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Radiotherapy and Cisplatin: outcome of combined modality treatment in
non-small cell lung cancer
Uitterhoeve, A.L.J.
Publication date
2007
Document Version
Final published version
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Citation for published version (APA):
Uitterhoeve, A. L. J. (2007). Radiotherapy and Cisplatin: outcome of combined modality
treatment in non-small cell lung cancer.
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Radiotherapy and Cisplatin:
outcome of combined modality treatment
in non-small cell lung cancer
Lay-out: Chris Bor, Medische Fotografie en Illustratie, AMC, Amsterdam Cover photograph: Laura Schuster
Printing: Buijten & Schipperheijn
Radiotherapy and Cisplatin:
outcome of combined modality treatment
in non-small cell lung cancer
ACADEMISCH PROEFSCHRIFT ter verkrijging van de graad van doctor aan de Universiteit van Amsterdam op gezag van de Rector Magnificus prof.dr. J.W. Zwemmer ten overstaan van een door het college voor promoties ingestelde commissie, in het openbaar te verdedigen in de Aula der Universiteit op woensdag 4 april 2007, te 10.00 uur door
Apollonia Léonie Joséphine Uitterhoeve
geboren te AmsterdamPromotiecommissie
Promotor Prof.dr. C.C.E.Koning Overige leden Prof.dr. G.M.M.Bartelink Prof.dr. H.J.M.Groen Prof.dr. D.J.Richel Prof.dr. E.M.Noordijk Prof.dr. M.Verheij Dr. N. van Zandwijk Faculteit der GeneeskundeContents
Chapter 1 Introduction Chapter 2 Feasibility of curative radiotherapy with a concomitant boost technique in 33 patients with non-small cell lung cancer Chapter 3 Feasibility of escalating daily doses of cisplatin in combination with accelerated radiotherapy in non-small cell lung cancer Chapter 4 Toxicity of high-dose radiotherapy combined with dailycisplatin in non-small cell lung cancer: results of the EORTC 08912 phase I/II study
Chapter 5 Randomized trial of sequential versus concurrent chemo-radiotherapy in patients with inoperable non-small cell lung cancer
Chapter 6 Accelerated radiotherapy alone or combined with either concomitant or sequential chemotherapy; patterns of care in patients with non-small cell lung cancer Chapter 7 Discussion Summary Samenvatting Dankwoord Curriculum 7 27 39 53 69 85 103 119 125 133 135
1
C
hapter
Introduction
Epidemiology
World-wide lung cancer is the most common cause of cancer related-death (1/4- female, 1/3- male); the global incidence is still increasing each year. Only in males in North America and North-West Europe the incidence and mortality are decreasing. In females its incidence is rising, except for Great-Britain and Ireland. In the most developed countries it has surpassed breast cancer as first cause of cancer-related death (1-3). In the Netherlands 6156 males and 2706 females died in 2003 because of lung cancer. One year after the diagnosis only 40 % of all patients are still alive, after two years 25% and after 5 years 15%. For males it is the first cause of cancer death in Holland, for females the second after breast cancer [www.ikc.nl]. These data indicate that the prognosis of lung cancer is very poor and urgently needs improvement. It is estimated that in 85 % of males and in 46 % of females the disease is related to the use of tobacco (1). The mean age at diagnosis is around 66 years. Therefore lung cancer is often found in elderly patients with a variety of co-morbidity (1;3;4). Lung cancer can be subdivided in two main pathological subtypes: Small Cell Lung Cancer (SCLC) and Non Small Cell Lung Cancer (NSCLC). Both categories have a different clinical behaviour. Small cell lung cancer is a disease which leads to a very early dissemination and is relatively sensitive to chemotherapy in contrast to NSCLC. Therefore treatment modalities are different for small cell and for non small cell lung cancer. The majority (80%) of patients has Non Small Cell Lung Cancer (NSCLC) and 75 % of them has advanced disease at the time of diagnosis (5).
Diagnostic procedures and staging
According to the clinical extent and spreading of the disease non small cell lung cancer can be divided into several stages. Different stages cluster patients according to prognosis and treatment. Generally the TNM-classification from 2002 is applied (6). The T-stage stands for extent of the primary tumour, the N-stage for the clinically affected lymph nodes and the M-stage for the presence of distant metastases. Patients with stage I cancer have only local tumour extension in the lung, in stage II regional lymph nodes can harbour tumour. Both stage I and II can be treated with a surgical resection. In stage III the tumour has extended into the mediastinal structures and patients with this stage cannot be cured with a primary resection. These patients have locally advanced disease. If distant metastases are present patients have stage IV disease and a treatment with a curative intent is not possible.
