Outcomes and Results of Treatment

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Historically, surgery in the form of total laryngectomy followed by adjuvant postoperative radiation therapy has been the standard treatment for most patients with advanced stage cancer of the larynx.10-12,41,42 Additionally, selected patients with advanced stage larynx cancer have been treated with definitive radiation therapy alone.13 4243 The results of these treatments are summarized in Table 8-2 with 5-year survival ranging from 54 to 91 percent.10-13,41-43

Figure 8-7. Schematic diagram of tracheoesophageal puncture (TEP).

More recently, chemotherapy/radiation therapy has evolved as an effective treatment for advanced stage cancer of the larynx. A summary of results from the various studies evaluating chemo/RT in the treatment of patients with advanced stage laryngeal cancer, with the goal of larynx preservation, are listed in chronologic order in Table 8-3.3-9,25 In all but one study, more than 90 percent of patients evaluated had stage III or IV disease. Most studies included only those patients who would have required a total laryngectomy if treated by conventional means with surgery and postoperative radiotherapy. Treatment results for patients treated with chemo/RT in these studies are fairly consistent with 2-year survival ranging from 50 to 77 percent, lar-

Table 8-2. RESULTS OF CONVENTIONAL TREATMENT OF ADVANCED CARCINOMA OF THE LARYNX

5 yr

Type of Stage Survival Author Year No. Therapy III/IV (%) (%)

Kirchner12

1977

308

S/RT

100

54-56*

Harwood13

1979

353

RT

54

70

Harwood43

1983

410

RT

66

57

Yuen41

1984

192

S

100

77

50

S/RT

100

91

Mendenhall42

1992

100

RT

100

74

65

S±RT

100

63

Nguyen11

1996

116

S/RT

100

68

Myers10

1996

65

S±RT

100

62t

Survival rates refer to disease-free survival when available, otherwise they refer to overall survival.

* study included both laryngeal and non-laryngeal sites. S = Surgery; RT = Radiation therapy;f 2-year survival.

Survival rates refer to disease-free survival when available, otherwise they refer to overall survival.

* study included both laryngeal and non-laryngeal sites. S = Surgery; RT = Radiation therapy;f 2-year survival.

ynx preservation rates ranging from 64 to 79 percent, locoregional failure rates ranging from 20 to 33 percent and distant failure rates ranging from 8 to 21 percent.3-9,25 It should be noted, however, that only one of these studies was limited only to patients with laryngeal primaries,3 while the remainder of the studies included patients with hypopharynx, oropharynx, oral cavity and even paranasal sinuses as sites of primary tumors.4-925 The majority of these studies that included non-laryngeal sites did so because surgical treatment of the primary would have required total laryngectomy. The data presented

Table 8-3. RESULTS OF TREATMENT OF ADVANCED CARCINOMA OF THE LARYNX UTILIZING CHEMOTHERAPY AND RADIATION THERAPY

Author

Year

No.

Type of Therapy

Survival (%)

Jacobs4

1987

30

C/RT

100

52*

Demard5

1990

50

C/RT

64

74*

(Response

rate)

Veterans Affairs

1991

166

C/RT

100

68

Larynx Group3

166

S/RT

100

68*

Pfister6

1991

13

C/RT

98

77*

Karp7

1991

14

C/RT

92

50*

Urba8

1994

8

C/RT

93

75*

Clayman9

1995

26

C/RT

96

68*

(includes data

52

S/RT

96

Survival rates refer to disease-free survival when available, otherwise they refer to overall survival.

* Study included both laryngeal and non-laryngeal sites. C = chemotheapy; S = surgery; RT = radiation therapy.

from Shirinian)25

Survival rates refer to disease-free survival when available, otherwise they refer to overall survival.

* Study included both laryngeal and non-laryngeal sites. C = chemotheapy; S = surgery; RT = radiation therapy.

Table 8-2. RESULTS OF CONVENTIONAL TREATMENT OF ADVANCED CARCINOMA OF THE LARYNX

5 yr

Type of Stage Survival Author Year No. Therapy III/IV (%) (%)

in this table refers, whenever possible, to the subset of patients with laryngeal primaries, although this information was not always available.

