0360.3016190 $3.00 + .I0 Copyright 0 ,990 Pel.gmmn press plc
1m J. Radiarmn Oncology RIO/. Phys Vol. 19, pp. 1321-1324 Printed in the U.S.A. All rights resewed.
??Editorial
ALTERNATE
STRATEGIES R. W.
FOR LIMITED BYHARDT,
Medical College of Wisconsin, Department
M.D.
STAGE
SMALL
AND J. F. WILSON,
CELL
LUNG
CANCER
M.D.
of Radiation Oncology, 8700 W. Wisconsin Ave., Milwaukee, WI 53226
“Let us not waste our time in idle discourse (Pause. Vehemently.) Let us do something while we have the chance!” Waitingfor Godot, Samuel Beckett (1954) Radiation/chemotherapy strategies, Small cell lung cancer. with RT (usually split course) interdigitated between CT Despite many previous studies of limited stage small cell cycles, and concurrent, RT given during 1 or 2 cycles of lung cancer (SCLC) treated with various combined moCT, early or late. Hybrid variations of these are also posdality approaches incorporating chemotherapy (CT) and sible, for example, concurrent-alternating, in which an radiation therapy (RT), there is no clear consensus as to abbreviated RT course is given concurrently with each which of these strategies constitutes “standard” therapy. cycle of CT. Also, in addition to possible variations in Optimistic results obtained with the benchmark regimen of Cyclophosphamide, Doxorubicin, and Vincristine intensity of the CT, the RT may vary in daily or total (CAV) in the late 1970’s, and the later identification of dose, course (split or continuous), duration, volume, and Etoposide and Cisplatin (EP) as equally active “non-cross other parameters. resistant” agents, kindled hope that limited SCLC would A generally held concept is that small cell tumors are rapidly join the list of oncologic success stories. Yet, deheterogeneous neoplasms at risk for developing CT or RT spite impressive gains in response rates, local recurrence resistant clones, through mechanisms which are probably rates remained high, necessitating the integration of thodifferent. Effective combinations of CT and RT must racic irradiation (TI) into the treatment scheme. Contromesh the two to avoid establishment of resistant cell lines, versy abounded as to the optimal dose-time relationships, without compromising the intensity of either modality or timing and sequencing of TI with chemotherapy. Alincreasing toxicity. The results from many early trials have though it is now accepted that TI reduced the risk of local suffered from compromises in drug dosage or the use of recurrence, any survival advantage has been hotly debated, suboptimal radiation doses or schedules. Impressive gains as has the most efficacious way to add TI without increasin response rates have, on the other hand, sometimes been ing treatment-related morbidity/mortality. nullified by significant treatment-related lethality. Multiple trials, including many randomized cooperative The current article by Arriagada et al. represents the group studies, examined the issue of TI in the late 1970’s long term results of an intriguing alternating CT-RT regand early 1980’s. By 198 1, participants in an international imen used at the Institute Gustave-Roussy since the early 1980’s (2). Enticing preliminary results of this work were workshop determined that reasonably achievable results reported here in 1985 (1). To place this experience in following CT and TI could be characterized by complete perspective, some comparisons with other recent results response rates of 50-60%, median survivals of 12- 14 from institutional and cooperative group efforts (outlined months, and 15 to 25% disease-free 2- to 3-year survivals (3,5,7, 17). Some oncologists concluded that true progress in Table 1) are valid to consider. With sequential treatment, following up to 6 cycles of would not be made until the advent of more effective CT, CT, complete responders and patients without disease while others have worked to clarify the CT-RT relationprogression or treatment complications commonly receive ship, evaluate the potpourri of CT-RT regimens, and to “consolidative” TI, usually providing moderate radiation maximize available modalities. In this regard, the report doses to areas of prechemotherapy tumor bulk. This apby Arriagada et al. in this month’s issue reflects the product proach allows evaluation of the response to CT and perof nearly a decade of careful investigation at one major institution and provides us important new knowledge (2). mits maximum doses of CT for best chance of complete response (CR) of occult metastases while avoiding co-toxThree basic CT-RT combinations can be defined: seicity with RT. Some of the more recent sequential trials quential, 3 to 6 cycles of CT followed by RT, alternating,
