Study reference

Study characteristics

Patient characteristics ²

Intervention (I)

Comparison / control (C) ³

Follow-up

Outcome measures and effect size ⁴

Comments

30 mg/m2

Mashhour, 2020

Type of study:

Randomized controlled trial

Setting and country:

Egypt

Funding and conflicts of interest: The authors reported there was no funding for the trial. No conflicts of interest were reported.

Patients with locally advanced head and neck squamous cell carcinomas

Intent of treatment

Adjuvant

I: 53% / C: 50%

Definitive

I: 47% / C: 50%

Inclusion criteria:

- patients with locally advanced head and neck cancers (stages 3 and 4)

- histo-pathologically

confirmed squamous or undifferentiated carcinoma

- age

range from 18 to 70 years

- Eastern Co-operative Oncology

Group (ECOG) performance status (PS) from 0-2

- creatinine clearance> 60 ml/min

Exclusion criteria:

- metastatic

disease

- neo-adjuvant chemotherapy

- history of another malignant disease

N total at baseline:

60 (I: 30 / C: 30)

Important characteristics:

Age in both groups: median 61 years (range 56-65)

Male gender

I: 73% / C: 80%

Primary tumour site

Oral cavity

I: 17% / C: 20%

Oropharynx

I: 20% / C: 17%

Nasopharynx

I: 13% / C: 23%

Larynx

I: 33% / 27%

Hypopharynx

I: 17% / 13%

Stage at diagnosis

Stage III

I:  33% / C: 30%

Stage IVa

I: 37% / C: 37%

Stage IVb

I: 30% / C: 33%

Groups were comparable at baseline

30 mg/m² cisplatin once a week (for 6-7 weeks) given concurrently

with intensity modulated radiation therapy (IMRT)

Radiotherapy prescribed dose was 70Gy in 33 fractions, delivered 5 days a week.

Supportive treatment:

Pre and post- treatment

hydration, corticosteroids, antiemetics, intravenous

Mannitol 20% and supportive treatment was administrated for each patient. Potassium chloride and magnesium sulfate infused over 60 minutes each was necessary with

each infusion.

100 mg/m² cisplatin every three weeks (on days 1, 22 , and 43) given concurrently with intensity modulated radiation therapy (IMRT)

Radiotherapy prescribed dose was 70Gy in 33 fractions, delivered 5 days a week.

Supportive treatment:

Pre and post- treatment

hydration, corticosteroids, antiemetics, intravenous

Mannitol 20% and supportive treatment was administrated for each patient. Potassium chloride and magnesium sulfate infused over 60 minutes each was necessary with

each infusion. Cisplatin at a dose of 100mg/m2 was given intravenously in 1 litre 0.9% sodium chloride over 2 hours every 3 weeks at days1, 22 and 43.

More vigorous hydration and anti-emetics were adjusted to the every 3 weeks protocol in view of being a higher nephrotoxic and ematogenic risk protocol.

Length of follow-up:

Median 24 months (range 15-37 months)

Loss-to-follow-up:

none

Overall survival

Not reported

Recurrence

Complete response

I: 77% / C: 76%

Partial response

I: 13.2% / 12.6%

Stable disease 2 months after treatment

I: 4.6% / 4.1%

2 year locoregional control rate

I: 57.6% / C: 72.8%

HR: 1.78, p=0.015

Disease-free survival

Not reported

Quality of life

Not reported

Adverse events (% grade ≥3)

Non-haematological

Mucositis

I: 53% / C: 47%

p>0.05

Dysphagia

I: 47% / C: 67%

p>0.05

Nausea/vomiting

I: 13% / C: 20%

p>0.05

Xerostomia

I: 17% / C: 20%

p>0.05

Dermatitis

I: 13% / C: 10%

p>0.05

Laryngeal oedema

I: 17% / C: 17%

p>0.05

Acute toxicity grade 3 or higher

I: 57% / C: 77%

p=0.007

Haematological

Anemia

I: 17% / C: 30%

p>0.05

Leukopenia

I: 20% / C: 37%

P<0.05

Neutropenia

I: 10% / C: 20%

P<0.05

Thrombocytopenia

I: 3% / C: 10%

p>0.05

Human papilloma virus (P16) testing was not

done due to unavailability.

Evaluation of toxicity was based on the fourth

version of Common Toxicity Criteria for Adverse Events

(CTCAE v. 4.03)

Compliance to treatment

75% of the patients who received cisplatin

high dose every 3 weeks had a higher cumulative cisplatin

dose (at least 200 mg/m2) versus 46% of patients who received weekly low dose cisplatin with a statistically significant p-value of 0.003 (Figure 2).

Sahoo, 2017               

Type of study: randomized controlled trial

Setting and country: Regional Cancer Centre, India

Funding and conflicts of interest: The authors reported no competing interests

Patients with locally advanced head and neck squamous cell carcinomas

Intent of treatment:

100% definitive in both groups

Inclusion criteria:

- histo-pathologically proven

advanced stage (T3-4, N0-3, M0) squamous cell carcinoma of oral

cavity, oropharynx, hypopharynx and larynx

- age more than 18 years and less than 70 years

- normal haematological and biochemical

parameters,

- Karnofsky Performance score of 70 or above

- no

history of prior chemotherapy or radiotherapy

Exclusion criteria:

- evidence of distant metastases by clinical or

radiological examination

- recurrent disease

- prior radiotherapy or

chemotherapy to head and neck, widely disseminated diseases

- synchronous double primary malignancies

- pregnant women

- simultaneous participation in another clinical study

N total at baseline:

30 (I: 15 / C: 15)

Important characteristics:

Age: median 57.6 years (only reported for total of 30 patients)

Male gender: 90% (only reported for total of 30 patients)

Primary tumour site (only reported for total of 30 patients):

Oropharynx 53%

Hypopharynx 30%

Larynx 13%

Oral cavity 3%

Stage (only reported for total of 30 patients)

Stage III 57%

Stage IV 43%

Histology grading (only reported for total of 30 patients)

Well differentiated 50%

Moderately differentiated 43%

Poorly differentiated 7%

It was not possible to assess whether the groups were comparable at baseline, because demographics were only reported for the total group and not per study arm

30 mg/m² cisplatin once a week (for 6 weeks) along with radiation

Radiotherapy was delivered to a total dose of 66 Gy in conventional fractionation schedule

100 mg/m² cisplatin every three weeks (on days 1, 22 , and 43) along with radiation

Radiotherapy was delivered to a total dose of 66 Gy in conventional fractionation schedule

Length of follow-up:

Median 7 months

Loss-to-follow-up:

Intervention:

N=0 (0%)

Control:

N=1 (7%)

Reasons: one patient did not come for follow up.

