Clinical promise tempered by reality in the delivery of combined chemoradiation for common solid tumors☆

Chemotherapy evolution in head and neck cancer 

Early studies of chemotherapy in H&N cancer dating back to the 1960s and 1970s primarily involved patients with recurrent or metastatic disease. This provided the opportunity to examine single-agent and multiagent response rates and their potential to influence disease progression and survival. In the late 1970s and 1980s, intense evaluation regarding the role of chemotherapy in the definitive treatment setting was undertaken. This most notably involved the use of neoadjuvant (induction, upfront) chemotherapy administered before the delivery of high-dose radiation for nonoperative patients. This era included many single-institution as well as randomized clinical trials that confirmed several regimens (most notably 5-fluorouracil/cisplatin) capable of producing high clinical response rates but yielded no significant impact on locoregional tumor control or patient survival. In the 1990s, the use of chemotherapy moved increasingly toward concurrent administration with radiation. It is this most recent era of chemotherapy use that has provided the most promising results regarding tumor control and survival over that achieved with radiation alone for advanced H&N cancer patients.

Randomized studies that examine survival for patients treated with concurrent chemoradiation regimens are identified in Table 1.3, 4, 5, 6, 7, 8, 9, 10, 11 These trials vary considerably in terms of radiation fractionation, delivery schedule, and specific chemotherapy agent used. However, they do have in common a randomized allocation of patients to chemoradiation versus radiation alone. This advantage for concurrent chemotherapy with radiation has been further examined by meta-analyses regarding the use of chemotherapy in H&N cancer published between 1990 and 2001.12, 13, 14, 15, 16 In summary, these meta-analyses generally identify a small overall survival benefit for the use of chemotherapy on the order of 1% to 8%. Subset analyses suggest no significant survival benefit for the use of neoadjuvant or adjuvant chemotherapy but do suggest a benefit for the use of concurrent chemoradiation. These conclusions are now being borne out by recently reported randomized trials and have led to the increasingly common use of concurrent chemoradiation as a standard of care for advanced H&N cancer patients not receiving surgery.

Table 1. Randomized trials comparing chemoradiation versus radiation alone in advanced H&N cancer

	Study	Publication Year	No. of Patients	SurvivalAdvantage
	Merlano3	1996	157	Yes
	Wendt4	1998	270	Yes
	Brizel5	1998	116	Borderline P = .07
	Calais6	1999	226	Yes
	Adelstein7	2000	295	Yes
	Jeremic8	2000	130	Yes
	Corvo9	2001	136	No
	Staar10	2001	263	Oropharynx-yes
				Hypopharynx-no
	Bourhis11	2002	109	No

The randomized clinical trials with concurrent chemoradiation represent an important and long-awaited advance. Nevertheless, many questions remain unanswered, not the least of which is what specific chemoradiation schedule to recommend outside the context of controlled clinical trials. The trials summarized in Table 1 all used distinctly different treatment regimens of varying complexity. Some studies used once daily radiation; others used twice daily radiation. Some studies used cisplatin alone, whereas others used 5-fluorouracil or carboplatin. The dose/delivery schedule of platinum varies dramatically from every 3 weeks (100 mg/m2) to low-dose daily (6 mg/m2). In addition, not all of the published randomized trials show a survival advantage for chemoradiation over radiation alone.9, 10, 11 To date, there remains no clearly defined consensus for practitioners to embrace as a standard chemoradiation regimen for H&N cancer.12 Hopefully, this can be better defined in the coming years through the completion and maturation of additional randomized clinical trials.

Toxicity issues 

A variety of additional questions remain regarding the use of concurrent chemoradiation for advanced H&N cancer patients. These include optimization of the balance between increased efficacy and enhanced toxicity. In general, combined chemoradiation studies show increased toxicity over that encountered with radiation alone. In some studies, these enhanced toxicities are modest, whereas in others they are much more significant. Indeed, enhanced acute toxicities can sometimes lead to interruptions or alterations in the schedule of radiation delivery, thereby potentially compromising the effectiveness of the definitive treatment modality. This is particularly concerning with the ad hoc use of concurrent chemoradiation (outside the context of controlled clinical trials) when treatment interruptions, delays, and reductions in total radiation dose may be quite common. Moreover, toxic chemoradiation regimens can be difficult to transfer from academic center clinical trial to community practice at large. Patients recruited into clinical trials are generally of moderate to good performance status, and many advanced H&N cancer patients in the community would not meet the entry criteria for the trials on which their therapy is now based. The frequent requirement for gastric feeding tubes before or during treatment, intravenous rehydration, high-dose narcotics for severe mucositis pain, and other issues renders this complex patient cohort an acute care challenge for even the most seasoned of health care providers.

