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Chemotherapy plus Radiation
 

Read the recent reviews on the increasing use of chemotherapy in the treatment of head and neck cancer here and here.

Combining chemotherapy with radiation  results in greater tumor shrinkage (but more side effects, especially acute mucositis, read editorial) and overall improved cure rates (see studies below by Brizel (see graph) and Calais which show significant survival improvements, (see the recent intergroup trial) and see the meta-analysis by Pignon below, see summary of some studies , the new Erbitux trialmore summarized trials).   

Other recent data here , here, here, and here.  Also using chemotherapy first to shrink the tumor (induction chemotherapy) then using combined chemo-radiation may be very effective (see TAX 324 study).

The outcome for patients with advanced head and neck cancer in the past was poor, with radical surgery and postOp radiation or radiation alone the 5 year survival rate of 30 - 50%. Now most patients get combined chemoradiation or accelerated radiation techniques and the long term survival is now in the 70 to 80% range as noted here with cisplatin. (The results just adding Erbitux to radiation may not be as good as chemotherapy, see charts further below).

Treatment Outcomes of Locally Advanced Oropharyngeal Cancer: A Comparison Between Combined Modality Radio-Chemotherapy and Two Variants of Single Modality Altered Fractionation Radiotherapy

 

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see the list of active chemotherapy regimens from the NCCN here 

 

 

 

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Chemotherapy plus radiation provides a better chance of avoiding a laryngectomy over radiation alone (see RTOG 91-11.)

The most common drug regimen is Cisplatinum plus 5FU by infusion, other agents active in head and neck cancer include methotrexate, bleomycin (Blenoxane), cisplatin, carboplatin (Paraplatin), ifosfamide (Ifex), and the taxanes, paclitaxel (Taxol) and docetaxel (Taxotere). The taxanes are the most active of these agents, with overall response rates of 40% in patients with recurrent or metastatic disease. The evaluation of taxane-based combinations as neoadjuvant therapy and as radiosensitizers during concurrent radiation is ongoing.

 

RTOG 8117 used Platinol 100mg/M2 w 1,4,7 while RTOG 9703 used weekly Platinol (20mg/M2) plus Taxol (30mg/M2), RTOG 0129 uses Platinol 100mg/m2 d1,22,43 with concurrent XRT (standard or AF) and  RTOG 0234 combined Erbitux (Cetuximab) with either weekly Platinol (30mg/M2) or Taxotere (15mg/M2) with concurrent postOp radiation (66Gy.)

 

NCCN 2005:  The choice of chemotherapy should be individualized based on patient characteristics (performance status, goals of therapy). Examples of useful agents include:
Single agent:  Cisplatin, Carboplatin, Paclitaxel, Docetaxel, 5-FU, Methotrexate, Ifosfamide, Bleomycin. Gemcitabine (nasopharyngeal)
Combination therapy:  Cisplatin/carboplatin + 5-FU,   Cisplatin/carboplatin + taxane

ChemoRad versus Rad for Stage III/IV H&N
(ONI 2002)
Therapy Survival at 1 Year Survival at 2 Years
Radiation Alone (70Gy) 59% 35%
RTOG 8117 (70Gy, platinol w1,4,7) 58% 46%
RTOG 9703 (70Gy, weekly platinol/taxol) 80% 70%
 

A recent comparison of the RTOG head and neck trails for advanced throat cancer showed better survivals (50 -63% .3y) with planned chemoradiation over just radiation alone (34 - 38%/3y) as noted below from the RTOG 97-03 trial

rtog_97_03.gif (9940 bytes)

There are no standards in this rapidly changing area, we generally follow the following strategy:
1. for small tumors (T1 or T2N) use standard radiation alone (200cGy) to 66 - 72Gy
2. for patients with larger tumors without node spread (T2-4N0) we generally use hyperfractionation alone (120 bid to 74-76Gy)
3. for those with T2-T4N1-2 we use chemo-radiation (any of the regimens below)
4. and those with very bulky tumors or neck masses, we use chemotherapy alone first (neoadjuvant) followed by chemo-radiation.
5. all high risk postop patients should probably get chemoRad (see RTOG 88-24 below and Bachad)

