percentage of non-smokers (61.2% vs 16.7%; p = 0.000) and lower of alcohol users (28.6% vs 58.3%; p = 0.000) were treated with the 3w-CDDP schedule. Less patients treated with the 3-weekly schedule, of this subgroup, interrupted chemotherapy (32% vs 50%; p = 0.081) and received < 200mg/m² of CDDP (24.5% vs 63.3%; p = 0.000).

Acute toxicity

The rate of G3-4 acute hematological toxicity was 19.9% in the whole group (18.4% and 23.1% in 1w-CDDP and 3w-CDDP respectively (p = ns). G1-2 anemia and leucopenia were similar in the two groups; G1-2 thrombocytopenia was slightly more frequent in patients treated with w-CDDP (p = 0.01) (Table 4). Overall G3-4 mucositis, dermatitis and dysphagia rate were 33%, 10.8% and 19% respectively. G 3–4 emesis was higher in the group treated with w-CDDP (p = 0.007) while G1-2 acute xerostomia was more frequent in the group treated with 3w-CDDP (p = 0.009). No severe renal toxicity was recorded (Table 4).

Table 4

Acute toxicity as registered during the treatment.
Acute toxicity	1w-CDDP (n.114)	3w-CDDP (n.52)	χ²	Entire serie
Whole hematol tox G0 G1-G2 G3-G4	9 (7.9%) 84 (73.7%) 21 (18.4%)	1 (1.9%) 39 (75%) 12 (23.1%)	0.285	10 (6%) 123 (74%) 33(20%)
Anemia G0 G1-G2 G3-G4	11 (9.6%) 102 (89.5%) 1 (0.9%)	6 (11.5%) 44 (84.6%) 2 (3.8%)	0.37	17 (10.2%) 146 (88%) 3 (1.8%)
Leucopenia G0 G1-G2 G3-G4	16 (14%) 80 (70.2%) 18 (15.8%)	7 (13.5%) 33 (63.5%) 12 (23.1%)	0.524	23 (14%) 113 (68%) 30 (18%)
Thrombocytopenia G0 G1-G2 G3-G4	26 (22.8%) 85 (74.6%) 3 (2.6%)	24 (46.2%) 27 (51.9%) 1 (1.9%)	0.01	50 (30%) 112 (67.5%) 4 (2.5%)
Kidney Injury G0 G1-G2 G3-G4	89 (78.1%) 25 (21.9%)	46 (88.5%) 6 (11.5%)	0.111	135 (81.4%) 31 (18.6%)
Mucositis G0 G1-G2 G3-G4 Nd	2 (1.8%) 72 (63.2%) 39 (34.2%) 1 (0.9%)	- 36 (69.2%) 16 (30.8%) -	0.637	2 (1.2%) 108 (65%) 55 (33.2%) 1 (0.6%)
Dermatitis G0 G1-G2 G3-G4 Nd	4 (3.5%) 88 (77.2%) 14 (12.6%) 8 (7%)	- 48 (92.3%) 4 (7.7%) -	0.067	4 (2.5%) 136 (81.9%) 18 (10.8%) 8 (4.8%)
Xerostomia G0 G1-G2 G3-G4 Nd	29 (25.4%) 68 (59.6%) 4 (3.5%) 13 (11.4%)	9 (17.3%) 43 (82.7%) - -	0.009	38 (22.9%) 111 (66.9%) 4 (2.4%) 13 (7.8%)
Dysphagia G0 G1-G2 G3-G4	18 (15.8%) 72 (63.2%) 24 (21.1%)	5 (9.6%) 39 (75%) 8 (15.4%)	0.312	23 (13.8%) 111 (66.9%) 32 (19.3%)
Legend: 1w-CDDP: weekly Cisplatin; 3w-CDDP: three-weekly Cisplatin; Nd: not declared

The rate of CDDP interruption was slightly higher (p = 0.052) in patients treated with higher fractional dose (44% and 56% in the 2 Gy/fr and > 2 Gy/fr, respectively); the same was true for cutaneous toxicity (8.3% vs 15.8%, 2 vs > 2Gy/fr). Patients with CDDP interruption had mostly G3-G4 vs G1-2 hematological toxicity (66.7% vs 33.3% p = 0.81).

