RU2689875C2 - Method for treating oropharyngeal squamous cell carcinoma - Google Patents

Abstract

FIELD: medicine.SUBSTANCE: invention relates to oncology and radiation therapy, and can be used for treating oropharyngeal squamous cell carcinoma. Introducing cetuximab in the starting dose of 400 mg/mfollowed by dose of 250 mg/monce a week. From 8day of treatment with cetuximab, a radiation therapy is conducted daily on 5-day work week from a total dosage of 1.8 Gy to a total dosage of 54 Gy for 6 weeks on a locoregionic region, including regional lymphocytes: peropharyngeal lymph nodes and lymphocoal collectors of the neck to group IV on both sides (CTV2/PTV2). During last 12 days, after SOD 32.4 Gy, additionally with an interval equal to or more than 6 hours, a tumour and metastatic lymph nodes (GTV/CTV1/PTV1) are irradiated daily in amount of 1.5 Gy to SOD 72 Gr.EFFECT: method provides higher rate and degree of primary tumour regression, inhibition of subclinical disseminated metastases by combined radiotherapy and drug exposure to the tumour and metastatic lymph nodes.1 cl, 1 dwg, 2 ex

Description

The invention relates to the field of medicine, namely to Oncology, and can be used in the treatment of squamous cell carcinoma of the oral cavity and pharynx by the combined radiation and drug effects.

There is a method of increasing the effectiveness of radiation therapy for tumors of various localization (RU 2088288 C1), including remote γ-therapy in combination with chemotherapy, in which 5-fluorouracil is administered to the patient from 1 to 5 days daily at a daily dose of 600 mg / m2, then for 7 -9 days every day immediately before irradiation platydiam is administered in a daily dose of 20 mg / m ² . Radiation therapy therapy is started on the 7th day in the mode of dynamic multifractionation: the first 3 days of the fraction of 1.8 Gy twice in 4-6 hours, then 1.2 Gy twice a day in 4-6 hours to the total focal dose 30-32.4 Gy. After a 10–12-day break, treatment is repeated in a similar pattern to a total focal dose (hereinafter referred to as SOD) 60–64.8 Gy.

The disadvantage of this method is that in 40% of cases radiation reactions from the mucous membranes of the oropharyngeal region occur, requiring an unplanned interruption in treatment, which negatively affects its effectiveness. On the other hand, at least 30% of patients suffer from common toxic effects. In addition, this method of chemoradiation treatment, which is quite effective in the case of a primary focus (78.6% of complete resorption for oropharyngeal tumors), is ineffective in affecting regional metastases.

Also of particular interest is the work of Sewit Teckie and co-authors of 2016, in which the authors retrospectively evaluated the results and side effects of radiation treatment of patients with head and neck tumors in hypofractionation mode, including ultrahypofractionation with supplying 8 Gy per fraction. The study included 48 patients with a mean follow-up of 6 to 54.3 months. The average doses were 30 Gy for 5 fractions, whereas in 20 cases a single focal dose (hereinafter - ROD) was 8 Gy. The overall response to treatment was 79%. One-year locoregional control reached 50%. Multifactor analysis showed that the locoregional control was higher when summing up doses of ionizing radiation in a LAVA 6 Gy (p = 0.04). The full response to radiation was also significantly associated with better patient survival (p = 0.01).

At the same time, the side effects were not more pronounced, even with 8 Gy irradiation in the genus. Thus, the researchers emphasize the positive role of hypofractionation (ROD 6 Gy or more) in the treatment of patients with head and neck tumors and suggest further research in this direction.

The prototype adopted the method of chemoradiation treatment of patients with locally advanced head and neck cancer, developed by Pfister DG and co-authors (Concurrent cetuximab, cisplatin, and concomitant stimulation) paradigm. J Clin Oncol 2006).

A pilot phase II study included 22 patients who received cisplatin (100 mg / m ² 1 time per week) and cetuximab (at a starting dose of 400 mg / m ² followed by a dose of 250 mg / m ² 1 time per week) in combination with radiation therapy with the use of boost (local dose escalation directly on the tumor lesion focus, with normal tissue cleansing due to exclusion of regional metastasis from the amount of radiation). Doses of ionizing radiation were delivered by 1.8 Gy per day for four weeks and then by 1.8 Gy + 1.6 Gy boost after 4-6 hours for two weeks to an SOD of 70 Gy. As a result of the use of such an aggressive regimen, good long-term results of treatment were obtained - 3-year overall survival and locoregional control were 76% and 71%, respectively.