Altered fractionation 

Several additional questions warrant brief comment regarding modern therapy strategies for the advanced H&N cancer patient. Altered radiation fractionation (most notably hyperfractionation and/or acceleration) represents a valuable and well-studied approach reflecting successful translation of classical radiobiology into clinical gain, with the broadest wealth of data deriving from the treatment of H&N cancer patients.17, 18, 19 The rapid proliferation kinetics common to most H&N squamous cell carcinomas render this tumor particularly well suited to intensification of radiation dose delivery to minimize the adverse impact of tumor cell repopulation during a protracted 7- to 8-week treatment course. Many promising (although often retrospective) single-institution experiences led to randomized clinical trials showing improvement in locoregional disease control but borderline enhancement of overall survival.20, 21 As additional trials, as well as meta-analyses, were poised to “nail down” the altered fractionation benefit, the surprising success of several concurrent chemoradiation trials triggered a veritable leap frog of chemoradiation into global practice patterns. However, the majority of concurrent chemoradiation studies to date have used once daily radiation as the control arm, thereby vexing the radiation oncologist regarding the choice of optimal radiation fractionation when the drug is to be delivered concurrently. This arena remains ripe for further investigation because there is relatively little mature data examining the success and feasibility for the use of intensified radiation fractionation concurrent with chemotherapy. Studies that have specifically compared intensified radiation fractionation versus chemoradiation show quite variable results.5, 9, 10, 11

Quality of life 

Questions regarding optimal strategies to facilitate organ preservation and quality of life in H&N cancer patients continue to evolve. Controlled clinical trials suggest that chemoradiation offers a reasonable alternative to surgery for patients with advanced laryngeal and hypopharyngeal tumors that would require laryngectomy or laryngopharyngectomy without compromise in ultimate survival.22, 23, 24 However, the organ preservation approach for advanced H&N cancer patients is toxic, costly, and requires a motivated patient as well as a motivated and experienced multidisciplinary care team because the evaluation of locoregional disease recurrence is technically challenging. For those patients whose tumors recur locally, some can proceed to salvage surgery but often with higher morbidity quotients than had they undergone de novo surgery. For those who successfully retain the H&N organs of interest (ie, larynx, tongue base), there is not universal success in preserving functional organs that provide the quality of life that was originally desired. Carefully designed and executed studies that examine patient-driven quality of life analysis are important for this population, and the follow-up must be carried forward for several years after therapy to provide meaningful information.

H&N cancer conclusions 

H&N cancer patients are burdened with excessive cosmetic and functional morbidities from their tumors and from our current therapies. As we gradually increase the percentage of patients who are cured, we may face increasing numbers of patients with chronic H&N dysfunction with regard to swallow and speech capacity, cervical fibrosis, and other toxicities. Although the recent outcome improvement with concurrent chemoradiation for advanced H&N cancer patients appears quite real, the overall impact on the broad H&N cancer population is modest at best, and the approaches are certainly toxic, complex, and expensive to achieve. None of the randomized trials in Table 1 enrolled more than 300 patients, reflecting the challenge of completing large-scale trials in this cancer population. Conformal delivery of radiation dose (3-dimensional, intensity-modulated radiation therapy, tomotherapy, and so on) offers high promise to diminish long-term radiation toxicity in selected H&N normal tissue structures (ie, salivary gland, auditory apparatus, mandible, spinal cord).25 New molecular agents that target growth factor receptors that appear central to the growth of many H&N cancers similarly offer promise to provide less toxic and more discriminate approaches for the future.26 For these new treatment strategies, as with the current chemoradiation studies, a rigorous, thorough, and dispassionate evaluation of the overall impact of treatment on the welfare of the H&N cancer patient population will be required.