Univariate analysis before and after propensity score matched analysis

After a median follow-up of 32 months (respectively 35 and 26.5 mm for the 1w and 3w-CDDP), the 1, 2 and 5 yy actuarial OS of the entire series were 97%, 88% and 81.5%. Median OS was not reached neither in entire series nor in the two groups separately (1w and 3w-CDDP).

Before Propensity scored analysis, only female patients showed a statistically significant better OS compared with male patients (Table 5). OS was significantly better in patients with oropharyngeal disease as opposed with hypo-pharyngeal/laryngeal disease (p = 0.04): 1-year survival rates were 99.1%, 88%, 95.5%, and 2-and 5-year rates of 92.3%, 75.1%, 70.6% and of 89%, 59.1%, 73.3% for oropharyngeal, hypo-pharyngeal and laryngeal cancers, respectively.

Table 5

One - and two year overall (OS) survival before and after the propensity score matched analysis (PS)
Characteristic	OS univariate pre-PS			OS multivariate pre-PS		OS univarite after PS			OS multivariate after PS
	1 Y	2Y	p =	Exp B	p =	1 Y	2Y	p =	Exp B	p =
Gender			0.004		NS			0.022		0.034
Male	95	83.7				95.9	80.9		1
Female	100	100				100	94.9		0.217
Age			NS		NS			NS		NS
< 70 yrs	96.3	88.2				96.2	84.7
> 70 yrs	100	85.9				100	81.2
KPS			NS		NS			NS		NS
90–100	96.3	89.9				96.1	84
70–80	98	83.4				98.1	83.7
Tobacco use			NS		NS			NS		NS
Currently < 10 cig/die	94.1	94.1				94.1	94.1
Currently 10–20 cig/die	96.8	90.1				96.7	89.7
Currently > 20 cig/die	97.1	75.3				97.1	75.3
Stopped > 5 years	96.6	88.2				96.6	84.7
Never smoked	98	93				97.8	83.5
Alcohol			NS		NS			NS		NS
Currently	95.4	85.3				95.3	85.1
Past	100	82.4				100	82.4
Never	98	93.1				97.9	77.9
Stage T			NS		NS			NS		NS
T1-2	96.3	88.4				96	83.2
T3-4	97.5	87.4				97.5	84.9
Stage N			NS		NS			0.010		0.047
0	100	93.3				100	93.3		1
1	95.7	91.3				95.7	91.3		0.780 (IC 0.09–6.773)	0.822
2	97.4	86.8				97.3	82.3		2.933 (IC 0.582–14.768)	0.192
3	80	80				60	60		14.936 (IC 1.665-133.985)	0.016
Stage of disease			NS		NS			NS		NS
II	100	100				100	100
III	96.8	79.5				96.8	79.5
IV	96.8	89.6				96.6	84.7
Site of disease			0.04		0.027			0.034		0.007
Oropharynx	98.2	92.3		1		99.1	87		1
Hypopharynx	88	75.1		6.238 (IC 1.549–25.4)	0.10	88	75.1		5.5 (IC 2.1.918–16.03)	0.002
Larynx	95.5	80.6		1.399 (IC 0.27–7.236	0.689	95.5	80.6		2.02 (IC 0.586–7.481)	0.255
RT technique			NS		ns			NS		ns
IMRT/VMAT	94.9	85.9				94.7	80
Helical IMRT	100	89.7				100	89.7
Type of CHT			0.026		0.007			NS		ns
1w CDDP	96.4	84.6		1		97.8	82.9
3w CDDP	98	95.4		0.006 (0.000-0.241)		96.4	84.6
Total CDDP/m²			NS		0.006			NS		ns
<= 200 mg/m²	95.7	87.6		1		90	58.3
> 200–250 mg/m²	100	88.4		0.567 (IC 0.123–2.627	0.469	100	78.6
> 250 mg/m²	93.1	88.7		235.838 (IC 7.565–7352.1)	0.002	97	86.7
CDDP interruption			NS		ns			NS		ns
yes	97.5	87.6				97.3	85.7
no	96.4	88.2				96.3	82.8
Legend: RTT: radiotherapy; IMRT: Intensity Modulated Radiation Therapy; VMAT: Volumetric Modulated Arch Therapy; 1w-CDDP: weekly Cisplatin; 3w-CDDP: three-weekly Cisplatin; NS: not significant