Standard diagnostic procedures for staging include physical examination, long function tests, biochemical and haematological blood tests, contrast enhanced spiral (multi-slice) CT-scan of the thorax and upper abdomen, bronchoscopy with histological examination and mediastinoscopy if indicated. Recently a PET scan has C ha pt er 1 In tr od uc tio n
become part of the diagnostic procedure for NSCLC stage I-III, in patients for whom a potentially curative treatment might be an option (7).
Endo-oesophageal echography with cytological puncture of mediastinal lymph nodes has replaced the mediastinoscopic staging partly. Presence of distant metastases other than in the liver or in the supra-renal glands is only examined if suspicion exists according to the results of routine staging procedures. Especially with the PET scan data more patients migrate to stage IV (9%-18%), (8). In the region of the IKCA (Netherlands, North-Holland and Flevoland) during the period 1999-2001, of the patients with NSCLC 18 % had stage I disease, 7 % stage II, 35 % stage III and 37% stage IV disease. The 5-yr survival for locally advanced disease is approximately 15 % for stage IIIA and 5 % for stage IIIB, according to Mountain 1986 (9). In the region of the IKCA these figures are 9 % for stage IIIA and 4 % for stage IIIB in the period 1989-2003. The 3- and 5 yr-relative survival rates have not changed from 1988 until 2003, despite all efforts in cancer research. Only in early stage (TNM) I and II NSCLC improvement was seen, 3-yr survival rates for stage IA, IB, and II increased from 66 %, 39% and 29 % to 86%, 54% and 42 % respectively. Visser concludes that this is probably related to better staging and stage migration (5). The same, so called Will Rogers, phenomena, but less impressive, has been observed in NSCLC stage IIIA and IIIB, the main patient population of this thesis. Three year survival increased from 13 to 18 % in stage IIIA and from 6 to 9 % in stage IIIB from 1989-1991 to 1999-2001. As the incidence of stage IV increased from 26 % to 37 % in these periods it is clear that the general survival figures are dominated by the results in stage IV ( 3-yr s 2-3 %). Compared to other European countries in the IKA region 5-year survival rates are amongst the highest, 13 %, compared to 15 % in the SEER database of the USA and 10 % for Europe (3;5).
Treatment modalities
Surgery
Radical resection is the treatment of choice for patients with NSCLC, early disease, stage I-IIB. If patients are medically inoperable because of age, cardio-vascular evaluation or because of poor lung function tests radiotherapy or chemo-radiotherapy are the next treatment options (7). Phase II studies with dose escalation using 3-dimensional conformal radiotherapy showed improved local control rates of at least 50 % at 4-5 years (10-12). Phase II studies with 4-dimensional stereo-tactic radiotherapy report excellent local control rates up to 90 % and minimal toxicity (13-17). Follow-up of these studies is still limited. Being aware of this restriction, this technique yet should be considered in patients with early disease stage IA and IB lesions up to 5 cm diameter with a peripheral localisation. Treatment of early disease is not the subject of this thesis.
10
In locally advanced disease stage III, surgery adjuvant to chemotherapy or chemo-radiotherapy has failed so far to improve significantly the survival (18-20). It is possible that adjuvant surgery for subgroups of patients can offer an advantage however (18). Radiotherapy Dose Perez et al found that higher radiation doses given to patients with NSCLC were related to a higher chance for local tumour control (21). In several randomized trials higher doses result in better survival in a palliative setting as well (22-24). Several other authors described an increased possibility for loco-regional control at doses > 50 Gy (25-30) (31;32).
