Adjuvant Treatment for

Recurrent Oral Cancer

Diani Kartini

Division of Surgical Oncology, Department of Surgery

Faculty of Medicine University of Indonesia/
Dr. CiptoMangunkusumo Hospital
• HNSCC recurrence remains a difficult condition to treat

• Despite improved means of diagnosis and treatment,

recurrence remains the biggest obstacle to long-term
survival in patients with HNSCC.
• Patients with advanced- stage disease may expect only
a 30% to 60% cure rate

• Depending on site, recurrence rates : 25% - 50%,

 Treatment Goal
• The primary goal of oncologic treatment is either
curative or palliative
• Secondary goals :
- preservation of form and function
- to restore form and function to a degree that a
reasonable quality of life is restored also.
 Treatment of Oral Cancer
• Surgery

• Radiotherapy
• Chemotherapy
• Targetted Therapy
• Immunotherapy ??
 Recurrent Oral Cancer

Several factors guide treatment selection for

recurrent/metastatic head and neck cancer:

Performance status, comorbidities, prior

treatment, symptoms, patient preference and
logistics, and biomarkers.
 Type of Recurrency
Recurrence Location
•Primary alone
•Neck alone
•Primary and neck

Laterality of neck recurrence

•Ipsilateral alone
•Contralateral alone
•Bilateral

Distant metastasis
Sean R. Quinlan–Davidson, MD et al Recurrent oral cavity cancer: Patterns of failure after salvage multimodality
therapy ., 2016
 2014

*Best Supportive Care

 Chemotherapy
• Post operative adjuvant concurent
chemoradiotherapy ( CRT) for patient with high-risk
features
• Post operative adjuvant chemotherapy
• Preoperative concurrent CRT followed by surgery for
advanced resectable patients
• CRT as primary treatment for patients who are unable
to tolerate or unsuited for surgery or as salvage
treatment in the persistent or recurrent disease
setting
• Neoadjuvant chemotherapy
• Palliative chemotherapy
Tahara M and Kirita T. Systemic chemotherapy. In Kirita T and Omura K. Oral Cancer Diagnosis and
Therapy. 2015
 Main Classes of active cytotoxic chemotherapeutic
agents for head and neck squamous cell carcinomas

Class of Agent Examples Main mechanism of action

Platinum Cisplatin, carboplatin Form DNA cross links
Taxane Paclitaxel, Docetaxel Stabilize microtubules to
block M – Phase
Antifolate ( antimetabolite) Methotrexate Inhibit dihydrofolate
reductase (DHFR) during S-
phase
Fluoropyrimidine ( antimetabolite) 5-FU Inhibit thymidylate synthase
(TS) during S-phase
 Targeted Therapy

EGFR Inhibitor have been approved in head and neck cancer

 Epidermal growth factor receptor
• EGFR = ErbB1
• Overexpression of the epidermal growth factor
receptor (EGFR) is recognized in more than 80% of
SCCs
• EGFR levels increase in in advanced stage tumors
and in poorly differentiated tumors.
• Increased EGFR correlates with poorer clinical
outcome

Cohen, Ezra Role of Epidermal Growth Factor Receptor Pathway-Targeted Therapy in Patients With Recurrent and/or
Metastatic Squamous Cell Carcinoma of the Head and Neck J Clin Oncol 2006 24:2659-2665
 Cetuximab
• Cetuximab is a human–murine chimeric
monoclonal antibody against EGFR
220 of 442 eligible patients with untreated
recurrent or metastatic squamous-cell
carcinoma of the head and neck

Adding cetuximab to platinum-based

chemotherapy with fluorouracil (platinum–
fluorouracil) significantly prolonged the
median overall survival from 7.4 months in the
chemotherapy-alone group to 10.1 months in
the group that received chemotherapy plus
cetuximab (p= 0.04).
 2018

First- line cetuximab plus platinum-based chemotherapy is

suitable and well-tolerated for the systemic therapy of
recurrent or metastatic OSCC.

The best overall response and the disease control rates were 46.2 and
67.7%, respectively. The median overall survival and progression-free
survival rates were 12.1 and 7.8 months, respectively.
 Immunotherapy
• The recurrence and metastasis of squamous- cell
carcinoma of the head and neck Immune Evasion

• Expression of the programmed death ligands (PD-L1 and

PD-L2), immunoreceptor facilitating the
immunosuppressive phenotype

Increase tumor growth and reduce survival

human IgG4 anti–PD-1

monoclonal antibody
( Nivolumab, Pembrolizumab
 2016

• June 2014 -August 2015, 240 patients to receive nivolumab

and 121 to receive standard therapy (methotrexate,
docetaxel, or cetuximab).
• The median overall survival was 7.5 mo (95% CI, 5.5 to 9.1)
in the nivolumab group vs 5.1 mo (95% CI, 4.0 to 6.0) in the
group that received standard therapy.
• OS was significantly longer with nivolumab than with
standard therapy (hazard ratio for death, 0.70; 97.73% CI,
0.51 to 0.96; P=0.01)
On January 2016, this trial was amended to permit cross-
over to nivolumab for patients on SOC
 2018

• The objective response rate (ORR) of nivolumab was

significantly better than SOC (13.3 vs. 5.8%, respectively)

• OS nivolumab > IC
• Median OS in the intention- to-treat population was
8·4 mo (95% CI 6·4–9·4) with pembrolizumab and
6·9 mo (5·9–8·0) , p=0·0161)
 Metronomic Chemotherapy
• “metronome”
• regular administration of CHT that results in a constant
low blood level of the drug
• not refer to the mechanism of action of the
antineoplastic drug, but it reflects the frequent
administration of low doses (1/10th–1/3rd of the
maximum tolerated dose [MTD]) of drugs, at shorter
intervals without interruption.

MC inhibiting tumor angiogenesis, stimulating anticancer

immune response and inducing tumor dormancy
 2014

oral celecoxib 200 mg twice daily and oral low dose methotrexate 15
mg/m2 weekly.

Cisplatin MC

p = 0.036
• Patients in the MCT arm had significantly longer PFS
(median 101 days, 95% CI: 58.2– 143.7 days) compared
to the IP arm (median 66 days, 95% CI; 55.8–76.1 days)
(p = 0.014).

• The overall survival (OS) was also increased significantly

in the MCT arm (median 249 days, 95% CI: 222.5–275.5
days) compared to the IP arm (median 152 days, 95% CI:
104.2–199.8 days) (p = 0.02).
 2015

• Metronomic combination of methotrexate and celecoxib failed

to meet its prespecified efficacy limit and should not be used in
these patients as routine.

• The threshold considered : 30% OS at 6 mo, while the proportion

of patients surviving was below this, 26.4% at 6 mo.

Oral metronomic chemotherapy has promising results when

used in a selected cohort of patients but has dismal results in
patients who failed within 6 months of previous treatment.
 Summary
• HNSCC recurrence remains a difficult condition to
treat, requiring consideration of multiple factors and
active partnership with the patient to provide optimal
care

• The treatment of recurrent oral cancer depends on:

Patients’ condition, Previous therapies, Surgeon ability,
The availability of the drugs, Supporting examination,
Multidisciplinary Team
THANK YOU