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ORIGINAL ARTICLE
Year : 2016  |  Volume : 12  |  Issue : 2  |  Page : 920-925

Comparison of outcome and toxicity of two different regimes of neoadjuvant chemotherapy followed by external beam radiotherapy in stages III and IV larynx and laryngopharyngeal malignancies in years 2013–2014


Department of Radiotherapy and ENT, Government of Cancer Hospital, MGM Medical College, Indore, Madhya Pradesh, India

Date of Web Publication25-Jul-2016

Correspondence Address:
Sonu Goyal
c/o R.K Goyal, 3-k-13 Vigyan Nagar, KOTA - 324 005, Rajasthan
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0973-1482.172122

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 > Abstract 


Introduction: Both induction chemotherapy (ICT) followed by irradiation and concurrent chemotherapy and radiotherapy have been reported as valuable alternatives to total laryngectomy in patients with advanced larynx/hypopharynx cancer.
Materials and Methods: Of the 60 enrolled patients, randomly assigned into two groups (30 in each group) previously untreated patients with stages III to IV larynx/hypopharynx squamous cell carcinoma were assigned to received two cycles of ICT with interval of 3 weeks (a) Group A paclitaxel 175 mg/m 2 on day 1 and carboplatin 450 mg on day 2 (PC), (b) Group B docetaxel and cisplatin 75 mg/m 2 each on day 1 and ifosfamide 2 g/m 2 on day 1–3 along with mesna (docetaxel-ifosfamide-cisplatin). Both groups were followed by conventional radiotherapy (60–70 Gy/5#/week). Primary end point was a response after ICT. Secondary endpoints included acute toxicities and overall response.
Results: Baseline patient and tumor characteristics were well balanced between both groups, the response after ICT seen was 80% in Group A complete response (CR) 36.6% and partial response (PR) 43.3% and in Group B 79% response, CR 33% and PR 46%; whereas toxicities in Group B grade 3/4 neutropenia and grade 2/3 vomiting more severe than Group A. Radiation therapy was well tolerable to both groups with mild side effects.
Conclusions: Definite role of neoadjuvant chemotherapy in locally advanced larynx/laryngopharyngeal cancer as organ preservation therapy. The efficacy found was quite similar and improved response in both groups except toxicity profile of Group B more severe, requiring the use of colony stimulating factors and supportive care along with.

Keywords: Neoadjuvant chemotherapy, organ preservation, toxicity


How to cite this article:
Goyal S, Pounikar T, Jain P, Arya R, Verma J, Fakhruddin. Comparison of outcome and toxicity of two different regimes of neoadjuvant chemotherapy followed by external beam radiotherapy in stages III and IV larynx and laryngopharyngeal malignancies in years 2013–2014. J Can Res Ther 2016;12:920-5

How to cite this URL:
Goyal S, Pounikar T, Jain P, Arya R, Verma J, Fakhruddin. Comparison of outcome and toxicity of two different regimes of neoadjuvant chemotherapy followed by external beam radiotherapy in stages III and IV larynx and laryngopharyngeal malignancies in years 2013–2014. J Can Res Ther [serial online] 2016 [cited 2019 Dec 7];12:920-5. Available from: http://www.cancerjournal.net/text.asp?2016/12/2/920/172122




 > Introduction Top


Head and neck cancer in India comprises 30% of all cancers. Nearly, 80,000 head and neck cancers are diagnosed every year in our country. In India, 60% to 80% of these patients present with advanced and inoperable diseases around 40,000 cases of pharyngeal cancers excluding nasopharyngeal cancers (31% of global cases) and nearly 29,000 cases of laryngeal cancers (18% of global cases) occur in India every year.[1] The quality of life can be further worsened by treatment of head and neck tumors which can induce additional mutilation. Cancer of larynx and hypopharynx are strongly related to cigarette smoking and alcohol, occupational exposure to coal dust, steel dust, iron compounds, and fumes, increase risk of developing cancer of postcricoid region for patients with Plummer Vinson syndrome.[2],[3] The conventional treatment of patients with advanced (stage III or IV) squamous carcinoma of the larynx consists of total laryngectomy or a combination of laryngectomy and postoperative radiation therapy (RT); this treatment results in overall 5-year survival rates ranging from 0% to 50%.[2],[4] Because laryngectomy results in substantial functional morbidity, including the loss of the natural voice, alterations in deglutition, and the creation of a permanent tracheostoma in the neck, and alternative forms of treatment have been developed.[5],[6],[7],[8] The recent addition of chemotherapy before surgery or radiation in patients with advanced cancer of the head and neck resulted in high rates of complete tumor regression that are associated with prolonged survival and that predict a favorable response to subsequent RT contributes to organ preservation.[9],[10],[11],[12],[13],[14]


