Toxicity of two cisplatin-based radiochemotherapy regimens for the treatment of patients with stage iii/iv head and neck cancer

TOXICITY OF TWO CISPLATIN-BASED RADIOCHEMOTHERAPYREGIMENS FOR THE TREATMENT OF PATIENTS WITH STAGEIII/IV HEAD AND NECK CANCER Dirk Rades, MD,1 Fabian Fehlauer, MD,2 Mashid Sheikh-Sarraf, MD,2 Nadja Kazic, MD,3 Hiba Basic, MD,3Robert Poorter, MD,4 Samer G. Hakim, MD,5 Steven E. Schild, MD,6 Juergen Dunst, MD1 1 Department of Radiation Oncology, University Hospital Schleswig-Holstein, Campus Luebeck, Luebeck,Germany. E-mail: [email protected] Department of Radiation Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany3 Department of Radiation Oncology, University Hospital, Sarajevo, Bosnia-Herzegovina4 Department of Radiation Oncology, Dr. Bernard Verbeeten Institute, Tilburg, The Netherlands5 Department of Oral and Maxillofacial Surgery, University Hospital Schleswig-Holstein, Campus Luebeck,Luebeck, Germany6 Department of Radiation Oncology, Mayo Clinic, Scottsdale, Arizona Accepted 2 April 2007Published online 26 July 2007 in Wiley InterScience (www.interscience.wiley.com). DOI: 10.1002/hed.20683 icity than were 3 courses cisplatin (100 mg/m2/d).
Wiley Periodicals, Inc. Head Neck 30: 235–241, 2008 pared 2 radiochemotherapy regimens for toxicity in 128 patientswith stage III/IV head and neck cancer.
Keywords: head and neck cancer; stage III/IV; radiochemo- Methods. Patients therapy; cisplatin; toxicity radiotherapy. The total dose to primary tumor and involvedlymph nodes did depend on preceding surgery. Patientsreceived 66 to 70 Gy if surgery was not performed, 60 to 66 Gyafter R0 resection, 66 Gy after R1 resection, and 70 to 72 Gy af- Locally advanced head and neck cancer carries a ter R2 resection. Concurrent chemotherapy consisted of 3 poor prognosis. Surgery followed by radiotherapy courses cisplatin (100 mg/m2/d1,22,43) (group A, N ¼ 61) or 2 or radiochemotherapy is the treatment of choice.
courses cisplatin (20 mg/m2/d1–5 þ 29–33)/5-fluorouracil (5-FU) Several retrospective studies have suggested that (600 mg/m2/d1–5 þ 29–33) (group B, N ¼ 67).
Results. Acute toxicity was more severe in group A, espe- postoperative radiotherapy improves locoregional cially nausea/vomiting (p ¼ .002), nephrotoxicity (p ¼ .001), oto- control in patients with head and neck cancer toxicity (p ¼ .034), and hematotoxicity (p ¼ .049). Forty-eight when compared with surgery alone.1–4 The poten- percent of group A and 10% of group B patients could not com- tial benefit of postoperative radiochemotherapy plete chemotherapy due to toxicity (p ¼ .018). Late toxicity was when compared with postoperative radiotherapy similar (p ¼ .99).
Conclusion. Two courses of fractionated cisplatin (20 mg/ alone is still controversial. The Intergroup study m2/d) and 5-FU were associated with significantly less acute tox- 0034 did not demonstrate a significant differencebetween radiotherapy plus 3 preceding courses of Correspondence to: D. Rades cisplatin/5-fluorouracil (5-FU) chemotherapy and C 2007 Wiley Periodicals, Inc.
radiotherapy alone with respect to locoregional Cisplatin-Based Radiochemotherapy Regimens HEAD & NECK—DOI 10.1002/hed control and overall survival.5 In the study 95-01 of the least toxicity possible. The present study com- the Radiation Therapy Oncology Group (RTOG), pares ‘‘standard'' radiochemotherapy with 3 concurrent chemoradiotherapy with 3 courses of courses of 100 mg/m2 cisplatin on days 1, 22, and cisplatin was superior to radiotherapy alone for 43 to another cisplatin-based chemotherapy regi- locoregional control, but not for overall survival.6 men consisting of 2 courses of fractionated cispla- The trial 22931 of the European Organization for tin (20 mg/m2/d on days 1–5 and 29–33) and 5-flu- Research and Treatment of Cancer (EORTC) sug- orouracil (600 mg/m2/d on days 1–5 and 29–33) gested a benefit for chemoradiotherapy with 3 with respect to toxicity in the treatment of locally courses of cisplatin when compared with radio- advanced head and neck cancer.
therapy alone for both estimated 5-year locore-gional control and survival.7 However, the com-bined approach was associated with a substantial MATERIALS AND METHODS increase in acute toxicity.