Escalation of the radiation dose > 60 Gy has been tested in clinical studies. Theoretically, a dose of > 84 Gy is necessary to obtain a chance for a definite local control in small tumours of 50 % (33). Using 3-dimensional conformal techniques escalation doses of 77.4 Gy-83.8 Gy (depending on the irradiated volume) are feasible and result in 2-yr local control rates of 50-78%, and 2-yr survival of 60-70% in these small tumours (RTOG 93-11) (11). Kong et al. observe a 2-yr survival of 37 % and a 2-yr local control rate of 40% in patients with treatment of escalating doses > 63 Gy/2.1 Gy. If the dose was above 70 Gy the 2-yr survival was > 45% (12). In the Netherland Cancer Institute escalation of the radiation dose to 74.3-81.0 Gy was feasible within an overall treatment time of 6 weeks. This resulted in a response rate of 80% (10;34). Fractionation Hyper-fractionation is defined as the use of a fraction size less than 180 cGy given generally two or three times per day. The radiobiological background for hyper-fractionation is based upon differences in occurrence of acute and late radiation damage. This damage is characterised by the α/β ratio of tissues. Acutely responding tissues express their damage within a period of days to weeks after irradiation. The α/β ratios of these tissues range from 7-20 Gy. Late responding tissues express their damage months to years after irradiation. The α/β ratio of late responding tissues varies from 0.5-6 Gy (35). Theoretically, in tissues with an α/β of < 10 Gy improved tolerance for late toxicity might be expected with the use of small fractions. As in locally advanced lung cancer limiting late toxicity is oesophageal, (α/β 3-5 Gy) or pulmonary, α/β 3-4 Gy), hyper-fractionation could result in better treatment outcome because higher total doses can be applied and are better tolerated (35). Hyper-fractionation with moderate increase of the total radiation dose did not result in improved treatment outcome however (36-39). Accelerated fractionation means by definition shortening the overall treatment time by giving a higher dose per week than 10 Gy given in a conventional fractionation C ha pt er 1 In tr od uc tio n
scheme of 2 Gy per day. Often more fractions per day are administered. Response of normal and tumour tissues to fractionated radiotherapy is influenced by several biological factors, the so-called “four R’s”. Repair is defined as the cellular recovery during the few hours after exposure. Repopulation concerns the proliferation of cells surviving radiotherapy during an extended course of treatment. Reduction of the overall treatment time can prevent tumour repopulation. Re-oxygenation means the phenomena that reduction of the number of cells in a partially necrotic tumour can result in an improved vascularisation of the remaining cells. As hypoxic cells are less radiosensitive, this process can lead to a higher radio-sensitivity during the course of radiation. Redistribution is a cell-cycle progression effect, by which cells can pass in a more radiosensitive phase of the cell cycle after an administered fraction dose. After accelerated fractionation better results can be expected in tumours in which repopulation plays an important role. Early normal tissue reactions are expected to occur earlier as they depend mainly upon the totally administered dose. If recovery from sub-lethal damage between fractions is complete no increase in late reactions are to be expected (compared to equivalent does given in fractions of 1.8-2.0Gy). Improved survival was observed in the CHART trial, where accelerated fractionation was given and the overall treatment time was reduced to 12 days(40). Moderate reduction of the OTT did not result in significant improvement (36;39). The CHART trial indicates that a repopulation plays a role in outcome of radiotherapy in NSCLC. Jeremic pointed out that in his studies in 536 patients an inter-fraction interval < 5.5 hours is an independent prognostic factor for overall survival and local-recurrence free survival, which is compatible with differences in time for repair of sub-lethal damage between normal tissue and tumour cells and repopulation of tumour cells (41). El Sharouni describes a mean tumour doubling time of 46 days after neo-adjuvant chemotherapy as compared to 93-452 days before treatment, in patients with NSCLC (42). This could be explained by accelerated repopulation after induction chemotherapy. Prolonged treatment time of concurrent chemo-radiation in NSCLC patients was correlated with poorer survival in the study of Machtay, also pointing out the clinical importance of repopulation (43). Finally in a randomised study Belani observes an increased survival in patients treated with sequential chemo-radiation if the overall treatment time of the radiotherapy was reduced from 5 weeks to 2.5 weeks by hyper-fractionated accelerated fractionation, although the difference was not statistically significant (44). Planning Target Volume (PTV) Historically, the PTV encompassed the gross tumour volume (GTV) and areas with possible microscopic tumour involvement (elective nodal irradiation). In general the next non-pathologically enlarged lymph node station was irradiated to a dose of 40-50 Gy. This resulted often in very large PTV-s. As volume is a dose-limiting
factor for toxicities, methods to reduce the PTV were analyzed. Several publications demonstrate that after introduction of the PET scan elective nodal irradiation can safely be left out and that delineation of the GTV by means of PET-CT scans leads to reduction of the irradiated volume (45-49). If the tumour changes in position due
to respiratory movement, respiratory gated radiotherapy might further reduce the margins around the GTV (13;50;51). In the studies, described in this thesis, the large majority of the patients were not staged by the PET-scan; therefore in general elective nodal irradiation has been given. No respiratory gated techniques were used. Chemotherapy Patients with non small cell lung cancer, especially patients with stage IV disease, are frequently treated with cytostatic drugs. These are drugs with a cell killing effect, mainly active upon cells in mitosis. They have a systemic activity, this means that they can reach the primary tumour cells but also tumour cells disseminated in lymph nodes metastases and in organs. They can be classified, according to their point of action, as alkylating agents and platinum compounds, topo-isomerase inhibitors, anti-metabolites and anti-mitotic drugs. The first cytostatic drugs are of the so-called first generation [1], newer drugs are of the second [2] and more recently developed drugs of the third generation [3].
