|Year : 2016 | Volume
| Issue : 3 | Page : 372-376
Induction chemotherapy with cisplatin and ifosfamide in locally advanced inoperable squamous cell carcinoma of the head and neck: A single-institution experience
S Zaheer1, SA Siddiqui1, M Akram1, SA Hasan2
1 Department of Radiotherapy, Jawaharlal Nehru Medical College, Aligarh, Uttar Pradesh, India
2 Department of Otorhinolaryngology, Jawaharlal Nehru Medical College, Aligarh, Uttar Pradesh, India
|Date of Web Publication||24-Feb-2017|
Department of Radiotherapy, Jawaharlal Nehru Medical College, Aligarh, Uttar Pradesh
Source of Support: None, Conflict of Interest: None
BACKGROUND: Induction chemotherapy (ICT) in patients with head and neck cancer has been studied since a long time. The addition of taxanes to the cisplatin and 5-fluorouracil (5FU) (PF) regimen results in superior antitumor activity. We did this study to see the response and toxicity of ICT with cisplatin and ifosfamide followed by concurrent chemoradiotherapy (CRT) in locally advanced, unresectable squamous cell carcinoma of head and neck (SCCHN). AIMS: The aim of this study was to see the results of ICT using cisplatin and ifosfamide regimen in locally advanced unresectable SCCHN in terms of acute and chronic toxicity and response to treatment. MATERIALS AND METHODS: Patients with Stage III and IV, nonmetastatic SCCHN were enrolled in the study. They were given two cycles of ICT with cisplatin and ifosfamide followed by CRT. RESULTS: After ICT, the overall response rate (ORR) was 75.0% at the primary site and 70.0% at the nodal site. ORR for combined primary and nodal disease was observed to be 67.5%. The complete response (CR) and partial response (PR) for combined primary and nodal site were seen in 4 (10.0%) and 23 (57.5%) patients. Of 32 patients who received CRT after ICT, CR was 53.1% and PR was 31.3%. Mucositis, skin reaction, and pharyngeal and laryngeal toxicities were the most common but tolerable. CONCLUSION: ICT with cisplatin and ifosfamide gives comparable results to the standard paclitaxel, PF regimen. We conclude that this combination regimen for ICT is not only an economical alternative of taxol-based regimen but also well tolerated by the patients.
Keywords: Cisplatin and ifosfamide, head and neck, induction chemotherapy, squamous cell carcinoma, TPF regimen
|How to cite this article:|
Zaheer S, Siddiqui S, Akram M, Hasan S. Induction chemotherapy with cisplatin and ifosfamide in locally advanced inoperable squamous cell carcinoma of the head and neck: A single-institution experience. Indian J Cancer 2016;53:372-6
|How to cite this URL:|
Zaheer S, Siddiqui S, Akram M, Hasan S. Induction chemotherapy with cisplatin and ifosfamide in locally advanced inoperable squamous cell carcinoma of the head and neck: A single-institution experience. Indian J Cancer [serial online] 2016 [cited 2019 Sep 19];53:372-6. Available from: http://www.indianjcancer.com/text.asp?2016/53/3/372/200661
| » Introduction|| |
Head and neck cancer ranks sixth among the most common cancers worldwide accounting for approximately 6% of all cases of cancer., In India, due to the habit of chewing tobacco and smoking, the incidence is even higher. Head and neck cancer in Asia accounts for 57.5% of all cases worldwide, whereas in India, it accounts for 30% of all cancer cases. As against 40% patients in developed countries, 60–80% of patients in India present with advanced disease for which prognosis is poor.,
Most clinical trials show the superiority of combined radiotherapy (RT) and chemotherapy to RT alone for the treatment of locally advanced, nonmetastatic squamous cell carcinomas of the head and neck (SCCHN). Meta-Analysis of Chemotherapy on Head and Neck Cancer (MACH-NC) demonstrated that adding chemotherapy to RT in both definitive and adjuvant postoperative settings resulted in a 12% reduction in the risk of death from head and neck cancer corresponding to an absolute improvement of 4% in 5-year survival. An update that included an additional 24 trials revealed that the majority of this benefit resulted from the use of concurrent chemotherapy, a 19% reduction in the risk of death and an overall 8% improvement in 5-year survival compared to treatment with RT alone. Similar results were shown by the multi-institutional French trial, GORTEC 94-01., However, it was accompanied by significant increase in acute mucositis.