Definitive radiotherapy alone or definitive Patients. Between January 1998 and January radiochemotherapy are both an option for patients 2006, 128 patients with stage III/IV carcinoma of with unresectable disease and serve as an alterna- the head and neck (17 nasopharynx, 48 orophar- tive to surgery in appropriate cases. Radiotherapy ynx, 34 oral cavity, 16 hypopharynx, 13 larynx) alone, which had been the standard treatment for received concurrent radiochemotherapy, either as patients with unresectable tumors for many years, definitive or as adjuvant treatment. Criteria for resulted in survival rates of less than 25% and 2- inclusion in this retrospective study were as fol- year locoregional control rates of less than 20%.8–11 lows: histologically proven carcinoma arising The treatment outcome may be improved by add- from the nasopharynx, the oropharynx, the oral ing concurrent chemotherapy.8,11–13 cavity, the hypopharynx, or the larynx, and tumor The majority of the available studies compar- stage III or IV according to the American Joint ing radiochemotherapy versus radiotherapy alone Committee of Cancer (AJCC) criteria based on for definitive head and neck cancer treatment sug- CT and direct examination with endoscopy.
gested a survival benefit if concurrent chemother- According to the administered chemotherapy regi- apy was administered,8,12–17 whereas a few stud- men, the patients were divided in 2 groups (see ies did not demonstrate such a benefit.18,19 section Chemotherapy). The treatment regimen The optimal radiochemotherapy regimen is a was mainly related to interdisciplinary (study) matter of debate, because most of the currently protocols being favored at the institutions at cer- used regimens are associated with severe acute tain periods of time. These protocols varied due to toxicity and even treatment-related deaths. Ra- the controversy in determining the best treatment diochemotherapy with 3 courses of 100 mg/m2 cis- for locally advanced head and neck cancer. Each platin on days 1, 22, and 43 is the most frequently series of patients from the contributing centers applied regimen, either as definitive or as adju- represents a series of patients treated with a spe- vant treatment. However, the acute toxicity of cific regimen over a certain period of time. Group this program is considerable. Marcial et al20 A consisted of 61 patients who came from Ham- burg (N ¼ 27, 2003–2004 and 2006), Sarajewo (N patients receiving definitive radiochemotherapy.
¼ 24, 2003–2005), Luebeck (N ¼ 6, 1999–2000), Al-Sarraf et al21 reported 20% severe toxicities and Tilburg (N ¼ 4, 2003–2004); Group B con- and 12% life-threatening toxicities in patients sisted of 67 patients who came from Hamburg (N receiving adjuvant radiochemotherapy with 60 ¼ 67, 1998–2003 and 2004–2006). In addition to Gy plus 3 courses of 100 mg/m2 cisplatin. An alter- the investigators from the participating centers, native radiochemotherapy program associated the principal investigator reviewed the patient with less acute toxicity appears desirable.
files in order to assure that there was no relevant The vast majority of head and neck cancer variation of treatment factors, which might have studies that included chemotherapy have com- introduced a selection bias. The patient character- pared radiotherapy alone versus radiochemother- istics related to the 2 treatment groups are listed apy but have not compared different radiochemo- in Table 1. These patients have not been reported therapy schedules. Thus, studies comparing dif- ferent radiochemotherapy schedules for head andneck cancer treatment are required to determine Chemotherapy. Group A (n ¼ 61): The concurrent regimens that provide effective treatment with chemotherapy consisted of cisplatin, which was Cisplatin-Based Radiochemotherapy Regimens HEAD & NECK—DOI 10.1002/hed Group B (n ¼ 67): The concurrent chemother- Table 1. Patient characteristics, related to treatment groups.