Overall survival

Not reported

Recurrence

Complete response after a median follow up of seven months:

I: 73% / C: 86%

p>0.05

Disease-free survival

Not reported

Quality of life

Not reported

Adverse events (% grade ≥3)

Mucositis

I: 40% / C: 60%

p=0.729

Dermatitis

I: 27% / C: 7%

p=0.360

Dysphagia

I: 0% / C: 7%

p>0.05

Vomiting

I: 7% / C: 20%

p=0.360

Anaemia

I: 7% / C: 7%

p>0.05

Leukopenia

I: 13% / C: 7%

p>0.05

There was almost

no difference in late toxicities in both the arms (xerostomia and skin

fibrosis). No further details were provided.

Compliance:

A 66.67% (10/15) patients completed six cycles of CT in weekly cisplatin arm, whereas, only 46.67% (7/15)

patients were able to complete three cycles of three weekly cisplatin

in arm B. A total of 13 patients (86.67%) completed 66 Gy RT in

weekly arm, whereas, 12 patients (80%) in three weekly arm completed 66 Gy RT.

Toxicities were assessed using the Radiation Therapy Oncology Group Acute Radiation Morbidity Criteria.

Noronha, 2018

Type of study: phase III randomized noninferiority trial

Setting and country: academic oncology hospital in India

Funding and conflicts of interest: The Tata Memorial Center Research Administration Council funded the study. No conflicts of interest were reported by the authors.

Patients with locally

advanced head and neck squamous cell cancer (mainly oral cavity)

Intent of treatment

Adjuvant, for high-risk features

I: 93% / C: 93%

Definitive

I: 7% / C: 7%

Inclusion criteria:

HNSCC of the oral cavity, oropharynx, hypopharynx, or larynx, or

metastatic cervical lymphadenopathy of unknown primary

- disease had to

be locally advanced (ie, stage III or IV), with no distant metastases

- planned for curative CRT, either adjuvant for one or more high-risk features

(extracapsular extension, close (ie,≤ 5mm), or positive margins, more than

two lymph nodes positive, T4 primary) or for definitive CRT for unresectable

disease or organ preservation

- ≤70 years of

age

- Eastern Cooperative Oncology Group performance status ≤2

- calculated

creatinine clearance ≥ 50mL/min

- no moderate or severe sensorineural

Deafness

- adequate organ function

- no induction chemotherapy

N total at baseline:

300 (I: 150 / C: 150)

Important characteristics:

Median age (range)

I: 41.5 (26-65)

C: 47 (25-67)

Male gender

I: 90% / C: 88%

Primary tumour site

Oral cavity

I: 91% / C: 84%

Oropharynx

I: 1% / C: 2%

Larynx

I: 2% / 5%

Hypopharynx

I: 1% / 2%

Cervical lymphadenopathy of unknown primary

I: 5% / C: 7%

T-stage

Tx or T0

I: 5% / C: 7%

T1

I: 9% / C: 8%

T2

I: 19% / C: 17%

T3

I: 7% / C: 7%

T4

I: 60% / C: 61%

N-stage

N0

I: 3% / C: 7%

N1

I: 27% / C: 21%

N2

I: 69% / C: 70%

N3

I: 1% / C: 1%

TNM stage

Stage III

I: 9% / C: 9%

Stage IV

I: 91% / 91%

Histologic differentiation

Well differentiated

I: 4% / C: 7%

Moderately differentiated

I: 53% / C: 59%

Poorly differentiated

I: 40% / C: 31%

Unknown

I: 3% / C: 3%

Groups were comparable at baseline

30 mg/m² cisplatin once a week (for 6 or 7 weeks) along with radiation

Patients received conventional external-beam radiotherapy. The total dose planned was 70 Gy in 35 fractions over 7 weeks for definitive CRT; 60 Gy was planned for high-risk areas

(tumour bed and involved nodal regions) for adjuvant treatment.

Patients received routine hydration, antiemetics, corticosteroids, and other

supportive medications.

100 mg/m² cisplatin every three weeks (on days 1, 22, and 43) along with radiation

Patients received conventional external-beam radiotherapy. The total dose planned was 70 Gy in 35 fractions over 7 weeks for definitive CRT; 60 Gy was planned for high-risk areas

(tumour bed and involved nodal regions) for adjuvant treatment.

Patients received routine hydration, antiemetics, corticosteroids, and other

supportive medications.

Length of follow-up:

Median 22 months

Loss-to-follow-up:

none

Incomplete outcome data:

Intervention:

N=2 (1%)

Reasons: two patients were not included in the analysis of toxicity because they did not start treatment with cisplatin

Control:

N =1 (%)

Reasons: one patient was not included in the analysis of toxicity because the patient did not start treatment with cisplatin

Overall survival

Median overall survival

I: 39.5 months

C: not reached

HR 1.14 (95%CI 0.79 to 1.65)

P=0.48

Recurrence

Locoregional relapse

I: 38% / C: 24%

2-year locoregional control rate

I: 59% / C: 73%

p=0.014;

HR 1.76 (95%CI 1.11 to 2.79)

Disease-free survival

Disease progression

I: 49% / C: 39%

Median progression-free survival

I: 17.7 months (95%CI 0.42 to 35.1)

C: 28.6 months (95%CI 15.9 to 41.3)

HR 1.24 (95%CI, 0.89 to 1.73); P = 0.21.