Accepted for publication
Reprint requests to: Roger W. Byhardt, M.D. 1321
24 July 1990.
1322
I. J. Radiation Oncology 0 Biology 0 Physics
Table 1. Representative
Group author Sequential NCI-C Coy et al. (8) Memorial Shank ef al. (18) Alternating G. Roussy Arriagada et al. (2) SEG Perez et al. ( 15) Concurrent C-LTG Murray ef al. (13) U. Penn. Turrisi et al. (20) NC1 Bunn et al. (4) CALGB Perry et al. (16)
November 1990, Volume 19, Number 5
results of current combined modality strategies in limited stage small cell lung cancer
Chemotherapy
%
Local control % (years)
Median survival months
2-year survival %
Long-term survival % (years)
-18 -24
- 17 (3a) -22 (3a)
TI
CR
GY/w~
Lethal toxicity %
CAV-EP
2512 37.513
65 69
20 (3) 30 (3)
14 14
CAV-EP
4515
65
88 (2)
21
CAEM or CAEP CAV
15.2012, 15-2012, 15-2512 15/l, 15/l, IO/l
75
60 (5)
17
-27
18 (5)
10
63
64 (3)
14
-28
20 (3a)
0
CAV-EP
3012
76
62 (1.5)
19.5
17 (3.5)
2
EP
45 (bid)/3
90
100 (2)
56 (3a)
0
CML-VAP
4013
81
87 (5)
15
28
-15
CEV
5015 early 5015 delayed
49 58
60 (4) 59 (4)
13 14.6
15 25
-9 (4a) -20 (4a)
>24
46
32 -56
33 (3a)
0 0 -6
11 9 6
NCI-C = National Cancer Institute of Canada; Memorial = Sloan-Kettering Memorial; G. Roussy = Institute Gustave Roussy; SEG = Southeastern Oncology Group; C-LTG Canadian Lung Tumor Group; U. Penn. = University of Pennsylvania; NC1 = National Cancer Institute; CALGB = Cancer & Leukemia Group B. C = Cyclophosphamide; A = Adriamycin; V = Vincristine; E = Etoposide; P = Platinol; M = Methotrexate; L = Lomustine; bid = twice daily radiation; a = actuarial.
have used alternating cycles of CAV and EP as “noncross resistant” cytotoxic combinations with dissimilar (non-overlapping) normal tissue toxicities. It follows the rationale expressed by the Goldie-Coldman theory (10, 11) that when two agents are used, delay in administration of one of them increases the probability of doubly-resistant cell lines. The National Cancer Institute-Canada study (8) was hampered by a low effective dose schedule of TI (7), which is reflected in a 30% local control rate, as well as a modest median survival (14 months) and long term survival (22%). Lethal toxicity, however, was absent. The Memorial series used a higher dose of TI (45 Gy/5 weeks) with the same CAV-EP schedule, resulting in an 88% local control rate, 2 1-month median survival, 46% 2-year survival, and 33% actuarial 3-year survival (18). Comparing these two studies, it is tempting to ascribe this survival benefit to enhanced local control with the more aggressive TI on the basis that residual chemotherapy-resistant tumor cells that could disseminate were eradicated. What is troublesome about this argument, in addition to the use of maintenance chemotherapy for CR patients in the Memorial series, is the 4- to 6-month delay in treating chemotherapy resistant cell lines with the sequential strategy. One way to place TI earlier in the regimen is the alternating approach, as in the Gustave-Roussy regimen. The rationale for this was previously discussed by Tubiana et al. (19) and the details of the RT described in the preliminary report of Arriagada et al. in 1985 (1). The CT and RT are considered as true “non-cross resistant” agents, again following the Goldie-Coldman logic and
based on Looney’s extensive animal tumor modelling work, which suggests a benefit from alternating CT and
RT relative to growth kinetics (10, 11). Alternating modalities with different toxicities may allow more time for normal tissue recovery from each and reduce overall morbidity/mortality. Tubiana concluded that late toxicity should be as low as with sequential therapy and the preliminary data supported that view. The Gustave-Roussy regimen uses Cyclophosphamide, Adriamycin, Etoposide (CAE) with either Methotrexate (M), early protocol, or Cisplatin (P), later protocol, alternating with 3 courses of 15-15-I 5 Gy, 20-20-15 Gy, or 20-20-25 Gy in 2 weeks each course, using 250 cGy per fraction (I). Total radiation dose was increased incrementally from 45 to 55 to 65 Gy over the course of the study, attempting to increase local control from a low of 48% seen at 45 Gy (1). There is no significant difference in 3-year local control between the three dose levels. Combining all three dose schedules, the overall local control rate is 60% at 5 years and is at the low end of the range described in Table 1. It is consistent, however, with the 64% local control rate reported by the Southeastern Cancer Study Group (SEG) using CAV courses alternating with 2 courses of 15 Gy/ 1 week and 1 course of 10 Gy/ 1 week ( 15). Complete response rates (63% vs 75%) median survivals ( 14 vs 17 months), and long term survivals ( 18% vs 20%) are quite similar in the two studies, but not, apparently, superior to results of more recent sequential regimens using alternating “non-cross resistant” CT cycles. The Gustave Roussy results now indicate a 10% (7%, if
Limited small cell lung cancer 0 R. W. BYHARDT
