- Email: [email protected]
Concomitant chemotherapy-radiation therapy followed by hyperfractionated radiation therapy for advanced unresectable head and neck cancer
Inf. J. Radiarion Oncologv Bid Phys Vol Pnntcd in the lJ.S.A All rights reserved.
0360.3016191 $3.00 + .OU Copyright 0 1991 Pergamon Press plc
21, pp. 703-708
??Phase IIII Clinical Trials
CONCOMITANT CHEMOTHERAPY-RADIATION THERAPY FOLLOWED BY HYPERFRACTIONATED RADIATION THERAPY FOR ADVANCED UNRESECTABLE HEAD AND NECK CANCER LOUIS B. HARRISON, M.D.,* DAVID G. FFISTER, M.D.,?
DANIELE. FASS, M.D.,* JOHNG. ARMSTRONG, M.R.C.P.I.,” ROY B. SESSIONS,M.D.,$ JATINP. SHAH,M.D.,+ RONALDH. SPIRO, M.D.,$ ELLIOT W. STRONG, M.D.,$ STEVEN WEISEN, B.A.7 AND GEORGE J. BOSL, M.D.? Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, New York 10021 In January 1988, we initiated a prospective study evaluating a new treatment approach with chemotherapy and radiotherapy for unresectable head and neck cancer. Weeks l-4 were the initial debulking phase. Radiotherapy was delivered using 1.8 Gy/day to large portals including gross disease and all areas at risk. Cisplatinum, lOOmg/m*, was given concomitant with radiotherapy on days 1 and 22. Weeks 5 and 6 were the boosting phase. This involved twice-a-day irradiation. The AM fraction of 1.8 Gy was given to the entire area at risk, whereas the PM dose of 1.6 Gy was limited to the gross disease alone. Thus a total of 70 Gy/6 weeks was delivered. A total of 24 patients were treated, 22 of whom have completed this protocol and are evaluable. All patients had massive disease, with 15 having gross involvement of brain, orbit, skull base, or carotid artery. Fdlow-up ranged from 3-22 months (median 12 months). Major responses were achieved in %%, with 64% complete responses and 32% partial responses. Two patients with PR were able to undergo complete surgical resection, making the overall rate of complete response, including surgery, 73%. At 1 year, actuarial survival was 69%) and local progression-free survival was 56%. Distant metastases developed in 5 (23%). This approach sppears both safe and effective in producing excellent regression and local control for far advanced bead and neck cancer. More time is needed to see if these results are sustained. Effortsto build upon this experience appear warranted. Unresectable head and neck cancer, Radiotherapy, Chemotherapy.
INTRODUCTION
with concomitant chemotherapy (CT) and radiotherapy (RT) (1,2,10). Also, there is evidence to suggest a therapeutic advantage to twice a day irradiation (BID-RT) for selected head and neck cancers (6,9,11,12,15-18). Because data exist suggesting accelerated tumor repopulation after approximately 30 days of RT (9), the therapeutic ad-
Advanced, unresectable epithelial cancer of the head and neck is a challenging oncologic problem. Local control with standard radiation therapy is suboptimal, with long term survival less than 10% (13). Although chemotherapy programs using neoadjuvant cisplatinum-based regimens have produced high response rates, there has been no proven impact on local control or survival (3-8,14,19). On the other hand, there has been early promising experience
vantage to BID-RT may be most significant at that point in treatment, and it may not he required through the entire
course of treatment. Using these concepts we initiated a prospective study evaluating a new treatment approach.
*Brachytherapy Service, Department of Radiation Oncology. tThe Solid Tumor Service, Department of Medicine. SHead and Neck Service, Department of Surgery. Reprint requests to: Louis B. Harrison, M.D., Department of
Radiation Oncology, Brachytberapy Service, Memorial SloanKettering Cancer Center, 1275 York Ave., New York, NY 10021. Accepted for publication 22 February 1991. 703
704
I. J. Radiation Oncology 0 Biology 0 Physics Table 1. Distribution
August 1991, Volume 21, Number 3
of patients by primary site
Table 2. Analysis of response to treatment No.
Site Paranasal sinus Nasopharynx (all T4) Oropharynx Oral cavity Larynx Hypopharynx Total
10 3 7 2 1 1 24
This involves concomitant CT and RT for the first 4 weeks of treatment, followed by BID-RT for the fifth and sixth weeks of treatment. The last 2 weeks used a “field within a field” concomitant boosting cone down technique. This report describes our preliminary results.