The problem of distant metastatic failure persists despite the improvement in locoregional control and survival attributable to the addition of concurrent chemotherapy.
Induction chemotherapy (ICT) has been a new approach in the management of locally advanced SCCHN. It helps in organ preservation/conservation, provides good locoregional control, as well as is useful for the treatment of patients with unresectable disease and may prevent distant failure. However, the real impact of ICT is still debatable. Combination chemotherapy consisting of taxanes, cisplatin and 5-fluorouracil (5FU) (PF) is currently considered the standard regimen for ICT. The results of many Phase III trials showed that adding taxane to the standard PF regimen improved the overall survival (OS) rate and led to better organ preservation over a cisplatin and 5 flourouracil (PF) regimen.,
In this study, we used cisplatin and ifosfamide combination for ICT assuming that this regimen is an effective, less toxic, and more economic alternative of taxol-based combination.
The aim of this study was to see the results of ICT using cisplatin and ifosfamide regimen in locally advanced unresectable SCCHN in terms of toxicity (acute/chronic) and response to therapy.
| » Materials And Methods|| |
It was a prospective study and included all the eligible previously untreated patients of SCCHN with histologically confirmed diagnosis.
The inclusion criteria were advanced locoregional, unresectable disease with no evidence of distant metastasis (Stage III or IV; M0). The patients with tumors of nasal cavity, paranasal sinuses, and salivary gland were excluded from the study.
The patients were given ICT in the form of cisplatin 100 mg/m 2 on day 1 and ifosfamide 1500 mg/m 2 on day 1–3 every 21 days for two cycles. The patients with complete or partial response (PR) and stable disease (SD) were given weekly cisplatin-based concurrent chemoradiation (CRT). Radiation was delivered by conventional fractionation schedule to a total dose of 70 Gy/2 Gy per fraction/5 fractions in a week.
Response was evaluated according to the Response Evaluation Criteria in solid tumors (RECIST) criteria. This was done after two cycles of ICT and again after completion of CRT. Toxicity was evaluated using Radiation Therapy Oncology Group criteria.
| » Observations And Results|| |
Forty-three patients were enrolled in the study. One patient expired 10 days after receiving the first cycle of ICT and two patients did not turn up for further treatment after receiving the first cycle of neoadjuvant chemotherapy. Therefore, forty patients were left for evaluation [Table 1].
After ICT complete response (CR) was 40% at the primary and 17.5% at the nodal site. CR for combined primary and nodal disease was 10%. PR was observed in 35% at the primary and 52.5% at the nodal site whereas PR for combined primary and nodal disease was 57.5%. Overall response rate (ORR) for combined primary and nodal disease was 67.5%. Eight patients who had progressive disease (PD) at both primary and the nodal sites were taken off the study and treated on individual basis whereas one patient who had progression only at the nodal site was continued in the study. Thus, 32 patients received CRT after ICT. The response rates after ICT are shown in [Table 2].
Postinduction chemotherapy hematological toxicity (neutropenia)
After ICT Grade 0 neutropenia was observed in 5 (12.5%), Grade 1 in 10 (25%) and Grade 2 in 13 (32.5%) patients. 9 (22.5%) patients developed Grade 3 neutropenia and 3 patients (7.5%) experienced Grade 4 neutropenia. Two patients (5%) had febrile neutropenia.
The toxicities during CRT are described in [Table 3]. At first follow up CR after administration of ICT followed by CRT was seen in 17 (53.1%) patients, PR in 10 (31.3%) and PD in 3 (9.4%). 2 (6.3%) patients had stable disease (SD). Late skin and subcutaneous toxicities are shown in [Table 4].
| » Discussion|| |
The treatment of patients with locally advanced head and neck cancer continues to evolve. There are two different, nonsurgical approaches to treat these patients: CRT and ICT followed by CRT.
ICT in patients with head and neck cancer has been studied since a long time. Initial trials used PF combination. Later on, it was shown that addition of taxanes to the standard PF regimen results in superior antitumor activity.,, However, it is still not clear whether the addition of ICT to CRT improves efficacy compared with CRT alone, which is the current standard of care.
