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ORIGINAL ARTICLE
Year : 2017  |  Volume : 54  |  Issue : 1  |  Page : 16-19
 

Impact of induction chemotherapy to concurrent chemoirradiation over radiotherapy alone in advanced oral cavity


1 Department of Radiotherapy, Cama and Albless Hospital, Mumbai, India
2 Department of Radiation Oncology, Government Medical College and Hospital, Nagpur, Maharashtra, India

Date of Web Publication1-Dec-2017

Correspondence Address:
Dr. V K Mahobia
Department of Radiation Oncology, Government Medical College and Hospital, Nagpur, Maharashtra
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ijc.IJC_166_17

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 » Abstract 

BACKGROUND: Oral and oropharyngeal carcinomas representing about 90% of all oral malignancies are the sixth most common cancers worldwide. Basic modalities of cancer treatment are surgery, radiotherapy, and chemotherapy (CT) either alone or in combination. For squamous cell carcinoma (SCC) patients, induction CT followed by radiotherapy and concurrent CT are effective methods for improving response rates. MATERIALS AND METHODS: Fifty patients with advance stage oral cavity cancer with performance status >60% on Karnofsky performance scale and having no prior exposure to CT, radiotherapy, and surgery were included in the study. CT including bleomycin, methotrexate, and cisplatin was given on day 1 and repeated at an interval of 21 days. After the completion of three cycles, two groups (n = 25 each) were formed. One group was treated with radiotherapy alone and other group of patients treated with radiotherapy and concurrent cisplatin infusion. The patient toxicities and response were evaluated. RESULTS: After completion of induction CT, both the groups responded with almost similar result. Nausea, vomiting, mucositis, and skin reactions during radiotherapy were observed in both groups but comparatively higher in Group “B.” In Group B, 84% (vs. 60% in Group A) of patients showed complete response (CR) after completion of treatment, and out of 13 patients who responded partially to induction CT, 9 patients showed CR after concurrent chemoradiotherapy. CONCLUSION: This study showed the superiority of induction followed by concurrent chemoradiotherapy over induction plus radiotherapy alone in the treatment of advanced oral cavity neck SCC.


Keywords: Concurrent chemoradiotherapy, oral carcinoma, squamous cell carcinoma


How to cite this article:
Rewadkar M S, Mahobia V K. Impact of induction chemotherapy to concurrent chemoirradiation over radiotherapy alone in advanced oral cavity. Indian J Cancer 2017;54:16-9

How to cite this URL:
Rewadkar M S, Mahobia V K. Impact of induction chemotherapy to concurrent chemoirradiation over radiotherapy alone in advanced oral cavity. Indian J Cancer [serial online] 2017 [cited 2020 Apr 5];54:16-9. Available from: http://www.indianjcancer.com/text.asp?2017/54/1/16/219549



 » Introduction Top


Oral and oropharyngeal carcinomas representing about 90% of all oral malignancies are the sixth most common cancers worldwide.[1],[2] Oral cancer is the second most frequent form of cancer in Southeast Asia and also the second most frequent cause of death from cancer among males. One-third of global cases are reported in Southeast Asia.[3] In India, oral cancer ranks the first among male and the third among female population which is related to the use of tobacco chewing in the form of betel quid, tobacco smoking, reverse smoking as well as other factors such as alcohol consumption, low socioeconomic status, poor hygiene, poor diet and viral infections, ill-fitting dentures, and chronic irritation from rough or fractured teeth.[3] Persons exposed to smoking, drinking, and betel quid chewing together are at high risk compared to individuals exposed to any one of these factors.[3] The male:female ratio is 2:1 and the average age of diagnosis is 57.1 years in males and 52.5 in females with the highest prevalence in the sixth decade of life.[4] In Southeast Asia, most cases of oral squamous cell carcinoma (SCC) occur in the buccal and commissural areas of the oral cavity.[4] According to the American Joint Committee on Cancer, the different OC stages and treatment options are:[5]

