Abstract
To compare the locoregional control rates, survival outcome and toxicity profiles between two groups of patients of squamous cell carcinoma (SCC) of Head and Neck (Stage III & IV) receiving concomitant chemo-radiotherapy with Paclitaxel and Cisplatin. A prospective study was done on 94 previously untreated patients of histopathologically proved squamous cell carcinoma of head and neck region-AJCC stage III & IV (T3 & T4 with N0 -N3, M0) treated with concomitant chemoradiation. The patients were divided into two groups. Group A (44 patients) received concomitant chemotherapy (C.T.) with Paclitaxel 40 mgm/m2 while Group B (50 patients) received concomitant chemotherapy with Cisplatin 40 mgm/m2. All the patients in both the groups responded. In Group A (Paclitaxel + R.T.), complete response was seen in 72.7% and partial response in 27.3%. In Group B (Cisplatin +R.T.) complete response was seen in 52% and partial in 48%. At one year follow up, the locoregional control rate (LRC) in Group A was significantly higher as compared to that in Group B (65.9 vs. 46%, P<0.05) while there was no difference in the disease free survival (DFS) and the overall survival (OS). A 3 year estimate of the LRC, DFS and OS using Kaplan Meier Estimator revealed no difference in the LRC, DFS and OS between the 2 groups. There was a higher incidence of skin and mucosal toxicity with Paclitaxel while the gastro-intestinal and hematological toxicity was more with Cisplatin. No significant chronic toxicity except xerostomia was observed in either group. Paclitaxel has better complete response and locoregional control rates at 1 year as compared to cisplatin. However, there is no difference in the estimated 3 year rates of locoregional control, disease free survival and overall survival between the 2 groups.
Keywords: Chemoradiation, Paclitaxel, Cisplatin
Introduction
With a paradigm shift towards organ preservation, combined modality treatment employing radiation and chemotherapy has taken a more centralized place in the management of head and neck cancers. Most of the cancers (70–80%) of head and neck are diagnosed with locally advanced disease [1]. In the past, the 5-year survival of locoregionally advanced disease was reported to be only 40% [2] and locoregional failure was the predominant cause of recurrence. In addition, almost half of the patients who die from head and neck cancer (HNC) have locoregional disease as the only site of failure and 90% of patients who develop distant metastasis also have persistent locoregional disease. Thus the efficacy of any curative approach is measured by its ability to achieve locoregional control [3]. The traditional method of management of patients with locoregionally advanced disease has been surgery followed by postoperative radiotherapy with chemotherapy reserved for palliative purposes. The 5 year survival rates with these approaches have been poor due to frequent local or regional recurrences [4]. The addition of chemotherapy to these approaches has increased the locoregional control with a marked improvement in survival and organ preservation [5–7]. In 1987, the Radiation Therapy Oncology Group (RTOG) first reported results from a phase II trial testing radiation and concurrent high dose Cisplatin (100 mg/m2 given every three weeks during radiation therapy). A complete response rate of 71% and a 4-year survival rate of 34% were reported in a cohort of 124 patients [8]. Since then a number of clinical trials have consistently proved the increased rate of locoregional control and survival with combined chemoradiation [7, 9–11]. Chemotherapy has been used in various combinations with standard local treatment. This includes induction chemotherapy, post-definite chemotherapy and concurrent chemotherapy. The rationale behind the combination of chemotherapy with radiotherapy is three fold. Firstly, concomitant chemoradiotherapy can be used with organ preserving intent, resulting in improved cosmesis and function compared with surgical resection with or without adjuvant treatment. Secondly, chemotherapy can act as a radiosensitizer improving the probability of local control and survival, by aiding the destruction of radioresistant clones. Thirdly, chemotherapy may eradicate distant micrometatasis [12].