CNS deaths are excluded) treatment-related toxicity versus 0% in the SEG study. Pulmonary (three cases) and cardiac (two cases) lethality suggest the combined effect of Adriamycin and RT, despite the reduced dose of TI and the alternation. Delayed or recall toxicity may be a factor, although the SEG alternation study also included Adriamycin with similar timing between courses. Splitting the TI for alternation with chemotherapy may possibly confer some of the detrimental effects of split course RT on tumor control. If TI is relied upon to sterilize CT resistant cell populations, then proliferation and repopulation of these could occur between TI courses and the total TI dose would be less effective in controlling resistant cell lines. Thus, the biologically effective radiation dose, in alternating schedules, may be only marginally successful in achieving maximal local tumor control. Even at a total dose of 65 Gy, the detrimental effect of split course delivery may be only partially compensated for by the CT. Several authors have argued that maximally effective techniques of combining TI and CT must not compromise effective dose scheduling of either ( 14, 15). In a non-randomized study of one alternating regimen, Yale reported a 96% local control rate using 60 Gy/6 weeks between cycles 3 and 4 of 6 cycles of CEM chemotherapy. Despite this, median (14 months) and 2-year survival (30%) was about average ( 14). Some of the most promising improvements in response and survival have been reported with concurrent schedules of CT and TI, although early regimens were associated with a high morbidity and a lethal toxicity incidence of 10% or greater ( 17). Much of this was related to esophageal and pulmonary co-toxicity of TI and Adriamycin. Newer concurrent regimens often replace Adriamycin with Etoposide or eliminate Adriamycin during the concurrent CT cycles. Some concurrent regimens (Table 1) also used alternating CT schedules and some downward modification of TI dose scheduling to limit toxicity. Most used continuous, single fraction per day TI which overlapped one cycle of drugs, although the CALGB study, using 50 Gy/5 weeks either early or late in the CT cycles, overlapped two cycles of CT. These approaches yielded CRs of 49-8 l%, local control rates of 59-87%, median survival of 13-19.5 months, and long term survival of 9-l 7%. Despite a suggestion of an upward trend in some of the parameters, the ranges are generally similar to the best
AND J. F. WILSON
1323
sequential or alternating regimens, especially long term survival. Lethal toxicity ranged from 2 to 1 l%, somewhat higher than sequential, but similar to the Arriagada alternating scheme. Turrisi et al., in a non-randomized pilot study (20) with relatively small numbers, obtained a 90% CR rate, 100% local control rate, >24 month median survival, and a 56% actuarial 3-year survival, which surpasses the results of most other studies, regardless of size. This protocol uses only two drugs (EP), chosen for proven tumor effect and minimal co-toxicity with TI. Twice daily irradiation of 150 cGy per fraction (45 Gy/3 weeks) is used to take advantage of in vitro survival curves showing lack of a “shoulder” for SCLC and to decrease risk of late damage to normal tissues. This pilot experience supports the speculations of Choi and Carey (6) and others that TI, possibly with altered fractionation schedules, might be key to improving local-regional control and, ultimately, survival. Just as CR of extrathoracic disease to CT is essential for overall disease control, local-regional control is mandatory to prevent both regrowth and distant reseeding from residual, CT-resistant local tumor. Tunisi’s regimen is currently being tested by the Eastern Cooperative Oncology Group and the Radiation Therapy Oncology Group in an intergroup study. Few of the approximately 11,000 new cases of limited stage SCLC seen yearly are treated on investigational studies. Although the development of new cytotoxics or biologics that will dramatically increase complete and durable responses is eagerly awaited, new patients continue to require therapy with existing modalities. Treatment “off protocol” with various approaches loosely based on best available data, as interpreted by the treating physician and modified by patient acceptance, is frequently selected. Choosing “best data” is difficult, for the benchmark standard has not yet clearly declared itself. Many new pilot studies are in progress, testing novel integrations of CT and TI based on theoretical and biological modelling as well as clinical leads. Tantalizing results yielded by some of these studies should arouse us out of complacency, as we wait for Godot. These tastes of success reinforce the need to propel more limited stage SCLC patients into prospective trials, seeking to verify theory in the clinic, for timely identification of a new “standard.”