METHODS AND MATERIALS Between January 1988 and December 1989, 24 consecutive patients have been treated. All patients met the following eligibility requirements: a) histologically confirmed cancer in the head and neck, including any histology except lymphoma, melanoma, and sarcoma; b) unresectable disease (all T, or Ns) as determined by an experienced head and neck surgeon; c) Kamofsky performance status > 50%; d) WBC > 4000 cells/mm, platelets > 100,000, creatinine clearance > 55cc/min; e) no prior cancer, and no previous treatment of the presenting cancer; f) the ability to give informed consent to this protocol. There were 15 males and 9 females whose ages ranged from 17 to 66 (median = 49). This histologic diagnosis was squamous cancer in 21 patients, adenocarcinoma in 2 patients, and mucoepidermoid carcinoma in 1 patient. Table 1 shows the distribution of patients according to the primary site. All patients had massive disease, which was considered surgically unresectable. The criteria for unresectability included gross involvement of brain parenchyma, orbit-eye, skull base, encasement of carotid artery, and massive fixed soft tissue disease with or without skin involvement. Patients who had resectable disease, but whose medical condition precluded operation, were not included. The treatment program involved initial concomitant CT and RT, followed by BID-RT. Weeks l-4 were the initial debulking phase. RT was delivered using 1.8 Gy/day to large portals including gross disease and all other areas at risk. Cisplatinum, 100 mg m’, was given concomitant with RT on days 1 and 22. The details of cisplatinum administration and reconstitution have been previously described (19). Weeks 5 and 6 were the boosting phase. This involved BID-RT, theoretically designed to address the accelerated tumor cell proliferation which occurs at this point. The AM fraction of 1.8 Gy was given to the entire area at risk, whereas the PM fraction of 1.6 Gy was lim-
Reseponse Complete response Partial response Minimal reponse
No.
(%)
14122 7122 l/22
(64) (32) ( 4)
Note: Of partial responders (7): 2 pts. had complete resection, 2 pts. has continued regression, 3 pts. had progression locally. Overall % CR including surgery = 73%.
ited to the gross disease alone. Fractions were separated by 4-6 hr. Thus, a total of 70 Gy/6 weeks was delivered. The spinal cord is shielded after 45 Gy. Standard criteria were used to assess response. A complete response (CR) implies total regression of all evaluable tumor. A partial response (PR) implies greater than 50% reduction in evaluable tumor. Clinical evaluation as well as CT scan was used in response evaluation. Follow-up ranged from 3 to 22 months, with median of 12 months. Survival and local control rates were determined by the Kaplan-Meier method (7).
RESULTS To date, 24 patients have been treated and 22 are evaluable. Two patients have just completed treatment and are too early to assess. Response data are summarized in Table 2. Major responses were achieved in 96%, including 64% CR and 32% PR. Two patients with PR were able to undergo surgical resection, making the overall rate of CR, including surgery, 73%. Although only three patients had nonsquamous histology, there was no obvious difference in response rate in these patients. At 1 year, local disease-free survival was 56% (Fig. 1). Distant metastasis developed in five patients (23%). At 1 year, overall actuarial survival was 69% (Fig. 2). Figures 3-5 show three patients who were treated on this protocol. These cases are illustrative of the massive disease exhibited by most of our patients. Note that we had more paranasal sinus patients than any other primary site, creating a
1.0 w'
.a 13)
WI
.6 .4 .2 0 I-lY'r_ 0
12
24
36
Time (months)
Fig. 1. Local progression-free
survival: all patients.
Unresectable
“?
head and neck cancer
72 Time (months)
Fig. 2. Actuarial survival: all patients.
??L. B.
705
HARRISON et al.
Despite the intensity of this treatment regimen, it was well tolerated. Although all patients had mucositis, no patients required significant treatment interruption. There were four patients who could not get their day 22 chemotherapy because of decreased renal function (Creatinine clearance < 55 cc/min). One patient did suffer a treatmentrelated death caused by granulocytopenia and sepsis. Finally, there was one patient with unresectable poorly differentiated squamous cancer of the maxillary antrum, destroying the maxillary bone. This patient did have osteoradionecrosis which required surgical debridement. However, she remains NED at 20 months following treatment, and her necrosis has healed.
DISCUSSION site imbalance. Although it is too early to determine whether the long term results for this subsite are better than other head and neck subsites, it is hoped that longer follow-up will address this question.
