Keywords unresectable oral cancer - OMCT - targeted therapy - head and neck squamous cell carcinoma
- recurrence
Case Presentation
A 70-year-old lady presented with an ulcer in her right cheek and swelling over the
left side of her lower neck and upper chest wall. She was previously operated on two
times for carcinoma buccal mucosa on the same side. The first incident was 20 years
back. She had also received adjuvant radiotherapy. The second incident was 1 year
ago and underwent segmental hemimandibulectomy and reconstruction with a pectoralis
major myocutaneous (PMMC) flap followed by adjuvant radiotherapy.
On current examination, there was a 1.5 × 2cm ulcer over the previously operated right
buccal mucosa and a 4 × 3.5cm hard fixed swelling over the contralateral supraclavicular
region extending over the clavicle and upper chest wall. Biopsy from the buccal mucosa
lesion and fine-needle aspiration cytology from the left nodal mass was suggestive
of moderately differentiated squamous cell carcinoma. The positron emission tomography-computed
tomography (PET-CT) showed uptake in the right buccal mucosa and bulky hypermetabolic
contralateral left cervical level III, IV, and supraclavicular conglomerate lymph
node mass adherent to the medial end of the clavicle, sternum, and upper chest wall
([Figs. 1A ]
[1B ]
[2A ] and [2B ]). There was no other distant metastasis. In view of their unresectability and multiple
recurrence status, she was planned for chemotherapy by a multidisciplinary tumor board.
Having a good disease-free interval and no distant metastasis, she was planned for
reassessment for surgery. She was started on targeted triple-agent therapy including
cetuximab, paclitaxel, and carboplatin in the titrated dosage of 325 mg, 120mg, and
130mg weekly, respectively. The challenge during chemotherapy was the tolerability
and completion of treatment because of old age.
Fig. 1 (A , B ) Axial and coronal positron emission tomography-computed tomography sections, respectively,
showing disease uptake.
Fig. 2 (A , B ) Axial and coronal computed tomography sections, respectively, showing lymph node
mass (the arrow and the circle are depicting the disease).
The patient completed nine divided cycles of chemotherapy without any significant
toxicity. She had a complete clinical response in the right buccal mucosa and contralateral
lymph node mass at the end of chemotherapy. The response assessment, PET-CT, and CT
scans suggested interval resolution in size in the primary site and the number and
size of contralateral lymph node mass ([Figs. 3A ]
[3B ]
[4A ] and [4B ]). Given the excellent response, she was planned for excision of the right buccal
mucosa lesion and contralateral lymph node mass. Considering her age, there were two
challenges during surgery, including reconstruction at the primary site and the extent
of resection at the contralateral neck and chest wall mass. Because of old age and
the long duration of surgery, we did not plan any free flap reconstruction, which
was the ideal option considering previous surgery and previous reconstruction with
PMMC flap. We performed a completion hemimandibulectomy and a pedicled latissimus
dorsi flap was used for reconstruction. The contralateral neck mass clearance was
challenging because of extensive fibrosis due to chemotherapy. The left internal jugular
vein was ligated. The lymph node mass was cleared from the base of the neck, medial
end of the clavicle, and upper chest wall to achieve R0 resection. The patient developed
a postoperative chyle leak, which was managed with surgical exploration in the neck
and ligation of the chyle duct posterior to the left common carotid artery. The patient
was recovered without any other complications.
Fig. 3 (A , B ) Axial and coronal positron emission tomography-computed tomography sections, respectively,
showing lesser disease uptake compared with the previous scans.
Fig. 4 (A , B ) Axial and coronal computed tomography sections, respectively, showing partial response
compared with the previous scans (the arrow and the circle are depicting the disease).
The histopathology was reported to be ypT1N0M0. The patient was started on oral metronomic
chemotherapy (OMCT) that comprised celecoxib 200mg twice a day and methotrexate 15 mg/m2 once weekly, which continued for 18 months. At the end of 24 months of follow-up,
the patient has remained disease free.
Discussion
A high incidence of locoregional recurrences in oral cavity cancers (OCC) following
definitive surgery and adjuvant radiotherapy remains the biggest challenge leading
to treatment failures[1 ] Recurrent OCC displays an aggressive and invasive form of their preceding counterparts.