We included patients with primary disease in oral cavity, oropharynx, hypopharynx, and larynx. The majority of the patients had primary disease in oropharynx (52.5%) followed by larynx (27.5%). In oropharynx, the most common primary site was the base of tongue (25.0%). A recent study done by Haddad et al. had patient characteristics that were similar to our study.
In our study, after ICT, the ORR was 75.0% at the primary site and 70.0% at the nodal site. ORR for combined primary and nodal disease was observed to be 67.5%. The CR and PR for combined primary and nodal site were seen in 4 (10.0%) and 23 (57.5%) patients, respectively, whereas 4 (10.0%) patients had SD and 9 (22.5%) patients had PD.
A Phase III study was done by Hitt et al. The patients were randomized to receive three cycles of ICT - either two-drug regimen of PF or three-drug regimen consisting of cisplatin, 5FU, and paclitaxel (TPF), both followed by cisplatin-based CRT. CR rate after ICT was 14% in the PF arm compared to 33% in TPF arm whereas the PR rates were 54% and 47%, respectively, in the two arms. ORR was 68% for the PF arm and 80% for the TPF arm.
Thus, the CR (10.0%) and ORR (67.5%) in our study after ICT were consistent with the PF arm of the study by Hitt et al. However, CR and ORR observed in our study after ICT were less than the TPF arm of the above-discussed study.
The CR of 10.0% observed in our study was higher than PF (6.6%) as well as TPF (8.5%) arms of the TAX 323 trial. Furthermore, the ORR of 67.5% in our study was higher than the PF arm (54%) and similar to the TPF arm (68%).
Although our results in terms of CR were inferior (10.0% in our study vs. 17.0% in the TPF and 15.0% in the PF arm), ORR (67.5%) observed in our study was consistent with that reported by Posner et al., in the TAX 324 trial (72% in the TPF and 64% in the PF group). Paccagnella et al., in their study reported ORR of 69.5% and CR of 6.5% after ICT with TPF. Thus, our ORR (67.5%) was similar and CR (10.0%) was higher than that reported by this study. However, more patients had PD in our study (22.5% vs. 10.8%).
Our results are also consistent with those shown by Somani et al., who showed an overall response rate of 70.45% after ICT with docetaxel, PF. However, in their study, all patients had Stage IV disease and the most common site of primary disease was oral cavity or oropharynx.
In the recent DeCIDE trial by Cohen et al., the overall response rate to ICT was 64% which is consistent with ORR of 67.5% observed in our study group after ICT.
During ICT, the most frequently observed adverse events were neutropenia, alopecia, nausea, vomiting, anorexia, fatigue, and decreased hearing.
Neutropenia observed in our study group after ICT (30%) was less than both the PF (52.5%) and TPF (76.9%) arms of the TAX 323 trial whereas febrile neutropenia in our study (5%) was comparable to the TPF arm (5.2%) but higher than the PF arm (2.8%).
Neutropenia in our study was much less than that seen in TAX 324 trial in which 83% of patients in the TPF group and 56% of patients in the PF group experienced Grade 3 or 4 neutropenia. In TAX 324 study, febrile neutropenia was seen in 12% of patients in TPF arm and 8% of patients in the PF arm, whereas in our study, febrile neutropenia was seen in only 5% of patients.
Thus, the rates of neutropenia as well as febrile neutropenia were less in our study compared to most of the data published in literature for the TPF ICT regimen. However, some studies have also reported lower rates. Thus, even though we used less toxic and more cost-effective regimen, we could obtain results consistent with that published in literature for the PF and even TPF ICT.
Furthermore, we obtained comparable results after two cycles of ICT as against three to four cycles which have been used in most of the studies.
During CRT, acute toxicities in the form of skin reactions, mucositis, laryngeal, pharyngeal and salivary gland toxicities, and neutropenia were observed.
Cohen et al. reported Grade 3 or higher dermatitis in 18% of patients in ICT + CRT arm which is less when compared to our study.
We observed combined Grade 3 and 4 mucositis in 56.2% of patients and combined Grade 1 and 2 mucositis in 43.8% of patients.
In the study done by Paccagnella et al., overall Grade 3 and 4 mucositis was seen in 27.7% of patients in TPF followed by CT + RT arm. Thus, we observed higher grades of mucositis compared to this study.
