Abstract

INTRODUCTION

Head and neck cancer is the third most common cancer in India with 60% presenting in advanced stages.[1,2] The prognosis depends upon the stage of the disease. Early stage cancers have 5 years survival of 80-90%. Advanced stage cancers have a poor prognosis with 5 years survival of 25-50%.[3]

Surgery for nonmetastatic advanced head and neck cancer is an important prognostic marker.[4] Complete surgical resection of the tumor with free margins remains an important goal. Management of advanced cancers involves multidisciplinary treatment, but guidelines are not defined for very advanced cancers. There is the emerging role of neoadjuvant chemotherapy (NACT) in these advanced cancers.

NACT is useful in reducing the tumor volume and thus making unresectable tumors resectable.[4,5] It may be helpful in organ preservation and thus avoiding complex morbid surgeries with functional disabilities.[6] NACT is useful in assessing tumor response to chemotherapy, selecting appropriate local treatment and improving survival. It has a theoretical benefit in control of micrometastasis, thus improving local and systemic control.[7,8,9,10,11] We routinely use neoadjuvant at our center for locally advanced head and neck cancers, when it is questionable to achieve free margins of resection following surgery.[4]

Various factors play a role in wound healing in the postoperative period in cancer patients. These include nutritional status, disease stage and the type of treatment planned. Radiation therapy is known to impair wound healing when doses larger than 50 Gy are given, or radiotherapy is given < 3 weeks before surgery.[7,8,9,10,11,12,13] The toxicity associated with NACT can contribute to postoperative mortality and morbidity. However, most of the studies have shown that NACT does not increase postoperative morbidity.[14,15,16,17,18] There are no similar studies in head and neck cancers. The aim of this study was to find out if the use of chemotherapy was associated with increased complications in the postoperative period.

MATERIALS AND METHODS

This is a retrospectively collected data of head and neck cancer patients operated at our hospital from March 2013 to September 2014. The aim was to compare complications and mortality in first 30 days in the postoperative period between patients receiving NACT followed by surgery and those treated with surgery alone in head and neck cancer. A total of 205 patients were included in the study. The data were collected from the electronic medical record of the hospital.

Since this was a retrospective collection of data, we divided patients into two groups depending upon whether patients received NACT followed by surgery or upfront surgery without NACT. Group 1 included 153 patients who underwent surgery immediately after diagnosis, and Group 2 included 52 patients who received 2-3 cycles of NACT followed by surgery. Cases were selected based on the following eligibility criteria:

1. Biopsy confirmed squamous cell carcinoma of oral cavity, larynx and hypopharynx,
2. Treatment naïve patients, and
3. All T4 primary tumors.

The reasons for giving NACT in these groups of patients included edema reaching up to zygoma in buccal mucosa-alveolus complex lesions, tongue cancers close to mandible, extensive exolaryngeal disease in soft tissues of neck in carcinoma of larynx, and hypopharynx.

The complete preoperative evaluation was done in all patients including examination under anesthesia, direct laryngoscopy, imaging with contrast enhanced computed tomography scans; magnetic resonance imaging or positron emission tomography scans whenever indicated.

The primary objective of the study was to assess the difference in complication rates between Groups 1 and 2. The NACT drug regimens used included two or three drug chemotherapy. NACT was given as two drug regimen with 3 weekly regimens of cisplatin and docetaxel as 75 mg/m2 each on day 1 or three drug regimen with 5-flurouracil as 750 mg/m2 as 24 h intravenous infusion for 5 days for 3 cycles along with cisplatin and docetaxel. Patients receiving three drug regimens were given granulocyte-colony stimulating factor prophylactically from day 6 to day 12. Tablet levofloxacin 500 mg once daily was given for the same duration as a primary prophylaxis for bacterial infections.

Forty-one patients received two drug regimen and 11 patients received three drug regimen. Carboplatin as AUC 6 was given to those with compromised glomerular filtration rate of < 60 ml/min. The reasons for using two drug regimens in the majority of the patients were logistic reasons, economical constraints, and comorbidities.

The complication details were grouped as a major and minor complications. Major complications were those in which surgical intervention was needed; patients were re-hospitalized or hospitalized for more than 14 days. Minor complications were defined as those in which conservative management was followed.