apy consisted of cisplatin administered intrave- No. of patients (%) nously at a dose of 20 mg/m2 of body-surface areaon days 1 to 5 and 29 to 33 of the course of radio- therapy, as well as of 5-fluorouracil (5-FU) admin- istered intravenously as a continuous infusion for 120 hours at a daily dose of 600 mg/m2 of body-sur- face area on days 1 to 5 and 29 to 33 of the course of radiotherapy. On each day of cisplatin adminis- tration, the patients received 1000 mL of hydra- tion given over 60 minutes before administration Eastern Cooperative Oncology Group (ECOG) performance of cisplatin plus 20 to 40 mg of furosemide, and mostly 4 to 8 mg of ondansetrone. Cisplatin was administered over 30 minutes, followed by another 1000 mL of hydration. Also in this group, the chemotherapy was administered by the radia- tion oncologists.
The median cumulative cisplatin dose admin- istered in group B patients was 200 mg/m2 (range, 100–200 mg/m2) of body-surface area.
Radiotherapy. All patients received convention- ally fractionated radiotherapy (5 fractions per week) with doses per fraction of 2.0 Gy. Maximal and minimal target-volume doses and the maxi- T classification mal dose delivered to the spinal cord were recorded. Radiotherapy was performed with a lin- ear accelerator and 4 to 6 megavoltage (MV) pho- N classification tons, as well as 10 to 12 MV electrons for parts of the posterior cervical lymph nodes, to limit the American Joint Committee on Cancer (AJCC) stage dose to the spinal cord to 45 Gy. The total dose delivered to the primary tumor and to the involved lymph nodes (according to CT) depended on preceding surgery. The total doses and the extent of resection related to the 2 treatment Hemoglobin level pre-radiotherapy, g/dL groups A and B are summarized in Table 2. The total dose to the other cervical and supraclavic- ular lymph nodes was 50 to 60 Gy. The total radia- Note: Group A: radiotherapy plus 3 concurrent courses of cisplatin; Group tion doses also depended on interdisciplinary B: radiotherapy plus 2 concurrent courses of cisplatin/5-fluororuracil.
(study) protocols favored at the various treatinginstitutions.
administered intravenously at a dose of 100 mg/m2 of body-surface area on days 1, 22, and 43 of Study Endpoints, Follow-Up, and Statistics. Both the course of radiotherapy. The patients received treatment groups were compared for acute and 1500 mL of hydration given over 90 minutes late toxicity. Acute toxicity was evaluated accord- before administration of cisplatin plus 20 to 40 mg ing to the Common Toxicity Criteria (CTC version of furosemide, and usually 4 to 8 mg of ondanse- 2.0),22 and late toxicity according to the RTOG cri- teria.23 Late toxicity was defined as toxicity occur- minutes, followed by another 1500 mL of hydra- ring later than 90 days after radiochemotherapy tion. The chemotherapy was administered by the was started.
radiation oncologists. The median cumulative cis- During radiotherapy the patients were pro- platin dose administered in group A patients was spectively and consistently followed for toxicity 300 mg/m2 (range, 100–300 mg/m2) of body-sur- once a week, and after radiotherapy the patients were followed at regular intervals (usually every Cisplatin-Based Radiochemotherapy Regimens HEAD & NECK—DOI 10.1002/hed 60 Gy of irradiation (after R0 resection). In these Table 2. Extent of resection and total radiation doses related 8 patients, only 2 courses of 100 mg/m2 cisplatin to the treatment groups A and B.
were planned. However, the patients experienced No. of patients (%) serious acute toxicity after the first course (grade3–4 hematotoxicity in 5 patients, grade 2 nephro- Total radiation dose toxicity in 3 patients, grade 3 vomiting in 3 R0 resection plus 60 Gy (N ¼ 24) patients, grade 2 ototoxicity in 1 patient), and the R0 resection plus 64 Gy (N ¼ 13) second course cisplatin was either not adminis- R0 resection plus 66 Gy (N ¼ 4) tered or given with a dose reduction of at least R1 resection plus 66 Gy (N ¼ 15) R2 resection plus 70 Gy (N ¼ 8) R2 resection plus 72 Gy (N ¼ 3) 66 Gy without surgery patients developed at least 1 grade 3–4 toxicity 70 Gy without surgery considered to be chemotherapy induced (59% vs Note: R0, no residual tumor; R1, microscopically residual tumor; R2, 21%, p ¼ .003), such as nephrotoxicity, ototoxicity, macroscopically residual tumor.