The use of radiosensitizers has reduced the failure rates of radiotherapy alone. The radiosensitivity of a cell is dependent on the phase of cell cycle; cells in the S phase are more radioresistant while cells in the G2–M phase of the cell cycle are most radiosensitive [13, 14]. The various radiosensitizers arrest cell cycle at G2–M phase thus enhancing the cytotoxic effect of radiation. ‘True’ radiosensitizers like hypoxic cells sensitizers (e.g., misonidazole), and thymidine analogues (e.g., bromodeoxyuridine) do not have inherent cytotoxic activity. However the most commonly used radiosensitizers (cisplatin, 5-FU, and taxanes) do have inherent cytotoxic activity and can increase damage to normal tissues [12]. Cisplatin is a potent radiosensitizer and the drug most commonly used for chemoradiotherapy in HNC [3]. Various studies using Cisplatin as a single agent chemoradiotherapy have demonstrated survival rates ranging from 37–73% [11, 15]. Taxanes are another group of radiosensitizers which have a unique mechanism of action which leads to the formation of high affinity bonds with microtubules promoting tubulin polymerization and stabilization. Both Paclitaxel and Docetaxel have demonstrated single agent activity in patients with SCC of head and neck in several trials [16–19].
As compared to developed countries the scenario of cancer in a developing country like ours is quite different. The burden of cancer is significantly higher and the cost of therapy becomes an important factor. Also most of the cancer patients are from a rural background with limited education and this hampers the post-operative rehabilitation of these patients. The follow up is also poor and significant proportion of patients decline surgery as the primary modality. The standard of treatment in our institution for concurrent chemoradiation in advanced cases of head and neck cancer is Cisplatin. With the establishment of the efficacy of Paclitaxel in advanced cases of head and neck cancer, another option became available. The present study was aimed to compare the locoregional response rates in advanced head and neck cancers in two groups receiving concomitant chemoradiation using Cisplatin and Paclitaxel.
Materials and Methods
Patient Selection
This prospective study was carried out on previously untreated patients of histologically proven squamous cell carcinoma of head and neck AJCC stage III and IV (T3–T4 with N0–N3, M0). The patients either refused surgery or were ineligible for curative resection. Patients with obvious metastatic disease on diagnostic imaging were excluded from the study. Additional inclusion criterion included are as follows: (1) Age greater than 18 years. (2) Karnofsky performance status (KPS) >80. (3) Adequate bone marrow function: Absolute neutrophil count (ANC) >2 × 109/l, Platelet count >100 × 109/l, and a normal PT and aPTT. (4) Adequate renal function (creatinine <1.5 mg/dl). (5) Adequate hepatic function (Bilirubin <2 mg/dl, Albumin >3.5 g/dl, SGOT less than four times upper limit of normal). Patients specifically excluded from the study were: (1) Patient with distant metastasis. (2) Patients with associated medical conditions like uncontrolled hypertension, ischemic heart disease, diabetes mellitus, and pulmonary tuberculosis. (3) Patients with prior or synchronous malignancy. (4) Previous radiotherapy or chemotherapy.
Pretreatment Evaluation
All the patients were evaluated jointly by an otolaryngologist, head and neck surgeon and radiation oncologist. Pretreatment evaluation included complete history and physical examination, assessment of KPS, endoscopic biopsy and examination under general anesthesia for assessing the exact extent of the tumor, ultrasound mapping of neck nodes, computed tomography and magnetic resonance imaging of head and neck, chest X-ray and ultrasound abdomen. Complete blood cell count, serum electrolytes, blood urea nitrogen, serum creatinine, glucose, total protein, albumin, calcium, phosphate, uric acid, bilirubin, coagulation studies, HIV antibody.
Premedication
The patients were premedicated with dexamethasone 20 mg at 12 and 6 h before Paclitaxel administration and then promethazine 25 mg IM, Ondensetrone and H2 blocker 1 h before infusion of the drugs.
Drug Schedule
Paclitaxel and Cisplatin were delivered concurrent with radiotherapy in a dose of 40 mg/m2 as continuous infusion over 2 h. In each group 6 cycles of chemotherapy were given on weekly basis starting two day before the start of radiation therapy. Chemotherapy was given at weeks 0, 1, 2, 5, 6, and 7. No dose modification was required during the course of the treatment due to toxicity.
Radiation Therapy
Radiotherapy was delivered by a cobalt 60 beam using parallel opposite fields. Patient was immobilized with ORFIT immobilization casts. Total dose was 6,600 cGy (6,400–7,000 cGy) delivered over 6–7 weeks (Av. 6.5 weeks) in 32–35 fractions. Cord shields were used after 4,400 cGy.