Patients with unresectable squamous cancer of the head and neck have a very poor survival with conventional RT alone (1). Over the years, efforts to improve upon these
Fig. 3. (A,B) 29-year-old woman with a poorly differentiated adenocarcinoma involving ethmoids, sphenoid, and both frontal sinuses. Disease extended into both orbits, through the skull base, with extensive brain invasion. (C,D) Same patient as (A,B), 6 weeks after completion of protocol therapy. This patient remains locally controlled at 2 years, but has developed liver metastases.
706
I. J. Radiation
Oncology
0 Biology 0 Physics
August 1991, Volume 21, Number 3
Fig. 4. (A,B) 27-year-old male with squamous cell cancer involving nasal cavity, ethmoid sinuses, frontal sinuses with maxillary antrum extension. Disease eroded through the base of skull, into both orbits, and into brain. (C,D) Same patient as in Figure 4 A & B, 6 weeks after completion of protocol therapy. This patient remains locally controlled and is without disease at 13 months.
results have included new RT fractionation schedules and the addition of chemotherapy to the treatment program. Clearly, optimal treatment remains to be defined. In terms of RT, there are emerging data that treatment with multiple fractions per day may be superior to one fraction per day therapy for patients with advanced head and neck cancer (6,9,11,12,15-18). Also, Withers (17,18) and Maciejewski et al. (9) have produced evidence that the cells that remain approximately 30 days after the initiation of RT appear to proliferate at an exponential rate in excess of proliferation prior to that point. It can be postulated that these cells may require a more aggressive RT fractionation regimen, and that BID-RT would be most applicable to this cellular subpopulation. Indeed, an indirect test of this hypothesis has already been done by C.C. Wang (15). He compared his patients with oropharyngeal cancers treated in two different time periods, by two different fractionation schedules. From October 1979 to July 1982 patients were given 160 cGy BID to 3820 cGy in 12 days. After a 2-week break (approximately day 30), treatment resumed at 180 cGy daily (QD) up to a total dose of 6500 cGy. This
regimen is called BID-QD. From August 1982 onward, patients were given the same initial RT, but after the break were treated with 160 cGy BID up to a total dose of 6400 cGy. This regimen is called BID-BID. When the actuarial local control at 36 months is compared for T, - 4 tumors, it is 85% versus 41% in the BID-BID versus BID-QD groups, respectively. These differences were statistically significant, and support the hypothesis that BID therapy at the end of the RT treatment program, to the cells remaining at that point, may be a rational approach. Although our treatment program is new, there are other data for concurrent RT and CT for inoperable squamous cell carcinoma of the head and neck. Al-Sarraf et al. (1) have reported the RTOG experience. This involved conventional external beam radiotherapy to total doses of 6600 to 7380 cGy with concomitant cisplatinum (lOOmg/m’) on days 1, 22, and 43. The complete response rate was 69%. The disease control and survival rates were 61% and 60%, respectively, at 1 year. Our data show a complete response of 64%, a local progression-free survival at 1 year of 56%, and a 1-year actuarial survival of 69%. This compares quite
Unresectable head and neck cancer 0 L. B. HARRISON et al.
707
Fig. 5. (A) 51-year-old male with muco-epidermoid cancer of the frontal sinuses with extensive brain invasion; (B) Same patient 6 weeks after completion of protocol therapy. This was called a partial response, with only a small area of disease along the posterior frontal sinus remaining. It was resected completely. Patient died 9 months later, NED, with infection.
favorably with the RTOG experience; however, note that the RTOG patients had far less advanced disease than our patient group. All of our patients had Stage IV disease, whereas 22% of the RTOG patients had Stage III cancer. Fifty-three percent (53%) of the RTOG patients had T,, T,, or T, disease and 61% had NO-2 disease. All of our patients had either T, primary disease (22) or N, disease (2) that was fixed to surrounding structures or the carotid artery. Clearly, our group represents a far more advanced selection of patients. Even so, the results in terms of CR,
local control, and survival are similar. This disparity leads us to believe that our multi-modality CT-RT program, with BID-RT at the end of treatment, may yield a better therapeutic result. We believe that our preliminary experience suggests that this approach is both safe and effective in producing excellent regression and local control for far advanced head and neck cancer. More time is needed to see if these results are sustained. Meanwhile, efforts to build upon this experience appear warranted.
REFERENCES 1. Al-Sarraf,
2.
3.
4.
5.
6.