In one-third of OCC, it usually presents as clinically occult ipsilateral or contralateral
cervical node metastasis due to freely communicating lymphatics across the midline
allowing for spread from the primary subsite to any level of the neck.[2 ] These are responsible for 90% of treatment failures.[3 ]
[4 ]
[5 ] The recurrence rate can vary from 18 to 76% for patients post standardized treatment,
and it is associated with poor survival rates. Literature on OCC also specifies the
median time to recurrence as 7.5 months after treatment, and it can also stretch as
86% of the recurrences occur within 24 months[2 ]
[4 ]
[6 ]
Chemotherapy remains the only option for patients who are deemed unfit for salvage
surgery or reradiation; however, its efficacy is limited by the development of drug
resistance.[1 ] A combination of standard chemotherapeutic drugs with modulating agents to combat
drug resistance has opened a gateway to achieve various therapeutic benefits. With
the growing arena of cancer research, the introduction of targeted agents against
selective sites and molecules responsible for cancer progression has optimized superior
therapeutic activity even in refractory cancers.[1 ]
The agents conventionally chosen in OCCs can be single such as cisplatin or an addition
to the same with cisplatin backbone and paclitaxel (Taxanes) with or without 5 fluorouracil.[7 ] Patients with recurrent OCC can be filtered into two categories—cisplatin-sensitive
or cisplatin–refractory based on prior exposure to the drug in the last 6 months.
According to the EXTREME trial, which demonstrated the effectiveness of cisplatin/5FU/cetuximab,
cisplatin-sensitive groups can also benefit from cisplatin-based combinations. The
KEYNOTE-048 validated a new regimen for cisplatin-refractory cases using pembrolizumab
alone or in combination.[8 ] The TAX 323 and TAX 324 studies demonstrated the efficacy of the triplet regimen,
composed of 5-fluorouracil, cisplatin, and docetaxel, in the management of locally
progressed head and neck cancers.[9 ]
[10 ] Cetuximab is a savior in both cisplatin-sensitive and refractory cases. Even in
a palliative situation, its addition to the standard combination of cisplatin and
5-fluorouracil has improved survival outcomes.[7 ]
[9 ]
[11 ] In situations where cisplatin is ineffective, cetuximab has similarly demonstrated
a response rate of 13% as a single drug.[12 ] However, in developing nations with limited resources, it is not always feasible
to apply this regimen. Hence, OMCT has come into the picture in India as it brings
in a practical yet affordable option.
The OMCT refers to the continuous introduction of low doses of anticancer agents in
the bloodstream. It works by various phenomena including but not limited to antiangiogenesis,
modulating immune response, and promoting tumor cells inactivity[8 ] As per the conventional regimen, patients get a dose of 200 mg of celecoxib twice
daily and 15 mg/m2 of methotrexate once a week until the disease progresses or until severe side effects
arise.[8 ] Glück et al, in their pilot study, reported an effective combination of methotrexate
and celecoxib in head and neck cancer with appreciable efficacy and nominal after-effects.[13 ] In a randomized phase 3 trial of OMCT in head and neck cancer including 422 patients
with newly diagnosed, recurrent, or relapsed head and neck squamous cell carcinoma
conducted at Tata Memorial Center, Mumbai, the median overall survival was found to
be 7.5 (range: 4.6–12.6) months in the OMCT group compared with 6.1 (3.2–9.6) months
in the intravenous cisplatin group. It also concluded a 22% reduction in the risk
of death and was associated with a 50% decrease in the risk of disease progression.[14 ] In a retrospective study by Pandey et al, where adjuvant OMCT was used after completion
of standard surgery and adjuvant chemoradiotherapy/radiotherapy in locally advanced
oral squamous cell cancer, the use of metronomic chemotherapy showed improvement in
disease-free survival (8 vs. 14 months) and overall survival (14 vs. 26 months).[15 ] Pai et al also assessed the effectiveness of OMCT in advanced operable oral malignancies.
A significant improvement in disease-free survival was observed in the group that
received at least 3 months of OMCT in the adjuvant setting without any major toxicities.[16 ]
There were many challenges in the management of our patient. First, the recurrent
nature of her disease despite former R0 resection with adjuvant radiotherapy each
time. However, the patient had a good disease-free interval between the recurrences,
recurrence only at locoregional sites without any distant metastases, and good response
to the treatment pointing toward good disease biology. Second, the age and tolerability
of chemotherapy were of concern. Instead of a conventional docetaxel, cisplatin, fluorouracil
regimen, our patient received paclitaxel, and carboplatin with cetuximab, which was
well tolerated by her.[17 ] Third, major surgery on a 70-year-old lady who had previously undergone two major
resections was a challenge. Current surgery was well tolerated by her including postoperative
chyle leak, which required re-exploration.
Sandwiching the surgery between a combination of chemo-targeted therapy and OMCT has
resulted in control of recurrence to date[14 ]
[15 ] This approach signifies the individualized multidisciplinary treatment for each
case of recurrent head and neck cancer rather than deeming it unresectable or palliative
upfront in this era of precision oncology.
Conclusion
Oral malignancies that are recurrent and incurable can be successfully treated with
personalized therapy that includes surgery, metronomic chemotherapy, and combinations
of chemo-targeted therapy. The factors that favor good biology are good disease-free
interval between the recurrences, recurrence only at locoregional sites without any
distant metastases, and response to the treatment. Hence, “no one size fits all” and
every treatment or therapeutic regimen should be individualized per the patient's
requirement.
