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\begin{document}

\title{A PHARMACOLOGICAL REVIEW ON HEAD AND NECK CANCER}



\author[1]{Mahesh Pavan Kontheti}%
\author[1]{Upajna Vamaraju}%
\author[1]{Navya Deepika  Burreddy}%
\author[1]{Rushi Naidu Tarra}%
\affil[1]{Affiliation not available}%


\vspace{-1em}



  
  \date{May 24, 2024}


\begingroup
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\selectlanguage{english}
\begin{abstract}
Head and neck cancer are a group of cancers of the mouth, sinuses, nose
or throat, where smoking is considered a major risk factor. Symptoms may
appear in mouth, sinuses, nose or throat and include a sore or lump that
doesn't heal, a persistent sore throat, trouble swallowing and changes
in the voice. Prognosis in this type of cancer generally depends on the
size of tumor, primary site, causative factor, and presence of local or
distant metastases. In general, the prognosis is favourable if diagnosis
is early and treatment is timely and appropriate. Treatment includes
surgery, radiation therapy or chemotherapy. Staging of tumor can be done
using TNM classification and the can be evaluated through RECIST
guidelines. Removing risk factors is very much important in preventing
this type of cancer, and patients should stop the usage of tobacco and
limit alcohol consumption.%
\end{abstract}%



\sloppy


A PHARMACOLOGICAL REVIEW ON HEAD AND NECK CANCER

Dr. Tarra Rushi Naidu\textsuperscript{1}, Kontheti Mahesh
Pavan*\textsuperscript{2}, Vamaraju Upajna\textsuperscript{2}, Burreddy
Navya Deepika\textsuperscript{2}

1 Associate professor in Avanthi Institute of Pharmaceutical Sciences,
cherukupally, Vizianagaram.

2 Student of Avanthi Institute of Pharmaceutical Sciences, Cherukupally,
Vizianagaram.

*Corresponding author:

Kontheti Mahesh Pavan,

Contact: 9494579837;

E-mail: maheshpavankontheti@gmail.com

Andhra Pradesh, India

ABSTRACT: Head and neck cancer are a group of cancers of the mouth,
sinuses, nose or throat, where smoking is considered a major risk
factor. Symptoms may appear in mouth, sinuses, nose or throat and
include a sore or lump that doesn't heal, a persistent sore throat,
trouble swallowing and changes in the voice. Prognosis in this type of
cancer generally depends on the size of tumor, primary site, causative
factor, and presence of local or distant metastases. In general, the
prognosis is favourable if diagnosis is early and treatment is timely
and appropriate. Treatment includes surgery, radiation therapy or
chemotherapy. Staging of tumor can be done using TNM classification and
the can be evaluated through RECIST guidelines. Removing risk factors is
very much important in preventing this type of cancer, and patients
should stop the usage of tobacco and limit alcohol consumption.

KEY WORDS: head and neck cancer, squamous cell carcinoma, tobacco use,
lesion, chemotherapy.

INTRODUCTION:

Cancers of the upper nasopharyngeal tract which are collectively known
as head and neck cancers, arise from many of sites. These tumours cause
major problems in management, and skilled healthcare team is necessary
to achieve the highest level of service and research. Previously,
surgery and radiotherapy have been widely used in the treatment while,
chemotherapy is now increasingly employed but not yet fully established.
Current research efforts majorly concentrate on defining the importance
of chemotherapy and determining the advantage of unconventional
radiation approaches\textsuperscript{1}. These malignancies develop in
areas responsible for eating, talking, and breathing and are associated
with substantial morbidity and mortality despite advances in treatment.
We need to understand the advances in head and neck cancer (HNC)
management to study the patients across the cancer care continuum.
Additionally, the recent Coronavirus Disease 2019 (COVID-19) pandemic
has necessitated adaptations to HNC care to accommodate mitigation of
COVID-19 risk and ensure timely treatment\textsuperscript{2}. Smoking
and alcohol abuse are major risk factors for the development of this
disease. Majority of the cases are squamous cell carcinomas, and it
arises in the oropharynx, oral cavity, hypopharynx, or larynx. HNSCC
develops as a result of the both environmental factors and genetic
inheritance, and is thus called multifactorial. Human papillomavirus
(HPV) is also considered risk factor in about 25\% of the disease. Now,
there are many surgical procedures, which include robotic surgery, that
decreases the tracheotomy rate, and allows a faster oral swallowing
recovery and shorter hospital stay\textsuperscript{3}.