REFERENCES 1.
Arriagada, R.; Le Chevalier, T.; Baldeyrou, P.; Pica, J. L.; Ruffie, P.; Martin, M.; El Bakry, H. M.; Duroux, P.; Bignon, J.; Lenfant, B.; Hayat, M.; Rouesse, J. G.; Sancho-Garnier,
H.; Tubiana, M. Alternating radiotherapy and chemotherapy schedules in small cell lung cancer, limited disease. Int. J. Radiat. Oncol. Biol. Phys. 11:1461-1467; 1985. 2. Arriagada, R.; Le Chevalier, T.; Ruffie, P.; Baldeyrou, P.; De Cremoux, H.; Martin, M.; Chomy, P.; Cerrina, M. L.; Pellae-Cosset, B.; Tarayre, M.; Sancho-Gamier, H.; the GROP, the French Cancer Centers Lung Group. Alternating
radiotherapy and chemotherapy in 173 consecutive patients with limited small cell lung carcinoma. Int. J. Radiat. Oncol. Biol. Phys. 19:1135-l 138; 1990. 3. Bleehen, N. H.; Bunn, P. A.; Cox, J. D.; Dombemowsky, P.; Fox, R. M.; Host, H.; Joss, R.; White, J. E.; Wittes, R. E. Role of radiation therapy in small cell anaplastic carcinema of the lung. Cancer Treat. Rep. 67: 11- 19; 1983. 4. Bunn, P. A.; Lichter, A. S.; Makuch, R. W.; Cohen, M. H.; Veach, S. R.; Matthews, M. J.; Johnston Anderson, A.; Edison, M.; Glatstein, E.; Minna, J. D.; Ihde, D. C. Chemo-
1324
5.
6.
7. 8.
9.
10.
11.
12.
13.
I.
J. Radiation Oncology 0 Biology0 Physics
therapy alone or chemotherapy with chest radiation therapy in limited stage small cell lung cancer. Ann. Int. Med. 106: 655-662; 1987. Byhardt, R. W.; Cox, J. D. Is chest radiotherapy necessary for any or all patients with small cell carcinoma of the lung? Yes. Cancer Treat. Rep. 67:209-2 15; 1983. Choi, N. C.; Carey, R. W. Importance of radiation dose in achieving improved loco-regional tumor control in limited stage small cell lung carcinoma: an update. Int. J. Radiat. Oncol. Biol. Phys. 17:307-310; 1989. Cox, J. D. Dose-response in small cell carcinoma. Int. J. Radiat. Oncol. Biol. Phys. 14:393-394; 1988. Coy, P.; Hodson, I.; Payne, D. G.; Evans, W. K.; Fled, R.; MacDonald, A. S.; Osoba, D.; Pater, J. L. The effect of dose of thoracic irradiation on recurrence in patients with limited stage small cell lung cancer. Initial results of a Canadian multicenter trial. Int. J. Radiat. Oncol. Biol. Phys. 14:2 19226; 1988. Goldie, J. H.; Coldman, A. J.; Gudrauskas, G. A. Rationale for the use of alternating non-cross resistant chemotherapy. Cancer Treat. Rep. 66:439-449; 1982. Looney, W. B.; Goldie, J. H.; Little, J. B.; Hopkins, H. A.; Read, E. J.; Wittes, R. Alternation of chemotherapy and radiotherapy in cancer management. I. Summary of the division of cancer treatment workshop. Cancer Treat. Rep. 69:769-775; 1985. Looney, W. B.; Hopkins, H. A. Alternation of chemotherapy and radiotherapy in cancer management. III. Results in experimental solid tumor systems and their relationship to clinical studies. Cancer Treat. Rep. 70: 14 1- 162; 1986. McCracken, J. D.; Janaki, L. M.; Taylor, S. B.; Shankar Giri, P. G.; Weiss, G. B.; Gordon, W.; Vance, R. B.; Crowley, J. Concurrent chemotherapy and radiotherapy for limited small-cell carcinoma of the lung: a Southwest Oncology Group Study. Sem. Oncol. 13:31-36; 1986. Murray, N.; Shah, A.; Brown, E.; Kostashuk, E.; Laukkanen, E.; Goldie, J.; Band, P.; Van den Hoek, J.; Murphy, K.; Sparling, T.; Noble, M. Alternating chemotherapy and tho-
November 1990, Volume 19, Number 5
14.