Cisplatin.
The mode of action consists on the formation of intra- and inter-strand cross links between the DNA strings and cisplatin, thus forming DNA-adducts. This results in single and double strand-DNA breaks. It is active in the S phase of the cell cycle. Toxicity is mainly renal, but can be prevented by pre- and post-treatment hyper-hydration.
Carboplatin.
This is another platinum compound, with a comparable mode of action, it inhibits the DNA-synthesis. The toxicity is haematological.
Etoposide and teniposide
These drugs are topo-isomerase II inhibitors. Topo-isomerase II has an activity in the cleavage of the double strand-DNA. With etoposide or teniposide its action is disturbed and therefore the normal process of cleavage is prevented and finally it results in DNA double strand breaks of the DNA-strings. Etoposide is a semi-synthetic derivate of podofyllotoxine. Point if action is the mitose. The toxicity is haematological. Vinca-alcaloids.
Vincristin [1], vinblastin, vindesin [2] and vinorelbine [3]. The point of action is the mitosis. They bind on the tubulin, and prevent polymerisation of the tubulin. Therefore the formation of microtubuli from the tubulin is disturbed. Microtubuli are necessary for the mitotic action. Thus the cell is arrested in mitosis and apoptosis C ha pt er 1 In tr od uc tio n
will follow. Main toxicity is neurological as micro-tubuli also plays a role in transport of molecules in the axons. Vincristin is very neurotoxic and is not used in NSCLC. Vinblastin and Vinorelbin are less neurotoxic, but more myelotoxic. Vinorelbin and vindesine are frequently used in NSCLC. Vinorelbin is a third generation drug. Other cytostatic drugs of the third generation used in NSCLC are: -Gemcitabin
This is an anti-metabolite and interacts with the formation of the nucleosides. Mode of action is the inhibition of ribo-nucleotidase (which stimulates formation of de-oxyribonucleoside-triphosphate). Besides it is competitive with cytidine in the formation of cellular DNA and inhibits normal DNA-synthesis. Its activity takes place in the S-phase of the cell cycle. Main toxicity is myelotoxicity and pulmonary. -Paclitaxel and docetaxel
These drugs bind to the tubulin and therefore prevent depolymerisation of the micro-tubuli.
Therefore the cell cannot finish the normal process of mitosis. So its point of action is the end of the mitosis. Toxicity: myelotoxicity, hand-foot syndrome, neuropathy (52;53).
In 1995 the Non-Small Cell Lung Cancer Cooperative Group published the results of meta-analyses in which cisplatin based combinations offered a better survival avantage than single agent treatment in stage IIIB/IV disease (54;55)). In 2004 Hotta emphasized in a meta-analysis a possible reduction in risk of death for cisplatin based combinations compared with carboplatin-based regimens (55). Pujol concluded that platinum-based combinations with a third generation drug induced a statistically significant reduction in the risk of death when compared with platinum-free combinations containing at least one third generation anti-cancer drug. Platinum combinations showed a increased risk of haematological and gastro-intestinal toxicity, without a significant increase of toxic death (56). Platinum combinations with gemcitabin provided more benefit than other platinum containing regimens in a meta-analysis of Le Chevalier in 2005 (57). In Europe gemcitabin and cisplatin has become a common doublet combination for the treatment of advanced NSCLC. Combined modality Combination of radiotherapy and chemotherapy is useful if this results in a therapeutic gain. This means that a combined modality regimen results in an improved tumour response, when compared to each treatment modality alone with an acceptable, less than additive, increase in toxicity. If both modalities are independent, a therapeutic gain may be present in terms of increased total cell kill, killing sub-populations resistant to the other treatment modality, different targets (local or distant disease), reduced tumour volume with improved oxygenation in case of neo-adjuvant chemotherapy. In NSCLC patients the log10 post-chemotherapy GTV was predictive for survival
14
in patients treated with sequential chemo-radiation (58). If both modalities are interactive, combined modality may result in enhanced tumour response (35). This may be due to inhibition of radiation damage repair, or selective cell killing in a radio-resistant phase of the cell cycle (late G1 and S).