EPIDEMIOLOGY:

Head and neck squamous cell carcinoma (HNSCC) include mucosal squamous

cell carcinomas of the upper aerodigestive region and represents more
than 65,000 new cancer cases and 14000 plus cancer-related deaths in the
United States annually. Head and neck cancer is mainly associated with
smoking and alcohol consumption and have been decreasing in incidence in
recent years. In contrast, the primary cause for oropharyngeal SCC is
now HPV. The incidence of HPV-associated OPSCC has been exponentially
rising, with an annual increase of 3.8\% in Caucasian men between for
about two and half decades since 1992. The incidence of HPV-positive
OPSCC has become more common than HPV-related cervical
cancer\textsuperscript{4}. A majority of patients can be cured with
surgery or radiation with early-stage SCCHN, and those with aggressive
disease and those with locally advanced stages, there are mor chances
for the cancer to recur\textsuperscript{5}. There are about 350,000
deaths yearly which are associated with SCCHN worldwide. In the United
States, head and neck cancer cases

accounted for more than 40.000 new cancer cases in 2007, corresponding
to 3\% of all

new cancer diagnoses in the country. Although there are several advances
in treating this cancer, approximately 11,210 head and neck cancer
related deaths have been noted during 2007 in the United
States\textsuperscript{6}.

ETIOLOGY \& PATHOGENESIS:

Tobacco smoking is considered as a major risk factor for HNSCC, and this
is associated with the intensity and duration of smoking habit. The
cigarette contains nitrosamines and polycyclic hydrocarbons carcinogens
elements that cause toxic effects to genes and therefore may increase
the risk of occurrence of disease. These factors are responsible for the
alterations in the molecular profile of the individual and cause gene
mutations. Alcohol acts as a medium to enhance exposure of the mucosa to
carcinogens, thereby increasing cellular uptake of these cancer-causing
compounds. The acetaldehyde, can form DNA adducts, which interfere with
DNA synthesis and repair. According Marur \& Forastiere, tobacco intake
along with alcohol consumption increases the HNSCC the risk to 40
times\textsuperscript{7}. Figure 1 represents the sites of occurrence of
head and neck cancer.\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image1/image1}

\end{center}
\end{figure}

Figure 1: Representation of regions of head and neck
cancer\textsuperscript{8}

RISK FACTORS:

\textbf{Tobacco, alcohol, pan:}

Cigarette smoking and excessive alcohol consumption represent the most
important factors for the development of HNSCC and they have a
synergistic effect. Reverse smoking is a technique in which the lighted
end of the cigarette is kept inside the mouth while smoking is a habit
practiced in some areas of India and South America, leads to HNSCC of
the hard palate. Chewing of the ``betel quid', which is popularly known
as `pan' is also considered an important risk factor for the development
of HNSCC of the buccal mucosa and the mandibular buccal sulcus. The
habit of betel quid chewing is highly practiced in countries such as
India, Pakistan, Bangladesh and Sri Lanka. Although alcohol is not
considered to be a carcinogenic agent, heavy alcohol intake along with
tobacco use acts synergistically to cause HNSCC.

\textbf{Human papilloma virus (HPV):}

Infection with high-risk HPV types (HPV 16, 18. 31 and 33) also

play a role in the pathogenesis of OPSCC. Specifically, HPV type 16
accounts for \textgreater{} 90\% of HPV associated cancer. The shift in
biology to HPV over tobacco associated SCC accounts for the improvement
in overall survival rates in HNSCC patients

\textbf{Other contributing factors:}

Ultraviolet light radiation associated with chronic sun exposure is
linked to the development of SCCs on the lips. Other less known risk
factors for HNSCC include iatrogenic immunosuppression for solid organ
or bone marrow transplant, family history of HNSCC, diet poor in
antioxidants and increasing age\textsuperscript{9}.

\textbf{Diagnosis and staging:}

To determine tumor extension, diagnostic imaging is needed:

-Imaging diagnosis before a biopsy avoids misinterpretation from
anatomical distortion.

-Computed tomography (CT scan) and Magnetic Resonance Imaging (MRI sacn)
are also used in diagnosis. MRI can be beneficial than CT for evaluating
tongue, perineural spread, invasion to skull base and intracranial
extension.

-CT of chest is preferred, or X-ray is done in early stages.

-Positron emission tomography-CT (PET-CT) is useful in diagnosis of node
and metastases and some primary tumors. It is recommended in patients
with stage III and IV disease when definitive treatment is indicated.

-Esophagoscopy is carried out in case of dysphagia.

-Histological evaluation is mandatory by primary tumor biopsy or fine
needle aspiration (FNA) of lymph nodes.

-Functional evaluation: actions like chewing, swallowing, breathing,
odontology and nutritional status are assessed.