 > Materials and Methods Top


The prospective randomized interventional study, out of the total patients reported with advanced cancer larynx/laryngopharynx during the period of September 2013 to September 2014, 60 identical cases were studied in this work on a random basis.

Patients were randomly selected in two groups:

  1. Group A: The drugs paclitaxel and carboplatin were administered in the following manner:

    • Paclitaxel 175 mg/m 2 on day 1
    • Carboplatin was dosed by the Calvert formula to an area under the concentration-time curve of 5 on day 2.


  2. Group B: The drugs docetaxel, cisplatin, and ifosfamide were administered in the following manner:

    • Docetaxel 75 mg/m 2 on day 1
    • Cisplatin 75 mg/m 2 on day 1
    • Ifosfamide 2000 mg/m 2 on days 1–3 along with mesna.




In each group, two cycles of chemotherapy were administered every 21 days. Prior to the administration of chemotherapy each patient was given premedication viz., steroid, H2 blockers, and 5-HT3 antagonists and chemotherapy was administered along with adequate hydration.

After these, two cycles of chemotherapy the patients were assessed by clinically by palpation and nodal status as well as by ENT oncosurgeon, if the patient found to have a complete response (CR) or partial response (PR). Each of these two groups after neoadjuvant chemotherapy (NACT) received definitive external beam radiotherapy (EBRT) of 60–70 Gy in 30–35 fractions @200 cGy/#, 5#/week over a period of 6–7 weeks. The EBRT was delivered by theratron 780-C Co-60 machine using conventional parallel opposing portals with the source to surface distance technique with reducing fields. The total duration of therapy was 3 months (chemotherapy f/b radiotherapy) plus every monthly follow-up.

Informed and written consent were taken before enrolling the patient into the study

  • All the necessary precautions were taken in administering radiation and chemotherapy
  • The proposal was reviewed by the Scientific Review Committee, and ethical clearance was obtained. Permission was sought from the concerned authorities.


Inclusion criteria

(a) Patients of either sex, (b) patients of any age preferably up to 60 years, (c) patients with performance status (Karnofsky status) of 50 or more, (d) patients with histological proved squamous cell carcinoma/metastatic carcinoma with American Joint Committee on Cancer staging 3 and 4 locally advanced, (e) no plan for surgery, and (f) patients having no distant metastasis.

Exclusion criterion

(a) Patients not willing to give consent, (b) patients who have already received chemotherapy or radiotherapy, (c) patients with early stages I and II of ca laryngopharynx, (d) patients with other major medical comorbidities e.g., coronary heart disease, diabetes mellitus, renal disease, and bronchial asthma, and (e) patients who have undergone surgery.

Reassessment of the patient will done by: (a) Symptom relief, (b) clinical examination, (c) general examination, and (d) ENT examination indirect laryngoscopy/direct laryngoscopy/Hopkin's examination. (a) Investigations-routine investigation (b) contrast enhanced computed tomography neck after two cycles of chemotherapy and 3 months postcompletion of EBRT.

Response will be described as either:

  • CR
  • PR
  • No response/progression
  • Stable disease.


Patients will be assessed for toxicities mainly myelosuppression (neutropenia), gastrointestinal (GI) toxicities (nausea, vomiting, and diarrhea), peripheral neuropathy, alopecia, mucositis and as per CTCAE version 4 criteria.

Statistical analysis was done using the software SPSS 20.0 (IBM, NY, USA). P values were calculated using Chi-square or t-tests. P <0.05 was considered significant.