Radiobiological data point out that best results are achieved if chemotherapy and radiation are given in close sequence (which means separated by days in pre-clinical or by weeks in clinical situation). Theoretically concurrent chemo-radiation should result in better tumour cell kill, but also in increased toxicity. Sequential chemo-radiation is less toxic, but might be less effective. Besides, (accelerated) repopulation after chemotherapy or radiation might counterbalance the reduced total cell kill (35). Interaction between chemotherapy and radiation has been demonstrated for cisplatin, adriamycin, bleiomycin, gemcitabin, taxanes and hydroxyurea. Cisplatin inhibits repair of radiation induced single-strand or double-strand breaks. In vitro an enhanced effect of cisplatin and radiation has been demonstrated (59). Animal data showed an enhanced effect if cisplatin was given 4 hours to 30 minutes before irradiation(60-62). Both homologous recombination and non-homologous end joining are affected (63-65). Enhanced effects are also demonstrated for combination of carboplatin and radiation in in vitro studies, although Skov decribes a better interaction for cisplatin than for other platinum compounds (66;67). Indication for enhancement of tumour cell apoptosis after combined treatment of platinum analogues and radiation are shown in vitro (68). Experiments in mice indicated that late damage of normal organs was less enhanced (69). Gemcitabin is also a potent radio-sensitizer in vitro and in vivo, also in a NSCLC cell line (70-73). Normal tissue reactions are also increased; as gemcitabin is toxic for lung tissue concurrent administration has led to high pulmonary toxicity. This seems to be dependent of the irradiated volume and dose of gemcitabin (74;75). Low dose of gemcitabin given concurrently with radiotherapy can be tolerated (76;76;77;77;78). If high doses are given an interval of 3-4 weeks between chemotherapy and radiation seems safe in clinical practice (75;79).
Neo-adjuvant chemotherapy followed by radiation (sequential chemo-radiation)
Neo-adjuvant chemotherapy showed an improvement of median survival and overall survival in several randomised studies (38;80;81). Interpretation of these studies suggested that this effect was mainly due to elimination of micro-metastases. In 1995 a meta-analysis showed improved survival of combined platinum containing chemo-radiation compared to radiotherapy alone in NSCLC patients, with a hazard ratio of 0.87 and a gain in 5 yr survival of 2% (54). The majority of the studies in this meta-analysis concerned neo-adjuvant sequential chemo-radiation. C ha pt er 1 In tr od uc tio n
Concurrent chemo-radiation
In 2005 a large meta-analysis confirmed the benefit of concurrent platinum-containing combined modality treatment wit a HR of 0.93, compared to radiation alone (2 yr survival 13-43%) (82). This effect was independent of the radiation dose (> 50 Gy/2Gy), only valid for fractionation of 1 x per day, and only valid for standard doses of platinum-containing chemotherapy (cisplatin>150 mg/m2, carboplatin
> 700mg/m2). For low, sensitizing doses only trials using cisplatin were positive
(Schaake: HR 0.89, 95% CI:0.81-0.99, Soresi: HR 0.78, 95%CI:0.59-1.03, Blanke: HR0.94, 95%CI:0.83-1.05) (83-85). For 2-yr loco-regional progression-free survival a HR of 0.84 (CI 0.72-0.98) was found. Another trial using daily cisplatin which is not included in the meta-analyses also demonstrated an increased loco-regional control and survival in the cisplatin-arm (86). In patients with non-small cell lung cancer and in patients with head and neck cancer, treated with concurrent cisplatin-radiation a significant correlation has been observed between the survival and presence of DNA-adducts in the cells of the buccal mucosa (87;88).
Aupérin published a more recent meta-analysis, based on individual patient data and observed a HR of 0.89 (0.81-0.98) for survival if radiation was combined with concurrent cisplatin (89). Again an absolute gain in 5-yr survival was seen of 2.2% (6-8.2%) in favour of concurrent platinum-based chemo-radiation. The 2-yr survival rates were 25.4-21.4 %. The effect was independent of the radiotherapy or chemotherapy schedule. Combination of two-drugs was better than a one-drug schedule, but this is only seen for combinations of carboplatin and another drug. A better effect of combined modality was seen in patients > 60 yrs.