Quality of life

Not reported

Adverse events

Acute (first 90 days from the start of treatment)

Any acute toxicity grade 3 or higher

I: 72% / C: 85%

p=0.006

Statistically significant differences were found for:

Vomiting (I: 1% / C: 7%)

Infection (I: 21% / C: 34%)

Deafness (I: 5% / C: 13%)

Hyponatremia (I: 23% / C: 52%)

Leukopenia (I: 3% / C: 16%)

Neutropenia (I: 1% / C: 12%)

Febrile neutropenia (I: 1% / C: 6%)

Lymphocytopenia (I: 72% / C: 89%)

No statistically significant differences were found for:

Mucositis (I: 17% C: 18 %)

Dysphagia (I: 42% / C: 39%)

Odynophagia (I: 41% / C: 52 %)

Xerostomia (I: 0% / C: 1%)

Dysgeusia (I: 0% / C: 1%)

Dermatitis (I: 7% / C: 8%)

Diarrhoea (I: 1% / C: 5%)

Fatigue (I: 1% / C: 1%)

Weight loss (I: 1% / C: 0%)

Hoarseness (I: 9% / C: 9%)

Hypertension (I: 4% / C: 7%)

Hypokalemia (I: 1% / C: 5%)

Transaminase elevation (I: 1% / C: 5%)

Anemia (I: 2% / C: 5%)

Thrombocytopenia (I: 3% / C: 2%)

No grade ≥3 toxicity was observed for neuropathy and renal dysfunction.

Chronic (> 90 days from the start of treatment)

Any chronic toxicity grade 3 or higher

I: 10% / C: 14% (p=0.55)

A statistically significant difference was found for:

Deafness (I: 4% / C: 16%)

No statistically significant differences were found for:

Mucositis (I: 0% / C: 1%)

Dysphagia (I: 4% / C: 4%)

Odynophagia (I: 2 % / C: 4%)

Infection (I: 5% / C: 5%)

Xerostomia (I: 1% / C: 1%)

Subcutaneous (I: 0% / C: 2%)

Trismus (I: 2% / C: 0%)

Hypertriglyceridemia (I: 2% / C: 1%)

No grade ≥3 toxicity was observed for dysgeusia, skin, hypothyroidism, and thromboembolic events.

Compliance

There were no significant differences between the two arms in terms of treatment completion and

compliance to therapy (P = .1). Overall compliance was 91%.

The median cumulative

cisplatin dose was 300 mg/m2 (IQR, 200-300 mg/m2) in the weekly treatment group and 210 mg/m2 (IQR, 180-210 mg/m2) in the three-weekly treatment group.

The study was powered for the primary outcome locoregional control, therefore the study was not powered to show statistically significant differences in progression-free survival and overall survival.

Toxicities were assessed using the Common Terminology Criteria for Adverse Events (version 4.03).

35 mg/m2

Rawat, 2016

Type of study: randomized controlled trial

Setting and country: single centre study, India

Funding and conflicts of interest: no information provided by authors

Patients with locally advanced squamous cell carcinoma of the head and neck

Intent of treatment:

100% definitive in both groups

Inclusion criteria:

- histologically proven squamous cell carcinoma

- locally advanced (stage III - IV B) disease

- oral cavity, oropharynx, hypopharynx and larynx primary tumours

- age 18 – 65 years

- normal haemogram, renal and liver function tests

Exclusion criteria:

- previously treated head and neck malignancy

- evidence of distant metastasis

- patients with comorbid conditions, such as uncontrolled hypertension, uncontrolled diabetes,

or active cardiac disease

N total at baseline:

60 (I: 30 / C: 30)

Important characteristics:

Age (mean ± SD)

I: 50.7 ± 8.1

C: 51.4 (10.1)

Male gender

I: 90% / C: 100%

Primary tumour site

Oral cavity

I: 20% / C: 30%

Oropharynx

I: 60% / C: 47%

Larynx

I: 17% / 17%

Hypopharynx

I: 3% / 7%

T-stage

T1/Ts

I: 40% / C: 20%

T3/T4

I: 60% / 80%

p=0.04

N-stage

N0/N1

I: 30% / C: 60%

N2/N3

I: 70% / C: 40%

P=0.01

Stage

Stage III

I: 23% / C: 40%

Stage IV (non-metastatic)

I: 77% / C: 60%

Differentiation

Well

I: 17% / C: 17%

Moderate

I: 57% / C: 70%

Poorly

I: 27% / C: 13%

The weekly arm had fewer men and more advanced stage patients (N2/N3)

as compared to the three-weekly arm.

35 mg/m² cisplatin once a week (for 6 weeks) along with radiation

Radiotherapy was delivered to a total dose of 70 Gy in 35 fractions.

Weekly cisplatin was provided on an outpatient basis in day care ward with similar hydration and other measures, as compared to the control group.

Supportive treatment like hospitalization,

administration of colony stimulating factor and insertion of Ryle’s tube feeding was done as and when indicated.

100 mg/m² cisplatin every three weeks (on days 1, 22 , and 43) along with radiation

In the 3-weekly arm, the patient was admitted one

day before and cisplatin was given intravenously over 2

days in equal divided dose in 500 ml of normal saline

with adequate hydration, anti-emetic prophylaxis, and

mannitol infusion while

Supportive treatment like hospitalization,

administration of colony stimulating factor and insertion of Ryle’s tube feeding was done as and when indicated.

Length of follow-up:

Median 8 months (range 4-13)

Loss-to-follow-up:

Intervention:

N=0 (0%)

Control:

N =1 (3%)

Reasons: one patient died during treatment because of a medical cause unrelated to the treatment (dengue)

Overall survival

Not reported

Recurrence

Complete response three months after treatment:

I: 67% / C: 62%

Partial response three months after treatment:

I: 33% / C: 38%

p=0.20

Disease-free survival

Not reported

Quality of life

Not reported

Adverse events (% grade ≥3 3)

Mucositis

I: 70% / C: 76%

p=0.20

Vomiting

I: 20% / 35%

P=0.03

Anemia

I: 33% / C: 31%

P=0.22

Neutropenia

I: 27% / C: 55%

p=0.01

Thrombocytopenia

I: 7% / C: 10%

P=0.32

Hypomagnesemia (20% versus 60%; p=0.001) occurred less frequently in the study arm receiving weekly cisplatin. However, it was not clear whether this involved grade ≥3 adverse events.

The frequency of significant weight loss (23% versus 41%; p=0.08) and hyponatremia  (33% versus 40%; p=0.18) was comparable between the groups. It was not clear whether this involved grade ≥3 adverse events. 

Compliance

Mean RT dose was similar between the weekly (69.86 Gy ± 0.73) and three-weekly (69.22 Gy ± 4.38) study arms.