 > Results Top


NACT according to our study contributed to a fair amount of local control and systemic control with laryngeal preservation achieved in 75% to 80%. Patients and tumor characteristic listed in [Table 1].
Table 1: Patient and tumor characteristics

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The overall response of two different regimes of CT used in the study was quite similar in both groups. The toxicities of docetaxel + cisplatin + ifosfamide group were higher than that of paclitaxel + carboplatin group which exhibited higher grades of hematological and GI toxicity, requiring administration of colony stimulating factors along with it, and symptomatic treatment. The study showed the response in Group A, after chemotherapy treatment was 80% (CR 36.6%, PR 43.3%) and in Group B was 79% (CR 33%, PR 46%) almost similar with P = 0.912 and the overall response after EBRT completion was in 83% in Group A and 80% in Group B with P = 0.870 [Table 2].
Table 2: Comparison of response according to recist criteria version (1.0) 2000

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However, the toxicities of Group B hematological and GI toxicity were greater (grade 3/4) than Group A, one patient developed intestinal obstruction with grade 4 neutropenia Group B and Group A had more neurosensory toxicity but which is of moderate grade and easily tolerable with less side effects [Table 3].
Table 3: Comparison of hematological and G.I toxicity (neutropenia, vomiting, peripheral neuropathy) CTCAE version 4.0

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Radiation-induced side effects were mild to moderate grade in both groups, e.g., mucositis, dermatitis, laryngeal edema, and not affected by different chemotherapy regimens. No long-term side effects of chemotherapy observed.


 > Discussion Top


India has a high incidence of head and neck squamous cell carcinoma, mostly presenting in advanced stages. In the treatment of head and neck cancer, two issues are of utmost importance, first is survival and the second is the preservation of organ function. Although, survival differs by cancer site within head and neck, it is generally poor in stages III and IV. In these advanced cases, concomitant chemoradiotherapy is considered to be the treatment of choice. However, retrospective studies have shown that patients treated with concomitant therapy, there was an increase in systemic relapse due to lack of systemic control.

Induction chemotherapy (ICT) has been established as an effective therapy for squamous cell carcinoma of the head and neck; it has been shown to reduce tumor volume, allow for organ preservation and improve survival. Hence, evolved the rationale of incorporating ICT in advanced head neck malignancies. Since the end of the 1970s, numerous studies have published on induction or NACT in patients with head and neck cancer which suggests that NACT may play an important role in preserving laryngeal function (phonatory speech).[15],[16],[17]. However, ICT has failed to demonstrate any significant survival benefit in these patients.[18]

Organ preservation therapy is intended to control the disease without compromise in survival while optimizing function or cosmesis. The term implies that the tumor is potentially resectable for a cure in the first place and that the associated morbidity from surgery is significant. Although conservation surgical procedures can achieve the same goals, more commonly, the label of organ preservation is applied to nonsurgical approaches. In that regard, the role of chemotherapy integrated with irradiation is best established for more advanced primary tumors.

Over the past 15 years, larynx preservation has been extensively assessed but only in the light of ICT. From these evaluations, it appeared that the use of ICT was safe and adequate for patient selection; neither the ultimate local control nor survival worsened, and at least, half the patients retained their larynxes. No compromise in survival was associated with the delay in surgery and radiotherapy in whom chemotherapy failed. The response to initial chemotherapy was used to triage patients to either definitive irradiation (a) PR or better at the primary site; surgery to the primary site was reserved for salvage) or primary surgical management (less than a PR).

The veterans' administration study published in 1991 established the fact that the response to NACT predicts the response of a tumor to RT. Patients with advanced tumors that responded either partially or completely to CT were treated with RT, and total laryngectomy was reserved for nonresponders. This resulted in the ability to preserve the larynx in a significant number of patients with locally advanced laryngeal cancer while achieving local control and overall survival results equivalent to those achieved with initial total laryngectomy.

By 2003, results of the radiation therapy oncology group 93-11 trial, utilizing Centre for Cultural Resources and Training as initial treatment, were published, demonstrating a higher rate of laryngeal preservation with this protocol. Surgery was reserved for treatment failures. This concept changed the paradigm for management of advanced laryngeal cancer, greatly reducing the number of laryngectomies performed. While supracricoid laryngectomy has been employed for selected patients, total laryngectomy is the usual procedure for salvage of failure after nonsurgical treatment.