We have also been treating patients with advanced cancer similar to USF (200cGy to 7000cGy combined with 5FU/Platinol with a treatment break after 30Gy.)  Or similar to UF (120cGy bid to 7440cGy with PI to 4560 and PII to 6000 / or combined HF with Platinol 30mg/M2/w and stop PI at 4080cGy.) In some of the more frail patients we have used the Yale Mitomycin protocol (as below.) The current RTOG trials suggest some options for therapy. RTOG 9501 for postOp XRT compares 60Gy or 60Gy + Platinol (100mg/M2 d1,22,43.) in RTOG 9111 compares induction 5FU/platinol and sequential XRT to chemoRx (concurrent platinol/XRT) in a laryngeal preservation trial. in RTOG 9703 for advanced tumors they use conventional XRT (70Gy) with three different concurrent chemoRX regimens (platinol/taxol or 5FU/HU or 5FU/platinol.) and finally RTOG 9914 uses concurrent platinol with AF XRT. For details on the protocols see RTOG 97-03 or RTOG 99-14. Some of the recent studies on chemoradiation are noted below

Concomitant weekly cisplatin and altered fractionation radiotherapy in locally advanced head and neck cancer

Department of Radiation Oncology, University of Florida College of Medicine, Gainesville, Florida

Both concomitant chemotherapy and altered fractionation radiotherapy (RT) have been shown to improve outcomes for patients with locoregionally advanced head and neck squamous cell carcinomas. However, both strategies also increase acute toxicity, and it is questionable whether the 2 can be safely combined. Traditional concomitant chemotherapy regimens include high-dose cisplatin given at 100 mg/m2 every 3 weeks. The authors' purpose was to report efficacy and toxicity after weekly cisplatin (30 mg/m2/wk) concurrent with altered fractionation RT.

One hundred twenty-one patients with American Joint Committee on Cancer stages II (3%), III (13%), or IV (84%) squamous cell carcinomas of the oropharynx (70%), hypopharynx (20%), or larynx (10%) were treated between 2000 and 2006 at the University of Florida with hyperfractionated RT (55 patients) or concomitant boost RT (66 patients) and concomitant cisplatin (30 mg/m2/wk).

Median follow-up was 2.9 years; median follow-up on survivors was 3.6 years. Seventy-nine percent of patients completed 6 cycles of chemotherapy; 94% received 7200 centigrays. Seven (6%) patients changed from cisplatin to carboplatin because of bone marrow toxicity. Gastrostomy tube feeding was required in 54% of patients either before (16%) or during RT (38%). Two (1.6%) patients died from therapy-related complications.

The 5-year outcomes were: local control, 83%; locoregional control, 79%; distant metastasis-free survival, 88%; cause-specific survival, 76%; and overall survival, 59%. Seven (6%) patients had severe late complications. Three (3%) patients required a permanent gastrostomy tube.

CONCLUSIONS:

Concomitant weekly cisplatin with altered fractionation RT is a safe and effective treatment regimen. Cancer 2010. 2010 American Cancer Society.

Lancet 2000 Mar 18;355(9208):949-55

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.

Pignon JP, Bourhis J, Domenge C, Designe L

Department of Biostatistics and Epidemiology, Institut Gustav-Roussy, Villejuif, France. jppignon@igr.fr

BWe updated data on all patients in randomised trials between 1965 and 1993. We included patients with carcinoma of the oropharynx, oral cavity, larynx, or hypopharynx. The main meta-analysis of 63 trials (10,741 patients) of locoregional treatment with or without chemotherapy yielded a pooled hazard ratio of death of 0.90 corresponding to an absolute survival benefit of 4% at 2 and 5 years in favour of chemotherapy. There was no significant benefit associated with adjuvant or neoadjuvant chemotherapy. Chemotherapy given concomitantly to radiotherapy gave significant benefits, but heterogeneity of the results prohibits firm conclusions. Meta-analysis of six trials (861 patients) comparing neoadjuvant chemotherapy plus radiotherapy with concomitant or alternating radiochemotherapy yielded a hazard ratio of 0.91 (0.79-1.06) in favour of concomitant or alternating radiochemotherapy. Three larynx-preservation trials (602 patients) compared radical surgery plus radiotherapy with neoadjuvant chemotherapy plus radiotherapy in responders or radical surgery and radiotherapy in non-responders. The hazard ratio of death in the chemotherapy arm as compared with the control arm was 1.19 (0.97-1.46). INTERPRETATION: Because the main meta-analysis showed only a small significant survival benefit in favour of chemotherapy, the routine use of chemotherapy is debatable. For larynx preservation, the non-significant negative effect of chemotherapy in the organ-preservation strategy indicates that this procedure must remain investigational.

Cancer 2000 Feb 15;88(4):876-83

Mature results of a phase III randomized trial comparing concurrent chemoradiotherapy with radiation therapy alone in patients with stage III and IV squamous cell carcinoma of the head and neck.

