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ORIGINAL ARTICLE
Year : 2014  |  Volume : 51  |  Issue : 1  |  Page : 20-24
 

Weekly chemotherapy as Induction chemotherapy in locally advanced head and neck cancer for patients ineligible for 3 weekly maximum tolerable dose chemotherapy


1 Department of Medical Oncology, Tata Memorial Hospital, Mumbai, Maharashtra, India
2 Department of Radiodiagnosis, Tata Memorial Hospital, Mumbai, Maharashtra, India
3 Department of Head and Neck Surgery, Tata Memorial Hospital, Mumbai, Maharashtra, India
4 Department of Radiation Oncology, Tata Memorial Hospital, Mumbai, Maharashtra, India

Date of Web Publication18-Jun-2014

Correspondence Address:
Prabhash Kumar
Department of Medical Oncology, Tata Memorial Hospital, Mumbai, Maharashtra
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0019-509X.134608

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 » Abstract 

Objective: To study the safety and efficacy of weekly chemotherapy as part of induction chemotherapy, in locally advanced head and neck cancer for patients, who are unfit for upfront radical treatment. Materials and Methods: It is a retrospective analysis of on-use weekly chemotherapy as Induction chemotherapy in locally advanced head and neck cancer, who are technically unresectable are unfit for upfront radical treatment. Induction chemotherapy given was a 2 drug combination of paclitaxel (80 mg/m 2 ) and carboplatin AUC 2. The decision to give weekly induction chemotherapy was given on the basis of presence of 2 more following features: Poor performance status (ECOG PS 2-3), presence of uncontrolled co morbidities, BMI below 18.5 kg/m 2 and age more than 60 years. The Statistical Package for the Social Sciences software (SPSS version 16.0) was used for analysis. The response rates, toxicity (accordance with CTCAE vs. 4.02), completion rate (Cp) of radical intent treatment post neoadjuvant chemotherapy (NACT), progression-free survival (PFS) and overall survival (OS) are reported. Results: Fifteen patients were considered for such therapy. Fourteen out of fifteen patients completed NACT. The median numbers of planned weekly cycles were 6 (3-8). Response (CR + PR) was seen in 10 patients. Overall grade 3-4 toxicity was seen in 6 patients. No toxicity related mortality was noted. The calculated completion rate (Cp) of radical intent treatment post NACT was 46.7%. The median PFS and OS were 10.36 months (95% CI 6.73-14.00 months) and 16.53 months (95% CI 4.22-28.84). Conclusion: Use of induction chemotherapy with weekly regimen is safe and effective selected cohort of patients with locally advanced disease who are unfit for upfront radical treatment.


Keywords: Head and neck cancers, neoadjuvant chemotherapy, poor performance status, technically unresectable, weekly induction


How to cite this article:
Patil VM, Noronha V, Joshi A, Muddu VK, Dhumal S, Arya S, Juvekar S, Pai P, Chatturvedi P, Devendra AC, Ghosh S, D'cruz A, Kumar P. Weekly chemotherapy as Induction chemotherapy in locally advanced head and neck cancer for patients ineligible for 3 weekly maximum tolerable dose chemotherapy. Indian J Cancer 2014;51:20-4

How to cite this URL:
Patil VM, Noronha V, Joshi A, Muddu VK, Dhumal S, Arya S, Juvekar S, Pai P, Chatturvedi P, Devendra AC, Ghosh S, D'cruz A, Kumar P. Weekly chemotherapy as Induction chemotherapy in locally advanced head and neck cancer for patients ineligible for 3 weekly maximum tolerable dose chemotherapy. Indian J Cancer [serial online] 2014 [cited 2020 Dec 3];51:20-4. Available from: https://www.indianjcancer.com/text.asp?2014/51/1/20/134608



 » Introduction Top


Neoadjuvant chemotherapy (NACT) in head and neck cancers is associated with significant grade 3-4 toxicities and 1-2% treatment-related mortality. [1],[2],[3] These patients included in the various NACT trials were relatively fit patients with good performance status. [1],[2],[3]

In the real world situation, a cohort of patients with advanced head and neck cancers have significant issues relating to poor nutrition, poor general condition, age and comorbidities, which make them unsuitable for standard 3 drug NACT regimens or radical treatment. [4],[5],[6]