*One group A patient did not complete radiotherapy due to treatment- nausea/vomiting, hematotoxicity, and treatment- related death.
related death due to pneumonia or sepsis follow- **Two group A patients did not complete radiotherapy due to treat-ment-related death.
ing neutropenia (Figure 1). Due to the fact that ***One group B patient did not complete radiotherapy due to treatment- the antiemetic regimen may be considered less related death.
than the standard treatment in many other 3–6 months) or until death. The median follow-up centers worldwide, the toxicity rates were recalcu- was 12 months (range, 0–66 months) in the entire lated without nausea/vomiting. Again, signifi- cohort, 13 months (range, 0–66 months) in group cantly more group A patients developed at least A, and 11 months (range, 0–66 months) in group one grade 3–4 toxicity considered to be chemo- B. The relatively short follow-up is a reflection of therapy induced (48% vs 18%, p ¼ .005).
early analysis rather than of low overall survival.
The acute toxicity most likely radiotherapy Uncompleted chemotherapy was defined ei- induced, such as mucositis, skin toxicity within ther as not all planned chemotherapy courses the radiation fields, and xerostomia, was compa- given or as a dose reduction of at least 25% during rable in both treatment groups (Figure 1). Late 1 or 2 courses. Patient characteristics and toxicity toxicity such as late xerostomia, late skin toxicity, were compared with the chi-square test.
cervical fibrosis, and cervical lymph edema wassimilar in both groups (Figure 2). Seven percent ofthe group A patients and 10% of the group B patients developed grade 3 late xerostomia, and Significantly (p ¼ .018) more group A patients (29/ 7% (group A) and 13% (group B) developed cervi- 61, 48%) could not complete the chemotherapy cal fibrosis. No grade 4 late toxicity was observed.
due to acute toxicity than group B patients (7/67, According to the Kaplan–Meier analyses24 for 10%). In group A, 14 patients received only 1 the entire cohort, the 2-year rate of locoregional course of chemotherapy (100 mg/m2 of cisplatin; control was 70%, the 2-year rate of metastasis- 33% of the prescribed cumulative dose), and free survival was 69%, and the 2-year rate of over- another 14 patients received only 2 courses of cis- all survival was 63%, respectively. The 2-year platin (200 m2 of cisplatin; 67% of the prescribed locoregional control rates were 72% for group A cumulative dose). One patient received 1 complete patients and 66% for group B patients (p ¼ .32).
course and 1 course with a 25% dose reduction The 2-year metastasis-free survival rates were (175 m2 of cisplatin; 58% of the prescribed cumu- 77% and 68%, respectively (p ¼ .92), and the 2- lative dose). In group B, 4 patients received only 1 year survival rates were 68% and 56%, respec- course of chemotherapy (100 mg/m2 of cisplatin; tively (p ¼ .82).
50% of the prescribed cumulative dose), and 3patients received 1 complete course of chemother-apy plus 1, 2, and 3 days of the second course, respectively (120, 140, and 160 mg/m2 of cisplatin; Very few reports have compared various radioche- 60%, 70%, and 80% of the prescribed cumulative motherapy regimens for locally advanced head and neck cancer. The present study compared 2 Of the 29 group A patients who did not com- different radiochemotherapy programs (group A: plete the chemotherapy, 8 patients received only 3 courses of 100 mg cisplatin alone on days 1, 22, Cisplatin-Based Radiochemotherapy Regimens HEAD & NECK—DOI 10.1002/hed FIGURE 1. Acute toxicity: Comparison of the 2 treatment groups for acute toxicity in terms of Common Toxicity Criteria (CTC) grade2–3 nephrotoxicity, grade 2–3 ototoxicity, grade 3–4 nausea/vomiting, grade 3–4 hematotoxicity, treatment-related deaths (pneumoniaor sepsis following neutropenia) (top), and grade 3–4 toxicity related to radiotherapy (mucositis, skin toxicity, xerostomia) (bottom).