Definitive radiotherapy for inoperable non–small-cell lung cancer 

In the 1970s, the Radiation Therapy Oncology Group (RTOG) conducted a landmark 4-arm randomized trial that explored external beam radiation doses in the 40 to 60 Gy range. Patients randomly allocated to the high-dose arm had superior short-term survival28 and 60 Gy in 6 weeks thus became an accepted US standard. The paradigm established by this RTOG trial involved treatment of micrometastatic disease to 50 Gy and boosting of gross disease to 60 Gy. This resulted in the inclusion of large volumes of mediastinum, lung, and, frequently, bilateral supraclavicular fossae in the portals. Because radiation toxicity is a function of both dose and volume, the large fields used precluded significant dose escalation beyond 60 Gy by using conventional approaches. This impasse was bridged with 2 different philosophies, combination chemoradiotherapy and altered fractionation, of which the former is the more frequent current practice pattern.

Combined chemoradiotherapy 

Several large randomized trials have tested preradiation induction chemotherapy over the last 10 years. This approach is predicated on targeting micrometastatic disease at the earliest phase, as well as the expectation that the primary disease site may respond to cytotoxic agents, thereby improving the efficacy of subsequent radiation. Sequential delivery was adopted to avoid overlapping toxicities and to ensure that both modalities could be delivered near their planned maximal doses.

Meta-analysis of randomized combination therapy trials 

Skeptics of combination chemoradiation regimens can point to a number of negative trials that fail to show survival benefit. In a recent large randomized trial of 302 patients from Sweden treated either with 56 Gy alone or 56 Gy preceded by 3 cycles of cisplatin and etoposide, no survival advantage was detected. This negative result is particularly alarming given the 80% increase in total cisplatin dose in comparison to the CALGB trial.31 Three meta-analysis that have recently addressed this question show a small benefit at best.32, 33, 34 The largest of these was published in 1995 by the Non-small Cell Lung Cancer Collaborative Group. This analysis included 22 trials with 3,033 patients comparing radical radiotherapy with combination regimens. The overall odds ratio of death of 0.9 indicated a 10% reduction in the risk of death for the combination regimens, with an absolute survival benefit at 2 and 5 years of a mere 3% and 2%. The strongest survival trend was observed in the cisplatin-based trials, with an odds ratio of death of 0.87 (13% reduction in risk of death) and an absolute survival benefit at 2 and 5 years of 4% and 2%.32 The most recent systematic overview data are electronically available on the Cochrane Database of Systematic Reviews35 and indicate that, “trials using cisplatin based chemotherapy provided the strongest evidence for an effect in favor of chemotherapy. The hazard ratio of 0.87 (P = .005), or 13% reduction in the risk of death, is equivalent to absolute benefits of 4% at 2 years and 2% at 5 years, improving survival from 5% to 7%.”35

Concomitant chemoradiotherapy 

This approach was developed with the expectation that both distant micrometastases and locoregional tumor could be addressed. Several cisplatin-based trials have been undertaken, and 3 of the 4 major trials failed to show a statistically significant survival advantage. The most widely quoted positive trial was conducted by the European Organization for Research and Treatment of Cancer and compared the addition of daily or weekly cisplatin to 55 Gy radiotherapy alone, with the daily cisplatin (6 mg/m2) arm yielding a statistically superior 2-year survival rate of 26% compared with 13% with 55 Gy alone. This approach resulted in net radiosensitization with improved locoregional control but did not influence metastatic patterns. Daily cisplatin provided “additional local control” at 1 and 2 years of 18% and 12%.36 Although this approach provides possible clues for future exploration, confirmatory evidence has not been forthcoming. A similar trial by Trovo et al37 comparing 45 Gy with the same radiation plus daily cisplatin (6 mg/m2) showed no differences in overall response, pattern of relapse, or median survival but doubled the incidence of grade 3 esophagitis.