OS is different in relation with 3 months nodal response: complete response, partial response and nodal progression are respectively linked with 1- and 2-years OS of 99%, 97%, 83% and 92%, 83%, 67%, respectively (p = 0.04).

Univariate analysis showed that OS was inferior with 1w-CDDP (p = 0.026); 12, 24- and 60-months survival rates were 96.4% vs 98%, 84.6% vs 95.4 and 75.9% vs 95.4, respectively in the 1w-CDDP vs 3w-CDDP. The different doses (CDDP/m²) did not impact significantly survival rates neither if used as categorical or continuous variables. Survival was better, without statistically significance, for patients who did not interrupt chemotherapy. The other clinical and therapeutic variables did not show statistically differences (Table 5).

After propensity score matched analysis the statistically significant better OS in female patients (p = 0.041) and in oropharyngeal disease (p = 0.047) was confirmed. The worse prognosis of patients with more extensive nodal involvement (N3, p = 0.011) was also demonstrated. Better OS for patients treated with 3w-CDDP was not confirmed (Table 5).

Multivariate analysis before and after propensity score matched analysis

The multivariate analysis before the propensity score analysis showed better survival in patients with oropharyngeal cancer, treated with 3w-CDDP and with higher total CDDP/m² (Table 5).

The analysis after PS demonstrated better survival in patients with oropharyngeal disease and low nodal disease burden. None of the therapeutic factors related to chemotherapy or radiotherapy, revealed impact on OS (Table 5).

Univariate analysis before and after propensity score matched analysis (PS)

Mean relapse free survival (RFS) was 69 months (range 63–75 months). Median RFS was not reached neither before nor after the propensity scored analysis.

At univariate analysis, before PS, RFS was not related to chemotherapy (1w-CDDP vs 3wCDDP) (p = 0.21) with 12- and 24-months survival rates of 85% vs 74%, 79% vs 67.5% in 1w-CDDP vs 3w-CDDP group, respectively. The other variables did not show statistically significant differences.

The results after the propensity score match were almost the same as those registered before applying the propensity analysis. (Table 6)