ICT predominantly improves systemic control, whereas concomitant chemoradiotherapy exerts its major effects through improved locoregional control. Therefore, it has been postulated that the sequential administration of both ICT and concurrent chemoradiotherapy (or bioradiotherapy with cetuximab) could result in additional improvement of survival and organ preservation compared with either strategy alone.

A comparison of chemoradiotherapy versus ICT followed by radiotherapy and chemoradiotherapy versus radiotherapy alone as strategies to preserve the larynx showed statistically significantly higher rates of locoregional control and larynx preservation (78% and 88%, respectively) with the concurrent chemoradiotherapy approach.[19],[20]

Chemoradiotherapy is now the standard of care for organ preservationin patients with this disease. Randomized comparisons of concurrent chemoradiation versus ICT followed by radiotherapy alone have shown that concomitant chemoradiotherapy is superior than e.g., Forastiere et al. Taylor et al. (1994). However, despite thisimprovement in locoregional control, it should be pointed outthat chemo-radiotherapy does not provide a survival advantage over ICT or radiotherapy alone for larynx cancer. This is principally because local recurrence of larynx cancer, unlike that of other head and neck cancer, can be effectively managed with salvage surgery.

In community practice, NACT followed by radiotherapy alone is often practiced in our country, the main reason being the toxicity of radiation and concurrent chemotherapy, that is, mucositis which can lead to frequent interruptions of treatment, which increases total treatment time, which in turn can adversely affect the success of radiotherapy in head and neck cancer. Further, the factors of poor nutritional status and presence of infection in the patients of the lower socioeconomic group in our country make concurrent chemoradiotherapy very difficult for patients to tolerate, and complete the schedule of treatment. Conformal radiation therapy (CRT) is associated with greater toxicity than with ICT or radiotherapy alone supported by Calais et al.[21] A study that compared PF, CRT, and radiotherapy alone found that the rate of high-grade toxic effects was greater with the chemotherapy-based regimens, that is, CRT > PF > radiotherapy.

Randomized studies demonstrated that ICT with a cisplatin 5-fluorouracil (5-FU) doublet (PF) prior to radiotherapy enabled larynx preservation in a substantial proportion of patients, compared with surgery plus radiotherapy, without compromising survival.[15],[16],[17],[22],[23]

Adding taxane docetaxel to PF, to create the TPF triplet regimen, led to significantly higher larynx preservation, and laryngectomy-free survival rates than with the PF doublet. TPF is now the accepted standard ICT regimen for future clinical trials in resectable disease.[24],[25],[26],[27],[28],[29],[30],[31],[32],[33],[34],[35]

The present study done in our hospital indicates that ICT may improve short-term locoregional control. The results of my study suggested that the response after NACT was in Group A CR was in 11/30 patients, and PR in 13/30 patients, CR in Group B was in 10/30 patients and PR in 14/30 patients, rest 4/30 in A, 5/30 in B Group patients had stable/no response with 2 and 1 patients had progressive disease in Groups A and B, respectively. The patients who responded to NACT were followed by EBRT had also shown good results 19/30 with CR in Group A and in Group B 17/30 achieved CR.

However, toxicity profile was different among both groups. More severe neutropenia and vomiting episodes with some unexplained anxiety were seen with Group B, required urgent hospitalization but all were managed requiring administration of granulocyte colony stimulating factor (GCSF)/peg GCSF along with symptomatic. Patients were closely followed after 5 days of receiving chemotherapy for follow-up with the search for any sign/symptoms of neutropenia. Rest all toxicities/side effects were manageable with some patients with numbness/tingling fingers/toes. Results of this study done found to be similar with previous laryngeal studies already done namely: The GORTEC 2000-01 trial, Holsinger et al., Laccourreye et al., and EL-Sawy et al.


 > Conclusions Top


Induction/NACT followed by radiotherapy in stages III and IV head and neck malignancies is a rational and feasible therapeutic modality, considering the encouraging response rates, and patients can enjoy organ preservation. Data from our own trials have suggested high tumor control and cure rates with patients of ca larynx/laryngopharynx received NACT. To conclude although large studies with large groups of patients and longer follow-up needed to reach definitive conclusion, it seems that ICT can be used successfully in locally advanced ca larynx/hypopharynx and can be effective in preserving larynx, in certain percentage of patients, without compromising overall survival.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
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