However, the study was interrupted at an early stage due to two fatal outcomes during its implementation (1 from pneumonia and 1 from unknown causes) and severe tolerance of treatment in other patients, including myocardial infarction, atrial fibrillation, bacteremia, etc.

Thus, the proposed treatment regimen showed its high efficacy due to the aggressive action of three agents (cetuximab, cisplatin, ionizing radiation) on tumor cells. At the same time, single and cumulative doses of cisplatin and cetuximab in combination with single doses of radiation and a schedule of their joint effects were unacceptable for the viability of normal cells.

The technical result of the invention is to develop a method that increases the rate and degree of regression of the primary tumor, the suppression of subclinical disseminated metastases due to the optimal mode of combined radiation and drug effects on the tumor.

This technical result in the implementation of the invention is achieved due to the fact that, as in the known method, cetuximab is administered in a starting dose of 400 mg / m ² followed by a dose of 250 mg / m ² once a week in combination with radiation therapy.

A feature of the proposed method is that from the 8th day of treatment with cetuximab radiation therapy is carried out daily for a 5-day working week in the locoregional area, including regional lymphoklelektory: pharyngeal lymph nodes and neck lymphocollectors to I-V groups on both sides (CTV2 / PTV2); at the same time, during the last 12 days, after summing up the SOD of 32.4 Gy, an additional irradiation of the tumor and metastatic lymph nodes (GTV / CTV1 / PTV1) is carried out at a rate of 1.5 Gy to the SOD 72 Gy with an interval equal to or more than 6 hours. .

The invention is illustrated by a detailed description, clinical examples and illustration, which depicts the scheme of biological radiation treatment.

The method is as follows (see Fig.):

Cetuximab 1st day. Intravenous administration of cetuximab at a dose of 400 mg / m2 for 120 minutes.

8th day. Intravenous administration of cetuximab at a dose of 250 mg / m ² for 60 minutes.

15th day. Intravenous administration of cetuximab at a dose of 250 mg / m ² for 60 minutes.

The 22nd day. Intravenous administration of cetuximab at a dose of 250 mg / m ² for 60 minutes.

29th day. Intravenous administration of cetuximab at a dose of 250 mg / m ² for 60 minutes.

36th day. Intravenous administration of cetuximab at a dose of 250 mg / m ² for 60 minutes.

43rd day. Intravenous administration of cetuximab at a dose of 250 mg / m ² for 60 minutes.

Radiation therapy 8th-47th day. Radiation therapy in ROD 1.8 Gy × 1 time per day for a 5-day working week per locoregional area of affected structures, including regional lymphocollectories (CTV2 / PTV2) up to SOD 54 Gy.

The 32nd is the 47th day. Daily additional irradiation (with ≥ 6-hour intervals) of the tumor (GTV / CTV1 / PTV1) in the GENUS 1.5 Gy (total GENERIC 3.3 Gy) to SOD 72 Gr.

In the first week, tumor cells are exposed to the targeted drug cetuximab (400 mg / m ² ), which, by binding to the receptors of the epidermal growth factor (EGFR), blocks the process of their phosphorylation. The signal to the cell nucleus stops, which leads to the suppression of cell proliferation, angiogenesis, tumor invasion, metastasis with simultaneous stimulation of apoptosis and increased sensitivity to radiation therapy. In addition, cetuximab contributes to the development of its own killer T cells, which cause lysis of tumor cells.

From the eighth day, the tumor cells are exposed to the dose of radiation necessary for their destruction and death (1.8 Gy), with an increase in antitumor effects after summing 32.4 Gy of SOD due to a local build-up of RPM up to 3.3 Gy to SOD 72 Gy. This radiation dose is acceptable to maintain the viability of normal cells (taking into account the previous mode of classical fractionation of 1.8 Gr × 1 r / day). In addition, the shift of a more aggressive radiation regime to the second half of the course of radiation therapy allows us to count on a less pronounced radiation response due to partial adaptation of normal tissues. As a result of summarizing the enlarged fractions, damage to tumor cells of various degrees - lethal and sublethal. At the same time, the most active tumor cells capable of metastasis are exposed to destructive radiation. At the same time, less active tumor cells become sub- and potentially lethal.