15.
16.
17.
18.
19.
20.
racic radiotherapy with concurrent cisplatin-etoposide for limited stage small-cell carcinoma of the lung. Sem. Oncol. 13:24-30; 1986. Papac, R. J.; Son, Y.; Bien, R.; Tiedemann, D.; Keohane. M.; Yesner, R. Improved local control of thoracic disease in small cell lung cancer with higher dose thoracic irradiation and cyclic chemotherapy. Int. J. Radiat. Oncol. Biol. Phys. 13:993-998; 1987. Perez, C. A.; Einhorn, L.; Oldham, R. K.; Greco, F. A.; Cohen, H. J.; Silberman, H.; Krauss, S.; Homback, N.; Comas, F.; Omura, G.; Salter, M.; Keller, J. W.; McLaren, J.; Kellermayer, R.; Storaasli, J.; Birch, R.; Dandy, M. for the Southeastern Cancer Study Group. Randomized trial of radiotherapy to the thorax in limited small-cell carcinoma of the lung treated with multiagent chemotherapy and elective brain irradiation: a preliminary report. J. Clin. Oncol. 2:1200-1208; 1984. Perry, M. C.; Eaton, W. L.; Propert, K. J.; Ware, J. H.; Zimmer, B.; Chahinian, A. P.; Skarin, A.; Carey, R. W.; Kreisman, H.; Faulkner, C.; Comis, R.; Green, M. R. Chemotherapy with or without radiation therapy in limited small-cell carcinoma of the lung. N. Eng. J. Med. 3 16:9 12918; 1987. Seydel, H. G. The light at the end of the tunnel for limited stage small cell lung cancer? Int. J. Radiat. Oncol. Biol. Phys. 15:243-244; 1988. Shank, B.; Scher, H.; Hilaris, B. S.; Pinsky, C.; Martin, M.; Wittes, R. E. Increased survival with high-dose multifield radiotherapy and intensive chemotherapy in limited small cell carcinoma of the lung. Cancer 56:2771-2778; 1985. Tubiana, M.; Arriagada, R.; Cosset, J. Sequencing of drugs and radiation. The integrated alternating regimen. Cancer 55:2131-2139; 1985. Turrisi, A. T.; Glover, D. J.; Mason, B. A. A preliminary report: concurrent twice-daily radiotherapy plus platinumetoposide chemotherapy for limited small cell lung cancer. Int. J. Radiat. Oncol. Biol. Phys. 15: 183-187; 1988.
1m J. Radiarmn Oncology RIO/. Phys Vol. 19, pp. 1321-1324 Printed in the U.S.A. All rights resewed.
??Editorial
ALTERNATE
STRATEGIES R. W.
FOR LIMITED BYHARDT,
Medical College of Wisconsin, Department
M.D.