Evaluation
The patients were assessed for objective tumor response according to WHO criterion [20] for response: (1) Complete response (CR): total tumor regression for at least 4 weeks. (2) Partial response (PR): 50% or more reduction in product of two major perpendiculars of the measurable tumor for at least 4 weeks. (3) Stable disease (SD): less than 50% reduction to less than 25% increase in cross product. (4) Progressive disease (PD): growth of measurable tumour by 25% or more or appearance of new lesions.
Toxicity Assessments
Toxicities were evaluated by history and physical examination and by blood cell counts and serum tests. Complete blood counts and kidney function and liver function were repeated in all patients before each cycle. In group 2, audiogram was done before each cycle and repeated monthly up to three months after treatment. The toxicities were considered acute if discovered during the first 12 weeks after the initiation of therapy. Toxicities were graded according to the Eastern Cooperative Oncology Group (ECOG) common toxicity criteria.
Follow up
During treatment patients were examined at least weekly. Once treatment ended patients were evaluated every 4 weeks until their acute reactions resolved, then every three months for 2 years, every 4 months during 3rd year and every 6 months there after.
Statistical Analysis
The patient’s characteristics, toxicity and response rate in the two treatment groups were compared using the Students t test for continuous variables and the Chi-square test for categoric variables. All reported P values were two sided and P < 0.05 was considered statistically significant. The 3 year estimation of locoregional control rates, disease free survival and overall survival were calculated using the Kaplan–Meier estimator and compared by log rank test.
Results
Patient and Tumour Characteristics
A total of 94 patients met the inclusion criterion and were enrolled in the study (Table 1). The patients were divided into 2 groups. Group A received Paclitaxel and group B Cisplatin. The median age of patients in group A was 58.5 years (range 33–73 years) while that in group B was 59 years (range 35–71 years). Majority of the patients (84%) were male and only 16 were females. Four patients had a KPS of 100, 38 a KPS of 90 and 52 patients a KPS of 80. Median length of follow up was 20 months with a range of 10–42 months. The primary site was hypopharynx in 41 cases, oropharynx in 12 and larynx in 41 cases. By TNM staging, 50 were stage III and 44 stage IV tumors.
Table 1.
Patient characteristics
| Characteristic | Group 1 | Group 2 | ||||
|---|---|---|---|---|---|---|
| No. of patients | % | No. of patients | % | |||
| 1. | Patients studied | 44 | 46.8 | 50 | 53.2 | |
| 2. | Male:Female | 37:7 | 41:9 | |||
| 3. | Age(years) | Median | 58.5 | 59 | ||
| Range | 33–73 | 35–71 | ||||
| 4. | Karnofsky performance status (KPS) | 100 | 1 | 2 | 3 | 6 |
| 90 | 20 | 45.5 | 18 | 36 | ||
| 80 | 23 | 52.27 | 29 | 58 | ||
| 5. | Primary site | Hypopharynx | 19 | 43.2 | 22 | 44 |
| Oropharynx | 5 | 11.3 | 7 | 14 | ||
| Larynx | 20 | 45.5 | 21 | 42 | ||
| 6. | T staging | T3 | 34 | 77 | 37 | 74 |
| T4 | 10 | 23 | 13 | 26 | ||
| 7. | N-staging | N0 | 5 | 11 | 7 | 14 |
| N1 | 20 | 45 | 23 | 46 | ||
| N2 | 10 | 23 | 11 | 22 | ||
| N3 | 9 | 21 | 9 | 18 | ||
| 8. | AJCC stage | III | 23 | 52 | 27 | 54 |
| IV | 21 | 48 | 23 | 46 | ||
Treatment Response
The patients were assessed for objective tumor response according to WHO criterion for response. The patients were evaluated after two months following completion of treatment. All the patients showed responses in both the groups. There was no evidence of progression or appearance of metastasis at two months evaluation. No deaths were seen at this point of time. In group A (Paclitaxel + R.T.), complete response was seen in 72.7% and partial response in 27.3%. In group B (Cisplatin + R.T.) complete response was seen in 52% and partial in 48%. At the primary site complete response rate was seen in 34 out of 44 patients in group A (77.2%). This was significantly higher (P < 0.05) than that seen in group B. (52%). At the nodal level, of the 39 patients who presented with neck nodes in group A, 27(69%) showed complete response while out of the 43 patients who presented with neck nodes in group B 19(44%) showed complete response. The difference was statistically significant (P < 0.05). Two patients in group A and 3 patients in group B with N3 staging who had complete response at the primary and had shown partial response at nodal level underwent neck dissection. Overall the complete response rate with Paclitaxel was significantly higher (P < 0.05) as compared to Cisplatin.
