Journal Reading

Neoadjuvant Chemotherapy or
Chemoradiotherapy In Head And Neck Cancer
Review Article
Indian Journal of Cancer | July–September 2008 | Volume 45 | Issue 3
Preetesh Jain, Prabhash Kumar, Vasanth Raghuvir Pai, Purvish Mahendra Parikh
Department of Medical Oncology, Tata Memorial Hospital

Supervisor :
Dr. Yussy Afriani Dewi, dr., M.Kes., Sp.T.H.T.K.L (K)., FICS

Presentant : Tita Puspitasari

DEPT OF OTORHINOLARYNGOLOGY – HNS

SCHOOL OF MEDICINE PADJADJARAN UNIVERSITY
BANDUNG
2019
INTRODUCTION
 Squamous cell carcinoma of the head and neck
(SCCHN) the sixth most common cancer in the
world.
 Distant metastases 10% of newly diagnosed.
 >50% relapse locally, distant site
 Recurrent and/or metastatic → poor prognostic →
median survival time < a year.
 Advanced loco regional disease: Non metastatic
stage III or stage IV, 60% of the diagnosed
patients, 50-60% recurrence within 2 years, and 20-
30% of metastatic disease.
 Loco regional disease : Surgery and/or
radiotherapy (RT).
 Unresectable loco regionally advanced SCCHN :
Combined-modality treatment with chemo
radiotherapy the standard treatment for most
clinicians.
 The Meta-Analysis (MACH-NC): Adding
chemotherapy to radiotherapy in both
definitive and adjuvant postoperative
settings : 12% reduction in the risk of
death, improvement of 4% in 5 years
survival→19% reduction in the risk of death
and 8% improvement in 5-year survival.
 Retrospective : CRT increase systemic
relapse due to a lack of systemic
control→ Induction Chemotherapy (IC)
failed to demonstrate any survival benefit
 MACH-NC analyzed > 5200 patients : Non
significant 2% improvement in overall
survival at 5-year was observed.
 However, significant survival benefits :15
trials using fluorouracil and platin
 2 studies : Survival benefit in inoperable
patients with oropharynx cancer.
Multimodality treatment approaches
1. Surgery followed by adjuvant concurrent
chemo radiotherapy.
Limitations : Poor organ preservation, tumors
unresectable.