Adelstein DJ, The Cleveland Clinic Foundation,

The current study presents mature results from a Phase III randomized trial comparing radiation therapy and concurrent chemoradiotherapy in patients with resectable American Joint Committee on Cancer Stage III and IV disease. METHODS: One hundred patients were randomized to receive either radiation therapy alone (Arm A) (at a dose of between 66-72 grays [Gy] at 1.8-2 Gy per day) and the identical radiation therapy with concurrent chemotherapy (Arm B) (5-fluorouracil, 1000 mg/m(2)/day, and cisplatin, 20 mg/m(2)/day, both given as continuous intravenous infusions over 4 days beginning on Days 1 and 22 of the radiation therapy). Primary site resection was planned for patients with residual or recurrent local disease. Cervical lymph node dissection was performed for regional persistent disease or recurrence, or if N2-3 disease was present at the time of presentation. RESULTS: After completing all therapy including surgery, 82% of the patients in Arm A and 98% of the patients in Arm B had been rendered disease free.. At a median follow-up of 5 years (range, 3-8 years), the 5-year Kaplan-Meier projections for overall survival for Arm A versus Arm B were 48% versus 50% (P = 0.55). Kaplan-Meier projections for the recurrence free interval were 51% versus 62% (P = 0.04), projections for a distant metastasis free interval were 75% versus 84% (P = 0. 09), projections for overall survival with primary site preservation were 34% versus 42% (P = 0.004), and projections for local control without surgical resection were 45% versus 77% (P < 0.001). Salvage surgery proved to be successful in 63% and 73%, respectively, of the Arm A and Arm B patients with primary site failure. Unrelated death while free of disease occurred in 22% and 32%, respectively, of Arm A and Arm B patients (P = 0.26). CONCLUSIONS: The addition of concurrent chemotherapy to definitive radiation in patients with resectable Stage III and IV squamous cell carcinoma of the head and neck improves the likelihood of disease clearance, a recurrence free interval, and primary site preservation. However, overall survival does not appear to be improved, reflecting both effective surgical salvage after local recurrence and competing causes of death.

N Engl J Med 1998 Jun 18;338(25):1798-804

Hyperfractionated irradiation with or without concurrent chemotherapy for locally advanced head and neck cancer.

Brizel. Patients with advanced head and neck cancer who were treated only with hyperfractionated irradiation received 125 cGy twice daily, for a total of 7500 cGy. Patients in the combined-treatment group received 125 cGy twice daily, for a total of 7000 cGy, and five days of treatment with 12 mg of cisplatin per square meter of body-surface area per day and 600 mg of fluorouracil per square meter per day during weeks 1 and 6 of irradiation. Two cycles of cisplatin and fluorouracil were given to most patients after the completion of radiotherapy. At three years the rate of overall survival was 55 percent in the combined-therapy group and 34 percent in the hyperfractionation group. The relapse-free survival rate was higher in the combined-treatment group (61 percent vs. 41 percent. The rate of locoregional control of disease at three years was 70 percent in the combined-treatment group and 44 percent in the hyperfractionation group.

Int J Radiat Oncol Biol Phys 2000 Apr 1;47(1):49-56

The use of carboplatin and paclitaxel with daily radiotherapy in patients with locally advanced squamous cell carcinomas of the head and neck.

Suntharalingam M, Haas ML, Conley BA, Egorin MJ, Levy S, Sivasailam S, Herman JM, Jacobs MC, Gray WC, Ord RA, Aisner JA, Van Echo DA

Department of Radiation Oncology, Greenebaum Cancer Center, University of Maryland Medical System,

From 1993-1998, 62 patients with Stage III-IV SCCHN were treated with 70.2 Gy of RT at 1.8 Gy/fraction/day to the primary site. Weekly chemotherapy was given during RT consisting of paclitaxel (45 mg/m(2)/wk) and CBDCA (100 mg/m(2)/wk). All patients presented with locally advanced disease; 77% had T4 disease and 21% had T3 disease. Fifty-eight percent had N2b-N3 disease. A clinical complete response (CR) at the primary site was obtained in 82%, with a total (primary site and neck) CR rate of 75%. The median survival for the entire cohort is 33 months.  The median survival for patients who attained a CR is 49 months versus 9 months in those who did not attain a CR (p < 0.0001). The 2- and 3-year overall survival for complete responders are 79% and 61%. CONCLUSIONS: Weekly carboplatin and paclitaxel given concurrently with definitive once-daily external beam radiation therapy is well tolerated with over 90% of patients completing prescribed therapy. An ultimate CR rate of greater than 70% was obtained, which translated directly into improved survival. With 48% 3-year overall survival for the entire group, this regimen is an excellent option for this group of patients with a historically poor prognosis.