The more aggressive concomitant regimens have attempted to combine conventional chemotherapy with radiation with at least 2 major phase 3 trials now reported. The most mature data supporting concomitant chemoradiotherapy have been reported from Japan.38 Three hundred fourteen patients were randomized to concurrent chemoradiotherapy or sequential chemoradiotherapy. Results show significant improvement in median as well as 3- and 5-year survival for concurrent chemoradiotherapy (7% absolute and 78% relative improvement in 5-year survival), thereby providing the first major randomized evidence in support of this strategy. The RTOG has recently completed a randomized trial in which patients received either preradiation chemotherapy or concurrent chemoradiotherapy with standard fractionation or concurrent chemoradiotherapy with hyperfractionated radiation. Follow-up duration in this trial needs to mature before the data can be meaningfully analyzed. Nevertheless, the concept of chemotherapy plus altered fractionation represents a significant new direction in non–small-cell lung cancer.39

Chemotherapy plus altered fractionation 

The RTOG has tested the 1.2 Gy twice a day regimen to 69.6 Gy with vinblastine and cisplatin in trial 90-15. Enhanced acute toxicities were substantial with 45% grade 4 or greater hematologic and 24% grade 3 or greater esophagitis. The median and 1- and 2-year survival was 12.2 months, 54% and 28%. These rather excessive toxicities led to RTOG 91-06, which substituted etoposide in place of vinblastine. Seventy-nine patients received 2 cycles of oral etoposide, cisplatin and hyperfractionated radiation therapy to 69.6 Gy. The median survival for patients comparable to CALGB 8433 was an impressive 21 months with 1- and 2-year survival figures of 70% and 42%. Unfortunately, the associated toxicities from this regimen were also substantial with 57% grade 4 hematologic toxicity, 53% ≥grade 3 esophagitis, and 25% ≥grade 3 pulmonary toxicity.40

The first statistically significant survival advantage (median survival, 34 v 77 weeks; P = .003) from chemo-hyperfractionated radiotherapy was reported in a 3-arm randomized trial in the group receiving carboplatin and etoposide weekly during the course of radiotherapy (64.8 Gy, 1.2 Gy twice a day) in comparison to the same radiation alone.41 However, both acute and late toxicities were increased with this approach. Grade 4 acute toxicities were seen in 2%, 4%, and 11% of patients receiving radiation alone, radiation with weekly chemotherapy and radiation with chemotherapy on alternate weeks; the late toxicity incidence rates were 2%, 4%, and 9%.

A phase III follow-up study was then performed to investigate the efficacy of concurrent hyperfractionated radiation therapy and low-dose daily chemotherapy in stage III non–small-cell lung cancer (NSCLC). One hundred and thirty-one patients were randomly treated as follows: 1.2 Gy twice a day to 69.6 Gy versus the same radiation with carboplatin and etoposide given daily with radiotherapy. The latter patients had a significantly longer survival time than radiation alone patients, with a median survival of 22 versus 14 months and 4-year survival rates of 23% versus 9% (P = .021). In contrast, the distant metastasis-free survival rate did not significantly differ in the 2 groups. The 2 groups showed similar incidence of acute and late high-grade toxicity.42

Further supportive evidence is necessary before combination chemo-altered fractionation radiotherapy can be recommended outside the protocol context. The RTOG has completed an important 3 arm randomized trial (RTOG 94-10) comparing the gold standard of sequential chemoradiotherapy with concurrent chemoradiotherapy in 1 experimental arm and concurrent chemoradiotherapy with twice daily radiation in the other arm; preliminary results have been reported but are not sufficiently mature to make definitive conclusions.39

What is the US community standard? 

The community treatment standard for lung cancer continues to evolve. From reliance on thoracic radiation alone, the CALGB and RTOG trials created a shift to sequential chemoradiotherapy, using cisplatin-based 2-drug regimens, generally for 2 cycles before radiation. With early results supporting concurrent chemoradiotherapy, this approach is now becoming the most widely used strategy. Survival results from the major phase III trials are summarized in Table 2.