Patterns of Failure at 1 Year
Failure was defined as occurrence of recurrence at local or distant site or both or death due to progressive disease. The patterns of failure are shown in Table 2. In group A receiving Paclitaxel, out of a total of 32 patients who showed a complete response rate, 9 showed recurrence at local, distant or both sites. Seven patients showing partial response died at the end of 1 year. Thus, the total number of patients who were disease free at the end of 1 year was 25 (32−9 + 2 patients who showed CR at the primary site but partial response at the nodal site and underwent neck dissection). In group B eight patients showed recurrence while 13 died at the end of 1 year. Thus the total number of patients who were disease free at the end of 1 year was 21 including 3 patients who showed CR at the primary site but partial response at the nodal site and underwent neck dissection.
Table 2.
Patterns of failure at 1 year
| Group A | Group B | |
|---|---|---|
| Local recurrence | 3 | 4 |
| Metastasis | 4 | 1 |
| Rec. + Meta. | 2 | 3 |
| Died of disease | 7 | 13 |
| Alive with disease | 12 (14 − 2) | 16 (19 − 3) |
| Disease free | 25 (23 + 2) | 21 (18 + 3) |
Locoregional Control Rates and Survival Outcome
At 1 year follow up, the locoregional control rates in group A receiving Paclitaxel was significantly higher as compared to that in group B.(65.9 vs. 44%, P = 0.03). The difference in the rates of disease free survival and overall survival was not statistically different (56.8 vs. 42%, P = 0.15; 84.1 vs. 74%, P = 0.23) (Table 3). An estimated 3 year rate of locoregional control rate using Kaplan–Meier estimator did not show any statistical difference (Fig. 1a). Similarly the estimated 3 year rates of disease free survival and overall survival were not significantly different (Fig. 1b, c respectively). The mean survival time in group A was 31.96 months which was slightly better than that of group B 28.7 months, though a statistical significance could not be established.
Table 3.
At 1 year follow up
| Paclitaxel (%) | Cisplatin (%) | P value | |
|---|---|---|---|
| Locoregional control | 65.9 | 44 | 0.03 |
| Disease free survival | 56.8 | 42 | 0.15 |
| Overall survival | 84.1 | 74 | 0.23 |
Fig. 1.
Kaplan–Meier analysis of locoregional control rate (a), Disease free survival (b) and Overall survival (c). The estimated 3 year locoregional control rate was calculated using Kaplan–Meier estimator which showed no statistical difference between the 2 groups (P > 0.05, using Log rank test). The disease free survival and overall survival also showed no difference between the 2 groups. (P > 0.05; P = 0.52 respectively, Log rank test)
Toxicity
The toxicity profile of patients in both groups is listed in Table 4. No dose limiting toxicity or grade 4 toxicity was seen in either group. The incidence of hematological side effects was greater in the Cisplatin group with 4 patients having grade 3 neutropenia. The incidence of grade 2–3 neutropenia was significantly higher in the Cisplatin group (21 or 42% patients) as compared to the Paclitaxel group (9 or 21% patients) (P < 0.05). However none of the patients developed febrile neutropenia. The incidence of anemia was also higher in group B with 3 patients developing grade 3 anemia requiring blood transfusion. In comparison the Paclitaxel group showed a significantly lesser number of hematological toxicity with no patient having grade 3 neutropenia or and 1 patient developing grade 3 anemia. Gastrointestinal toxicities were also higher with Cisplatin with 84% complaining of nausea and vomiting as compared to 63% with Paclitaxel. The incidence of local toxicities was higher with Paclitaxel. Mucositis was the commonest with all patients in the Paclitaxel group developing mucositis of varying grade with 7(16%) patients having grade 3 mucositis. In comparison grade 3 mucositis was seen in 2(4%) patients in group B. The incidence of grade 2–3 mucositis was significantly higher (P < 0.001) in Paclitaxel group as compared to cisplatin group. The development of higher grades of mucositis was reduced by management of patients at an early stage. Parenteral nutrition was started with antibiotics, antifungals, and analgesics. The incidence of dysphagia was also higher in group A with 25(56%) patients requiring Ryle’s tube feeding. In our observation the incidence of Ryle’s tube placement has decreased after the usage of antifungals for management of mucositis. Dermatological toxicities were also significantly higher (P < 0.001) with Paclitaxel with 11(25%) patients developing grade 3 toxicity as compared to none in Cisplatin group. The profile of non-hematological toxicities was similar in both groups. Xerostomia was seen in all the patients. Neurological side effects were also seen in a small number of patients in both the groups.