J Natl Cancer Inst 1999 Dec 15;91(24):2081-6

Randomized trial of radiation therapy versus concomitant chemotherapy and radiation therapy for advanced-stage oropharynx carcinoma.

Calais. A total of 226 patients have been entered in a phase III multicenter, randomized trial comparing radiotherapy alone (arm A) with radiotherapy with concomitant chemotherapy (arm B). Radiotherapy was identical in the two arms, delivering, with conventional fractionation, 70 Gy in 35 fractions. In arm B, patients received during the period of radiotherapy three cycles of a 4-day regimen containing carboplatin (70 mg/m(2) per day) and 5-fluorouracil (600 mg/m(2) per day) by continuous infusion. The rate of grades 3 and 4 mucositis was statistically significantly higher in arm B (71%) than in arm A (39%). Three-year overall actuarial survival and disease-free survival rates were, respectively, 51%  versus 31%  and 42% versus 20% for patients treated with combined modality versus radiation therapy alone. The locoregional control rate was improved in arm B (66%) versus arm A (42%).

Radiother Oncol 1997 Apr;43(1):23-8

Neoadjuvant chemotherapy with cisplatin and 5-fluorouracil in advanced squamous cell carcinoma of the head and neck: a randomized phase III study.

Lewin Four-hundred sixty-one patients with tumors in oral cavity, oropharynx, hypopharynx and larynx were randomized to receive either standard treatment (radiotherapy or radiotherapy followed by surgery) or neoadjuvant chemotherapy followed by standard treatment. Chemotherapy included three courses of cisplatin 100 mg/m2 i.v. infusion on day 1 followed by 5-fluorouracil 1000 mg/m2 per day continuous i.v. infusion for 120 hours. Radiotherapy 64-70 Gy in 2 Gy per fraction, 5 times/week, was given to patients in both treatment arms. RESULTS: Response rate was 71% for patients randomized to chemotherapy-radiotherapy and 66% for patients randomized to standard treatment (not statistically significant). Residual tumors were excised if possible. After surgery 62% of the patients randomized to chemotherapy-radiotherapy and 60% of the patients in the standard treatment group were clinically tumor free. CONCLUSIONS: No statistically significant benefit in survival was observed for patients treated with neoadjuvant chemotherapy followed by radiotherapy. Nor was there any impact of chemotherapy on the number of patients achieving loco-regional tumor control after primary treatment.

J Natl Cancer Inst 1996 May 1;88(9):583-9

Five-year update of a randomized trial of alternating radiotherapy and chemotherapy compared with radiotherapy alone in treatment of unresectable squamous cell carcinoma of the head and neck.

Merlano. One hundred fifty-seven patients with untreated, unresectable squamous cell carcinoma of the head and neck were randomly assigned to receive either chemotherapy (four courses of cisplatin [20 mg/m2] and fluorouracil [200 mg/m2], given daily for 5 consecutive days during weeks 1, 4, 7, and 10) plus radiotherapy (three courses of 20 Gy each, given in fractions of 2 Gy per day during weeks 2-3, 5-6, and 8-9) or radiotherapy alone (70 Gy total dose, given in fractions of 2 Gy per day, 5 days per week). Eighty patients received the combined therapy, and 77 were treated with radiotherapy alone. The combined treatment was associated with a statistically significant increase in the frequency of complete response (i.e., the disappearance of clinically detectable disease for at least 4 weeks) (43% for the combined-treatment group compared with 22% for the radiotherapy-only group). Five-year estimates of overall survival in the combined-treatment group compared with the radiotherapy-only group were 24%  and 10%  respectively. The estimates of progression-free survival at 5 years in the combined-treatment group compared with the radiotherapy-only group were 21%  and 9% respectively.

J Clin Oncol 1997 Jan;15(1):268-76

Chemotherapy as an adjunct to radiation in the treatment of squamous cell carcinoma of the head and neck: results of the Yale Mitomycin Randomized Trials.

Haffty.  Within each strata, patients were randomized to receive radiation therapy with or without mitomycin (trial 1) or mitomycin/dicumarol (trial 2). RESULTS: A total of 203 patients were enrolled onto both trials, 195 of whom were eligible for analysis. As of September 1995, with a median follow-up of 138 months, a statistically significant benefit occurred in the mitomycin arms with respect to cause-specific survival (0.74 v 0.51), local recurrence-free survival (0.85  v 0.66 ), and local regional recurrence-free survival (0.76  v 0.54). No statistically significant difference in overall survival was obtained (0.48 mitomycin arms v 0.42 radiation alone).