Table 6

Relapse Free Survival before and after the propensity score matched analysis (PS).
Characteristic	RFS univariate pre PS			RFS multivariate pre-PS		RFS Univariate post PS			RFS multivariate post-PS
	1 Y	2Y	p=	Exp B	p =	1 Y	2Y	p=	Exp-B	p=
Gender			NS		0.035			0.027		0.015
Male	78.7	71				78.7	71		1
Female	90.2	86.8				94.2	90.3		0.229 (IC 0.07-0.7488)
Age			NS		NS			NS		NS
< 70 yrs	80.6	75				81.2	74.1
> 70 yrs	87.7	82.2				87.7	82.2
KPS			NS		NS			NS		NS
90 − 10	80.9	74.9				81.7	75.4
70–80	82.5	74.8				82.5	74.8
Tobacco use			NS		NS			NS		NS
Currently < 10 cigarettes/die	83	75.4				83	75.4
Currently 10–20 cigarettes/die	87	77.6				86.5	76.6
Currently > 20 cigarettes/die	78.3	73.8				78.3	73.7
Stopped smoking > 5 years	82.5	78.7				81.8	77.9
Never smoked	79.5	72.9				82.3	74.9
Alcohol			NS		NS			NS		NS
Currently	85.8	79				85.7	78.7
Past	76.7	63.8				76.7	63.8
Never	78.4	76.2				78.7	76.3
Stage T			NS		NS			NS		NS
T1-2	82.5	77.9				83.6	78.9
T3-4	80.9	72.1				80.9	72.1
Stage N			NS		NS			NS		NS
0	88.9	82.1				88.9	82.1
1	91.1	85				91.1	85
2	79.8	74.2				80.4	74.5
3	53.3	26.7				26.7	26.7
Stage of disease			NS		NS			NS		NS
II	100	100				100	100
III	83.4	79.5				83.4	79.5
IV	80.4	72.8				81	73.1
Site of disease			NS		NS			NS		NS
Oropharynx	84.9	78.8				85.9	79.4
Hypopharynx	84	68.5				84	68.5
Larynx	63	63				63	63
RT technique			NS		NS			NS		NS
IMRT/VMAT	76.7	69.5				77.5	70
Helical IMRT	92.3	82.6				92.3	86.4
Type of CHT			NS		NS			NS		NS
1w-CDDP	85.2	78.9				75.2	67.6
3w-CDDP	74.3	67.5				85.2	78.9
Total CDDP/m²			NS		NS			NS		NS
< 200 mg/m²	66.7	53.3				48	48
200–250 mg/ m²	85.9	85.9				93.3	93.3
> 250 mg/ m²	82.3	75.6				82.9	76
CDDP interruption			NS		NS			NS		NS
yes	79.6	76.2				79.8	76.3
no	83.8	74.2				84.7	74.7
Legend RT: radiotherapy; IMRT:Intensity Modulated Radiation Therapy; CDDP: Cisplatin; 1w-CDDP: weekly Cisplatin; 3w-CDDP: three weekly Cisplatin

The loco-regional (T and N) median free survival was not statistically different between the two groups neither before (p = 0.453) nor after (p = 0.394) propensity score analysis.

Multivariate analysis after PS

The multivariate analysis confirmed the gender as independent factor predicting RFS. (Table 6)

Due to its ability to increase the tumoricidal activity of radiotherapy, cisplatin is the standard agent, in combination with radiotherapy, to treat LAHNSCC fit patients, both with curative and postoperative intent ^{(4, 2, 12, 13, 14)}.

Although several papers about the use of different CDDP schedules are present, the 3w-CDDP regimen, supported by level 1 data, show a significant increase in overall survival and loco-regional disease control compared to radiotherapy alone ^{(1, 2, 3, 4, 15)}. Despite benefit in terms of disease control, this chemotherapy schedule is burdened by severe toxicity, both acute and chronic, in particular myelotoxicity and mucositis ⁽⁶⁾.

Adequate pretreatment patients’ characteristics remain crucial and difficult to be determined upfront.

The factors affecting patient tolerance during combined radio-chemotherapy are really multifaceted and are related to patients and treatment characteristics (chemotherapy and/or RT fractionation). There is evidence that chemotherapy in old patients or in patients with bad performance status can negatively influence treatment compliance. For these patients, different chemotherapy schedules have been investigated ^{(16–17−18)}. Among them the availability of a CDDP schedule less toxic and as effective as the 3w-CDDP has been considered a fascinating hypothesis.

Many efforts have been made to identify an alternative CDDP schedule achieving optimal disease control with minimal complications in order to reduce toxicity and, possibly, treatment interruptions that could compromise the treatment efficacy.