RESULTS

The mean age of the population in the Group 1 was 51 years, and Group 2 had a younger population with a mean age of 45 years with a significant difference in P value. The majority of the patients were males and had an oral cavity (93%) as the major subsite with no statistical difference between the two groups. Fifty-one percent patients in Group 1 and 46% patients in Group 2 had pathological N+ (node positive) status. Nearly ¼ of the patients (24%) in Group 1 and 15.6% patients in Group 2 had comorbidities (P = 0.21) as shown in Table 1. The patients did not differ in terms of comorbidities in the two groups.

Table 1

This needs to be taken with caution since in Group 2 the data were available in 29 patients only (P = 0.11). Hence, this could be misleading due to small sample size of the patients.

DISCUSSION

The treatment of head and neck cancers involves resection of the tumor with wide margins and regional lymph node dissection. Resection in advanced cancers is associated with significant morbidity. There has been an increasing trend for the use of NACT in advanced head and neck cancers in the last decade. This was after the promising data showing the benefit of NACT in reducing the tumor volume, and organ preservation was published.[19]

Multiple experimental studies on animals have shown that chemotherapy drugs target rapidly dividing cells and thus cause apoptosis of tumor cells. But, the normal dividing cells like macrophages and fibroblasts are also susceptible. This affects the inflammatory phase delaying the wound healing.[20] This hypothesis suggests that we should have a more infective complication in the postoperative period, but infection rates were similar in both the arms. It is possible that patients after chemotherapy may have improvement in symptoms related to cancer which may result in better nutritional intake and thus lesser negative impact on immunity.

ANC has high sensitivity in detecting acute bacterial infections.[21] In this study, values below or above the normal range (2.0-7.0 × 109/L) were considered abnormal with the higher risk of infection. The mean preoperative ANC value was 5.6 × 109/L in Group 1 and 5.4 × 109/L in Group 2. The mean postoperative values ANC values were high (>7.0 × 109/L) in both the groups with no difference statistically. Thus, patients who received NACT did not have abnormal ANCs as compared to surgery group and hence no higher risk of infection.

Alkylating agents such as cyclophosphamide, cisplatin and antimetabolites such as methotrexate, 5-fluorouracil decrease wound tensile strength and impede wound healing during the early proliferative phase in animal studies.[22,23] However, most of the studies on humans have shown no increased risk of wound complications or delayed healing with neoadjuvant and adjuvant chemotherapy at therapeutic doses.[24,25] In our patients, we used taxanes with platinum. It is possible that there is the differential impact on wound healing by different drugs.

The meta-analysis of NACT in esophageal carcinoma,[14] gastric carcinoma,[15] and bladder carcinoma[17] has shown that there was no difference in rate or severity of preoperative or postoperative complications post-NACT. NACT did not prevent patients from undergoing cystectomy for bladder cancers[17] and was associated with a 6.5% absolute benefit in 5-year overall survival.[26]

Patients in the Group 1 (surgery) were older than those in Group 2 (P = 0.001). For analysis purpose, patients in both groups were divided according to age into those with age >65 years or ≤65. But patients with age >65 were not associated with the development of postoperative complications or longer hospital stay when compared with those with age ≤65 (P value not significant).

The numbers of readmissions and preoperative events were the same in the two groups. The mean hemoglobin level and albumin levels which are indicators of the nutritional status of the patient showed higher values in Group 1 (surgery) as compared to Group 2 (NACT). This could be due to larger tumors being given NACT, which had functional difficulty in swallowing. However, this did not reach a value of statistical significance.

Our study showed that the mean preoperative blood loss associated with Group 2 (NACT) was higher as compared to Group 1 (surgery). However, the blood loss was available in only 56% of patients in Group 2. Thus, it is difficult to infer the association of NACT with blood loss with our study. Most of the studies in the literature show no increased blood loss with the use of chemotherapy.[27,28]

The main limitation of the study was that it was a retrospective study. Retrospective studies always have their inherent biases. The details of blood loss were missing in 44% of the patients in Group 2 and could not retrieve due to retrospective nature of the study.

CONCLUSION

This is the first study of its kind in head and neck cancer comparing complications in NACT patients undergoing surgery versus upfront surgery. It appears that postoperative major or minor complication rate does not increase following chemotherapy in head and neck cancer. There is a concern of increase blood loss following surgery which needs to be confirmed in further study.