  • Stage 0: The cancer is in situ (Tis), and there are no regional lymph node and regional metastasis (N0-M0)
  • Stage 1: The cancer is <2 cm in size (T1) without metastasis. The treatment options are surgery and/or radiation therapy. Surgery is the preferential treatment, and its goal is to remove the entire malignant tissue reaching a negative surgical margin. Radiation therapy is performed if surgery is not realizable or as adjuvant therapy (if surgical margins are involved by cancer)[6]
  • Stage 2: The tumor is more than 2 cm and <4 cm in size (T1, T2) and no lymph node metastasis (N0). Surgery and radiation therapy are used to treat deeply infiltrative lesions, but radiation therapy is preferable with T2 lesions with minimal infiltration. The intensity-modulated radiation therapy is directed to the lesion to minimize damage to the surrounding tissue and other anatomical structures. The ionizing radiation destroys cells in the target area stopping the growth of cells. The dose prescribed depends on tumor size. For early-stage disease, doses of 66–74 Gy (2.0 Gy/fraction; daily: Monday–Friday in 7 weeks) are used [7],[8],[9],[10]
  • Stage 3: The tumor is more than 4 cm in size, or any size (T3), and can have spread to the one lymph node (N1). In T2 N1 and T3 tumors, surgery and radiation therapy represent the elective treatment options. The size and location of the tumor guide the techniques of both. Chemotherapy (CT) is appropriate in lesions where the surgical approach is not efficient (neoadjuvant treatment), and it is combined with radiotherapy for concomitant treatments. Radiation doses used are 66–74 Gy (2.0 Gy/fraction; daily: Monday–Friday in 7 weeks).[9] The advantage of CT is the ability to reach the metastatic cells of cancer because radiation and surgery have effect on localized areas only. Cisplatin, carboplatin, fluorouracil, and cetuximab represent the main agents used in CT protocols.[11] CT may be used in combination with radiotherapy (concurrent CT) or before it (induction CT).[8] Induction CT (common agents are docetaxel, paclitaxel, cisplatin, and fluorouracil) is given to shrink a primary tumor to reduce its bulkiness in preparation for future radiation therapy or surgery [10],[12]
  • Stage 4: The tumor of T4a or any size with N2 or N3 Lymph Nodes. Cancer has spread to other parts of the body (M1). Surgical approaches (i.e., total glossectomy, mandibulectomy) are dependent on the size and location of the lesions and are followed by postoperative radiation therapy. Although surgery is highly debilitating for the patient, minimally invasive procedures and surgical techniques of reconstruction have improved in the last years.[11] Palliative radiation therapy or CT can be used in patients with metastatic disease.



 » Materials and Methods Top


This study included fifty patients with advanced-stage oral cavity cancer who were attending the Department of Radiotherapy, Gandhi Medical College and Hamidia Hospital, Bhopal, from September 2004 to July 2005. Patients aged <70 years, histopathologically confirmed SCC oral cavity carcinoma with performance status >60% on Karnofsky performance scale, have no prior exposure to CT, radiotherapy, surgery, and having normal hematocrit, renal function, liver function, and no gross active infection were included in the study [Table 1] and [Table 2]. After prior hydration with 1 L of DNS/NS injection, ondansetron 8 mg intravenous (I/V) bolos, injection dexamethasone 8 mg bolos, and injection Avil 1 Ampuls bolus were given to the patients, and then injection bleomycin 15 IU I/V was given. Then, after 15 min, injection methotrexate 50 mg I/V was administrated to the patients. After 15 min of infusion of Injection of methotrexate, injection Cisplatin 120 mg diluted in 500 ml of NS, was infused for 10 hour. Immediately after the infusion of cisplatin injection, mannitol 350 ml was given in 20–30 min and then further hydration was done with NS, DNS, and D5 with 1 Ampule of MgSO4 in each cycle of CT. The cycle repeated at an interval of 21 days such that three cycles were administered. Before infusion of CT of the next cycle, complete blood picture including hemoglobin (Hb) platelet count, blood urea, serum creatinine, and serum bilirubin was done which should be within normal limit to start the next cycle. After the completion of CT of three cycles, two groups (n = 25 each) were taken for radiotherapy. One group was treated with radiotherapy alone at a dose of 200 cGy/day for 5 days in a week up to 6600–7000 cGy. Other group of patients were treated with radiotherapy and concurrent cisplatin infusion of 50 mg I/V for 6 h infusion weekly. The radiotherapy dose was same at 200 cGy for 5 days in a week up to 6600–7000 cGy. Radiotherapy field includes primary as well as lymphatic drainage area. Two parallel oppose portals were planned. After providing radiotherapy dose at 4600 cGy, spine was spare. The patient toxicities were evaluated daily during treatment and at subsequent follow-up. The response and side effects were evaluated after completion of the CT and radiotherapy.
Table 1: Characteristics of patients