The meta-analysis by Jian (2016)⁽⁵⁾, analyzed studies published from 2006 to 2014 comparing weekly Cisplatin (25–40 mg/m²) with the three-weekly one (Cisplatin at 80–100 mg/ m²), in combination with radiotherapy for the treatment of stage II-IV head and neck cancers (including nasopharynx). No significant differences in 2- (Hazard Ratio -HR- 1.05, p = 0.85) and 3-year OS (HR 1.12, p = 0.65) were evident between the two schedules; also, 1- and 2-years Local Relapse Free Survival (LRFS) were similar, (HR 1.26, p = 0.65 and 1.14, p = 0.74 respectively). Better 5-year OS (HR 1.75, p = 0.006) was registered for the 3w-CDDP schedule. In this paper, however, it is not clearly defined if patients treated with 3w-CDDP had a better KPS or if KPS influences the outcome. The reported better long-term survival, evaluated only on two included papers, could thus be related to this important clinical aspect. About acute toxicity is concerned, the two groups showed the same hematological toxicity (leukopenia, anemia, thrombocytopenia); less frequent severe intestinal toxicity (nausea and vomiting) was registered in the 1w-CDDP group (p = 0.006), whereas severe mucosal toxicity and CDDP delay/interruption were more common in patients with non-nasopharyngeal cancer in the 1-CDDP group (p < 0.0001). As far as treatment compliance is concerned, the data are very heterogeneous, since a significant proportion of patients (42% in the weekly CDDP group vs 30% in the three-weekly group) received neo-adjuvant chemotherapy, possibly reducing the tolerance to the concomitant phase. Another limitation of this study is the cumulative analysis of very different disease sites (including nasopharynx) and of different w-CDDP doses (range, 25–40 mg/m²/w).

The meta-analysis by Szturz⁽⁷⁾ ,including 52 studies, comparing adjuvant/radical 1w-CDDP and 3w-CDDP concomitant to radiotherapy did not show a statistically significant difference in OS and relapse rate between the two treatments. Three-weekly administration, however, appeared to be linked with more severe myelosuppression (leukopenia, p = 0.0083 and thrombocytopenia, p = 0.0024), gastrointestinal toxicity (p < 0.001) and severe nephrotoxicity (p = 0.0099), while there were no significant differences in mucosal toxicity. Three-weekly administration was also related to inferior compliance: only 71% of patients completed the full chemotherapy treatment as compared to 88% of the patients who had w-CDDP. It is also worth noting the different distribution of the disease sites in the two groups, with the higher prevalence of oropharynx cancer in the group undergoing three-weekly chemotherapy (49% vs 36%).

A very recent phase III randomized study by Noronha⁽⁶⁾, designed as a non-inferiority study, investigated the outcome of patients with LA head-neck carcinoma (except nasopharynx) treated with 30mg/m² w-CDDP compared to the 3w-CDDP 100 mg/m² in postoperative/radical setting. The main endpoint of the study was loco-regional control; the secondary ones included toxicity, compliance and OS. The study included 300 patients (150/arm) but 93% were in a postoperative setting (87.3% oral cavity tumors). The 2-year loco-regional control was significantly higher for the 3w-CDDP (p = 0.014). The results were confirmed after the comparison of patients receiving total CDDP dose > 200 mg/m². As for Progression Free Survival (PFS) and OS, however, no statistically significant differences were registered. Regarding toxicity, the 3w regimen was burdened by more frequent severe acute toxicity (p = 0.006) and the hospitalization rate was greater (p < 0.001). The main limitation of this study is the small rate of patients treated radically, due to the preponderance of oral cavity tumors, and the low dose of Cisplatin administered in the weekly schedule (30 mg/m²), compared to the standard of 40 mg/m².

There have also been several attempts to substitute chemotherapy with cetuximab in old and bad general conditions patients, although the Bonner’s Study wasn’t designed for such patients.^(19–20)The results of these studies are not uniform, but the data of the De-Escalate and RTOG 1016 prospective trials^(21–22)as well as those of a smaller Italian trial^(23–24) with an emphasis on toxicity, did not confirm the hypothesis of the better compliance and equal efficacy of bio-radiotherapy, particularly in patients with better prognosis (HPV positive disease).

In this context, our study aims to contribute to the body of literature on this controversial issue with a retrospective evaluation of the efficacy and tolerability of the two chemotherapy schedules (1w-CDDP 40 mg/m² and 3w-CDDP 100mg/m²) administered concurrently with radiotherapy in patients with LA head-neck cancer (oropharynx, hypopharynx and larynx).

The two treatment groups in our series are significantly different in relation to patient clinical characteristics (per arm number of patients, gender, age, performance status, alcohol and smoking habits); higher rates of women, young patients and subjects with better KPS and less smoking and alcohol consumption were registered in the 3w-CDDP group. Moreover, in the same group there was a prevalence of oropharynx cancer, even if they had more advanced nodal disease. Nevertheless, the propensity score method applied for the statistical analysis was able to mitigate these inhomogeneities thus rendering more reliable and robust the presented results.