Four randomized trials have been published concerning sequential neo-adjuvant versus concurrent chemo-radiation. All four (three of them are analysed in the meta-analysis of Rowell et al.) point out that concurrent chemo-radiation is better than sequential administration HR 0.86 (0.78-0.95 P=.003), but at the cost of more toxicity, mainly oesophageal (90-93). Curran used cisplatin with vinblastin, Fournel cisplatin and vinorelbin, Zatloukal cisplatin and vinorelbin, Furuse vindesin, cisplatin and mitomycin. So in all four trials cisplatin was used in combination with a vinca-alcaloid. In an overview Vokes suggests that concomitant chemo-radiation with full dose of chemotherapy might be too toxic for selected patient groups, especially elderly patients who often present with a variety of co-morbidity (94). In disseminated, advanced disease combination of a platinum-agent with another drug is more effective than single agent chemotherapy or combinations without a platinum-analogue for survival without inducing an unacceptable risk of increased toxicity (56).
Combination of a platinum-analogue with gemcitabin was superior to combination of platinum with another drug for progression-free survival (HR 0.88, 95% CI:0.82-0.93), for overall survival this was significant for platinum combination with second generation
drugs (HR 0.84, 95% CI:0.76-0.94), but only a trend was seen for third-generation drugs combined with a platinum-analogue (HR 0.93, 95% CI:0.86-1.01) (57).
In conclusion in combined modality with concurrent application a two-drug combination is used of a platinum-analogue with a second or third-generation drug. In NSCLC stage IIIA a combination of gemcitabin and cisplatin in 3 cycles has been tested in EORTC phase II study 08955 (79). The response rate (RR) was 70.2 %, only 2/38 patients (5%) had progressive disease. A randomised phase II study which analysed neo-adjuvant chemotherapy with either gemcitabin, paclitaxel or vinorelbin combined with cisplatin prior to concurrent chemo-radiation with the same drugs showed a trend towards a better survival for gemcitabin (CALBG 9431), (78).
Neo-adjuvant chemotherapy followed by concurrent chemo-radiation.
Theoretically it combines an optimal possibility to eradicate micro-metastases by systemic treatment, tumour-reduction before start of radiotherapy and enhancement of chemotherapy during RT. However, the study of Vokes did not show an advantage of the addition of neo-adjuvant chemotherapy prior to chemo-radiation (CALGB 39-801)(94).
Concomitant chemo-radiation followed by consolidation chemotherapy
Two phase II trials studied the efficacy of addition of consolidation chemotherapy to concurrent chemo-radiation. Gandara added Docetaxel after chemo-radiation with cisplatin-etoposide; 3-yr survival was about 40% (SWOG 9504) (95). In the LAMP trial concurrent chemo-radiation plus consolidation chemotherapy (carbo/paclitaxel) was superior to neo-adjuvant sequential chemo-radiation or to neo-adjuvant sequential plus concurrent chemo-radiation (44). All the above mentioned data have led to the following conclusions. 1. Combined modality improves treatment outcome compared to radiotherapy alone, independent of the radiation dose.
2. Concurrent radiation is better than sequential neo-adjuvant chemo-radiation in terms of survival and disease-free survival.
3. If standard doses of chemotherapy are used, platinum should be combined with a chemotherapeutic drug of the 3rd generation, of which gemcitabin possibly offers
the best results.
4. If low dose chemotherapy is used daily or weekly, cisplatin only is effective. 5. It is not proven that daily or weekly cisplatin is inferior to poly-chemotherapy in
standard dose concurrent with a high dose of radiotherapy (66Gy).
6. Neo-adjuvant chemotherapy given before concurrent chemo-radiation with standard doses of poly-chemotherapy does not improve survival. C ha pt er 1 In tr od uc tio n
7. Adjuvant chemotherapy given after concurrent chemo-radiation with standard dose of poly-chemotherapy might improve survival.
Patient related prognostic factors.
In the literature the following factors are described showing a correlation with the prognosis of the disease: age, sex, TNM stage, tumour volume, performance score, baseline haemoglobin level, weight loss (96-98).