M.; Pajak, T.; Martial, V.; Mowry, P.; Cooper. J.; Stetz, J .; Ensley, J.; Velez-Garcia, E. Concurrent radiotherapy and chemotherapy with cisplatin in inoperable squamous cell carcinoma of the head and neck. Cancer 59: 259-265; 1987. Crissman, J.; Pajak, T.; Zarbo, R.; Martial, V.; Al-Sarraf, M. Improved response and survival to combined cisplatin and radiation in non-keratinized squamous cell carcinoma of the head and neck. An RTOG study of 114 advanced stage tumors. Cancer 59:1397-1397; 1987. Haas, C.; Anderson, T.; Byhard, R.; Duncavage, J.; Grossman, T.; Haas, J.; Libnoch, J.; Malin, T.; Ritch, P.; Toohill. R. Randomized neoadjuvant study of 5-FU and CDDP for patients with advanced resectable head ana neck cancer. Proc. Am. Assoc. Cancer Res. 27:185; 1986. Hayes, D.M.; Esteban, C.; Golbey, R.B.; Scheiner, E.; Helson, L.; Krakoff, I. High dose cis-platinum diammine dichloride; amelioration of renal toxicity by mannitol diuresis. Cancer 39:1372-1381; 1977. Jacobs, C. The use of chemotherapy in combination with radiotherapy. In: Wolf, G.T., ed. The treatment of head and neck squamous cancers. Boston, Mass.: Martinus Nijhoff; 1984: 265-286. Jampolis, S.; Pipard, G.; Horiot, J.C.; Bolla, M.; LeDorze, C. Preliminary results using twice-a-day fractionation in the
7.
8.
9.
10.
11.
12.
radiotherapeutic management of advanced cancers of the head and neck. Am. J. Roentgenol. 129:1091-1093; 1977. Kaplan, E.L.; Meier, P. Non-parametric observation from incomplete observation. J. Am. Stat. Assoc. 53:457481; 1958. Knowlton, A.H.; Percarpio, B.; Bobrow, S.; Fischer, J.J. Methotrexate and radiation therapy in treatment of advanced head and neck tumors. Radiology 116(3):709-712; 1975. Maciejewski, B.; Preuss-Bager, G.; Trott, K.R. The influence of number of fractions and overall treatment time on the local tumor control of cancer of the larynx, Int. J. Radiat. Oncol. Biol. Phys. 9:321-328; 1983. Martial, V.; Pajak, T.F.; Al-Sarraf, M.; Kinzie, J.; VelezGarcia, E. Concurrent radiotherapy and cis-platinum in inoperablemucosal squamous cell carcinoma of the head and neck. A Radiation Therapy Oncology Group report. Int. J. Radiat. Oncol. Biol. Phys. 1 l(Suppl.1):89; 1985. Medini, E.; Rao, Y.; Kim, T.; Jones, T.K.; Levitt, S.H. Radiation therapy for advanced head and neck squamous cell carcinoma using twice-a-day fractionation. Radiology 134: 531-532; 1980. Parsons, J.T.; Cassisi, N.; Million, R.R. Results of twice-aday irradiation of squamous cell carcinoma of the head and neck. Int. J. Radiat. Oncol. Biol. Phys. 10:2041-2051; 1984.
708
I. J. Radiation Oncology 0 Biology 0 Physics
13. Percarpio, B.; Fischer, J.J. Irradiation of advanced head and neck cancer with large daily fractions. Radiology 121:489490; 1976. 14. Taylor, S.G. IV; Applebaum, E.; Showel, J.L.; Norusis, M.; Holinger, L.; Hutchinson, J.; Murthy, A.; Cardarelli, D. A randomized trial of adjuvant chemotherapy in head and neck cancer. J. Clin. Oncol. 3:672-679; 1985. 15. Wang, C.C.; Suit, H.; Blitzer, P. Twice-a-day radiation therapy for supraglottic carcinoma. Int. J. Radiat. Oncol. Biol. Phys. 12:3-7; 1986. 16. Wang, C.C.; Blitzer, P.H.; Suit H. Twice-a-day radiation
August 1991, Volume 21, Number 3 for cancer of the head and neck. Cancer 55:2100-2104; 1985. 17. Withers, H.R. Biological basis for altered fractionation schemes. Cancer 55:208&2095; 1985. 18. Withers, H.R.; Taylor, J.M.G.; Maciejewski, B. The clinical hazard from accelerated tumor growth during radiotherapy. Acta Radiol. (In press). 19. Wittes, R.; Brescia, R.; Young, C.W.; Magill, G.B.; Krakoff, I.H. Combination chemotherapy with cis-diamminedichloroplatinum (II) and bleomycin in tumors of the head and neck. Oncology 32:203-207; 1975.