A non-significantly higher rate of G3-4 hematologic toxicity was observed for the 3-weekly schedule. No significant differences were evident in terms of mucositis or dysphagia. A higher rate of G1-2 thrombocytopenia, mild gastrointestinal toxicity and CDDP interruptions were observed in patients treated with w-CDDP. The higher rate of toxicities could be attributed to the different characteristics of patients treated: more patients with low KPS, older than 70 years and smoke and alcohol addiction were treated with w-CDDP. The subgroup analysis showed that also within subgroup with KPS > = 90 patients of the 1w-CDDP group, are more frequently alcohol and smoking user.

The OS analysis of the present series, not corrected for age, performance status and disease stage, showed a statistically significant better survival for patients treated with 3w-CDDP compared to w-CDDP, with 2- and 5-years rates of 95.4% vs 84.6% and 95.4% vs. 75.9%, respectively (p = 0.026). This result is, probably, related with a selection bias of the patients in the 3w-CDDP group (younger age, better performance status, less smoking and alcohol consumption and higher rate of HPV positivity). This interpretation of the data is confirmed by the similar survival results registered in the two treatment groups with the propensity scored matched analysis.

The same results have been obtained also for RFS. The results from multivariate analysis after the propensity scored matched analysis, both for OS and RFS showed that neither the interruption of chemotherapy nor the CDDP total dose/m² can be identified as an independent prognostic factor.

Propensity score analysis is useful to decrease the biases related to the analysis of a non-randomized population, that however cannot be completely eliminated.

Three-weekly CDDP still represents the gold standard in curative and postoperative concurrent chemoradiation for LAHNSCC patients, despite the definition of the gold standard of the chemotherapy schedule is still much debated.

This is a retrospective, propensity score matched analysis, suggesting the equivalence of the two CDDP schedules in terms of survival outcomes. These data, since they are retrospective in nature, are not per se sufficient to modify current clinical practice, but could confirm, together with others already published data, that 1w-CDDP can be safely used in this group of patients. The lower patients’ compliance to the 1w-CDDP schedule could be justified by the worst patients prognostic factors (older age and lower performance status, alcohol consumption and smoking habits) compared to the 3w-CDDP cohort but it should be taken into account when we choose this personalized approach to support the frailty.

Ethics approval and consent to participate: The ethical committee of the two Institutions approved/notified the study.

Consent for publication: All patients gave written informed consent for the treatment and anonymous use of their data for educational and research purposes.

Availability of data and material: The datasets analysed during the current study available from the corresponding author on reasonable request.

Competing interests: Michela Buglione and Daniela Alterio declare conflict of interest with Merck Serono; Stefano M. Magrini declare conflict of interest with Merck Serono, Astellas, Roche, Janssen; Barbara Alicja Jereczek-Fossa declares conflict of interest with Janssen, Ferring, Bayer, Roches, Astellas, Elekta, Carl Zeiss, Ipsen, Accuray, IBA.

The other authors have nothing to disclose

Funding sources: none

Authors' contributions: All submitting authors have had full access to all data and certify to their integrity, and support the decision to submit them for publication.

Acknowledgements: IEO the institution of some Authors (DA, MAG, MA, GM, IT, MA, MCR, SMM, BAJF) receives Ricerca Corrente and 5x1000 research funds from the Italian Ministry of Health. The sponsor did not play any role in study design, execution and data analysis.

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Three weekly versus weekly concurrent cisplatin: a matter of safety in head and neck cancer

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Abstract

Background

Methods

Results

Conclusions

Introduction

Materials And Methods

STATISTICAL ANALYSIS

Results

Acute toxicity

Overall Survival

Univariate analysis before and after propensity score matched analysis

Multivariate analysis before and after propensity score matched analysis

Relapse Free Survival

Univariate analysis before and after propensity score matched analysis (PS)

Multivariate analysis after PS

Discussion

Conclusions

Declarations

References

Status:

Version 1