The radio modifying effect of cetuximab is expressed in blocking the recovery of sub-and potentially lethal damage in a tumor, which ultimately leads to increased radiation destruction of the tumor. Cetuximab, which does not have such toxic properties, taking into account its half-life of 70-100 hours, continues to be administered once every 7 days at a dose of 250 mg / m ² in order to maintain its effective concentration and preserve the above-described effects in full. Further escalation of the drug dose is limited by possible allergic reactions and pronounced disorders of the biology of the skin and mucous membranes. This combination of radiation and drug treatment with an increase in SOD up to 72 Gy with a reduction in the total duration of treatment up to 6 weeks leads to a significant increase in the antitumor effect.

Thus, the proposed method uses two mutually complementary methods of radio modification: cetuximab and unconventional fractionation of the dose of radiation exposure with an intense effect on the tumor array.

The inventive method has been successfully tested for the treatment of patients with locally advanced tumor lesions of the oropharyngeal region: squamous cell carcinoma of the oral mucosa, pharynx and tongue.

Example 1

Patient G., 60 years old. admitted with a diagnosis of Cancer of the oropharynx (right palatine tonsil) IV degree. cT2N2bM0. A history of 36 years ago, lymphadenectomy was performed on the neck to the right of lymphadenitis. The patient considers herself a patient since November 2016, when she noted pain in the throat when swallowing. Received without effect symptomatic therapy from the ENT doctor at the place of residence about the exacerbation of tonsillitis. In January 2017, an additional examination revealed a neoplasm of the oropharynx and the patient was referred to an oncologist. Independently appealed to the Moscow Research Institute of PA Herzen, where the real diagnosis was established and morphologically confirmed. Histological examination: biopsy from the formation of the right palatine tonsil: particles of the mucous membrane with a cover of a multi-layered flat non-thorny epithelium, in one of the particles with a picture of squamous carcinoma in situ and foci of the onset of invasive growth. Histological examination: biopsy from the formation of the submandibular region on the right: a fragment of fibrous tissue with lymphocytic infiltration and squamous non-squaring cancer complexes. Cytological examination of the material from the formation of the submandibular region on the right - cytogram of squamous cell carcinoma with a tendency to keratinization. IHH (p16 expression): an intense positive reaction was detected in all squamous cell carcinoma cells.

Asymmetry of the face is not. Trism is not. Mimic tests performed satisfactorily. Speech is not broken. In the right half of the oropharynx, along the back wall, a tumor is determined, of mixed growth, tight-elastic on palpation, 2.5 × 3 cm in size. In the / 3-neck right postoperative scar with no signs of inflammation is determined. Marked scar deformity in the upper third of the neck to the right. On the right side of the neck, single nodes are defined, up to 1.5 cm in size, dense on palpation, partially mobile. On the left neck without focal pathology.

Endoscopy: In the area of the right amygdala niche, a small-bumpy infiltration of the right palatine tonsil is defined in a bright pink color, protrudes into the lumen of the oropharynx, up to 1.5 cm in size. The posterior palatine arch is not visually altered. Left symmetric sections without features. The root of the tongue is symmetrical, anatomical, elastic, with no signs of tumor infiltration. The epiglottis of normal shape and size. All elements of the larynx are preserved, clearly visualized, and the mucous is smooth. Both throat mobile, phonation. Podskladochny department free. Conclusion: oropharyngeal artery with a lesion of the right palatine tonsil.

MRI with contrast enhancement: Right posterior wall of the oropharynx on the right, narrowing its lumen on the right and causing a mildly pronounced deviation of the right palatine tonsil, defines a submucosal multi-chamber cystic formation of an irregularly rounded shape, with clear, even contours, with MP-signs of pseudo-capsula, measuring about 13 × 23 × 35 mm, localized on the anterior surface of the long muscles of the neck and head at the level of the vertebral bodies of C3, C2, and partially adjacent parts of the tooth-like process of C2 vertebra, without convincing MP-signs of proliferation tions in the projection of the sympathetic trunk. In the upper-right portions of the neck area, along the lower medial contour, intimately adjacent to the right parotid salivary gland at the level of the vertebral body of the northwest and adjacent parts of the C2 body, compressing the gland, a multi-chamber cystic-solid formation of an irregularly rounded shape, with clear, even contours, is determined with MP - signs of pseudocapsules, dimensions about 21 × 20 × 23 mm. The right internal carotid artery and the right internal jugular vein are intimately adjacent to the medial contour of the formation in the projection of the course of the right hypoglossal, accessory and vagus nerves, without convincing MP signs of involvement of the above-described nerves. The internal jugular vein is compressed by education. Enlarged lymph nodes and destruction of bone structures at the studied level were not detected. After administration of the contrast agent (Magnevist 0.2 ml / kg body weight), no adverse reactions to the administration were noted. Its intensive and non-uniform accumulation is determined by the two formations described above. Other sites of its pathological accumulation are not revealed. Conclusion: MP-picture under the mucous multi-chamber cystic formation on the right back of the oropharynx without convincing MP-signs of the spread of education (multi-chamber cyst?) In the projection of the sympathetic trunk, the picture of the multi-chamber cystic-solid formation in the upper-right parts of the neck along the lower medial contour right parotid salivary gland (altered lymph node ?, right adenoma of the right parotid salivary gland?) without convincing MP-signs of involvement in the process of the right sublingual, secondary and the vagus nerve.