-Special evaluations if needed: psychological and social situation
assessmet, cessation of smoking or alcohol
dependence\textsuperscript{10}.

The diagnosis of HNSCC can be established by biopsy of the primary
tumour. The biopsy method depends upon the location of the tumor.
Primary tumours are approached incisional biopsy or excisional biopsy,
whereas the suspicious cervical neck mass should be diagnosed with the
help of fine needle aspiration (FNA).

A well-differentiated tumour would be similar to the stratified
epithelium, with mature-appearing cells organizing into layers with
irregular keratinization. A poorly differentiated tumour is
characterized by immature cells with nuclear pleomorphism and atypical
mitoses, with minimal to no organized keratinization. HPV-negative
HNSCCs are moderately or well differentiated, with preservation of
stratification and keratinization, whereas HPV-positive HNSCCs are
poorly differentiated and even display basaloid morphology on
histopathological examination. The histopathological diagnosis of HNSCC
can usually be made using haematoxylin and eosin staining. However, in
the case of poorly differentiated tumours, immunohistochemistry may be
necessary to confirm an epithelial origin\textsuperscript{11}.

TUMOR RESPONSE EVALUATION (RECIST GUIDELINES)

Evaluation of target lesions:

\begin{enumerate}
\tightlist
\item
  Complete Response (CR): Disappearance of all target lesions. Any
  pathological lymph nodes (whether target or non-target) must have
  reduction in short axis to \textless{}10mm.
\item
  Partial Response (PR): At least a 30\% decrease in the sum of
  diameters of target lesions, taking as reference the baseline sum
  diameters.
\item
  Progressive Disease (PD): At least a 20\% increase in the sum of
  diameters of target lesions, taking as reference the smallest sum on
  study (this includes the baseline sum if that is the smallest on
  study). In addition to the relative increase of 20\%, the sum must
  also demonstrate an absolute increase of at least 5 mm. (Note: the
  appearance of one or more new lesions is also considered progression).
\item
  Stable Disease (SD): Neither sufficient shrinkage to qualify for PR
  nor sufficient increase to qualify for PD, taking as reference the
  smallest sum diameters while on study.
\end{enumerate}

Evaluation of non-target lesions:

\begin{enumerate}
\tightlist
\item
  Complete Response (CR): Disappearance of all non-target lesions and
  normalisation of tumour marker level. All lymph nodes must be
  non-pathological in size (\textless{}10mm).
\item
  Non-CR/Non-PD: Persistence of one or more non-target lesion(s) and/or
  maintenance of tumour marker level above the normal limits.
\item
  Progressive Disease (PD): Unequivocal progression (see comments below)
  of existing non-target lesions.
\end{enumerate}

Measurability of tumour:

Measurable Tumour lesions:

Must be accurately measured in at least one dimension (longest diameter
in the plane of measurement is to be recorded) with a minimum size of:

* 10 mm by CT scan (CT scan slice thickness no greater than 5 mm

* 10 mm caliper measurement by clinical exam

* 20 mm by chest X-ray.

Malignant lymph nodes:

To be considered pathologically enlarged and measurable, a lymph node
must be \textless{}15 mm in short axis when assessed by CT scan. At
baseline and in follow-up, only the short axis will be measured and
followed.

Non-measurable:

All other lesions, including small lesions and non-measurable lesions
and these non-measurable include: leptomeningeal disease, ascites,
pleural or pericardial effusion, lymphangitic involvement of skin or
lung, abdominal masses/abdominal organomegaly identified by physical
exam that is not measurable by reproducible imaging techniques.

Special considerations regarding lesion measurability:

Bone lesions.

* Bone scan, PET scan or plain films are not considered adequate imaging
techniques to measure bone lesions. However, these techniques can be
used to confirm the presence or disappearance of bone lesions.

* Lytic bone lesions or mixed lytic-blastic lesions, with identifiable
soft tissue components, that can be evaluated by cross sectional imaging
techniques such as CT or MRI can be considered as measurable lesions if
the soft tissue component meets the definition of measurability
described above.

* Blastic bone lesions are non-measurable.

Cystic lesions:

* Lesions that meet the criteria for radiographically defined simple
cysts should not be considered as malignant lesions since they are
simple cysts.

* Cystic lesions thought to represent cystic metastases can be
considered as measurable lesions. However, if non-cystic lesions are
present in the same patient, these are preferred for selection as target
lesions.

Lesions with prior local treatment:

* Tumour lesions situated in a previously irradiated area, or in an area
subjected to other loco-regional therapy, are usually not considered
measurable unless there has been demonstrated progression in the lesion.
Study protocols should detail the conditions under which such lesions
would be considered measurable.