Table 2. Survival in NSCLC patients: Phase 3 trials

		Median Survival (mo)			% 2-yr Survival
	Study	RT	C→RT	CRT	RT	C→RT	CRT
	CALGB 843329	9.6	13.7	—	13	26	—
	RTOG 880830	11.4	13.6	—	20	31	—
	EORTC35*	—	—	—	13	—	26
	Trovo36	10.3	10	—	?	—	?
	Furuse37	—	13.3	16.5	—	26	37
	Jeremic 9540†	7.9	—	18	7	—	23
	Jeremic 9641‡	14	—	22	9	—	23
	RTOG 941038§	—	14.6	17	—	—	—
	*Daily cisplatin arm. †Weekly carboplatin and etoposide; hyperfractionated XRT; 3-year survival figures. ‡Daily carboplatin; hyperfractionated XRT; 4-year survival figures §Data for qd XRT arms.

In an attempt to administer concurrent chemoradiotherapy with manageable toxicities, the combination of low-dose weekly carboplatin/taxol chemotherapy and once daily radiotherapy has gained popularity, despite a lack of randomized data supporting its use in this context. Preliminary data from the Localized Advanced Multimodality Protocol trial were reported in 2001.49 In arm 2, 80 patients were treated with 2 cycles of paclitaxel and carboplatin every 3 weeks, followed by thoracic radiation to 63 Gy with concurrent weekly paclitaxel plus carboplatin. In 63 evaluable patients, the incidence of toxicities was as follows: grade 4 hematologic toxicity, 25%; grade 4 nonhematologic toxicity, 8%; and grade 3 esophagitis, 18%. Median survival was 12.5 months in 56 evaluable patients.

A variety of new agents have joined cisplatin in combination chemotherapy regimens for NSCLC. Randomized studies show that combinations containing paclitaxel, carboplatin, gemcitabine, vinorelbine, and docetaxel modestly improve response rates and survival in some studies but not in all. Several randomized studies have addressed the question of which new agent is superior. An Italian trial evaluated cisplatin/gemcitabine, cisplatin/vinorelbine, and carboplatin/paclitaxel in 200 patients per arm and found no difference in outcome.50 A 3-arm study from the EORTC, with about 160 patients per arm, also found no difference in outcome between gemcitabine/cisplatin, paclitaxel/cisplatin, and gemcitabine/paclitaxel.51 Only 1 trial claimed positive results. This international trial of about 400 patients per arm found a modest (and somewhat controversial) advantage to docetaxel/cisplatin over cisplatin/vinorelbine.52 ECOG 1594 examined docetaxel/cisplatin, paclitaxel/cisplatin, gemcitabine/cisplatin, and paclitaxel/carboplatin.53 All arms showed a median survival of about 8 months with 1-year survival in the low to mid 30% range. There were no significant differences among the arms. Based on such data, how do we answer the question, “Which agent and combination of agents to choose?” One interpretation of these findings is that there is no real difference in overall response rates or survival between the standard cytotoxic agents and, therefore, no major advantage of one over the other. Oncologists will decide to use 1 combination over another based primarily on toxicity and, in some cases, cost and schedule.

Lung cancer conclusions 

Although the overall prognosis for most lung cancer patients remains dismal, concerted effort over the last 2 decades has yielded some promising advances. Early strategies were predicated on the assumption that local control was of paramount significance, high rates of local control could be achieved with conventionally fractionated radiation to 60 Gy, and that chemotherapy was minimally active with no impact on micrometastatic disease. Induction chemoradiotherapy trials belied this assumption by showing a small but measurable survival gain. Simultaneously, better assessment of local control indicated that radiographic evaluation was highly inaccurate and falsely inflated previously reported control rates. This observation led to renewed efforts at controlling the disease locally, prompting intensification of radiation with altered fractionation. Combinations of chemotherapy and altered fractionation therefore represent a new frontier, and although too preliminary to judge its overall impact, this strategy has certainly resulted both in increased toxicity as well as improved survival in preliminary phase 3 trials.

Are we reaching a therapeutic ceiling? Future progress in this disease must balance toxicities with outcome, measured not just in survival terms but also as pertains to quality-of-life. Is it justifiable to treat the majority of advanced, nonmetastatic lung cancer patients with poor prognostic features with aggressive therapies when they have been excluded from the randomized trials? We certainly hope that new advances in molecularly targeted drug development and gene therapy will make these issues redundant.