TNM-stage
In 1997 Mountain published an analysis of 5200 patients with NSCLC in whom the anatomical tumour extent showed a correlation with prognosis (99). According to this analysis the TNM stage system was revised in 1997. In 2006 Kramer et al. concluded that staging by a PET scan shows a better correlation with prognosis than other clinical staging procedures in 266 cases, thus confirming outcomes of previous smaller studies (100). Tumour size > 6 cm was an independant factor for a poor prognosis in the study of Wigren (101). In the study of Martell 1997 the prognostic influence of tumour volume (> 200cm3) disappears after multi-variate analysis however (102). Age In 2000 Werner-Wasik analysed the data from 1999 patients with stage II or III treated in RTOG-studies. She concluded that age < 70 yrs was a favourable prognostic factor (103). However, afterwards a study of RTOG 94-10, in which patients with stage III were treated with combined modality, showed an improved survival for patients >70 yrs (104). Socinski analysed the CALGB data in 2004 of 694 patients with stage III. He does not observe an independant correlation between age and prognosis (105). In a meta-analysis of 1764 patients Aupérin describes a better survival for patients with stage III, older than 61 yrs if concurrent chemo-radiation is given (89). Wigren, analyzing 502 patients with stage I-III treated with radiotherapy did not find a relation of prognosis with age (101). Jeremic analysed prognostic factors in 536 patients treated with radiotherapy or chemo-radiation and did not observe an influence of age (41). So in conclusion data about age as a prognostic factor are conflicting. Age as such is not a reason to withhold combined modality treatment to patients with NSCLC stage III. Co-morbidity always has to be taken into account. Performance score This is an independent prognostic feature in all stages and for all treatment modalities. For radical radiotherapy or chemo-radiation a Karnofski performance score of at least 70 % is generally wanted. KPS> 70 is an independent favourable prognostic factor in the analysis of Jeremic (41). In patients with disease stage III receiving radiotherapy or
18
chemo-radiation several authors describe the performance score being an independent parameter for prognosis (91;101;103;105). However, Aupérin does not observe a correlation between performance status and treatment outcome (89).
Sex
In the SEER database (any histology) female gender was a favourable prognostic factor. This was also seen in patients treated with advanced disease, treated with chemotherapy, of the European Lung Cancer Working Party, in a very large Polish study, in the MSK series, in the analysis of the SWOG database and in the analysis of the ECOG 1594 trial (89;96;106-109). In patients treated with radiotherapy or chemo-radiation this is confirmed by Werner-Wasik, Jeremic and Fournel, but not by Socinski or Aupérin (41;89;91;103;105). Weight loss Weight loss was described as an important poor prognostic factor in 1980 by Stanley in an analysis of 5000 patients (98). In 1997 Scott describes that a dose-response relation is seen for patients treated with radiotherapy presenting with minimal weight loss (110). Jeremic observes a poorer survival in patients presenting with weight loss > 5% (41). In other recent analyses no significant influence of weight loss is seen (89;103;105;111).
Baseline haemoglobin level
A normal baseline haemoglobin level is recognized as a favourable prognostic factor for patients treated with radiotherapy or chemo-radiation by Wigren and Socinski (101;105). In the uni-variate analysis of the RTOG database it is a prognostic factor, but apparently its influence disappears after further analysis (103). For more advanced disease several authors describe a significant correlation (106;112).
Outline of this thesis
In this thesis five studies are described concerning the development of an improved chemo-radiation treatment strategy in patients with locally advanced non-small cell lung cancer.
Starting point was the result of EORTC study 08844. In this study improvement of outcome was seen if radiotherapy was combined with either daily or weekly cisplatin. The best results were seen if radiotherapy was combined with daily low dose cisplatin 6 mg/m2. This combination resulted in an improved local control and so in an improved survival in patients with locally advanced non-small cell lung cancer without distant metastases. The 2- and 3-year overall survival in the best arm was C ha pt er 1 In tr od uc tio n
25 and 16 % respectively, the local recurrence-free interval at 2 years 55%. Only an increase of severe gastro-intestinal toxicity, attributable to the general effect of cisplatin was observed. The effect was explained as a radio-sensitization, possibly due to an decreased repair of sub-lethal damage in tumour cells. Criticisms to this study were the applied radiation dose of 55Gray (Gy), which was relatively low, and the long overall treatment time of 7 weeks, which was the accepted way of treatment when the study was designed. Thus studies were initiated to increase the radiation dose as well as to reduce the overall treatment time. In chapter two the feasibility of reduction of the overall treatment time and increase of the radiation dose in radiotherapy for inoperable or irresectable non-small cell lung cancer is analysed. In chapter three reduction of the overall treatment time in a chemo-radiation schedule is studied. In chapter four result of further increase of the dose of radiotherapy and chemotherapy is described. Chapter five reports the outcome of a randomised EORTC phase III trial comparing sequential versus concurrent chemo-radiation in locally advanced non-small cell lung cancer. Finally in chapter six a retrospective analysis of treatment outcome in patients with inoperable or irresectable non-small cell lung cancer in our department from 1995-2004 is presented. This chapter studies the implementation of the treatment modalities studied in the EORTC trials described in chapter four and five.