Ultrasound: In the right submandibular region in the area of the scapula, at least three formations of reduced echogenicity to 24 × 14 × 24 mm are visualized. In the left submandibular region focal pathology was not detected. Hyperplastic lymph node up to 8 × 4 × 7 mm is visualized in the structure of the posterior process of the right parotid salivary gland. In the neck area, the hyperplassed lymph nodes of the largest sizes are visualized: in the upper third to the right to 10 × 4 × 12 mm, in the lower third to the left to 12 × 3 × 5 mm.

A 5-day course of biobeam therapy using cetuximab according to the above scheme was carried out up to SOD72 Gr for the primary tumor area and metastatic lymph nodes and SOD54 Gr for the loco-pharyngeal loco-pharyngeal lymph node and I-V neck lymphocollector of groups I and V on both sides. At the time of completion of treatment, resorption of the exophytic component of the tumor was noted.

The treatment was carried out with a 7-day break in treatment at the peak of radiation reactions. At the end of treatment, side effects in the form of epitheliitis II Art. CTC AE 4 versions of severity on the part of the pharyngeal mucosa, acne-like rash, I st. CTC AE 4 versions and dermatitis I Art. CTC AE 4 versions on the neck on both sides). Food through the mouth in full. According to the assessment of quality of life, the tolerability of the treatment is satisfactory.

The patient was discharged under the supervision of the place of residence.

At follow-up at 2 months - with no signs of relapse, regional and distant metastasis, as well as side effects of previous treatment, except for xerostomia, I st. CTC AE 4 versions. Left under observation. Currently no signs of relapse for 12 months.

Example 2

Patient Y., 47 years old, was admitted with a diagnosis of Cancer of the oropharynx (root of the tongue), stage III. CT3N0M0. The patient considers herself a patient since November 2015, when, under the control of an otolaryngologist at the place of residence, she received symptomatic therapy for chronic tonsillitis with a temporary positive effect. In the summer of 2016, pains of a whining character appeared in the area of the root of the tongue, aggravated by swallowing. In November 2016, due to an increase in complaints, as well as the appearance of interference with swallowing, I independently referred to an oncologist at the place of residence. Suspected malignant disease of the root of the tongue. Independently appealed to the Moscow Research Institute of PA Herzen, where the real diagnosis was established and morphologically confirmed. Histological examination - biopsy from a tumor of the root of the tongue - particles of the mucous membrane with a cover of flat epithelium, lymphoid basis, areas of growth of undifferentiated cancer with high mitotic activity. An immunohistochemical study is needed to clarify the histogenesis of a neoplasm. IGH of 12/21/2016 from CD 45, CK 5/6, CD 20, CD 3, BCL2, BCL 6, CD 10, PAX 5, MUMI, CD 4, CD 8, Ki67, Cytokeratin (AE 1 / AE3): B tumor cells reaction with SC 5/6 negative. They revealed a positive reaction with cytokeratin. With the rest of the markers, the reaction in the tumor cells is negative. There is a very large admixture of CD 45 positive lymphoid cells. Among the tumor cells, Ki 67 positives are detected in very large numbers. Cytological examination of oropharyngeal tumors - cytogram of squamous non-squamous cancer. Cytological examination of punctate l / w in / 3 neck on the right - cytogram of lymph node hyperplasia. Cytological examination of punctate l / w in / 3 of the neck on the right - the cellular composition of the lymph node. IHH (p16 expression): an intense positive reaction was detected in all cells of the tumor.