Head and neck cancers are seen commonly in after 5 th decade of life. [7] However, a substantial proportion of patients is elderly and account for around 18-24% of the total population. There are no clear guidelines on treatment of elderly patients as they are underrepresented in clinical trials. [8],[9] Studies have shown that the proportion of patients receiving non-standard treatment increases to around 64% with increasing age of the patient. [10],[11] The percentage of patient offered no treatment also increases to 18%, as the age of patient increases. [10],[11] This is an alarming statistic, especially in India, where the proportion of elderly patients is expected to increase due to increasing life expectancy and changing demographic profile in India. [7]

Impaired nutritional status secondary to poor nutritional intake in advanced head and neck cancers is a significant negative prognostic factor. [12],[13] In developing countries like India, poor socioeconomic conditions also contribute to impaired general condition of the patient. [7] Reduced nutritional status is known to lead to low tolerance for radiation, surgery and increased complications with chemotherapy. [10],[12],[13],[14],[15],[16] Uncontrolled comorbidities also contribute to poor PS and toxicity with chemotherapy and worse outcome. [17],[18] The performance status is objectively assessed by the Eastern Cooperative Oncology Group (ECOG) performance score. Patents with score of 2-3 are considered mainly for palliative treatment schedules in most guidelines. [19] Thus a significant proportion of patients in our country are ineligible for standard therapy. [4],[5],[6]

We believe that there might be a subset of patients with the above mentioned factors who still have a reasonably adequate physiological reserve and might tolerate lower intensity chemotherapy. If the chemotherapy is used in the neoadjuvant setting, it might help in shrinking the tumor and lead to treatment with radical intent, either surgery or radiotherapy. Local control of the disease would in addition give some time for building up the nutritional status of the patient. At our center, we have tried this approach using weekly chemotherapy. The regimen has been used previously in lung cancer with good efficacy and manageable toxicity even in elderly patients. [20] The present report details our experience with weekly chemotherapy in those patients who are not fit for standard treatment schedules upfront. To the best of our knowledge, this has not been reported previously.


 » Materials and Methods Top


The treatment plan of patients presenting with head and neck cancers is decided in a multidisciplinary meeting at our center. The patients with locally advanced cancers, who were technically unresectable were considered suitable for neoadjuvant therapy are then treated in the medical oncology department. The standard Neoadjuvant protocol used in our center is a double or triple regimen consisting of a taxane and a platinum agents with or without 5-fluorouracil. [3],[21] Some patients were considered unsuitable for the usual protocol as they were unlikely to tolerate the chemotherapy. The reason for opting for weekly protocol in such patients included factors like

• Poor performance status (ECOG PS 2 or 3)

• Uncontrolled comorbidities like hypertension, diabetes mellitus, cardiac dysfunction or any other uncontrolled disease

• Emaciation or poor nutritional status (BMI below20 kg/m 2 ) [22]

• Age 60 yrs or above.

Patients with 2 or more of these characteristics were previously treated with a palliative intent at our center. [5] However, in the present study, a more aggressive treatment was considered with the intent of enabling radical therapy. All patients received weekly chemotherapy with paclitaxel 80 mg/m 2 with carboplatin at a dose of AUC 2. The chemotherapy was planned for 6 weeks. After the completion of therapy, the patients were re-assessed clinically and radiologically in the multidisciplinary clinic. Based on the performance status, nutritional status, response to treatment and the status of comorbidities, further treatment could be surgery, radical radiation with or without chemotherapy, palliative chemotherapy or best supportive care alone.

The demographic details, status of disease, details of the chemotherapy including the toxicity according to the CTCAE version 4.02 (common terminology criteria of adverse events), response rate to NACT (RECIST version 1.1) and survival details were extracted from a prospectively maintained database in the medical oncology department along with review of the case files. We have considered radical intent to mean treatment with surgery or radical radiation following induction chemotherapy.

Statistical analysis

Descriptive statistics about the baseline demographics, tumor details, response rate, toxicity, post- induction therapy and details of the failure pattern are provided.

We used the following formula to calculate the completion of plan (Cp), which represents the proportion of patients whose treatment plan could be completed with radical intent.