In chapter seven the most important data are discussed.
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A.L.J. Schuster-Uitterhoeve
M.C.C.M. Hulshof
D. González González
M. Koolen
P. Sminia
Radiotherapy and Oncology 1993;28:247-251
2
C
hapter
Feasibility of curative radiotherapy with a
concomitant boost technique in 33 patients
with non-small cell lung cancer (NSCLC)
Abstract
Thirty-three patients with an inoperable NSCLC were treated with a dose of 60 Gy/20 fractions/25 days, using a concomitant boost technique. A dose of 40 Gy/2 Gy/25 days was given to the tumor area and a part (15 patients) or the whole (18 patients) mediastinum. During each session a simultaneous boost to the tumor of 1 Gy was administered. Moderate acute oesophageal toxicity was observed in 7/33 patients (22%). One out of 33 patients developed serious late oesophageal toxicity. A correlation between the oesophageal toxicity, absorbed oesophageal dose of irradiation and length of the elective field was observed. Five out of 33 patients developed subacute radiation pneumonitis grade 2 or 3. In selected patients with inoperable NSCLC radiotherapy, with a dose of 60 Gy/20 fractions/25 days, using a concomitant technique is feasible.
Key words: Lung cancer; Concomitant boost; Acute lung toxicity; Late lung toxicity; Oesophageal toxicity
1. Introduction
The prognosis of inoperable non-small cell lung cancer is poor and has not changed substantially during the past 30 years. In the favourable group of patients with early disease (T1-T2, N0-N1) considered inoperable for medical reasons, radiotherapy achieves a 5-year survival rate of about 20% [10,15,22,27]. The corresponding local control rate is 30-40% [2,10,15]. The 5-year survival rate in cases of locally advanced disease (T3-T4, N2-N3) is between 5 and 10% and the local control rate varies from 10 to 60% [16,18]. Probably the local control rate in this last group of patients would be lower if the patients do not die from distant metastases before having time to develop a local relapse.
Several factors such as administered total dose, overall treatment time, fraction size and interval can influence local control rate and survival. In general, by using conventional fractionation, the maximum tumor dose varies between 60 and 65 Gy in 6-7 weeks. Higher tumor doses seem to improve overall survival and local tumor control rate only in small tumors [7,11,18]. Hyperfractionation with a high total dose was tested in a prospective phase II study [4]. A phase III randomized study comparing conventional fractionation to hyperfractionation is on going. Recently published results from a randomized study in oropharynx carcinoma have shown better local control rate and survival with hyperfractionation than with a conventional schedule [12].
By using this hyperfractionated radiation regimes the overall time did not differ from that used in conventional fractionation. Because tumor repopulation during radiation treatment is considered to be an important factor for tumor control, treatment schedules are now been tested in order to reduce the overall time as much as possible. Accelerated radiotherapy, by using multiple fractions/day and eventually not stopping treatment during the weekends, allows administration of a relatively high radiation dose to the tumor in a short overall time [11,17]. In a pilot study, including patients with advanced lung cancer, local tumor control and overall survival seemed to be better for accelerated fractionation as compared to a historical control group of patients treated with conventional fractionation. A randomized study is on going under the auspices of the MRC. Because acute reactions in normal tissues are severe with accelerated fractionation the possible gain in overall time is contrapart by the necessity of reducing the total tumor dose.
In 1988 Emami reported the results of a phase I—II study using a rapid fractionation scheme in which a tumor dose of 75 Gy/28 fractions/5.5 weeks and a dose to the node bearing areas of 50.4 Gy/28 fraction/5.5 weeks was given by means of a concomitant boost scheme [5,8]. In the present pilot study a similar technique was used. The overall treatment time was reduced to 25 days, 20 fractions were given, the tumor dose was 60 Gy, and the electively treated lymph node stations received 40 Gy. C ha pt er 2 on co m ita nt b oo st 1 3