Asymmetry of the face and neck is not. Mimic tests performed satisfactorily. Trism is not. Speech is not broken. There is no language deviation. In the area of the root of the tongue on the right, a dense consistency tumor is determined by palpation, measuring 4.0 × 3.5 cm, with a partial transition beyond the middle line and involvement of the left sections of the tongue root. The tumor extends to the lateral wall of the oropharynx on the right in the lower pole of the tonsil. In the upper third of the neck, on the left and in the submandibular regions, on both sides, single knots of dense elastic consistency up to 1.5 cm in diameter, moving relative to the surrounding tissues, are determined. In the rest of the neck without focal pathology.

корня языка определяется усиленный, извитый подслизистый сосудистый рисунок на фоне гладкой блестящей слизистой. Надгортанноглоточная складка не изменена. Левые симметричные отделы без особенностей. Надгортанник обычной формы и размеров. Грушевидные синусы свободны с обеих сторон. Гортань все три отдела сохранены, слизистая гладкая, обе

подвижны. Трахея без особенностей. Заключение: cr правой 1/2 корня языка, эндофитная форма роста.Endoscopy: The root of the tongue is elastic, mobile. With retrograde examination in the back 1/3 of the right

the root of the tongue is determined by the reinforced, convoluted submucous vascular pattern on the background of a smooth shiny mucosa. The epiglottic fold is not changed. Left symmetric sections without features. The epiglottis of normal shape and size. Pear-shaped sinuses are free on both sides. Larynx all three departments saved, mucous smooth, both

are mobile. Trachea without features. Conclusion: cr right 1/2 root of the tongue, endophytic growth form.

MRI of the head and neck with intravenous contrast enhancement: The lingual on the right and the right palatine tonsils are enlarged due to the section of the modified MR signal (hyperintensive on T2 VI and STIR, hypointensive - on T1 VI) extending to the root of the tongue, 30 × 28 × 45 mm, deforming the lumen of the oropharynx. After the injection of a contrast agent, an intensive and uneven accumulation of the latter is noted, mainly by the peripheral sections with a visualized, hypointense central formation measuring 26 × 20 × 25 mm. Along the anterior and posterior edge of the sternocleidomastoid muscles, mainly to the right, enlarged lymph nodes are measured in sizes from 9 mm to 42 × 12 mm.

Ultrasound of the neck: In a / 3 neck on the right (1/2) a lymph node with an uneven contour of a heterogeneous structure measuring 19.5 × 16 × 27 mm (puncture) is determined. In cf. / 3 and in / 3 of the neck, lymph nodes with preserved structure without signs of atypia are defined on the right side with dimensions up to 11 × 5 mm, to the left up to 10 × 4 mm.

A course of bioradiation was performed using cetuximab according to the above scheme up to SOD 72 Gy for the primary lymph node tumor and SOD54 Gy for the locoreopharyngeal locoregional region, including the pharyngeal lymph nodes and lymph collectors of the neck of the Ib-IV groups on both sides.

The treatment was carried out with a 7-day break in treatment at the peak of radiation reactions. At the end of treatment, side effects in the form of epitheliitis III Art. CTC AE 4 versions of severity on the part of the mucous membranes of the mouth and pharynx, acne-like rash, II Art. CTC AE 4 version and dermatitis II Art. CTC AE 4 versions on the neck on both sides. Food through the mouth in full. According to the assessment of quality of life, the tolerability of the treatment is satisfactory.

The patient was discharged under the supervision of the place of residence.

At follow-up at 2 months - with no signs of relapse, regional and distant metastasis, as well as side effects of previous treatment, except for xerostomia, I st. CTC AE 4 versions. Left under observation. Currently, no signs of relapse for 14 months.

Using the proposed method in the clinic allows you to achieve a cure for the patient with minimal side effects in contrast to the known chemo-radiotherapy regimens, namely: regression of the primary tumor and suppression of subclinical disseminated metastases due to the optimal mode of combined radiation and drug effects on the tumor.

Claims (1)

A method for treating squamous cell carcinoma of the oral cavity and pharynx, including the administration of cetuximab in a starting dose of 400 mg / m ² followed by a dose of 250 mg / m ² 1 time per week in combination with radiation therapy, characterized in that radiation is administered from day 8 of treatment ROD 1.8 Gy daily for a 5-day “working week” up to an SOD of 54 Gy per locoregional area, including regional lymphoklelektorny (CTV2 / PTV2), while in the last 12 days, after summing SOD 32.4 Gy with an additional ≥6 an additional irradiation of the tumor is carried out every hour (GTV / CTV1 / PTV1) in RPM ODS 1.5 Gy to 72 Gy.

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