However, a higher mean cisplatin dose was received by patients receiving three-weekly treatment (438.27 mg ± 65.03) as compared to  patients receiving weekly treatment (291.66 mg ± 23.05) during RT. Five patients in arm A and 10 patients in arm B had RT interruption due to

various reasons like mucositis, haematological toxicity and non-compliance. Although not statistically significant,

10% and 20.7% of patients receiving weekly or three-weekly treatment

did not complete the planned course of CT (p = 0.15).

Need for supportive treatment

Supportive treatment in the form of feeding procedure

(such as percutaneous endoscopic gastrostomy or Ryle’s tube) (p = 0.05), use of colony-stimulating factors (p =0.05) and hospitalization for supportive care during CRT were more for 3-weekly arm patients as compared to

weekly arm (p = 0.05).

Tumour response was evaluated according to the Response Evaluation Criteria in Solid Tumours (RECIST) version 1.1.

Toxicity was assessed using the CTCAE v. 4.03.

40 mg/m2

Kiyota, 2022

Type of study:

Randomized controlled non-inferiority trial

Setting and country: 28 institutions in Japan

Funding and conflicts of interest:

Supported by the National Cancer Center Research and Development

Funds (29-A-3, 25-B-2, and 2020-J-3), a Grant-in-Aid for Clinical

Cancer Research (H23-009 and H26-052) from the Ministry of Health, Labor and Welfare of Japan, and by AMED (Japan Agency for Medical Research and Development).

Several authors, including the first author, disclosed receiving honorary an research funding from the pharmaceutical industry (including Novartis).

Patients with postoperative

locally advanced squamous cell carcinoma of the head and neck (LA-SCCHN) with high risk for recurrence

Intent of treatment:

100% adjuvant in both groups

Inclusion criteria:

- the presence of histologically

proven squamous cell carcinoma in the resected specimen

- primary lesion located in the oral cavity, oropharynx,

hypopharynx, or larynx

- pathologic stages III, IVA, or IVB (UICC seventh edition)

- high-risk factors for recurrence (microscopically

positive margin and/or extranodular extension)

- within 56 days of surgery

- without distant metastasis

- age 20-75 years

- an Eastern Cooperative Oncology Group (ECOG)

performance status score of 0 or 1

- adequate organ function

- no clinically significant abnormal findings on electrocardiography

A microscopically

positive margin was defined as an invasive cancer at or close

to the resection margin (, 5 mm) on microscopic evaluation, with no evidence of residual gross tumor.

Exclusion criteria:

- active multiple primary cancers (synchronous primary double cancers and metachronous double cancers with 5 years or less of disease-free survival; carcinoma in situ and lesions consistent with intramucosal carcinoma judged to be curable with topical treatments, and lesions diagnosed as esophageal, gastric, or colon carcinoma in situ or intramucosal carcinoma based on endoscopic findings before registration are not regarded as active primary double cancers)

- infection requiring systemic treatment

- fever exceeding 38°C at registration

- women who are or may be pregnant, or who are nursing

- psychosis or psychiatric symptoms/signs that are judged to make participation in the study difficult

- long-term use of systemic steroidal treatment (oral/intravenous)

- uncontrolled diabetes mellitus

- complication with unstable angina (new onset within the last 3 weeks or aggravation of angina pectoris), or history of myocardial infarction within the last 6 months

- uncontrolled hypertension

- pleural effusion, pericardial effusion, or ascites that requires drainage

- HBs antigen-positive

- judged to have difficulty in abstaining from smoking or alcohol during the protocol treatment

N total at baseline:

I: 129 / C: 132

Important characteristics:

Age,  median (IQR)

I: 61 (53 to 66)

C: 62 (55 to 68)

Male gender

I: 85% / C: 85%

Primary tumour site

Oral cavity

I: 46% / C: 46%

Larynx

I: 9% / C: 9%

Oropharynx

I: 16% / C: 11%

Hypopharynx

I: 29% / C: 34%

T-stage

T1

I: 5% / C: 10%

T2

I: 31% / C: 20%

T3

I: 18% / C: 19%

T4

I: 46% / C: 51%

N-stage

No

I: 5% / C: 7%

N1

I: 12% / C: 7%

N2

I: 81% / C: 81%

N3

I: 1% / C: 4%

Nx

I: 1% / C: 1%

Stage

Stage III

I: 9% / C: 7%

Stage IVA

I: 88% / C: 88%

Stage IVB

I: 2% / C: 4%

Unknown

I: 1% / C: 1%

40 mg/m² cisplatin once a week (for 7 weeks) along with radiation

Radiotherapy was delivered to a total dose of 66 Gy in 33

fractions over 6.5 weeks.

100 mg/m² cisplatin every three weeks (on days 1, 22 , and 43) along with radiation

Radiotherapy was delivered to a total dose of 66 Gy in 33

fractions over 6.5 weeks.

Length of follow-up:

median follow-up of 2.2 (interquartile range 1.19-3.56) years

Loss-to-follow-up:

All patients were included in the survival analysis.

Intervention:

N=7 (5%)

Control:

N =3 (2%)

Reasons: these patients were not included in the analysis of adverse events because they did not start treatment with cisplatin

Overall survival

HR 0.69 (99.1% CI, 0.37 to 1.27

One-sided P for noninferiority = .0027 , .0043).

Recurrence

I: 29% / C: 39%

Disease-free survival

Relapse-free survival

HR 0.71 (95% CI, 0.48 to 1.06)

(in favour of weekly treatment)

Local relapse-free survival

HR 0.73 (95% CI, 0.47 to 1.13

Quality of life

Not reported

Adverse events (% grade ≥3 3)

Haematological

Anemia

I: 13% / C: 14%

Leukocytopenia

I: 62% / 55%

Neutropenia

I: 35% / 49%

Thrombocytopenia

I: 3% / 2%

Non-haematological

Mucositis

I: 28% / C: 23%

Radiation dermatitis

I: 12% / C: 15%

Nausea

I: 5% / C: 13%

Dysphagia

I: 12% / C: 19%

Infection

I: 7% / C: 12%

Hearing disturbance

I: 2% / C: 4%

Proportion of patients with at least one grade ≥3 adverse event

I: 81.1% / C 79.8%

Proportion of patients with at least one grade ≥3 haematological adverse event

I: 64.8% / C 61.2%

Compliance

Total RT dose in both groups: median 66 (IQR 66 to 66)

Cycles of cisplatin:

I: median 6 (IQR 5 to 7)

C: median 3 (IQR 3 to 3)

Cumulative dose of cisplatin

I: 239 mg/m² (IQR 199 to 277)

C: 280 mg/m² (IQR 250 to 299)

Toxicity was assessed using

CTACE version 4.0.