STAGING OF TUMOR (TNM CLASSIFICATION)

In the TNM system:

\begin{itemize}
\tightlist
\item
  The T refers to the size and extent of the primary tumor
\item
  The N refers to the number of surrounding lymph nodes that have
  cancer.
\item
  The M refers to whether the cancer has~metastasized.
\end{itemize}

When your cancer is described by the TNM system, there will be numbers
after each letter that give more details about the cancer, which
include:

Primary tumor (T)

\begin{itemize}
\tightlist
\item
  TX: Main tumor cannot be measured.
\item
  T0: Main tumor cannot be found.
\item
  T1, T2, T3, T4: Refers to the size and/or extent of the main tumor.
  The higher the number after the T, the larger the tumor or the more it
  has grown into nearby tissues. T's may be further divided to provide
  more detail, such as T3a and T3b.
\end{itemize}

Regional lymph nodes~(N)

\begin{itemize}
\tightlist
\item
  NX: Cancer in nearby lymph nodes cannot be measured.
\item
  N0: There is no cancer in nearby lymph nodes.
\item
  N1, N2, N3: Refers to the number and location of lymph nodes that
  contain cancer. The higher the number after the N, the more lymph
  nodes that contain cancer.
\end{itemize}

Distant metastasis~(M)

\begin{itemize}
\tightlist
\item
  MX:~Metastasis~cannot be measured.
\item
  M0: Cancer has not spread to other parts of the body.
\item
  M1: Cancer has spread to other parts of the body.
\end{itemize}

TNM classification is grouped into following stages:

\begin{itemize}
\tightlist
\item
  Stage 0: Abnormal cells are present but did not spread to surrounding
  tissue. Also called~carcinoma in situ. CIS is not cancer, but it may
  become cancer in future.
\item
  Stage I, Stage II, and Stage III: Presence of cancer. The higher the
  number, the larger the tumor and the more the spread into surrounding
  tissues.
\item
  Stage IV: Spread of cancer to remaining parts of the body.
\end{itemize}

TREATMENT AND PHARMACOLOGY:

By the end of the 20\textsuperscript{th} century, radiation had just
been discovered, and surgical outcomes were of great use due to the lack
of antibiotics and the limitations of anaesthesia. Because of these
reasons, radiation therapy (RT) had been used as a primary treatment for
the first half of

the century. After few decades, due to treatment failures of early RT
techniques, led to the

emergency development of primary surgical treatment for most head and
neck cancers. Subsequent advancements in RT improved cure rates and
decreased treatment failures.

Today, RT remains an important option in early-stage cancers and plays
an

important role in the adjuvant setting. Recently, combinations of
chemotherapy and

RT have been used majorly for advanced-stage cancers, both for primary
and adjuvant

treatment. Finally, targeted molecular therapies have been developed
that bring out new options in managing of HNSCC, which may further
improve survival rates\textsuperscript{12}. Figure 2 represents the
treatment options involving chemotherapy for locally advanced squamous
cell carcinoma of the head and neck.

\textbf{Hosted file}

\verb`image2.emf`  available at \url{https://authorea.com/users/730527/articles/710166-a-pharmacological-review-on-head-and-neck-cancer}

Figure 2: Treatment options involving chemotherapy for locally advanced
squamous cell carcinoma of the head and neck.\textsuperscript{13}

MOST COMMON CHEMOTHERAPEUTIC REGIMENS:

Table 1 represents the most common chemotherapeutic regimens.\selectlanguage{english}
\begin{longtable}[]{@{}lll@{}}
\toprule
chemotherapy & Dose, frequency and no.of cycles & Adverse
events\tabularnewline
Cisplatin (P) & (Every 3 weeks, RT days 1, 22, 43) P: 100 mg/m2 on day 1
& (Grade 3--5 increased frequencies, compared with control arm,
occurring in more than 10\% of patients) Nausea/vomiting (12--40\%)
Neutropenia (13\%) Infection (12\%) Peripheral neuropathy (10\%)
Nausea/vomiting (12--40\%) Neutropenia (13\%) Infection (12\%)
Peripheral neuropathy (10\%)\tabularnewline
Cetuximab & Loading dose: 400 mg/m2 (4--10 days prior to RT)
Maintenance: 250 mg/m2 weekly during RT) & (Grade 3--5 increased
frequencies) Infusion reactions (3\%) Acneiform rash (17\%)
Hypomagnesemia\tabularnewline
TPF (TAX 324) Docetaxel (T) Cisplatin (P) 5-FU (F) & (Every 3 weeks for
3 cycles) T: 75 mg/m2 on day 1 P: 100 mg/m2 on day 1 F: 1000 mg/m2 CI
days 1--4 & (Grade 3 or 4 frequencies) Neutropenia (33\%) Infection
(7\%) Febrile neutropenia (5\%)\tabularnewline
TPF (European) Docetaxel (T) Cisplatin (P) 5-FU (F) & (Every 3 weeks for
4 cycles) T: 75 mg/m2 on day 1 P: 75 mg/m2 on day 1 F: 750 mg/m2 by CI
days 1--5 & (Grade 3 or 4 frequencies) Neutropenia (77\%) Alopecia
(12\%) Infection (7\%) Febrile neutropenia (5\%)\tabularnewline
Cisplatin (P) 5-FU (F) & P: 100 mg/m2 on day 1 F: 1000 mg/m2 by CI days
1--5 & Nausea/vomiting (7--14\%) Hematologic (52--56\%) Infection
(5--6\%) Peripheral neuropathy (1--4\%)\tabularnewline
\bottomrule
\end{longtable}