0360.3016191 $3.00 + .OU Copyright 0 1991 Pergamon Press plc
21, pp. 703-708
??Phase IIII Clinical Trials
CONCOMITANT CHEMOTHERAPY-RADIATION THERAPY FOLLOWED BY HYPERFRACTIONATED RADIATION THERAPY FOR ADVANCED UNRESECTABLE HEAD AND NECK CANCER LOUIS B. HARRISON, M.D.,* DAVID G. FFISTER, M.D.,?
DANIELE. FASS, M.D.,* JOHNG. ARMSTRONG, M.R.C.P.I.,” ROY B. SESSIONS,M.D.,$ JATINP. SHAH,M.D.,+ RONALDH. SPIRO, M.D.,$ ELLIOT W. STRONG, M.D.,$ STEVEN WEISEN, B.A.7 AND GEORGE J. BOSL, M.D.? Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, New York 10021 In January 1988, we initiated a prospective study evaluating a new treatment approach with chemotherapy and radiotherapy for unresectable head and neck cancer. Weeks l-4 were the initial debulking phase. Radiotherapy was delivered using 1.8 Gy/day to large portals including gross disease and all areas at risk. Cisplatinum, lOOmg/m*, was given concomitant with radiotherapy on days 1 and 22. Weeks 5 and 6 were the boosting phase. This involved twice-a-day irradiation. The AM fraction of 1.8 Gy was given to the entire area at risk, whereas the PM dose of 1.6 Gy was limited to the gross disease alone. Thus a total of 70 Gy/6 weeks was delivered. A total of 24 patients were treated, 22 of whom have completed this protocol and are evaluable. All patients had massive disease, with 15 having gross involvement of brain, orbit, skull base, or carotid artery. Fdlow-up ranged from 3-22 months (median 12 months). Major responses were achieved in %%, with 64% complete responses and 32% partial responses. Two patients with PR were able to undergo complete surgical resection, making the overall rate of complete response, including surgery, 73%. At 1 year, actuarial survival was 69%) and local progression-free survival was 56%. Distant metastases developed in 5 (23%). This approach sppears both safe and effective in producing excellent regression and local control for far advanced bead and neck cancer. More time is needed to see if these results are sustained. Effortsto build upon this experience appear warranted. Unresectable head and neck cancer, Radiotherapy, Chemotherapy.
INTRODUCTION
with concomitant chemotherapy (CT) and radiotherapy (RT) (1,2,10). Also, there is evidence to suggest a therapeutic advantage to twice a day irradiation (BID-RT) for selected head and neck cancers (6,9,11,12,15-18). Because data exist suggesting accelerated tumor repopulation after approximately 30 days of RT (9), the therapeutic ad-
Advanced, unresectable epithelial cancer of the head and neck is a challenging oncologic problem. Local control with standard radiation therapy is suboptimal, with long term survival less than 10% (13). Although chemotherapy programs using neoadjuvant cisplatinum-based regimens have produced high response rates, there has been no proven impact on local control or survival (3-8,14,19). On the other hand, there has been early promising experience
vantage to BID-RT may be most significant at that point in treatment, and it may not he required through the entire
course of treatment. Using these concepts we initiated a prospective study evaluating a new treatment approach.
*Brachytherapy Service, Department of Radiation Oncology. tThe Solid Tumor Service, Department of Medicine. SHead and Neck Service, Department of Surgery. Reprint requests to: Louis B. Harrison, M.D., Department of
Radiation Oncology, Brachytberapy Service, Memorial SloanKettering Cancer Center, 1275 York Ave., New York, NY 10021. Accepted for publication 22 February 1991. 703
704
I. J. Radiation Oncology 0 Biology 0 Physics Table 1. Distribution
August 1991, Volume 21, Number 3
of patients by primary site
Table 2. Analysis of response to treatment No.
Site Paranasal sinus Nasopharynx (all T4) Oropharynx Oral cavity Larynx Hypopharynx Total
10 3 7 2 1 1 24
This involves concomitant CT and RT for the first 4 weeks of treatment, followed by BID-RT for the fifth and sixth weeks of treatment. The last 2 weeks used a “field within a field” concomitant boosting cone down technique. This report describes our preliminary results.