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Table 2: Distribution according to site of involvement and Histopathological grading

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 » Results Top


There was no significant relation between age and response and between sex and response.

The majority of patients presented in this study belong to buccal mucosa as a main site of cancer, and they showed good response [Table 2]. The most common presenting symptoms were ulcer in mouth, difficulty in swallowing, and neck swelling followed by pain in mouth. Most of the patients were in Stage IV (56%). Histopathology is explained in [Table 2]. All the patients were with ulceroproliferative growth. After completion of induction CT, both the groups responded with almost similar result [Table 3]. There was no significant difference in the incidence of marrow toxicity, but some patients showed high grade of toxicity in Group “B.” Nausea and vomiting and mucositis were observed in both groups; but, in Group “B,” comparatively, Grade III nausea and vomiting and Grade II/III mucositis were higher. The incidence of skin reaction during radiotherapy was more observed in Group “B” patients [Table 4]. The toxicities were noticed after 10 days and persist up to 3 weeks; then, gradually with the treatment, it was controlled. None of the patients needed hospitalization during the course of therapy. Six out of 50 patients required interruption of radiotherapy varying from 3 to 12 days because of mucositis and dysphagia, and this was more marked in Group “B.” Supportive treatment was given to control mucositis and dysphagia whenever it was required. Laryngeal edema was seen in three patients which was controlled with supportive management, and nausea and vomiting were reported in some patients which were controlled symptomatically. In Group B, 84% (vs. 60% in Group A) of patients showed a complete response (CR) after completion of treatment [Table 5]. Patients who did not respond with induction CT were also less responsive to radiotherapy. It was also noticed that the patients who responded partially with induction CT responded better when concurrent chemoradiotherapy was given. In Group “B,” out of 13 patients who responded partially to induction CT, CR was observed in 9 patients. During follow-up, it was noticed that few patients who did not show CR after radiotherapy showed CR later.
Table 3: Response after induction chemotherapy

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Table 4: Adverse effect during treatment

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Table 5: Response after radiotherapy