Table 1: Most common chemotherapeutic regimens\textsuperscript{14}

PHARMACOLOGY OF DRUGS:

CISPLATIN:

\begin{itemize}
\tightlist
\item
  It is hydrolysed intracellularly, producing a highly reactive moiety
  which causes cross linking of DNA. The favoured site is
  N\textsuperscript{7} of guanine residue.
\item
  It is bound to plasma proteins, penetrates tissues and is slowly
  excreted unchanged in urine.
\item
  Its t\textsuperscript{1/2} is about 72 hours.
\end{itemize}

CETUXIMAB:

The inhibitor of EGF receptor is a chimeric monoclonal antibody directed
to the extracellular domain of the receptor.

Binding to the receptor, it prevents signalling across the membrane
resulting in blockade of cell growth, proliferation and metastasis.

DOCETAXEL:

It binds to beta-tubulin and enhances its polymerization.

Microtubules are stabilized and their depolymerization is prevented.
This results in inhibition of normal dynamic reorganization of the
microtubule network that is essential for interphase and mitotic
functions.

FLUOROURACIL (5-FU):

It is converted in the body to the corresponding nucleotide
5-fluoro-2-deoxyuridine monophosphate which forms a covalent ternary
complex with methyl-THFA and thymidylate synthase (TS) resulting in
irreversible inhibition of TS.

It is rapidly metabolized by DPD resulting in plasma
t\textsuperscript{1/2} of 15-20 minutes after i.v
infusion.\textsuperscript{15}

In general, there are 3 main approaches to the initial treatment of
locally advanced disease: (1) concurrent platinum-based chemoradiation,
with surgery reserved for residual disease;

(2) surgery with neck dissection and reconstruction, followed by
adjuvant radiation or chemoradiation, depending on the presence of
adverse risk factors; or

(3) induction chemotherapy followed by definitive chemoradiation or
surgery.

Approximately 60\% of patients with HNSCC present at a locally advanced
stage, in which combined modality therapy with curative intent is
recommended. Data shows that radiation therapy combined with
simultaneous 5-fluorouracil (5-FU), cisplatin, carboplatin as single or
combinations therapy of 5-FU with other drugs results in a increasing
survival rate irrespective the radiation regimen. Cetuximab in
combination with platinum or 5- FU has emerged as a new alternative
regimen for patients who are not treated based on results from the first
line treatment. The data from a phase III trial support the role of
cetuximab plus radiotherapy as an effective treatment option for
patients with advanced HNSCC. Moreover, cetuximab plus radiotherapy led
to significant improvements in locoregional control and these survival
improvements may be maintained over a long time, with a nine-percentage
point advantage for cetuximab plus radiotherapy in the 5-year overall
survival rate, compared with radiotherapy alone\textsuperscript{16}.

CONCLUSION:

Head and neck squamous cell carcinoma is a severe type of cancer where
the survival rates are very less. Improper or negligence in treatment
may lead to fall in lifespan very rapidly. The main culprits of head and
neck cancers are tobacco and excess alcohol intake but, in some cases,
genetic factors and human papilloma virus. Preventive measures are much
more helpful than treating it, which include remission of tobacco and
alcohol intake. Early diagnosis is would be beneficial in increasing
lifespan of the patients. Treating with combination therapy is more
followed when compared to monotherapy.

ACKNOWLEDGEMENT:

We acknowledge the continuous support of Dr. M.B.V Raju(principal) for
successfully completing the work.

CONFLICT OF INTEREST:

There was no conflict of interest.

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