Cp = (number of patients treated with radical intent post NACT) ×100/total number of patients included

Kaplan Meier analysis was used for estimating progression-free survival (PFS) and overall survival (OS). Progression-free survival was calculated from the date of registration to the date of progression or death, whichever occurred earlier. Overall survival (OS) was calculated from the date of registration to the date of death. For patients lost to follow-up the date of last assessment of disease was considered for PFS calculation and the last date of contact was used for OS calculation.


 » Results Top


Baseline demographics and tumor details

In the time period between August 2010 and August 2012, 15 patients received weekly induction chemotherapy. The baseline parameters are shown in [Table 1]. All patients had stage IVA or IV B diseases. The majority of the patients had the primary in the oral cavity (73.3%) with the buccal mucosa being the most common sub site seen in 7 patients (46.7%).
Table 1: Important baseline parameters

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The reason for giving weekly chemotherapy is depicted in [Table 2]. All of the patients had advanced disease and in addition, several had significant comorbidities. Though there were patients with ischemic heart disease, none of them had an acute coronary event within the past 12 months and had cardiac ejection fraction above the limit, which is considered normal at our institution. One patient {number 9} had chronic hepatitis B infection with grade 2 transaminitis. Two other patients {number 1 and 5} had HCV hepatitis with grade 1 transaminitis.
Table 2: Chemotherapy details. Reason for choosing weekly chemotherapy

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Fourteen patients (93.3%) completed the scheduled chemotherapy. The median number of cycles delivered was 6 (3-8 cycles). Although 6 cycles were planned for patients, in 4 patients 2 more cycles were given as the local treatment was delayed. Only one patient required 25% dose reduction in view of grade 4 neutropenia and febrile neutropenia. An average relative dose intensity of more than 90% was maintained in 13 patients (86.66%). The toxicity details are shown in [Table 3]. There was no toxicity-related mortality.
Table 3: Toxicity details. The number depicts the number of patients. Toxicity details were available for 14 patients

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Response

The response was assessed in 14 patients after completion of chemotherapy. The responses seen were complete response in 1 patient (6.7%), partial response in 9 patients (60.0%), stable disease in 3 patients (20.0%) and progressive disease in 1 patient (6.7%). The median decrement in size of target was 35% (10-100%).

Post NACT therapy

Of the 14 patients completing chemotherapy, 3 underwent surgery followed by adjuvant.

treatment, 3 were treated with radical chemoradiation and 1 patient received radical radiation alone. The remaining patients were treated with palliative intent. Six patients underwent palliative radiation and one was found suitable for supportive care only. Thus, the calculated completion rate (Cp) of radical intent treatment was 46.7% as 7 of 15 patients completed radical intent treatment.

Post NACT resectability and suitability for surgery could be achieved in 7 patients. However, only 3 patients finally underwent surgical resection. One patient had persistent thrombocytopenia, 1 developed second malignancy in the form of plasmablastic lymphoma in rectum, 1 patient was unwilling for surgery and the last patient refused further treatment. All the 3 patients who underwent surgery had R0 resection. In the 4 patients receiving radical radiation, 2 were treated with a dose of 66 Gy while the other two received a dose of 70 Gy, all at a standard fractionation dose of 2 Gy/fraction. Only 1 patient had a gap of 4 days in radiation due to grade 3 mucositis. Concurrent chemotherapy given was 30 mg/m 2 of cisplatin in 3 of these 4 patients. All 3 completed 6 cycles of chemotherapy.

Failure pattern

The median follow-up was 18 months. At this point, 8 patients had progressed. The site of progression was both local with distant progression in 1 patient, regional nodal progression in 2 patients and local progression alone in the remaining 12 patients.

PFS and OS

The median progression free survival is 10.36 months (95% CI 6.73-14.00 months) [Figure 1]. The median OS was 16.53 months (95% CI 4.22 -28.84) [Figure 2]. As the number of patients is small, no univariate or multivariate analysis was possible.
Figure 1: Kaplan Meier estimate of progression-free survival

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Figure 2: Kaplan Meier estimate of overall survival