43 vs group B: 2 courses of 20 mg/m2 cisplatin/ The radiochemotherapy schedule adminis- 600 mg/m2 5-FU on days 1–5 and 29–33). How- tered in group A was associated with significantly ever, one has to be aware of the limitations of the more acute toxicity than the schedule adminis- study presented here. The retrospective nature of tered in group B, especially in terms of nephrotox- the study and the heterogeneity of the patients icity, hematotoxicity, and nausea/vomiting. This should be taken into account when interpreting may be explained by the fact that group A patients this analysis. The patient population included received more cisplatin than group B patients.
those treated with definitive chemoradiotherapy Adding 5-FU was tolerated in group B patients, alone as well as postoperative patients with R0, because they received less cisplatin and because R1, and R2 resections. Thus, a selection bias may cisplatin was fractionated. Fractionated adminis- have been introduced.
tration of cisplatin (20 mg/m2/day for 5 days) may FIGURE 2. Late toxicity: Comparison of the 2 treatment groups for Radiation Therapy Oncology Group (RTOG) grade 2–3 toxicity(xerostomia, skin toxicity, cervical fibrosis, cervical lymph edema).
Cisplatin-Based Radiochemotherapy Regimens HEAD & NECK—DOI 10.1002/hed be considered less toxic than a single dose of 100 The acute toxicity that was likely related to mg/m2 given in 1 day. Only 52% of the group A radiotherapy, such as mucositis, skin toxicity, and patients was able to receive the complete chemo- xerostomia, did not significantly differ between therapy as initially planned, whereas the other the 2 groups. The late toxicity such as late xerosto- 48% of the patients developed severe chemother- mia, late skin toxicity, cervical fibrosis, and cervi- apy-related acute toxicity, which did not allow the cal lymph edema was similar in both groups. Xero- administration of the complete chemotherapy. In stomia and cervical fibrosis rates in our series (7% the series of Forastiere et al, who treated patients to 10% and 7% to 13%, respectively) were compa- with laryngeal cancer for organ preservation, the rable to those of other schedules as reported by rate of high-grade toxic effects was greater with Calais et al,13 who treated patients with advanced- the chemotherapy-based regimens (81% with stage oropharynx carcinoma with definitive con- induction cisplatin/5-FU followed by radiotherapy current radiochemotherapy including 3 courses of and 82% with radiotherapy plus 3 courses of con- a 4-day regimen of 70 mg/m2 carboplatin and 600 current cisplatin) than with radiotherapy alone mg/m2 5-FU. They reported 9% grade 3–4 xerosto- (66%). Seventy percent of the patients who mia and 11% grade 3–4 cervical fibrosis.
received concurrent chemotherapy arms could In conclusion, for radiochemotherapy of stage receive all 3 courses of 100 mg/m2 cisplatin.19 This III/IV head and neck cancer, the regimen includ- rate may be higher than in our series, because the ing 2 courses of fractionated cisplatin (20 mg/m2/d authors did not consider patients who needed a on radiotherapy days 1–5 and 29–33) and 5-FU reduction of the chemotherapy dose. In our study, (600 mg/m2/d on radiotherapy days 1–5 and 29– both cessation of chemotherapy and dose reduc- 33) was associated with significantly less acute tions were considered as uncompleted chemother- toxicity than 3 courses of cisplatin (100 mg/m2 on radiotherapy days 1, 22, and 43). Adding 5-FU The randomized RTOG 97-03 study compared was tolerated by group B patients, because these 3 different radiochemotherapy regimens for toxic- patients received less cisplatin and because cis- ity and outcome in 241 patients with squamous platin was fractionated. The results of this retro- cell carcinoma of the oral cavity, oropharynx, or spective study need to be confirmed in a random- hypopharynx. The patients received either 70 Gy given in 7 weeks with 10 mg/m2 cisplatin and 400mg/m2 of 5-FU daily during the last 10 days ofradiotherapy (arm 1), 70 Gy in 13 weeks (givenon alternating weeks) with daily hydroxyurea (1 g BID) and 800 mg/m2 of 5-FU (arm 2), or 70 Gy 1. Arriagada R, Eschwege F, Cachin Y, Richard JM. The in 7 weeks with weekly paclitaxel (30 mg/m2) and value of combining radiotherapy with surgery in thetreatment of hypopharyngeal and laryngeal cancers.
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Cisplatin-Based Radiochemotherapy Regimens HEAD & NECK—DOI 10.1002/hed

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