METHODS AND MATERIALS Between January 1988 and December 1989, 24 consecutive patients have been treated. All patients met the following eligibility requirements: a) histologically confirmed cancer in the head and neck, including any histology except lymphoma, melanoma, and sarcoma; b) unresectable disease (all T, or Ns) as determined by an experienced head and neck surgeon; c) Kamofsky performance status > 50%; d) WBC > 4000 cells/mm, platelets > 100,000, creatinine clearance > 55cc/min; e) no prior cancer, and no previous treatment of the presenting cancer; f) the ability to give informed consent to this protocol. There were 15 males and 9 females whose ages ranged from 17 to 66 (median = 49). This histologic diagnosis was squamous cancer in 21 patients, adenocarcinoma in 2 patients, and mucoepidermoid carcinoma in 1 patient. Table 1 shows the distribution of patients according to the primary site. All patients had massive disease, which was considered surgically unresectable. The criteria for unresectability included gross involvement of brain parenchyma, orbit-eye, skull base, encasement of carotid artery, and massive fixed soft tissue disease with or without skin involvement. Patients who had resectable disease, but whose medical condition precluded operation, were not included. The treatment program involved initial concomitant CT and RT, followed by BID-RT. Weeks l-4 were the initial debulking phase. RT was delivered using 1.8 Gy/day to large portals including gross disease and all other areas at risk. Cisplatinum, 100 mg m’, was given concomitant with RT on days 1 and 22. The details of cisplatinum administration and reconstitution have been previously described (19). Weeks 5 and 6 were the boosting phase. This involved BID-RT, theoretically designed to address the accelerated tumor cell proliferation which occurs at this point. The AM fraction of 1.8 Gy was given to the entire area at risk, whereas the PM fraction of 1.6 Gy was lim-
Reseponse Complete response Partial response Minimal reponse
No.
(%)
14122 7122 l/22
(64) (32) ( 4)
Note: Of partial responders (7): 2 pts. had complete resection, 2 pts. has continued regression, 3 pts. had progression locally. Overall % CR including surgery = 73%.
ited to the gross disease alone. Fractions were separated by 4-6 hr. Thus, a total of 70 Gy/6 weeks was delivered. The spinal cord is shielded after 45 Gy. Standard criteria were used to assess response. A complete response (CR) implies total regression of all evaluable tumor. A partial response (PR) implies greater than 50% reduction in evaluable tumor. Clinical evaluation as well as CT scan was used in response evaluation. Follow-up ranged from 3 to 22 months, with median of 12 months. Survival and local control rates were determined by the Kaplan-Meier method (7).
RESULTS To date, 24 patients have been treated and 22 are evaluable. Two patients have just completed treatment and are too early to assess. Response data are summarized in Table 2. Major responses were achieved in 96%, including 64% CR and 32% PR. Two patients with PR were able to undergo surgical resection, making the overall rate of CR, including surgery, 73%. Although only three patients had nonsquamous histology, there was no obvious difference in response rate in these patients. At 1 year, local disease-free survival was 56% (Fig. 1). Distant metastasis developed in five patients (23%). At 1 year, overall actuarial survival was 69% (Fig. 2). Figures 3-5 show three patients who were treated on this protocol. These cases are illustrative of the massive disease exhibited by most of our patients. Note that we had more paranasal sinus patients than any other primary site, creating a
1.0 w'
.a 13)
WI
.6 .4 .2 0 I-lY'r_ 0
12
24
36
Time (months)
Fig. 1. Local progression-free
survival: all patients.
Unresectable
“?
head and neck cancer
72 Time (months)
Fig. 2. Actuarial survival: all patients.
??L. B.
705
HARRISON et al.
Despite the intensity of this treatment regimen, it was well tolerated. Although all patients had mucositis, no patients required significant treatment interruption. There were four patients who could not get their day 22 chemotherapy because of decreased renal function (Creatinine clearance < 55 cc/min). One patient did suffer a treatmentrelated death caused by granulocytopenia and sepsis. Finally, there was one patient with unresectable poorly differentiated squamous cancer of the maxillary antrum, destroying the maxillary bone. This patient did have osteoradionecrosis which required surgical debridement. However, she remains NED at 20 months following treatment, and her necrosis has healed.
DISCUSSION site imbalance. Although it is too early to determine whether the long term results for this subsite are better than other head and neck subsites, it is hoped that longer follow-up will address this question.