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 » Discussion Top


Locally advanced head and neck cancer patients with ECOG performance status of 2 or more, older age, uncontrolled severe co morbidities or poor nutritional status are frequently considered unsuitable for radical treatment and are often treated with palliative radiation alone. [4],[5],[6] Such an approach has been reported previously from India and is associated with unsatisfactory survival outcomes. Mohanti et al., treated 578 patients with a uniform palliative schedule of 20 Gy/5# over 5 days. [4] The median survival was only 200 days (6.67 months). Though all sub-sites in head and neck cancers were included in the study, oropharyngeal cancers were predominant (233 patients, 46%). Oropharyngeal tumors are frequently associated with HPV and such tumors normally have a favorable prognosis. [23],[24] All the patients had stage IV disease. However, only 30% had stage IVB while 43.16% had non T4 disease (T1-T3). Ghosal et al., reported the results of QUAD shot therapy from another center in north India. [6] Fifteen patients were treated with QUAD shot and had good symptom relief but with a median PFS of just12 weeks. Agarwal et al., published results of 110 patients treated with an alternative schedule of 40 Gy given in 16# over 3.1 weeks. Similar to the previous report, the most common subsite was the oropharynx (41%), 50% patient had a KPS (Karnosky performance status) equal to or above 70 and non T4 disease was present in 22% of patient. In this report, the median local progression free survival was around 1 year. The PFS (including local and distant progression) and OS were not reported. These series from major centers in India show that palliative radiation is often used for symptom relief when tumors are not considered curative. Interestingly, despite the majority of the tumors belonging to favourable subsites like the oropharynx, good performance status and stage IV A disease, palliative RT was preferred over radical chemoradiation. Though no reasons are mentioned by the authors, it can be surmized that extensive disease and limited resources may have swayed the decision to use palliative treatment only. [4],[5],[25] Considering the proportion of locally advanced cancers in India, such a treatment approach might be condemning a large population to palliation only. Similar reports of palliative treatment schedules have been reported from Western world too. [26],[27],[28]

Though the primary intent of our chemotherapy protocol is to enable surgical resection, minimal reduction and improvement in performance status may result in patients becoming eligible for radical chemoradiation, which is associated with improved survival. In the case series by Mohanti et al., and Agarwal et al., patients had favorable response with increased radiation and had an improvement in survival. [4],[5] Agarwal et al., showed that the hazard ratio in favor of dose of radiation more than 40 Gy was 4.36.

Our results show some noteworthy features. Despite nearly all the patients having a performance of 2 or above with other added adverse prognostic factors, the tolerance to weekly induction chemotherapy was acceptable. Fourteen out of fifteen patients completed the scheduled induction chemotherapy though there was serious toxicity (grade 3-4 toxicity in 6 of 14 patients), which required careful supervision; there was no toxicity related death in our study. Interestingly, nearly all the events occurred in the first two cycles. We believe that improved tolerance to chemotherapy after the first two cycles could reflect improved nutrition and dose adjustment, which was done after initial chemotherapy. The response rate of 66.7% noted in our study compares favorably with our own published literature. The response rate is especially surprising considering the large proportion of oral cavity tumors and adverse prognostic factors. In our study, the conversion rate to resectability was around 47% and similar number of patients received radical intent treatment post- induction therapy. The impact of multimodality treatment was seen in OS with 2 year survival being 34% and the median OS being 16.53 months. These results are better than the previously reported series with palliative radiation as shown in [Table 4].
Table 4: Table comparing PFS and OS of different palliative RT schedules with present series

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Our study has limitations, chiefly being the limited number of patients. Since this was a pilot observational study done to assess the benefit of weekly chemotherapy, we believe the numbers are enough for us to reject the subsequent use of such treatment schedule if it was not beneficial. We plan to compare a weekly schedule against the standard 3 drug regimen schedule of NACT in a larger study in the future.


 » Conclusion Top


Neoadjuvant chemotherapy with weekly schedule is reasonably well tolerated and feasible in a selected cohort of patients with locally advanced disease who are unfit for upfront radical treatment. Rather than treating with a palliative intent with poor outcome, our approach resulted in radical treatment in 47% of patients and can potentially improve outcomes in such patients.

 
 » References Top

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2.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.  Back to cited text no. 2
    
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27.Al-Mamgani A, Tans L, Van rooij Peter HE, Noever I, Baatenburg de jong RJ, Levendag PC. Hypofractionated radiotherapy denoted as the "Christie scheme": An effective means of palliating patients with head and neck cancers not suitable for curative treatment. Acta Oncol 2009;48:562-70.  Back to cited text no. 27
    
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    Figures

  [Figure 1], [Figure 2]
 
 
    Tables

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

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