Cohen et al. reported Grade 3 or higher mucositis in 51% of patients in ICT followed by CRT arm. These rates are consistent with our study.
Interruption of RT for a duration of >3 days was seen in four patients (12.5%). The reason for treatment interruption was G3 and G4 skin toxicities, G3 mucositis, and pharyngeal toxicities.
In the present study, of 32 patients who received CRT after ICT, CR was seen in 17 patients (53.1%) which is slightly higher than that reported by Paccagnella et al., who observed CR of 50% in TPF followed by CT + RT arm.
In our study, PR was seen in 10 (31.3%) patients which is slightly less than that seen in a study done by Paccagnella et al., who reported PR of28.2% in TPF followed by CT + RT arm.
After CRT, 3 (9.4%) patients in our study had PD whereas 2 (6.3%) patients had SD. In contrast, Paccagnella et al. noticed PD in 19.5% and SD in 2.2% of patients in TPF followed by CT + RT arm. SD was reported in patients in TPF followed by CT + RT arm.
The ORR of 84.4% in our study is comparable to that reported by Paccagnella et al., who reported ORR of 78.2% in TPF followed by CT/RT arm.
Furthermore, ORR of 84.4% in our study group is comparable to 79% seen in ICT + CRT arm of the DeCIDE trial by Cohen et al.
Only a few positive Phase III trials of ICT have been published to date: The Gruppo di Studio sui Tumori della Testa e del Collo,, which showed a survival benefit for patients who were considered ineligible for resection and the Groupe d'Etude des Tumeurs de la Teˆte et du Cou, which was limited to oropharynx cancer.
Updated findings from the MACH-NC trial have shown a small nonsignificant OS advantage for ICT followed by RT (2% at 2 and 5 years) over RT alone; however, when the analysis was limited to PF induction, OS was improved by 5.4% at 5 years (P = 0.05).,
An important limitation of our study is the small sample size and inadequate follow-up period. Definite conclusion on the effect of neoadjuvant chemotherapy on distant metastasis and OS would require longer follow-up. Furthermore, taxanes which are the current standard of care in neoadjuvant chemotherapy were not used in our study.
| » Conclusion|| |
- ICT is an important concept in the management of patients with locally advanced unresectable SCCHN based on the facts that ICT helps in organ preservation/conservation, good locoregional control, in addition to preventing distant failures
- Cisplatin and ifosfamide combination being less toxic and more cost-effective was used for ICT
- Acute toxicities (hematological, mucosal, laryngeal, and salivary gland) were manageable
- ICT resulted in downsizing the bulky nodal disease in sizeable number of patients, which made execution of radiation treatment possible
- The response rates observed in our study after ICT with cisplatin and ifosfamide are comparable to the trials using PF or TPF regimen for ICT; we may conclude that this combination regimen for ICT is not only economical but also well tolerated by the patients.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| » References|| |
Somani N, Goyal S, Pasricha R, Khuteta N, Agarwal P, Garg AK, et al.
Sequential therapy (triple drug-based induction chemotherapy followed by concurrent chemoradiotherapy) in locally advanced inoperable head and neck cancer patients-Single institute experience. Indian J Med Paediatr Oncol 2011;32:86-91.
Parkin DM, Bray F, Ferlay J, Pisani P. Global cancer statistics, 2002. CA Cancer J Clin 2005;55:74-108.
Kulkarni MR. Head and neck cancer burden in India. Int J Head Neck Surg 2013;4:29-35.
Seiwert TY, Cohen EE. State-of-the-art management of locally advanced head and neck cancer. Br J Cancer 2005;92:1341-8.
Pignon JP, Bourhis J, Domenge C, Designé L. Chemotherapy added to locoregional treatment for head and neck squamous-cell carcinoma: Three meta-analyses of updated individual data. MACH-NC Collaborative Group. Meta-analysis of chemotherapy on head and neck cancer. Lancet 2000;355:949-55.
Pignon JP, Baujat B, Bourhis J. Individual patient data meta-analyses in head and neck carcinoma: What have we learnt? Cancer Radiother 2005;9:31-6.
Calais G, Alfonsi M, Bardet E, Sire C, Germain T, Bergerot P, et al.
Randomized trial of radiation therapy versus concomitant chemotherapy and radiation therapy for advanced-stage oropharynx carcinoma. J Natl Cancer Inst 1999;91:2081-6.