Nanda, 2019

Type of study: randomized controlled trial

Setting and country: regional cancer centre in India

Funding and conflicts of interest: nil financial support and sponsorship, the authors reported no conflicts of interest

Patients with locally advanced oropharyngeal

squamous cell carcinoma

Intent of treatment:

100% definitive in both groups

Inclusion criteria:

- Histologically proven newly diagnosed oropharyngeal SCC Stage III–IV

- age 20–70 years

- Karnofsky Performance Scale >70

- well‑controlled medical

Comorbidities

- normal baseline haematological, hepatic, and

renal functions

Exclusion criteria:

- active tuberculosis

- retroviral infection

- cardiac abnormalities with ejection fraction <60

- received neoadjuvant chemotherapy or had undergone surgery

N total at baseline:

60 (I: 29 / C: 31)

Important characteristics:

Median age

I: 54.5 ± 7.9

C: 55.0 ± 6.5

Male gender

I: 93% / C: 97%

Primary tumour site (in oropharynx):

Base of tongue

I: 48% / C: 54%

Tonsil

I: 35% / C:23%

Soft palate

I: 10% / C: 16%

Posterior pharyngeal wall

I: 7% / C: 7%

T status

T2

I: 7% / C: 3%

T3

I: 62% / C: 55%

T4

I: 31% / C: 42%

p=0.67

N status

N0

I: 17% / C: 23%

N1

I: 31% / C: 32%

N2

I: 45% / C: 36%

N3

I: 7% / C: 10%

p=0.35

Stage

III

I: 35% / C: 36%

IV

I: 66% / C: 65%

p=0.91

Groups were comparable at baseline

40 mg/m² cisplatin once a week (for a minimum of four cycles and maximum of six cycles) along with radiation

Radiotherapy was delivered to a total dose of 70 Gy in 35 fractions, delivered 5 days a week.

All patients received prechemotherapy hydration 24 h prior. Premedication with antiemetics, ondansetron 8 mg and

dexamethasone 16 mg were given before chemotherapy,

and 20‑mmol potassium chloride and a vial of magnesium sulfate (1000 mg) diluted with saline were infused over 1 h each.

In the weekly arm, cisplatin of 40 mg/m2 was given

along with saline over 3 h.

Postchemotherapy hydration was given and antiemetics continued for the following 2 days.

100 mg/m² cisplatin every three weeks (for a maximum of two cycles) along with radiation

Radiotherapy was delivered to a total dose of 70 Gy in 35 fractions, delivered 5 days a week.

All patients received prechemotherapy hydration 24 h prior. Premedication with antiemetics, ondansetron 8 mg and

dexamethasone 16 mg were given before chemotherapy,

and 20‑mmol potassium chloride and a vial of magnesium sulfate (1000 mg) diluted with saline were infused over 1 h each.

In the three-weekly arm, cisplatin dose of 100 mg/m2 was given in divided doses over 2–3 days.

Postchemotherapy hydration was given and antiemetics continued for the following 2 days.

Length of follow-up:

Median 28 months (range 2.8-66.9 months)

Incomplete outcome data:

Intervention:

N=1 (3%)

Reasons not described, but toxicities were reported for 28/29 patients in the weekly treatment group

Control:

N=0 (0%)

Overall survival

Median overall survival

I: 35.4 months

C: 32.9 months

p=0.303

2-year survival rate

I: 55% / C: 58%

No statistically significant difference, p-value not provided

5-year survival rate

I: 42% / 32%

No statistically significant difference, p-value not provided

Recurrence

Complete response three months after treatment:

I: 81% / C: 75%

Partial response three months after treatment:

I: 14% / C: 13%

Stable disease 8 weeks after completion of treatment:

I: 5% / C: 4%

Stable or progressive disease three months after completion of treatment:

I: 29% / C: 42%

Locoregional relapses

I: 14% / C: 6%

Disease-free survival

Median disease‑free survival at two years

I: 26.4 months / C: 27.4 months

P=0.953

There were two nondisease‑related deaths in the weekly treatment arm and five in the three-weekly treatment arm.

Quality of life

Not reported

Adverse events (% grade ≥3)

Non- haematological

Mucositis

I: 32% / C: 29%

p=1.00

Dysphagia

I: 46% / C: 32%

p=0.27

Dermatitis

I: 14% / C: 19%

p=0.73

Larynx

I: 11%% / C: 10%

p=1.00

Nausea/vomiting

I: 7% / C: 0%

p=0.22

Haematological

Anemia

I: 0% / C: 3%

p=1.00

Leukopenia

I: 25% / C: 13%

p=0.32

Neutropenia

I: 18% / C: 7%

p=0.24

Thrombocytopenia

I: 0% / C: 3%

p=1.00

Two patients of Arm B died due to neutropenic sepsis and one in Arm A due to aspiration pneumonia.

Compliance

The median total cumulative dose of cisplatin was 271.8 mgs (range: 120–320 mgs) in the weekly arm and 303 mgs

(range: 180–350 mgs) in the three-weekly arm (p=0.02). Twenty‑five (89%) in Arm

A and thirty (96.8%) in Arm B received cisplatin >200 mg/m².

Both the groups of patients received radiation dose of 70 Gy in 35 fractions over 7 weeks. There was no difference in the overall

treatment time (OTT) in both the arms (weekly arm: 53.4 days (±5.2)

and three-weekly arm: 53.8 days (±7.7)).

Tumour response was evaluated according to the WHO criteria.

Toxicity was assessed using the Radiation Therapy Oncology Group criteria for radiotherapy-induced acute toxicities, and Common Toxicity Criteria  for chemotherapy-induced toxicity.