STAGE
SMALL
AND J. F. WILSON,
CELL
LUNG
CANCER
M.D.
of Radiation Oncology, 8700 W. Wisconsin Ave., Milwaukee, WI 53226
“Let us not waste our time in idle discourse (Pause. Vehemently.) Let us do something while we have the chance!” Waitingfor Godot, Samuel Beckett (1954) Radiation/chemotherapy strategies, Small cell lung cancer. with RT (usually split course) interdigitated between CT Despite many previous studies of limited stage small cell cycles, and concurrent, RT given during 1 or 2 cycles of lung cancer (SCLC) treated with various combined moCT, early or late. Hybrid variations of these are also posdality approaches incorporating chemotherapy (CT) and sible, for example, concurrent-alternating, in which an radiation therapy (RT), there is no clear consensus as to abbreviated RT course is given concurrently with each which of these strategies constitutes “standard” therapy. cycle of CT. Also, in addition to possible variations in Optimistic results obtained with the benchmark regimen of Cyclophosphamide, Doxorubicin, and Vincristine intensity of the CT, the RT may vary in daily or total (CAV) in the late 1970’s, and the later identification of dose, course (split or continuous), duration, volume, and Etoposide and Cisplatin (EP) as equally active “non-cross other parameters. resistant” agents, kindled hope that limited SCLC would A generally held concept is that small cell tumors are rapidly join the list of oncologic success stories. Yet, deheterogeneous neoplasms at risk for developing CT or RT spite impressive gains in response rates, local recurrence resistant clones, through mechanisms which are probably rates remained high, necessitating the integration of thodifferent. Effective combinations of CT and RT must racic irradiation (TI) into the treatment scheme. Contromesh the two to avoid establishment of resistant cell lines, versy abounded as to the optimal dose-time relationships, without compromising the intensity of either modality or timing and sequencing of TI with chemotherapy. Alincreasing toxicity. The results from many early trials have though it is now accepted that TI reduced the risk of local suffered from compromises in drug dosage or the use of recurrence, any survival advantage has been hotly debated, suboptimal radiation doses or schedules. Impressive gains as has the most efficacious way to add TI without increasin response rates have, on the other hand, sometimes been ing treatment-related morbidity/mortality. nullified by significant treatment-related lethality. Multiple trials, including many randomized cooperative The current article by Arriagada et al. represents the group studies, examined the issue of TI in the late 1970’s long term results of an intriguing alternating CT-RT regand early 1980’s. By 198 1, participants in an international imen used at the Institute Gustave-Roussy since the early 1980’s (2). Enticing preliminary results of this work were workshop determined that reasonably achievable results reported here in 1985 (1). To place this experience in following CT and TI could be characterized by complete perspective, some comparisons with other recent results response rates of 50-60%, median survivals of 12- 14 from institutional and cooperative group efforts (outlined months, and 15 to 25% disease-free 2- to 3-year survivals (3,5,7, 17). Some oncologists concluded that true progress in Table 1) are valid to consider. With sequential treatment, following up to 6 cycles of would not be made until the advent of more effective CT, CT, complete responders and patients without disease while others have worked to clarify the CT-RT relationprogression or treatment complications commonly receive ship, evaluate the potpourri of CT-RT regimens, and to “consolidative” TI, usually providing moderate radiation maximize available modalities. In this regard, the report doses to areas of prechemotherapy tumor bulk. This apby Arriagada et al. in this month’s issue reflects the product proach allows evaluation of the response to CT and perof nearly a decade of careful investigation at one major institution and provides us important new knowledge (2). mits maximum doses of CT for best chance of complete response (CR) of occult metastases while avoiding co-toxThree basic CT-RT combinations can be defined: seicity with RT. Some of the more recent sequential trials quential, 3 to 6 cycles of CT followed by RT, alternating,