Table 4.
Toxicity profile
| Toxicity | Grade of toxicity | |||||||||
|---|---|---|---|---|---|---|---|---|---|---|
| Group A | Group B | |||||||||
| 0 | 1 | 2 | 3 | 4 | 0 | 1 | 2 | 3 | 4 | |
| Hematological | ||||||||||
| Anemia | 12 | 22 | 09 | 1 | 0 | 10 | 23 | 14 | 3 | 0 |
| Neutropenia | 16 | 19 | 9 | 0 | 0 | 14 | 15 | 17 | 4 | 0 |
| Thrombocytopenia | 19 | 23 | 2 | 0 | 0 | 29 | 12 | 9 | 0 | 0 |
| Mucocutaneous | ||||||||||
| Mucositis | 0 | 21 | 16 | 7 | 0 | 0 | 37 | 11 | 2 | 0 |
| Dermatological | 0 | 10 | 23 | 11 | 0 | 0 | 27 | 23 | 0 | 0 |
| Gastrointestinal | ||||||||||
| Dysphagia | 0 | 13 | 23 | 8 | 0 | 6 | 15 | 26 | 3 | 0 |
| Nausea/Vomiting | 09 | 19 | 16 | 0 | 0 | 7 | 11 | 31 | 1 | 0 |
| Diarrhoea | 39 | 3 | 2 | 0 | 0 | 42 | 7 | 1 | 0 | 0 |
| Constipation | 42 | 2 | 0 | 0 | 0 | 46 | 3 | 1 | 0 | 0 |
| Renal (Bun) | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Neurological | 39 | 5 | 0 | 0 | 0 | 44 | 6 | 0 | 0 | 0 |
| Xerostomia | 0 | 34 | 10 | 0 | 0 | 0 | 43 | 7 | 0 | 0 |
Most of the acute toxicities were managed on an out patient basis. Only 12 admissions were made: 8 for dysphagia and 4 for blood transfusions. No chronic toxicity apart from xerostomia and alopecia was seen. No deaths due to toxicity occurred during the course of treatment.
Discussion
The present study was undertaken to determine any difference in the response rates, locoregional control rates and survival outcome in two groups of patients of advanced cancer of head and neck receiving concomitant radiotherapy with Paclitaxel and Cisplatin. We found that the complete response rates were higher in patients receiving Paclitaxel as compared to the Cisplatin group. However, although the locoregional control rates were higher with Paclitaxel at 1 year follow up, a 3 year estimate of LRC rate, DFS and OS showed no difference in the 2 groups. The mean survival in the Paclitaxel group though slightly better than the Cisplatin group showed no statistical significance.
Concomitant chemoradiation using radiosensitizers has significantly improved the response rates of radiotherapy alone. Radiosensitizers arrest cell cycle at G2–M phase the most radiosensitive phase of cell cycle, thus enhancing the cytotoxic effect of radiation. Cisplatin is a potent radiosensitizer and the drug traditionally used for chemotherapy in head and neck cancers [12]. Adelstein [11] using cisplatin in a dose of 100 mg/m2 every 3 weeks, as a single agent along with radiotherapy showed a complete response rate of 42% and an estimated 3 year overall survival of 37%. Al Sarraf [15] using similar dosage schedule reported a better response rate of 89.2% and an overall survival of 76%. Various studies using Cisplatin as a single agent chemoradiotherapy have demonstrated survival rates ranging from 37 to 73% [11, 15]. A low dose of Cisplatin (40 mg/m2 weekly) has been traditionally used in our institution so as to limit the incidence of side effects. Using this regime we achieved a complete response rate of 52%.