Nair, 2017

Type of study: randomized controlled phase IIb trial

Setting and country: regional cancer centre, India

Funding and conflicts of interest: nil financial support and sponsorship, the authors reported no conflicts of interest

Patients with locally advanced head and neck squamous cell carcinoma

Intent of treatment:

100% definitive in both groups

Inclusion criteria:

- Previously untreated patients with stage III and

IV squamous cell carcinoma of oropharynx, hypopharynx,

and larynx

- age in the range of 18–70 years

- Eastern

Cooperative Oncology Group (ECOG) performance status 0 or 1

- baseline hemoglobin ≥10 g/dl, white blood

cells count ≥4000 cells per cubic millimeter

- platelet

count ≥100,000 cells per cubic millimeter

- creatinine

clearance of ≥60 ml/min

Exclusion criteria:

- bone or cartilage involvement

- distant

metastasis

N total at baseline:

56 (I: 25 / C: 31)

Important characteristics:

Age > 60

I: 42% / C: 45%

Male gender

I: 96% / C: 90%

Primary tumour site

Oropharynx

I: 42% / C: 55%

Larynx

I: 42% / C: 23%

Hypopharynx

I: 17% / 23%

T status

T2

I: 21% / C: 35%

T3

I: 58% / C: 55%

T4

I: 21% / C: 10%

p=0.30

N status

N0

I: 29% / C: 23%

N1

I: 29% / C: 39%

N2

I: 42% / C: 39%

p=0.73

Stage

III

I: 63% / C: 58%

IV

I: 38% / C: 42%

p=0.78

Groups were comparable at baseline

40 mg/m² cisplatin once a week (for 6 weeks) along with radiation

Radiotherapy was delivered to a total dose of 66 Gy in 33 fractions over 6.5 weeks

For 40 mg/m2

cisplatin, 500 ml NS and 200 ml 10% mannitol were given

as prehydration followed by cisplatin in 1000 ml NS.

Posthydration consisted of 500 ml oral fluids.

Antiemetic prophylaxis consisted of 8 mg ondansetron, 12 mg

dexamethasone as intravenous bolus, and NK1 antagonist 125 mg orally on the day of chemotherapy. Dexamethasone

8 mg per day and NK1 antagonist 80 mg were continued on

the second and third days after each cycle.

100 mg/m² cisplatin every three weeks along with radiation

Radiotherapy was delivered to a total dose of 66 Gy in 33 fractions over 6.5 weeks

For 3 weekly cisplatin, 1000 ml normal saline (NS) with

20 mmol potassium chloride (KCl) and 10 mmol magnesium sulfate (MgSO4) followed by 200 ml 10% mannitol were given

as prehydration. This was followed by cisplatin 100 mg/m2 in 1000 ml NS. Posthydration consisted of 1000 ml NS with 20 mmol KCl and 10 mmol MgSO4.

Antiemetic prophylaxis consisted of 8 mg ondansetron, 12 mg

dexamethasone as intravenous bolus, and NK1 antagonist 125 mg orally on the day of chemotherapy. Dexamethasone

8 mg per day and NK1 antagonist 80 mg were continued on

the second and third days after each cycle.

Length of follow-up:

Median 26 months

Incomplete outcome data:

Intervention:

N=1 (4%)

Reasons : One patient in the weekly arm did not complete the treatment and was excluded from the

analysis.

Control:

N=0 (0%)

Overall survival

2 year overall survival rate

I: 61% / C: 71%

P=0.610

Recurrence

Complete response six months after treatment:

I: 75% / C: 90%

Partial response six months after treatment:

I: 12% / C: 6%

Residual disease at 12 weeks

I: 8% / C: 6%

Local recurrence or metastasized disease

I: 13% / C: 13%

Second primary tumour

I: 8% / C: 3%

Locoregional control at 2 years

I: 63% / C: 61%

Disease-free survival

2 year disease-free survival rate

I: 53% / C: 65%

P=0.674

Quality of life

Not reported

Adverse events (% grade ≥3)

Non- haematological

Mucositis

I: 54% / C: 52%

P>0.05

Dysphagia

I: 63% / C: 26%

P<0.05

Dermatitis

I: 13% / C: 3%

P>0.05

Haematological

Anemia

I: 4% / C: 0 %

P>0.05

Neutropenia

I: 8% / C: 3%

P>0.05

Compliance

The mean dose of cisplatin in 3 weekly arm was 356.6 mg and 339.1 mg in the weekly arm

Tumour response was evaluated using RECIST criteria.

Toxicity was assessed using the Radiation Therapy Oncology Group criteria for radiotherapy-induced toxicities, and Common Terminology Criteria version 4 for chemotherapy-induced toxicity.

Tsan, 2012

Type of study: phase III randomized trial

Setting and country: Taiwan

Funding and conflicts of interest: Funded by grants from Chang Gung Memorial Hospital.

The authors reported no conflicts of interest

Patients with high-risk oral cavity squamous cell carcinoma

Intent of treatment:

100% adjuvant in both groups

Inclusion criteria:

- histologically confirmed primary oral cavity squamous cell carcinoma, pathologic documentation for extracapsular spreading of the involved

lymph node, a positive surgical margin, or lymph node staging ≥

N2

- between 18 and

70 years old

- Eastern Cooperative Oncology

Group (ECOG) performance status (PS) of 0–2 - adequate

bone marrow, liver, and renal function

Exclusion criteria:

- suspected distant

metastatic lesions

- prior chemotherapy or

RT

- serious concomitant illness, such

as active cardiac disease, severe uncontrolled hypertension,

uncontrolled infection, or a history of other head

and neck malignancies

N total at baseline:

50 (I: 24/ C: 26)

Important characteristics:

Mean age (range)

I: 49.0 (32-65)

C: 49.2 (33-63)

Male gender

I: 96% / C: 96%

Primary tumour site (in oral cavity)

Buccal

I: 38% / C: 39%

Tongue

I: 46% / C: 39%

Gum

I: 13% / C: 19%

Others

I: 4% / C: 4%

T status

T1/T2

I: 46% / C: 54%

T3/T4

I: 54% / C: 46%

p=0.778

N status

N0

I: 8% / C: 0%

N1

I: 33% / C: 19%

N2

I: 58% / C: 81%

p=0.125

Stage

II

I: 4% / C: 0%

III

I: 17% / C: 12%

IV

I: 79% / C: 89%

p=0.549

Differentiation

Well

I: 21% / C: 27%

Moderate

I: 71% / C: 58%

Poor

I: 8% / C: 15%

Groups were comparable at baseline

40 mg/m² cisplatin once a week along with radiation

Radiotherapy was delivered to a total dose of 66 Gy in 33 fractions

100 mg/m² cisplatin every three weeks along with radiation

Radiotherapy was delivered to a total dose of 66 Gy in 33 fractions

Forced hydration with normal saline 500 ml infusion over 2 hours before and after cisplatin

infusion

Length of follow-up:

Median 12.0 months (range 2.7 to 32.8)

Loss-to-follow-up:

none

Incomplete outcome data:

none

Overall survival

1-yr overall survival rates

I: 72% / C: 79%

P=0.978

Recurrence

1-year locoregional

recurrence-free survival rates:

I: 60% / C: 71%

P=0.806

Disease-free survival

Not reported

Quality of life

FACT-H&N physical well-being subscale (range 0-28)

Week 2 (mean change from baseline)

I: -8.3 / C: -3.8

Difference: 4.5 (p=0.03)

Week 4 (mean change from baseline)

I: -9.9 / C: -4.2

Difference: 5.7 (p=0.02)

End of radiotherapy (mean change from baseline)

I: -10.3 / C: -2.5

Difference: 7.8 (p=0.007)

Follow-up at 3 months (mean change from baseline)

I: -3.8 / C: 0.5

Difference: 4.3 (p=0.04)

FACT-H&N social well-being subscale (range 0-28)

Week 2 (mean change from baseline)

I: -0.4 / C: -2.4

Difference: 2 (p=0.47)

Week 4 (mean change from baseline)

I: -0.2 / C: -3.1

Difference: 2.9 (p=0.29)

End of radiotherapy (mean change from baseline)

I: -1.6 / C: -7.3

Difference: 5.7 (p=0.02)

Follow-up at 3 months (mean change from baseline)

I: -0.7 / C: -5.7

Difference: 5 (p=0.10)

FACT-H&N emotional well-being subscale (range 0-24)

Week 2 (mean change from baseline)

I: -0.9 / C: -1.2

Difference: 0.3 (p=0.79)

Week 4 (mean change from baseline)

I: -0.8 / C: -1.4

Difference: 0.6 (p=0.46)

End of radiotherapy (mean change from baseline)

I: -1.1 / C: -1.0

Difference: 0.1 (p=0.98)

Follow-up at 3 months (mean change from baseline)

I: 0.1 / C: 0.5

Difference: 0.4 (p=0.70)

FACT-H&N functional well-being subscale (range 0-28)

Week 2 (mean change from baseline)

I: -1.9 / C: -2.0

Difference: 0.1 (p=0.74)

Week 4 (mean change from baseline)

I: -1.7 / C: -3.2

Difference: 1.5 (p=0.65)

End of radiotherapy (mean change from baseline)

I: -2.8 / C: -3.2

Difference: 0.4 (p=0.90)

Follow-up at 3 months (mean change from baseline)

I: -1.4 / C: 1.9

Difference: 3.3 (p=0.15)

FACT-H&N Head and neck cancer subscale (range 0-40)

Week 2 (mean change from baseline)

I: -3.7 / C: -3.0

Difference: 0.7 (p=0.48)

Week 4 (mean change from baseline)

I: -5.6 / C: -4.9

Difference: 0.7 (p=0.46)

End of radiotherapy (mean change from baseline)

I: -5.2 / C: -3.4

Difference: 1.8 (p=0.47)

Follow-up at 3 months (mean change from baseline)

I: -2.4 / C: -0.3

Difference: 2.1 (p=0.24)

FACT-H&N Trial Outcome Index (range 0-96)

Week 2 (mean change from baseline)

I: -14.6 / C: -8.8

Difference: 5.8 (p=0.14)

Week 4 (mean change from baseline)

I: -17.2 / C: -12.3

Difference: 4.9 (p=0.31)

End of radiotherapy (mean change from baseline)

I: -18.4 / C: -9.1

Difference: 9.3 (p=0.14)

Follow-up at 3 months (mean change from baseline)

I: -7.6 / C: 2.1

Difference: 9.7 (p=0.06)

Adverse events (% grade ≥3)

Overall toxicity

I: 92% / C 81%

P=0.020

Non-haematological

Mucositis

I: 75% / C: 39%

p=0.012

Pharyngitis

I: 54% / C: 54%

p=1.0

Stomatitis

I: 54% / C: 54%

p=1.0

Laryngeal oedema

I: 4% / C: 12%

p=0.611

Dermatitis

I: 8% / C: 8%

p=1.0

Nausea/vomiting

I: 21% / C: 12%

p=0.456

Haematological

Anemia

I: 4% / C: 4%

p=1.0

Leukopenia

I: 13% / C: 0%

p=0.103

Neutropenia

I: 4% / C: 0%

p=0.480

Thrombocytopenia

I: 0% / C: 0%

P not computed

The trial aimed to recruit 371 patients but due to slow recruitment, the trial was ended after only 55 patients were recruited over 30 months.

Compliance

Both groups of patients received the same mean doses of RT and cisplatin, and they also did not differ regarding the inadequate RT (RT dose < 60 Gy) or interrupted RT (RT duration > 8 weeks) rate. However, in terms of adequate

cisplatin dose, which was defined as cisplatin ≥

200 mg/m2, more patients in the three-weekly arm received an adequate cisplatin dose than did patients in the weekly treatment arm. In the three-weekly arm, 88.5% of patients received an adequate dose of cisplatin,

whereas only 62.5% of those in the weekly treatment arm received an adequate dose (p = 0.047).

Toxicity was assessed according to the Common Terminology Criteria for Adverse Events (CTCAE) version 3.0.

Study reference

(first author, publication year)

Was the allocation sequence adequately generated?

Definitely yes

Probably yes

Probably no

Definitely no

Was the allocation adequately concealed?

Definitely yes

Probably yes

Probably no

Definitely no

Blinding: Was knowledge of the allocated

interventions adequately prevented?

Were patients blinded?

Were healthcare providers blinded?

Were data collectors blinded?

Were outcome assessors blinded?

Were data analysts blinded?

Definitely yes

Probably yes

Probably no

Definitely no

Was loss to follow-up (missing outcome data) infrequent?

Definitely yes

Probably yes

Probably no

Definitely no

Are reports of the study free of selective outcome reporting?