J Clin Oncol 1998 Apr;16(4):1318-24

Simultaneous radiochemotherapy versus radiotherapy alone in advanced head and neck cancer: a randomized multicenter study.

Wendt . Patients with locoregionally advanced head and neck cancer were treated either with RT alone (arm A) or simultaneous RT plus CT (RCT; arm B). RT was identical in both arms and administered in three courses with 13 fractions of 1.8 Gy each twice daily. During one course, from day 3 to 11, 23.4 Gy was delivered. In arm B, cisplatin (CDDP) 60 mg/m2, fluorouracil (5-FU) 350 mg/m2 by intravenous (i.v.) bolus, and leucovorin (LV) 50 mg/m2 by i.v. bolus were given on day 2, and 5-FU 350 mg/m2/24 hour by continuous infusion and LV 100 mg/m2/24 hours by continuous infusion were given from day 2 to 5. Treatment was repeated on days 22 and 44; a total RT dose of 70.2 Gy was administered. Treatment breaks were scheduled from days 12 to 21 and days 34 to 43. Acute mucositis grade 3 or 4 was more frequent in arm B (38%) than in arm A (16%) (P < .001). The 3-year overall survival rate was 24% in arm A and 48% in arm B. The 3-year locoregional control rate was 17% in arm A and 36% in arm B.

Int J Radiat Oncol Biol Phys 1997 Mar 1;37(4):777-82

Postoperative radiotherapy with concurrent cisplatin appears to improve locoregional control of advanced, resectable head and neck cancers: RTOG 88-24.

Al-Sarraf M, Pajak TF, Byhardt RW, Beitler JJ, Salter MM, Cooper JS

Despite aggressive surgery and postoperative radiation therapy, only 30% of patients who have advanced, potentially resectable carcinomas of the head and neck survive for 5 years. In the hope of improving this situation we studied the effect of postoperative radiotherapy delivered concurrently with cisplatin. METHODS AND MATERIALS: Patients who had Stage IV tumors and/or involved surgical margins received 60 Gy in 30 fractions over 6 weeks plus 100 mg/m2 of cisplatin on radiotherapy days 1, 23 and 43. Fifty-two patients participated in this trial and 51 were evaluated. Forty-three (84%) patients had pathologic T3 or T4 disease, 43 (84%) had Stage IV disease, and 27 (53%) had histologically involved surgical margins. RESULTS: Severe and life-threatening toxicities occurred in 20% and 12% of patients, respectively; the most common drug-related toxicities were leukopenia, anemia, nausea, and vomiting. Seventeen patients (43%) remain alive with no evidence of disease. Four patients (8%) died with no evidence of neoplastic disease, and one patient has died of a second independent malignancy. By actuarial analysis at 3 years, 48% of patients are alive, 81% have locoregional control of disease, and 57% are free of distant metastases. CONCLUSIONS: Based on comparison with similar patients treated in a prior Radiation Therapy Oncology Group/Intergroup trial (RTOG), we conclude that postoperative radiotherapy with concurrent cisplatin may improve locoregional control rates and should be prospectively tested.

Int J Radiat Oncol Biol Phys 1996 Dec 1;36(5):999-1004

Combined postoperative radiotherapy and weekly cisplatin infusion for locally advanced head and neck carcinoma: final report of a randomized trial.

Bachaud JM, Cohen-Jonathan E, Alzieu C, David JM, Serrano E, Daly-Schveitzer

PURPOSE: To report the final results of a prospective randomized trial that aimed to evaluate efficacy and toxicity of concomitant postoperative radiotherapy and Cisplatin infusion in patients with Stage III or IV squamous cell carcinoma of the head and neck and histological evidence of extracapsular spread of tumor in lymph node metastase(s). METHODS AND MATERIALS: Radiotherapy was delivered using a daily dose of 1.7 Gy for the first 54 Gy and 1.8 to 2 Gy until the completion of the treatment. Cisplatin 50 mg i.v. with forced hydratation was given or not every week (i.e., seven to nine cycles) concurrently with radiotherapy. A total of 44 patients were treated by irradiation only (RT group) and 39 by irradiation with chemotherapy (CM group). RESULTS: The RT group displayed a higher rate of loco-regional failures as compared to CM group (41 vs. 23%; p = 0.08). The overall survival, the survival corrected for deaths by intercurrent disease, and the disease-free survival were better in CM group as compared to RT group with statistically significant differences.  The concomitant use of 50 mg weekly Cisplatin infusion and postoperative radiation improved loco-regional control and survival. No significant increase of late radiation complications was observed in the CM group.