Paclitaxel as a radiosensitizer was introduced in 1990s and has been shown to be one of the most active agents for squamous cell carcinoma of head and neck in metastatic and recurrent setting [16]. Several studies have reported various dosing schedules of Paclitaxel in the treatment of head and neck squamous cell carcinoma. In one of the earliest studies Hoffmann et al. [21] administered escalating weekly doses of Paclitaxel concomitant with standard radiotherapy (daily fractionation to total doses of 60 to 70 Gy) to 18 patients with unresectable head and neck cancer. The dose-limiting toxicity in this study was mucositis with a maximum tolerated Paclitaxel dose of 30 mg/m2/wk as 1-hour infusions. Of the seven patients who had undergone prior surgery, four (57%) had a CR after a median observation time of 8.2 months (range, 5–12 months). Of the 11 patients treated primarily with Paclitaxel and radiation, four (36%) had a CR after a median observation time of 9.4 months (range 1–15 months).
Steinberg et al. [22] reported a study in which 24 patients with stages III and IV HNSCC were administered radiotherapy in combination with Paclitaxel given as 24-hour continuous infusions on days 1, 22, and 43. This regimen achieved a CR of 72% at the primary site. Tishler et al. [23] administered Paclitaxel at a dose of 100 mg/m2 over 3 h every 3 weeks (dose-intensity = 100 mg/m2/3 weeks), in combination with external beam radiation (daily fractionation to total doses of 60 to 70 Gy). in 14 patients with stages III and IV HNSCC. Overall, the concurrent therapy achieved a CR in 13 (92%) of the 14 patients. Rosenthal et al. [24] used Paclitaxel administered as a continuous infusion 24 h/d, 7 days/wk, for the 7-week duration of radiotherapy (daily fractionation to total doses of 50 Gy) in patients with stages III and IV HNSCC. Their rationale for this dosing schedule was based on preclinical and clinical data that suggested that direct antitumor activity and radiosensitization are more dependent on the duration of Paclitaxel exposure than on the peak serum concentrations. Complete tumor clearance was documented in 74% of the patients with an overall response rate of 71% and a 2 year survival of 32%. Sunwoo et al. [25], administered Paclitaxel as a 120-hour continuous infusion every 3 weeks to 33 previously untreated patients with stage III or IV tumors. Sixteen patients received a Paclitaxel dose of 105 mg/m2, and 17 patients received 120 mg/m2. Radiation was delivered in a standard format at 1.8 Gy/d to a total dose of 70.2 to 72 Gy. Three months after therapy, a 76% complete response (CR) at the primary site and a 70% overall CR was reported. At 36 months, locoregional control was 55.7%, overall survival was 57.8%, and disease-free survival was 51.1%. The median survival duration for all 33 patients was greater than 50 months.
In the present study we have shown that Paclitaxel has significantly higher complete response rate as compared to Cisplatin. The complete response rate of 72.7% is comparable to those achieved by other authors [17, 21–25]. The most common major local toxicity associated with these various regimens of concurrent Paclitaxel and radiation has been mucositis. The same was found in our study with a significant proportion showing mucositis. As compared to Paclitaxel the incidence of hematological toxicities was higher in Cisplatin group. However local toxicities like mucositis and dermatological effects were significantly higher in the Paclitaxel group. No grade 4 toxicity was seen in either group. Though mucositis was common, higher grades of mucositis was avoided due to active management of patients.
A comparison of the 2 most common radiosensitizers used in head and neck cancer viz: Paclitaxel and Cisplatin in terms of control rates and survival outcome has not been reported prior to this study. The study demonstrates that although Paclitaxel offers a greater complete response rate as compared to Cisplatin, there is no difference in the 3 year estimated locoregional control rate, disease free survival and overall survival. However, Paclitaxel is associated with fewer systemic side effects as compared to Cisplatin.
The study however has its limitations. The study was not blinded and selection bias and reporting bias might have arisen. The attrition rate was high so the number of censored observations was high. The sample size was small. Future studies with large sample sizes, good study design and better follow are required to establish any difference in the survival outcome between the 2 drugs.
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