Patients with unresectable squamous cancer of the head and neck have a very poor survival with conventional RT alone (1). Over the years, efforts to improve upon these
Fig. 3. (A,B) 29-year-old woman with a poorly differentiated adenocarcinoma involving ethmoids, sphenoid, and both frontal sinuses. Disease extended into both orbits, through the skull base, with extensive brain invasion. (C,D) Same patient as (A,B), 6 weeks after completion of protocol therapy. This patient remains locally controlled at 2 years, but has developed liver metastases.
706
I. J. Radiation
Oncology
0 Biology 0 Physics
August 1991, Volume 21, Number 3
Fig. 4. (A,B) 27-year-old male with squamous cell cancer involving nasal cavity, ethmoid sinuses, frontal sinuses with maxillary antrum extension. Disease eroded through the base of skull, into both orbits, and into brain. (C,D) Same patient as in Figure 4 A & B, 6 weeks after completion of protocol therapy. This patient remains locally controlled and is without disease at 13 months.
results have included new RT fractionation schedules and the addition of chemotherapy to the treatment program. Clearly, optimal treatment remains to be defined. In terms of RT, there are emerging data that treatment with multiple fractions per day may be superior to one fraction per day therapy for patients with advanced head and neck cancer (6,9,11,12,15-18). Also, Withers (17,18) and Maciejewski et al. (9) have produced evidence that the cells that remain approximately 30 days after the initiation of RT appear to proliferate at an exponential rate in excess of proliferation prior to that point. It can be postulated that these cells may require a more aggressive RT fractionation regimen, and that BID-RT would be most applicable to this cellular subpopulation. Indeed, an indirect test of this hypothesis has already been done by C.C. Wang (15). He compared his patients with oropharyngeal cancers treated in two different time periods, by two different fractionation schedules. From October 1979 to July 1982 patients were given 160 cGy BID to 3820 cGy in 12 days. After a 2-week break (approximately day 30), treatment resumed at 180 cGy daily (QD) up to a total dose of 6500 cGy. This
regimen is called BID-QD. From August 1982 onward, patients were given the same initial RT, but after the break were treated with 160 cGy BID up to a total dose of 6400 cGy. This regimen is called BID-BID. When the actuarial local control at 36 months is compared for T, - 4 tumors, it is 85% versus 41% in the BID-BID versus BID-QD groups, respectively. These differences were statistically significant, and support the hypothesis that BID therapy at the end of the RT treatment program, to the cells remaining at that point, may be a rational approach. Although our treatment program is new, there are other data for concurrent RT and CT for inoperable squamous cell carcinoma of the head and neck. Al-Sarraf et al. (1) have reported the RTOG experience. This involved conventional external beam radiotherapy to total doses of 6600 to 7380 cGy with concomitant cisplatinum (lOOmg/m’) on days 1, 22, and 43. The complete response rate was 69%. The disease control and survival rates were 61% and 60%, respectively, at 1 year. Our data show a complete response of 64%, a local progression-free survival at 1 year of 56%, and a 1-year actuarial survival of 69%. This compares quite
Unresectable head and neck cancer 0 L. B. HARRISON et al.
707
Fig. 5. (A) 51-year-old male with muco-epidermoid cancer of the frontal sinuses with extensive brain invasion; (B) Same patient 6 weeks after completion of protocol therapy. This was called a partial response, with only a small area of disease along the posterior frontal sinus remaining. It was resected completely. Patient died 9 months later, NED, with infection.
favorably with the RTOG experience; however, note that the RTOG patients had far less advanced disease than our patient group. All of our patients had Stage IV disease, whereas 22% of the RTOG patients had Stage III cancer. Fifty-three percent (53%) of the RTOG patients had T,, T,, or T, disease and 61% had NO-2 disease. All of our patients had either T, primary disease (22) or N, disease (2) that was fixed to surrounding structures or the carotid artery. Clearly, our group represents a far more advanced selection of patients. Even so, the results in terms of CR,
local control, and survival are similar. This disparity leads us to believe that our multi-modality CT-RT program, with BID-RT at the end of treatment, may yield a better therapeutic result. We believe that our preliminary experience suggests that this approach is both safe and effective in producing excellent regression and local control for far advanced head and neck cancer. More time is needed to see if these results are sustained. Meanwhile, efforts to build upon this experience appear warranted.
REFERENCES 1. Al-Sarraf,
2.
3.
4.
5.
6.