In several of these aforementioned studies, single modality therapy in the form of definitive radiotherapy was utilized and yielded disease-specific survivals similar to those seen with the combination of induction chemotherapy and radiation therapy.3-9,13,25,42,43 Although the selected cohort of patients who received radiation therapy alone had less stage IV and node-positive patients, the contribution of chemotherapy to these larynx preservation protocols remains undetermined. While previous randomized prospective trials have not included a radiation therapy-only arm, an ongoing prospective randomized trial has included a radiation therapy-only arm, to address this question. This phase III trial has 3 treatment arms including: (1) radiotherapy alone, (2) sequential chemotherapy and radiotherapy and (3) concomitant chemotherapy and radiotherapy. Data from this study will help to further define the optimal treatment for patients with advanced larynx cancer. Additionally, 2 studies have recently been published which compared radiotherapy alone to concurrent chemotherapy (cisplatin/5-fluorouracil) and radiotherapy in patients with locoregionally-advanced squamous cell carcinoma of the head and neck.44,45 In these studies, between 36 and 56 percent of patients had either laryngeal or hypopharyngeal primaries. In both studies, a statistically significant increase in 3-year relapse-free survival was seen in the concurrent chemo/RT arm as compared to the RT-alone arm (p < 0.00444 and p < 0.0345).

The debate also continues regarding the optimal fractionation of radiation therapy, chemotherapeutic agents, and optimal timing of chemotherapy and radiation therapy (sequential vs. concomitant). Protocols with accelerated fractionation of radiotherapy and plans using concomitant chemotherapy and radiotherapy have been investigated. It has been postulated that part of the cause of increased locore-gional failures seen with chemo/RT protocols result from an accelerated tumor cell repopulation during the prolonged course of treatment.46,47 Clinical and experimental evidence suggest that tumor cell populations, after a lag period of several weeks, will decrease their doubling time and increase their rate of regrowth after the commencement of cytotoxic treatment, regardless of whether it is chemotherapy or radiation therapy.46,47 A longer treatment time will therefore result in high rates of failure.48

In order to minimize these problems, investigators have evaluated accelerated radiotherapy regimens and concomitant chemo/RT protocols. In the past, accelerated (twice a day) courses of radiation therapy have improved 3-year local control of advanced laryngeal tumors (T3-4) from 26 to 59 percent (p < 0.0001).4849 These gains in local control are not accomplished without cost with regards to treatment related morbidity. In this study, although the larynx was anatomically preserved, its function was profoundly impaired in a subset of patients, and significant long-term treatment related morbidity was seen in one-quarter of patients. Additionally, all patients in this series undergoing salvage surgery after radiotherapy experienced major wound complications.50 Ultimately a benefit in local or regional control or survival was not seen, although the power of this study was limited.

Another method of shortening treatment time, decreasing the effects of accelerated tumor cell repopulation and improving results involves the use of concomitant chemotherapy and radiation therapy. Prior studies using concomitant chemotherapy and radiation in advanced stage head and neck cancer have shown promising results with regard to locore-gional control, organ preservation and survival.51,52 Prospective randomized trials assessing the benefit of concomitant chemotherapy and radiation therapy as it applies to advanced stage laryngeal cancer, however, are limited. As mentioned earlier, a randomized prospective trial comparing sequential to concomitant chemotherapy and radiation therapy is currently underway.

Additionally, randomized prospective studies comparing sequential chemotherapy and radiation therapy to concomitant chemo/RT in patients with unresectable tumors of the head and neck have been reported.27,53 While an improvement in locoregional control was seen in the concomitant arm in the larger study,53 neither study showed a difference in overall survival.27,53 At this time, neither accelerated fraction radiation therapy nor concomitant chemo/RT have conclusively demonstrated a benefit in treating advanced stage laryngeal cancer relative to induc tion chemotherapy followed by conventional fraction radiation therapy. For this reason, along with the potential for treatment related morbidity, it remains investigational at this time.

Finally, novel treatment strategies continue to evolve which intend to further improve the survival and functional outcome in patients with advanced cancer of the larynx. One such unique strategy utilizes the high-dose intra-arterial cisplatin with a systemic neutralizing agent along with conventional radiation therapy.54 In this study, where the majority of patients had stage IV disease (86%) and clinically involved regional lymph nodes (79%), a major response rate was seen in 95 percent of patients. Nine of 10 patients retained their larynx and 2-year disease-specific survival was 76 percent. It should be noted that 3 of the 42 patients experienced central nervous system complications as a result of catheri-tization of the carotid system. Nevertheless, this remains a promising option and a novel approach in the treatment of advanced laryngeal cancer.

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