Accepted for publication
Reprint requests to: Roger W. Byhardt, M.D. 1321
24 July 1990.
1322
I. J. Radiation Oncology 0 Biology 0 Physics
Table 1. Representative
Group author Sequential NCI-C Coy et al. (8) Memorial Shank ef al. (18) Alternating G. Roussy Arriagada et al. (2) SEG Perez et al. ( 15) Concurrent C-LTG Murray ef al. (13) U. Penn. Turrisi et al. (20) NC1 Bunn et al. (4) CALGB Perry et al. (16)
November 1990, Volume 19, Number 5
results of current combined modality strategies in limited stage small cell lung cancer
Chemotherapy
%
Local control % (years)
Median survival months
2-year survival %
Long-term survival % (years)
-18 -24
- 17 (3a) -22 (3a)
TI
CR
GY/w~
Lethal toxicity %
CAV-EP
2512 37.513
65 69
20 (3) 30 (3)
14 14
CAV-EP
4515
65
88 (2)
21
CAEM or CAEP CAV
15.2012, 15-2012, 15-2512 15/l, 15/l, IO/l
75
60 (5)
17
-27
18 (5)
10
63
64 (3)
14
-28
20 (3a)
0
CAV-EP
3012
76
62 (1.5)
19.5
17 (3.5)
2
EP
45 (bid)/3
90
100 (2)
56 (3a)
0
CML-VAP
4013
81
87 (5)
15
28
-15
CEV
5015 early 5015 delayed
49 58
60 (4) 59 (4)
13 14.6
15 25
-9 (4a) -20 (4a)
>24
46
32 -56
33 (3a)
0 0 -6
11 9 6
NCI-C = National Cancer Institute of Canada; Memorial = Sloan-Kettering Memorial; G. Roussy = Institute Gustave Roussy; SEG = Southeastern Oncology Group; C-LTG Canadian Lung Tumor Group; U. Penn. = University of Pennsylvania; NC1 = National Cancer Institute; CALGB = Cancer & Leukemia Group B. C = Cyclophosphamide; A = Adriamycin; V = Vincristine; E = Etoposide; P = Platinol; M = Methotrexate; L = Lomustine; bid = twice daily radiation; a = actuarial.
have used alternating cycles of CAV and EP as “noncross resistant” cytotoxic combinations with dissimilar (non-overlapping) normal tissue toxicities. It follows the rationale expressed by the Goldie-Coldman theory (10, 11) that when two agents are used, delay in administration of one of them increases the probability of doubly-resistant cell lines. The National Cancer Institute-Canada study (8) was hampered by a low effective dose schedule of TI (7), which is reflected in a 30% local control rate, as well as a modest median survival (14 months) and long term survival (22%). Lethal toxicity, however, was absent. The Memorial series used a higher dose of TI (45 Gy/5 weeks) with the same CAV-EP schedule, resulting in an 88% local control rate, 2 1-month median survival, 46% 2-year survival, and 33% actuarial 3-year survival (18). Comparing these two studies, it is tempting to ascribe this survival benefit to enhanced local control with the more aggressive TI on the basis that residual chemotherapy-resistant tumor cells that could disseminate were eradicated. What is troublesome about this argument, in addition to the use of maintenance chemotherapy for CR patients in the Memorial series, is the 4- to 6-month delay in treating chemotherapy resistant cell lines with the sequential strategy. One way to place TI earlier in the regimen is the alternating approach, as in the Gustave-Roussy regimen. The rationale for this was previously discussed by Tubiana et al. (19) and the details of the RT described in the preliminary report of Arriagada et al. in 1985 (1). The CT and RT are considered as true “non-cross resistant” agents, again following the Goldie-Coldman logic and
based on Looney’s extensive animal tumor modelling work, which suggests a benefit from alternating CT and
RT relative to growth kinetics (10, 11). Alternating modalities with different toxicities may allow more time for normal tissue recovery from each and reduce overall morbidity/mortality. Tubiana concluded that late toxicity should be as low as with sequential therapy and the preliminary data supported that view. The Gustave-Roussy regimen uses Cyclophosphamide, Adriamycin, Etoposide (CAE) with either Methotrexate (M), early protocol, or Cisplatin (P), later protocol, alternating with 3 courses of 15-15-I 5 Gy, 20-20-15 Gy, or 20-20-25 Gy in 2 weeks each course, using 250 cGy per fraction (I). Total radiation dose was increased incrementally from 45 to 55 to 65 Gy over the course of the study, attempting to increase local control from a low of 48% seen at 45 Gy (1). There is no significant difference in 3-year local control between the three dose levels. Combining all three dose schedules, the overall local control rate is 60% at 5 years and is at the low end of the range described in Table 1. It is consistent, however, with the 64% local control rate reported by the Southeastern Cancer Study Group (SEG) using CAV courses alternating with 2 courses of 15 Gy/ 1 week and 1 course of 10 Gy/ 1 week ( 15). Complete response rates (63% vs 75%) median survivals ( 14 vs 17 months), and long term survivals ( 18% vs 20%) are quite similar in the two studies, but not, apparently, superior to results of more recent sequential regimens using alternating “non-cross resistant” CT cycles. The Gustave Roussy results now indicate a 10% (7%, if
Limited small cell lung cancer 0 R. W. BYHARDT