M.; Pajak, T.; Martial, V.; Mowry, P.; Cooper. J.; Stetz, J .; Ensley, J.; Velez-Garcia, E. Concurrent radiotherapy and chemotherapy with cisplatin in inoperable squamous cell carcinoma of the head and neck. Cancer 59: 259-265; 1987. Crissman, J.; Pajak, T.; Zarbo, R.; Martial, V.; Al-Sarraf, M. Improved response and survival to combined cisplatin and radiation in non-keratinized squamous cell carcinoma of the head and neck. An RTOG study of 114 advanced stage tumors. Cancer 59:1397-1397; 1987. Haas, C.; Anderson, T.; Byhard, R.; Duncavage, J.; Grossman, T.; Haas, J.; Libnoch, J.; Malin, T.; Ritch, P.; Toohill. R. Randomized neoadjuvant study of 5-FU and CDDP for patients with advanced resectable head ana neck cancer. Proc. Am. Assoc. Cancer Res. 27:185; 1986. Hayes, D.M.; Esteban, C.; Golbey, R.B.; Scheiner, E.; Helson, L.; Krakoff, I. High dose cis-platinum diammine dichloride; amelioration of renal toxicity by mannitol diuresis. Cancer 39:1372-1381; 1977. Jacobs, C. The use of chemotherapy in combination with radiotherapy. In: Wolf, G.T., ed. The treatment of head and neck squamous cancers. Boston, Mass.: Martinus Nijhoff; 1984: 265-286. Jampolis, S.; Pipard, G.; Horiot, J.C.; Bolla, M.; LeDorze, C. Preliminary results using twice-a-day fractionation in the
7.
8.
9.
10.
11.
12.
radiotherapeutic management of advanced cancers of the head and neck. Am. J. Roentgenol. 129:1091-1093; 1977. Kaplan, E.L.; Meier, P. Non-parametric observation from incomplete observation. J. Am. Stat. Assoc. 53:457481; 1958. Knowlton, A.H.; Percarpio, B.; Bobrow, S.; Fischer, J.J. Methotrexate and radiation therapy in treatment of advanced head and neck tumors. Radiology 116(3):709-712; 1975. Maciejewski, B.; Preuss-Bager, G.; Trott, K.R. The influence of number of fractions and overall treatment time on the local tumor control of cancer of the larynx, Int. J. Radiat. Oncol. Biol. Phys. 9:321-328; 1983. Martial, V.; Pajak, T.F.; Al-Sarraf, M.; Kinzie, J.; VelezGarcia, E. Concurrent radiotherapy and cis-platinum in inoperablemucosal squamous cell carcinoma of the head and neck. A Radiation Therapy Oncology Group report. Int. J. Radiat. Oncol. Biol. Phys. 1 l(Suppl.1):89; 1985. Medini, E.; Rao, Y.; Kim, T.; Jones, T.K.; Levitt, S.H. Radiation therapy for advanced head and neck squamous cell carcinoma using twice-a-day fractionation. Radiology 134: 531-532; 1980. Parsons, J.T.; Cassisi, N.; Million, R.R. Results of twice-aday irradiation of squamous cell carcinoma of the head and neck. Int. J. Radiat. Oncol. Biol. Phys. 10:2041-2051; 1984.
708
I. J. Radiation Oncology 0 Biology 0 Physics
13. Percarpio, B.; Fischer, J.J. Irradiation of advanced head and neck cancer with large daily fractions. Radiology 121:489490; 1976. 14. Taylor, S.G. IV; Applebaum, E.; Showel, J.L.; Norusis, M.; Holinger, L.; Hutchinson, J.; Murthy, A.; Cardarelli, D. A randomized trial of adjuvant chemotherapy in head and neck cancer. J. Clin. Oncol. 3:672-679; 1985. 15. Wang, C.C.; Suit, H.; Blitzer, P. Twice-a-day radiation therapy for supraglottic carcinoma. Int. J. Radiat. Oncol. Biol. Phys. 12:3-7; 1986. 16. Wang, C.C.; Blitzer, P.H.; Suit H. Twice-a-day radiation
August 1991, Volume 21, Number 3 for cancer of the head and neck. Cancer 55:2100-2104; 1985. 17. Withers, H.R. Biological basis for altered fractionation schemes. Cancer 55:208&2095; 1985. 18. Withers, H.R.; Taylor, J.M.G.; Maciejewski, B. The clinical hazard from accelerated tumor growth during radiotherapy. Acta Radiol. (In press). 19. Wittes, R.; Brescia, R.; Young, C.W.; Magill, G.B.; Krakoff, I.H. Combination chemotherapy with cis-diamminedichloroplatinum (II) and bleomycin in tumors of the head and neck. Oncology 32:203-207; 1975.