Definitely yes

Probably yes

Probably no

Definitely no

Was the study apparently free of other problems that could put it at a risk of bias?

Definitely yes

Probably yes

Probably no

Definitely no

Overall risk of bias

If applicable/necessary, per outcome measure

LOW

Some concerns

HIGH

30 mg/m2

Mashhour, 2020

Probably yes;

Reason: With the aid of a randomization table, patients were randomly assigned 1:1 into two arms ( Arm A: low dose

cisplatin and Arm B: high dose cisplatin).

No information;

Probably no;

Reason: No details were provided about blinding, but it is difficult to blind patients to the frequency of cisplatin infusions. Also, patients in the three-weekly group received additional supportive treatment.

Probably yes;

Reason: all patients were included in the analysis of adverse events. It was not explicitly described how many patients were included in the analysis of loco-regional control and tumour response.

Probably yes;

Reason: Outcomes listed in the methods section were all reported. However, this selection of outcomes could not be compared against a trial registration or study protocol.

Probably yes;

Reasons: no other problems were noted.

Some concerns (recurrence, adverse events)

Sahoo, 2017               

No information;

No information;

Probably no;

Reason: No details were provided about blinding, but it is difficult to blind patients to the frequency of cisplatin infusions.

Probably yes;

Reason: One patient in the control group was lost to follow up (7%)

Probably yes;

Reason: Outcomes listed in the methods section were all reported. However, this selection of outcomes could not be compared against a trial registration or study protocol.

Probably yes;

Reasons: no other problems were noted.

Some concerns (locoregional control, adverse events)

Noronha, 2018

Definitely yes;

Reason: Immediately before the start of CRT, patients were stratified by T stage (T0, T1, or T2 v T3 or T4), N stage (N0 or N1 v N2 or N3), and intent of therapy (adjuvant v definitive) and were randomly assigned (computer-generated block random assignment by independent statistician) 1:1 to cisplatin 30 mg/m2 once a week or cisplatin100 mg/m2 once every 3 weeks (on days 1, 22, and 43) with curative radiotherapy.

No information;

Probably no;

Reason: No details were provided about blinding, but it is difficult to blind patients to the frequency of cisplatin infusions.

Probably yes;

Reason: No patients were lost to follow up, a few patients were not included in the analysis of toxicity because they did not start treatment (I: 1% / C: 1%)

Probably no;

Reason: The outcome Quality of life was mentioned as a secondary outcome in the study protocol and the Methods section but no results were reported.

Probably yes;

Reasons: no other problems were noted.

Some concerns

(overall survival, locoregional control, progression-free survival, adverse events)

35 mg/m2

Rawat, 2016

No information;

Reason: After pre-treatment evaluation and staging, patients were randomized into two arms by sequential randomization according to their first visit in the RT department. No specific information about how the allocation sequence was generated.

No information;

Probably no;

Reason: No details were provided about blinding, but it is difficult to blind patients to the frequency of cisplatin infusions.

Probably yes;

Reason: One patient in the three-weekly treatment group was lost to follow up (3%)

Probably yes;

Reason: Outcomes listed in the methods section were all reported. However, this selection of outcomes could not be compared against a trial registration or study protocol.

Probably yes;

Reasons: no other problems were noted.

Some concerns (locoregional control, adverse events)

40 mg/m2

Kiyota, 2022

Probably yes;

Reason: Patients were randomly assigned in a 1:1 ratio to chemoradiotherapy with 3-weekly cisplatin or weekly cisplatin by the minimization method using a random component, with adjustment to balance high-risk

factors for recurrence and institution

Definitely yes;

Reason:

Investigators or subinvestigators must confirm that a patient fulfills all of the eligibility criteria and does not meet any of the exclusion criteria, and then register the patient via the JCOG Web Entry System. Details of the randomized assignment method will not be disclosed to the investigators at participating institutions.

Definitely no;

Reason: open-label study. It is difficult to blind patients to the frequency of cisplatin infusions.

Definitely yes;

Reason: all patients were included in the survival analysis, only a few patients did not receive cisplatin (I: 5% / C: 2%) and were excluded from the toxicity analysis

Definitely yes;

Reason: Outcomes listed in the methods section were all reported and were in accordance with the study protocol.

Probably yes;

Reasons: no other problems were noted.

LOW

(OS, recurrence, disease-free survival, adverse events)

Nanda, 2019

Probably yes;

Reason: Patients were prospectively randomized to two arms using

randomization table.

No information;

Probably no;

Reason: No details were provided about blinding, but it is difficult to blind patients to the frequency of cisplatin infusions.

Probably yes;

Reason: One patient in the weekly treatment group was lost to follow up (3%)

Probably yes;

Reason: Outcomes listed in the methods section were all reported. However, this selection of outcomes could not be compared against a trial registration or study protocol.

Probably yes;

Reasons: no other problems were noted.

Some concerns (overall survival, tumour response, locoregional control, disease-free survival, adverse events)

Nair, 2017

Probably yes;

Reason: Patients were randomized into either Arm A or Arm B using a computer‑generated randomization chart.

No information;

Probably no;

Reason: No details were provided about blinding, but it is difficult to blind patients to the frequency of cisplatin infusions.

Probably yes;

Reason: One patient in the weekly treatment group was lost to follow up (4%)

Probably no;

Reason: Outcomes listed in the methods section were all reported. However, the trial registration did not include overall survival, and did include chronic toxicity and quality of life.

Probably yes;

Reasons: no other problems were noted.

Some concerns (overall survival, tumour response, locoregional control, disease-free survival, adverse events)

Tsan, 2012

No information;

No information;

Probably no;

Reason: No details were provided about blinding, but it is difficult to blind patients to the frequency of cisplatin infusions.

Probably yes;

Reason: no patients were lost to follow-up, outcome data were presented for all randomized patients for the outcomes OS, locoregional recurrence-free survival and toxicities. It was not reported how many patients were included in the analysis of quality of life.

Probably yes;

Reason: Outcomes listed in the methods section were all reported. However, this selection of outcomes could not be compared against a trial registration or study protocol.

Definitely no;

Reason: The sample size calculation showed that 371 patients had to be recruited but due to slow recruitment, the trial was stopped after 55 patients were recruited (50 were randomized)

HIGH (overall survival, locoregional recurrence, quality of life, adverse events)