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 » Discussion Top


This disease has a major impact on the quality of life as it can affect one's ability to eat, talk, breathe, smell, and swallow. Appearance may also be cosmetically unacceptable. In past, CT consisted of the use of a single agent usually methotrexate (Mtx). The beneficial effect of CT remains controversial in terms of survival but has shown some promising improvement on locoregional control and quality of life. The treatment of patient with locally advanced inoperable oral cancer remains a challenge with poor locoregional tumor control and limited survival when surgery, radiotherapy, or both are used. Paccagnella et al. demonstrated improved survival after treatment with induction CT and definitive radiotherapy compared with radiation alone. The rationale behind is that, independent cytotoxic action of chemotherapy drugs reduce the total number of tumor cells, colonogen and it sensitize the tumor cells which enhance the cytotoxic effect of the radiation. CT agents are often combined with chemoradiation. With the Mtx, response rate varies from 8% to 60%, averaging 30%, and most of these are for short duration for 2 months. For bleomycin, response rate varies from 6% to 93% with a cumulative response rate of 18%. Whereas for platinum, response in different studies was 23%–70% with a 25% cumulative response rate. All the three drugs which act on different phases of cell cycle were combined in this study to reduce the tumor volume. Although the number of response increases, survival is not prolonged. The majority of the chemotherapeutic regimes is effective against the primary tumor but marginally effective against the lymph node metastasis. Uncontrolled cervical lymph node metastasis which is unresectable and not suitable for radiotherapy because of sheer bulk is reduced by the induction CT for radiotherapy. When external radiotherapy alone was used in conventional form of treatment, controlled rate was 80%–90% for Stage T1 lesion, 60%–65% for T2 lesion, and 25%–30% for T4 lesion.[13],[14] The long-term result in RTOG 73-03 trial, operable lesion was quite modest, therefore, combination of CT and radiotherapy was accepted; some studies have shown value for concurrent use of CT with radiotherapy.[15] In this study, induction chemotherapy was performed in all the patients, out of them 50% patients received chemoradiotherapy and 50 % patients received only radiotherapy to find out the superiority of both the combination in the management of advanced head and neck cancer. The most common presenting symptoms were ulcer on mouth difficulty in swallowing, neck swelling, pain as well as change in voice in order of frequency. Complaints of weakness and loss of appetite were also frequent. Ulceroproliferative lesions were found. Physical examination of patients revealed average general condition with infection which was controlled by the suitable antibiotics. Most of the patients had Hb level between 10 and 13 mg/dl. In majority of the patients, the total leukocyte count was on the higher side which may be due to infection. SCC was the only kind included in the present study. Based on Histopathological grading, well differentiated squamous cell carcinoma was most common (82%) and least common was poorly differentiated squamous cell carcinoma (2%). Site wise, majority of the patients presented with disease in buccal mucosa (44%) followed by tongue, alveolus, and retromolar trigone. Nausea and vomiting were the most frequent side effects of CT followed by marrow toxicity and loss of appetite. In Group “B,” the complication is more marked. Out of the 25 patients in Group “A,” 15 patients (60%) had CR, 8 patients (32%) had partial response (PR), and 1 patient (4%) neither respond at all nor had progressive disease. Whereas in Group “B,” out of 25 patients, 84% patients had CR, 16% had PR. These results are encouraging and are better than those reported by others whatever was the combination and mode of therapy in advanced oral cavity SCC. In this study, after induction CT, all patients have more or less same degree of objective response reported by others with induction CT. With induction, good objective response shown by other CT agents has been documented in the literature (Taxol, Vinorelbine, Gemcitabine, etc.) but they are very costly and not affordable by poor patients. Poor objective response was found in proliferative lesion in contrast to ulcerative and infiltrative lesion. The relationship between the stage of disease and type of radiation response in Group “A” showed that Stage III responded better than Stage IV whereas in Group “B,” the effect of concurrent chemoradiotherapy is more effective in Stage IV. It was found that the patient who had initial good response with induction CT alone also showed later a good response to radiotherapy as well. Ten patients in Group A and 11 patients in Group “B” (total 21 patients) showed CR initially with induction CT only. After completion of radiotherapy, 15 patients in Group “A” and 21 patients in Group “B” showed CR whereas only 14 patients in Group “A” and 1 patient in Group “B” showed PR surprisingly. One patient in Group “A” and no patients in Group “B” showed no response or progressive disease. This study indicates that after induction CT, concurrent CT is markedly effective in patients in whom after induction CT, the response is either PR or no response category. The patient who had responded CR after induction can be only managed by radiotherapy alone. It was observed that the follow-up is better in the patients who are in CR and PR category, and worst prognosis was found in the patient who showed no response.


 » Conclusion Top


This study showed the superiority of induction followed by concurrent chemoradiotherapy over induction plus radiotherapy alone in the treatment of advanced oral cavity neck SCC.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
 » References Top

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    Tables

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5]



 

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