CNS deaths are excluded) treatment-related toxicity versus 0% in the SEG study. Pulmonary (three cases) and cardiac (two cases) lethality suggest the combined effect of Adriamycin and RT, despite the reduced dose of TI and the alternation. Delayed or recall toxicity may be a factor, although the SEG alternation study also included Adriamycin with similar timing between courses. Splitting the TI for alternation with chemotherapy may possibly confer some of the detrimental effects of split course RT on tumor control. If TI is relied upon to sterilize CT resistant cell populations, then proliferation and repopulation of these could occur between TI courses and the total TI dose would be less effective in controlling resistant cell lines. Thus, the biologically effective radiation dose, in alternating schedules, may be only marginally successful in achieving maximal local tumor control. Even at a total dose of 65 Gy, the detrimental effect of split course delivery may be only partially compensated for by the CT. Several authors have argued that maximally effective techniques of combining TI and CT must not compromise effective dose scheduling of either ( 14, 15). In a non-randomized study of one alternating regimen, Yale reported a 96% local control rate using 60 Gy/6 weeks between cycles 3 and 4 of 6 cycles of CEM chemotherapy. Despite this, median (14 months) and 2-year survival (30%) was about average ( 14). Some of the most promising improvements in response and survival have been reported with concurrent schedules of CT and TI, although early regimens were associated with a high morbidity and a lethal toxicity incidence of 10% or greater ( 17). Much of this was related to esophageal and pulmonary co-toxicity of TI and Adriamycin. Newer concurrent regimens often replace Adriamycin with Etoposide or eliminate Adriamycin during the concurrent CT cycles. Some concurrent regimens (Table 1) also used alternating CT schedules and some downward modification of TI dose scheduling to limit toxicity. Most used continuous, single fraction per day TI which overlapped one cycle of drugs, although the CALGB study, using 50 Gy/5 weeks either early or late in the CT cycles, overlapped two cycles of CT. These approaches yielded CRs of 49-8 l%, local control rates of 59-87%, median survival of 13-19.5 months, and long term survival of 9-l 7%. Despite a suggestion of an upward trend in some of the parameters, the ranges are generally similar to the best
AND J. F. WILSON
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sequential or alternating regimens, especially long term survival. Lethal toxicity ranged from 2 to 1 l%, somewhat higher than sequential, but similar to the Arriagada alternating scheme. Turrisi et al., in a non-randomized pilot study (20) with relatively small numbers, obtained a 90% CR rate, 100% local control rate, >24 month median survival, and a 56% actuarial 3-year survival, which surpasses the results of most other studies, regardless of size. This protocol uses only two drugs (EP), chosen for proven tumor effect and minimal co-toxicity with TI. Twice daily irradiation of 150 cGy per fraction (45 Gy/3 weeks) is used to take advantage of in vitro survival curves showing lack of a “shoulder” for SCLC and to decrease risk of late damage to normal tissues. This pilot experience supports the speculations of Choi and Carey (6) and others that TI, possibly with altered fractionation schedules, might be key to improving local-regional control and, ultimately, survival. Just as CR of extrathoracic disease to CT is essential for overall disease control, local-regional control is mandatory to prevent both regrowth and distant reseeding from residual, CT-resistant local tumor. Tunisi’s regimen is currently being tested by the Eastern Cooperative Oncology Group and the Radiation Therapy Oncology Group in an intergroup study. Few of the approximately 11,000 new cases of limited stage SCLC seen yearly are treated on investigational studies. Although the development of new cytotoxics or biologics that will dramatically increase complete and durable responses is eagerly awaited, new patients continue to require therapy with existing modalities. Treatment “off protocol” with various approaches loosely based on best available data, as interpreted by the treating physician and modified by patient acceptance, is frequently selected. Choosing “best data” is difficult, for the benchmark standard has not yet clearly declared itself. Many new pilot studies are in progress, testing novel integrations of CT and TI based on theoretical and biological modelling as well as clinical leads. Tantalizing results yielded by some of these studies should arouse us out of complacency, as we wait for Godot. These tastes of success reinforce the need to propel more limited stage SCLC patients into prospective trials, seeking to verify theory in the clinic, for timely identification of a new “standard.”
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