2. Definitive concurrent chemo radiotherapy

with surgery as an optional salvage or
completion treatment.
Improved organ preservation.
3. Induction chemotherapy followed by
definitive local therapy.
Decrease the risk of distant failure and a
rapid reduction in tumor bulk responders.
Response to induction → Predict
responsiveness to chemo radiotherapy.
Prolonged treatment and additional
chemotherapy-related toxic effects.
Definitive Chemo Radiotherapy for
Locally Advanced-SCCHN
 Conventional : Once-daily, fractionation
radiotherapy in 2 Gy fractions up to a total of
66 to 70 Gy over 7 weeks in unresectable
SCCHN and sometimes in resectable tumors
instead of surgery.
 Relapse (50% to 60% at 2-year), survival of
40% at 3-year.
 Chemotherapy as an adjunct to loco regional
treatment : Improve local control and survival.
Benefits of concurrent chemo radiotherapy
(1) Local antitumor activity of radiotherapy
is enhanced by the simultaneous use of
chemotherapy as radio sensitizers.
(2) the systemic activity of chemotherapy :
Eradicate possible micro metastases
outside the irradiated field and improve
survival.
Meta-analyses have shown : Concurrent
chemo radiotherapy is superior to other
sequences of chemotherapy and
radiotherapy.
Toxicities Associated with
Chemo Radiotherapy
 Radiotherapy acute toxicities : Mucositis,
stomatitis, and dermatitis.
 Late toxic effects : Chronic xerostomia,
dysgeusia, dysphagia, skin fibrosis, trismus,
feeding-tube dependence, aspiration, and
thyroid dysfunction.
 Acute toxicities longer + increase in patients
receiving chemo radiotherapy.
 Chemotherapy-specific toxicities : Nausea,
vomiting, neuropathy, nephropathy, and
ototoxicity occur with the use of systemic
doses of chemotherapy.
 Biologic Agents in Frontline
Therapy
 Epidermal growth factor receptor (EGFR) → higher
disease stage, lymph node metastasis, and poorer
survival.
 Randomized trial comparing radiotherapy with or
without cetuximab (anti-EGFR monoclonal antibody)
was performed in patients with LA-SCCHN.
 The 2-year loco regional control rates increased from
48% to 56% with concurrent cetuximab radiotherapy.
 Major toxicities : Dermatitis, mucositis, dysphagia, and
acneiform rash
Future Challenges
 Concurrent chemo radiotherapy with a
platinum agent is the current standard
when a chemo radiation regimen is
selected for therapy of LASCCHN.
 Patient selection for primary surgery or
definitive concurrent chemo radiotherapy
becomes more complex.
Postoperative Chemo
Radiotherapy for LA-SCCHN
 Surgery alone may be adequate treatment
for early-stage SCCHN, additional therapy is
required to prevent recurrence.
 Pathologic poor risk factors associated with
higher recurrence rates after surgery→
Positive margins of resection, lymph node
extra capsular extension.
 Adjuvant radiotheraphy reduces reccurance
rate, but 1/3 distant metastasis →
radiosensitizing dose chemotheraphy.
 Cisplatin weekly with radiotherapy : Improvement
survivals over radiotherapy alone (5-year overall
survival (36% versus 13%).
 Distant disease control rates were similar → failure,
20% to 30% metastatic disease.
 Additional effective drugs should be investigated in
the adjuvant setting.
Update of Induction
Chemotherapy: New Roles
 Better delivery of the drug in untreated, well-
vascularized tumors.
 Eradication of the micrometastatic disease.
 Three drug : fluorouracil, cisplatin, and a
taxane → > 90% complete responses in more
than 50% of patients.

358 patient unresectable disease :

DPF : PF → radiotheraphy, PFS 11 : 8,2 months,
OS 18,8 : 14,5 moths
Sequential Therapy
 Combination IC followed by concurrent.
 Classical IC : Effect distant and loco
regional disease.
Toxicity with IC is usually transient, but IC
does require a longer course of therapy.
 CRT increases loco regional dose intensity
in order to increase loco regional control.
Ineffective sistemic theraphy, significant
local and systemic toxicity.
 Machtay et al.
Two cycles of carboplatin and paclitaxel 200
mg/m2, followed by re-evaluation.
Patients with major response continued definitive
radiotherapy (70 Gy over seven weeks) plus
concurrent once-weekly paclitaxel (30 mg/m2/wk).

 Vokes et al,
Six weekly cycles of intensive carboplatin and
paclitaxel (CP)
followed by chemo radiotherapy with paclitaxel,
hydroxyurea, 5-FU, and radiotherapy twice a day
every other week.
With a median follow-up of 28 months, the 3-year
overall survival rate and progression free survival was
70% and 80%, respectively.
 Cmelak
Paclitaxel and carboplatin followed by CRT
with carboplatin and paclitaxel. The 1 and
2-year-event free survival was 72% and 57%.
Integration of Novel Agents in the
Sequential Approach
 Cetuximab combination with platinum in
metastatic SCCHN, and in combination with
radiotherapy in locally advanced head and
neck cancer.
 Randomized 424 patients with loco regionally
advanced SCCHN to receive high-dose
radiotherapy alone or high-dose radiotherapy
plus weekly cetuximab → median control 24,4
moths : 14,9 months, distant metastase 1-2
years similiar, median OS 49 months : 29,3
months.
 Eastern Cooperative Oncology Group :
Cetuximab combination with weekly
Carboplatin + Paclitaxel as IC → CRT in
operable patient.
 60 % Complete patologic response, 100 %
after chemoradiotheraphy
Conclusion
 Controversy still exists regarding the
composition of the standard regimen.
 Consider that the role of chemotherapy is
to sensitize local and regional disease to
the effects of radiotherapy.
 The future role of CRT in combination with
cetuximab should be defined.