Denis F, Garaud P, Bardet E, Alfonsi M, Sire C, Germain T, et al.
Final results of the 94-01 French Head and Neck Oncology and Radiotherapy Group randomized trial comparing radiotherapy alone with concomitant radiochemotherapy in advanced-stage oropharynx carcinoma. J Clin Oncol 2004;22:69-76.
Hitt R, López-Pousa A, Martínez-Trufero J, Escrig V, Carles J, Rizo A, et al.
Phase III study comparing cisplatin plus fluorouracil to paclitaxel, cisplatin, and fluorouracil induction chemotherapy followed by chemoradiotherapy in locally advanced head and neck cancer. J Clin Oncol 2005;23:8636-45.
Posner MR, Haddad RI, Wirth L, Norris CM, Goguen LA, Mahadevan A, et al.
Induction chemotherapy in locally advanced squamous cell cancer of the head and neck: Evolution of the sequential treatment approach. Semin Oncol 2004;31:778-85.
Haddad RI, Shin DM. Recent advances in head and neck cancer. N Engl J Med 2008;359:1143-54.
Vermorken JB, Remenar E, van Herpen C, Gorlia T, Mesia R, Degardin M, et al.
Cisplatin, fluorouracil, and docetaxel in unresectable head and neck cancer. N Engl J Med 2007;357:1695-704.
Posner MR, Hershock DM, Blajman CR, Mickiewicz E, Winquist E, Gorbounova V, et al.
Cisplatin and fluorouracil alone or with docetaxel in head and neck cancer. N Engl J Med 2007;357:1705-15.
Pointreau Y, Garaud P, Chapet S, Sire C, Tuchais C, Tortochaux J, et al.
Randomized trial of induction chemotherapy with cisplatin and 5-fluorouracil with or without docetaxel for larynx preservation. J Natl Cancer Inst 2009;101:498-506.
Haddad R, O'Neill A, Rabinowits G, Tishler R, Khuri F, Adkins D, et al.
Induction chemotherapy followed by concurrent chemoradiotherapy (sequential chemoradiotherapy) versus concurrent chemoradiotherapy alone in locally advanced head and neck cancer (PARADIGM): A randomised phase 3 trial. Lancet Oncol 2013;14:257-64.
Paccagnella A, Ghi MG, Loreggian L, Buffoli A, Koussis H, Mione CA, et al.
Concomitant chemoradiotherapy versus induction docetaxel, cisplatin and 5 fluorouracil (TPF) followed by concomitant chemoradiotherapy in locally advanced head and neck cancer: A phase II randomized study. Ann Oncol 2010;21:1515-22.
Cohen EE, Karrison TG, Kocherginsky M, Mueller J, Egan R, Huang CH, et al.
Phase III randomized trial of induction chemotherapy in patients with N2 or N3 locally advanced head and neck cancer. J Clin Oncol 2014;32:2735-43.
Paccagnella A, Orlando A, Marchiori C, Zorat PL, Cavaniglia G, Sileni VC, et al.
Phase III trial of initial chemotherapy in stage III or IV head and neck cancers: A study by the Gruppo di Studio sui Tumori della Testa e del Collo. J Natl Cancer Inst 1994;86:265-72.
Zorat PL, Paccagnella A, Cavaniglia G, Loreggian L, Gava A, Mione CA, et al.
Randomized phase III trial of neoadjuvant chemotherapy in head and neck cancer: 10-year follow-up. J Natl Cancer Inst 2004;96:1714-7.
Domenge C, Hill C, Lefebvre JL, De Raucourt D, Rhein B, Wibault P, et al.
Randomized trial of neoadjuvant chemotherapy in oropharyngeal carcinoma. French Groupe d'Etude des Tumeurs de la Tête et du Cou (GETTEC). Br J Cancer 2000;83:1594-8.
Bourhis J, Le Maître A, Baujat B, Audry H, Pignon JP; Meta-Analysis of Chemotherapy in Head, Neck Cancer Collaborative Group; Meta-Analysis of Radiotherapy in Carcinoma of Head, et al.
Individual patients' data meta-analyses in head and neck cancer. Curr Opin Oncol 2007;19:188-94.
[Table 1], [Table 2], [Table 3], [Table 4]